encyclopedia of arthritis

THE ENCYCLOPEDIA OF

ARTHRITIS

THE ENCYCLOPEDIA OF

ARTHRITIS

C. Michael Stein, M.D.

Guy Taylor, M.D.

The Encyclopedia of Arthritis

Copyright © 2004 by C. Michael Stein and Guy Taylor

All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage or retrieval

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Stein, C. Michael (Charles Michael)The encyclopedia of arthritis / C. Michael Stein, Guy Taylor.

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ISBN 0-8160-4810-X 1. Arthritis—Encyclopedias. I. Taylor, Guy, M.D. II. Title.

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CONTENTS

Preface vii

Introduction ix

Entries A–Z 1

Appendixes 295

Glossary 339

Bibliography 345

Index 353

This book is intended to provide educational infor-mation to the public about arthritis and related

illnesses. It is not intended to substitute for any aspectof medical care. The authors have made every effortto provide information that is up-to-date, accurate,and useful. However, the diagnosis and treatment of

the various conditions described and the monitoringof patients must be performed by their physicians.Readers should use the knowledge gained to workwith their physicians to optimize their medical careand should not alter their medical care based oninformation provided in this book.

PREFACE

vii

INTRODUCTION

ix

Arthritis and related conditions affect millions ofpeople and cause pain, disability, and, for some

conditions, increased mortality. Arthritis is difficultto understand because there are hundreds of differ-ent arthritis-related conditions and many differenttreatments for them. It is difficult to obtain accu-rate, unbiased information because much of thepopular literature focuses on miracle cures. Thisbook sets out to provide concise and accurate infor-mation about a wide range of arthritis-related top-ics and to act as a comprehensive resource for

patients with arthritis, their families, and anyoneinterested in understanding musculoskeletal illness.

Small-capital terms for arthritis and related con-ditions in each section are cross-referenced in the main text of entries. Drug names in small-cap-ital letters are further detailed in Appendix I.Finally, terms in small capitals relating to labora-tory and diagnostic tests are expanded upon inAppendix II. Occasionally, a reference to AppendixI or to Appendix II appears following a term in themain text.

ENTRIES A–Z

Achilles tendon This powerful tendon, some-times called the heel cord, attaches the two major calfmuscles (gastrocnemius and soleus) to the calca-neum (heel bone) and transmits the propulsiveforces needed for walking, running, and jumping.The tendon is composed of spirals of collagen thatare wrapped into bundles forming a thick cord thatis both strong and able to stretch. Because of theproperty of viscoelasticity, a sudden rapid musclecontraction will find the tendon relatively stiffwhile slower contractions allow greater stretch.With repeated stretching, the tendon becomes moreflexible. Although this applies to all ages, maximumflexibility does slowly decreases with increasing age.The frequency of Achilles tendon injuries appears tobe increasing, with about 8 percent of top-level run-ners having some Achilles problem each year.

Rupture of the achilles tendon The ability oftendons to stretch and become more elastic duringuse is the rationale for warming up before partici-pating in sports. The typical Achilles tendon rupturehappens when a relatively untrained middle-agedathlete plays a sport such as tennis and makes asudden forward movement. The rapid stretch of arelatively stiff tendon can cause it to rupture andthe athlete feels sudden pain, as if kicked on theback of the leg. He or she is unable to walk or standon tiptoes and may hear a pop as the tendon snaps.The midtendon rupture of the Achilles is unusualfor a tendon. Like most tendons the Achilles isnearly twice as strong as the muscles it joins.Because of this, tendons normally tear in the areawhere they join onto their muscle since this is theweakest part. Therefore, for the midtendon to rup-ture there is usually a preexisting abnormality thathas weakened it. The tendon may have been dam-aged by previous trauma, TENDINITIS, long-term corticosteroid use, local steroid injections into or

around the tendon, and other chronic medical ill-nesses such as kidney failure. A few cases of tendonrupture have been described in people takingquinolone antibiotics, for example ofloxacin (seeDRUG-INDUCED RHEUMATIC DISEASE). The treatment ofa ruptured Achilles tendon can be either conserva-tive, with the leg immobilized in a plaster cast forabout six weeks, or surgical, with open repair ofthe tendon again followed by immobilization forabout six weeks. Surgical repair decreases the riskthat the tendon will rupture again from 10 percentto 2 percent. However, surgery may not always bethe best option, particularly if the person has othermedical problems or is not athletic and is thereforeless likely to stress the tendon in the future.

Other conditions affecting the achilles tendon

Inflammation of the tendon at the point where itjoins bone is called enthesitis and is common inANKYLOSING SPONDYLITIS and REITER’S SYNDROME.

Treatment includes an orthotic shoe insert or a spe-cial shoe designed to raise the heel, rest, ice, localcorticosteroid injection, and NSAIDs followed byrehabilitation stretches.

Inflammation of the Achilles tendon (tendinitis)occurs particularly in long-distance runners andathletes involved in jumping sports or in thoseusing unsuitable footwear or having a biomechan-ical problem. All these will place unusual or abnor-mal stresses on the tendon. Tendinitis causes painin the area around the tendon, particularly when itis stretched during activities such as walking orrunning. The tendon is often visibly enlarged,warm, and very tender to the touch. It can be verydifficult to decide whether the inflammation ismostly in the tendon or around it (peritendinitis),and both are often present. Sometimes the tendini-tis occurs because of a partial tendon rupture, andultrasound scanning is excellent at showing this.

A

1

The treatment of Achilles tendinitis is similar tothat of enthesitis except that local steroid injectionsnear the middle of the tendon are avoided becausethey may weaken the tendon and increase thechance that it will rupture. Surgery to remove sur-rounding inflamed tissue and chalky material fromwithin the tendon where it has degenerated is per-formed if conservative treatment fails. This is suc-cessful in 80 percent of competitive athletes.

If the person’s shoes or biomechanics of walkingor running are faulty, the condition may be cor-rected with appropriate shoes. Bursae between theskin and tendon and between the tendon andunderlying bone can become inflamed (see BURSITIS)and cause symptoms similar to tendinitis. The treat-ment of bursitis around the Achilles tendon is simi-lar to that of tendinitis.

acne arthralgia Severe acne that causes cysts andnodules on the buttocks, thighs, and upper arms aswell as in areas more usually affected by acne canbe associated with attacks of arthralgia and myalgiathat can last several weeks or months. Joint prob-lems related to acne are rare and occur most oftenin adolescent males. In addition to arthralgia andmyalgia, fever, loss of weight, and arthritis canoccur. The cause of this illness is not known, but itmay be a reaction to the bacteria that cause acne.Treatment of the arthralgia is symptomatic withNSAIDs and is combined with treatment to controlthe acne. This can include long-term antibiotictreatment, often with a tetracycline type of antibi-otic, topical creams, retinoids, or in females, drugsthat block their male hormones (androgens) thatstimulate acne. Severe acne is occasionally compli-cated by the SAPHO SYNDROME.

acquired immunodeficiency syndrome (AIDS)See HUMAN IMMUNODEFICIENCY VIRUS.

acromegaly A syndrome due to excessive forma-tion of growth hormone (GH) by a tumor in thepituitary gland and characterized by coarse facialfeatures, enlargement of hands and feet, headache,sweating, neuropathy, SLEEP APNEA, and muscu-loskeletal symptoms. Acromegaly affects 40 to 60people per million population.

Cause

An adenoma (a benign tumor) of the pituitary glandthat produces GH is the cause of acromegaly in 99percent of patients. Other rare causes include tumorsof the gut, pancreas, and lung that produce GH.

Symptoms

Acromegaly results in gigantism if it develops inchildren before puberty. More commonly, how-ever, it develops slowly between the ages of 20 and40 years. Symptoms may be due to either excessiveproduction of GH or pressure effects caused by theadenoma itself. GH causes enlargement of the softtissues, resulting in a characteristic coarse facialappearance with an enlarged jaw and tongue, sep-aration of the teeth, and large hands and feet. Be-cause of this, unrelated patients with acromegalyare said to look more like each other than like anyof their family members. Internal organs such asthe heart, liver, and kidneys also enlarge. Hyper-tension (30 percent) and diabetes (20 percent) arecommon. If the adenoma in the pituitary enlarges,it can cause pressure effects in the brain. The opticnerves that run from the eye to the brain pass very close to the pituitary gland. If the adenomapresses on an optic nerve, it can cause partial blind-ness. The tumor can also affect normal pituitary tis-sue and cause reduced production of somehormones, for example gonadotrophins (hormonesthat regulate the release of sex hormones) andincreased production of others, for example pro-lactin, a hormone that regulates the secretion ofbreast milk.

Musculoskeletal symptoms Bone and jointproblems develop in at least 50 percent of patientswith acromegaly. Initially the cartilage in the jointsincreases in amount, and the capsule of the jointand the ligaments close to it soften and thicken,resulting in hypermobility. Later degenerativechanges develop in joints perhaps because of thealtered biomechanics caused by the changes in car-tilage and soft tissues. The arthritis associated withacromegaly causes pain, stiffness, and reducedrange of movement, as happens in OSTEOARTHRITIS

of any cause. The fingers, spine, and knees are com-monly involved, and the shoulders, elbows, andankles are affected more frequently than occurs inthe usual type of osteoarthritis. OSTEOPOROSIS may

2 acne arthralgia

develop because of reduced sex hormone produc-tion as well as increased loss of calcium in the urine.CARPAL TUNNEL SYNDROME is common because themedian nerve runs through a narrow tunnel in thewrist, and if the soft tissues increase in size, as hap-pens in acromegaly, it causes pressure on the nerveand the symptoms of carpal tunnel syndrome. Sim-ilarly, other nerves that run through narrow chan-nels can become trapped by soft tissue, resulting inneuropathy.

Premature coronary artery disease, heart failure,and sleep apnea all contribute to the increased mor-tality rate in people with acromegaly. The mortalityrate in untreated acromegaly is twice that of thegeneral population. However, if treatment is suc-cessful in reducing GH levels in the blood to lessthan 5 mU/L, there is no increased risk of death.The concentration of calcium in the blood is ele-vated (hypercalcemia) in 5 percent of patients, andthe increased excretion of calcium in the urine canincrease the risk of developing kidney stones. Theosteoarthritis that often accompanies acromegalymay cause considerable pain and disability, andthere is an increased risk of CALCIUM PYROPHOSPHATE

DIHYDRATE DEPOSITION DISEASE and pseudogout. Alarge pituitary tumor can cause permanent loss ofvision, particularly peripheral vision.

Diagnosis

The characteristic appearance of the face and handsusually prompts the diagnosis. X rays can supportthe diagnosis, showing characteristic tufting of thebones at the ends of the fingers. Other X raychanges include widened joint spaces (because ofthe increased amount of cartilage) and typicalchanges of osteoarthritis. They include the forma-tion of osteophytes sometimes occurring in jointssuch as shoulders and elbows, which are not usu-ally affected by osteoarthritis. In the spine the X rays have an appearance similar to that of DISH.

Blood tests such as elevated levels of GH orsomatomedin C are useful for making the diagno-sis. Abnormalities of other pituitary hormones suchas prolactin or gonadotrophins may be found butare not specific. An MRI scan is useful because thepituitary adenoma can often be seen. Eye tests mayshow loss of peripheral vision that the patient hadnot noticed.

Treatment and Outcome

The aim of treatment is to relieve symptoms ofacromegaly, reduce GH levels to less than 5 mU/L,treat the local pressure effects of the tumor, andmaintain normal pituitary function. The treatmentof choice, transsphenoidal surgery, achieves a curerate of between 40 and 90 percent. Radiotherapymay be used to treat the tumor in patients who arenot healthy enough to undergo surgery or thosewho choose not to have it. After treatment withradiotherapy the GH levels decline slowly over afew years, and with time there is an increasedchance that production of other pituitary hor-mones will also decline.

Treatment of acromegaly with drugs such asoctreotide and bromocriptine decreases GH pro-duction. These drugs are used when GH levelsremain raised after surgery or radiotherapy orsometimes as the only therapy in elderly patientswho prefer not to undergo surgery or radiotherapy.Joint symptoms are treated with analgesics,NSAIDs, and physical therapy as appropriate. Sur-gical removal of large osteophytes is sometimeshelpful, and total joint replacement may becomenecessary if a hip or knee joint is badly affected.The symptoms caused by carpal tunnel syndromeimprove with adequate control of GH levels, butthose caused by arthritis do not.

acupuncture People with arthritis frequently usecomplementary and alternative therapies such asacupuncture, an ancient Chinese art that seeks tocorrect imbalances in the flow of energy by select-ing appropriate acupuncture points for stimulation.Such stimulation often involves the puncturing ofthe skin with needles. However, practitioners canalso use needle manipulation, heat, pressure, suc-tion, and electrical current to stimulate the chosenpoints. The concept of yin and yang is the mostimportant theory in traditional Chinese medicine. Itclaims that all things have two aspects, yin andyang, that are at the same time both opposite anddependent on each other. They are in a constantstate of change and balance. Disease results fromloss of this balance, and treatment is directed atrestoring it. Qi is the life force that governs the func-tions of the organs and flows through meridians orchannels to all parts of the body. Pain results from

acupuncture 3

disturbances of this flow. Several types of acupunc-ture practice may be found in the Western world.

• Traditional Chinese acupuncture is based on tra-ditional diagnoses and aims at restoring yin andyang and normal qi flow.

• Cookbook acupuncture consists of techniquesborrowed from Chinese acupuncture but used totreat disorders based on a Western medical diag-nosis. An example is the commonly used auricu-lar acupuncture to help with smoking cessation.A small but increasing number of Western med-ical practitioners are using this type of acupunc-ture as well as trigger point acupuncture.

• Trigger point acupuncture is used to relieve mus-culoskeletal pain. The trigger points so oftenfound in FIBROMYALGIA have been scientificallystudied in the West only in the past 70 years. Aslong ago as 600 B.C. the Chinese were insertingneedles into these ah shi (ah yes) points.

• Scientific acupuncture is based on modern sci-entific interpretations of the physiological effectsof traditional methods.

The insertion of the needles is not particularlypainful. However, for maximum benefit a needlingsensation should be felt. This is variously describedas dull, aching, heavy, sore, distending, or warm,and it may travel away from the needle site. Patientsmay feel relaxed afterward and can get quite drowsyand occasionally euphoric, presumably as a result ofendorphin release. An average treatment involvesfive to 10 sessions, and most acupuncturists con-tinue treatment until the patient is cured or no fur-ther improvement occurs.

Determining if acupuncture is useful for thetreatment of arthritis has been difficult. Clinical tri-als examining the effectiveness of acupuncture forthe treatment of rheumatological problems havebeen criticized because the number of patients stud-ied was often small and because it was difficult tocontrol for a placebo effect occurring in response tothe needles (see CLINICAL TRIAL). Some studies havetried to overcome this criticism by using needles tostimulate sham or placebo points that should notresult in benefits and then comparing these resultswith those of active acupuncture. There has, how-

ever, been disagreement whether a nonacupunc-ture type of treatment or acupuncture at a shampoint is the most appropriate control group.

There are few well-designed studies, and somehave shown a small improvement in pain in patientswith OSTEOARTHRITIS and fibromyalgia. Several trialshave shown modest benefits in treating particularlytroublesome joints in RHEUMATOID ARTHRITIS. Therisks from acupuncture are small, provided that nee-dles are adequately sterilized and are not insertedinto a nerve, vital organ, or artery. Puncture of thelung (pneumothorax), transmission of HEPATITIS B orHEPATITIS C, nerve damage, and bleeding are uncom-mon complications.

adult-onset Still’s disease See JUVENILE ARTHRITIS.

Alexander technique This technique was devel-oped by an actor, F. M. Alexander, to improve hisvoice. He believed that the way we breathe affectsthe function of our bodies and that the relationshipbetween the head, neck, and upper body are the pri-mary controls of posture. Abnormal posture causesabnormal muscular tension in one muscle groupand can adversely affect the whole body. Treatmentwith the Alexander technique usually involves indi-vidual or group lessons during which a teacherobserves the posture and tension in a student. Theteacher then explains, using touch and instructions,more efficient posture, movement, and breathing.The Alexander technique has not been adequatelyevaluated in well-designed studies. Apart from anec-dotal experience, little scientific evidence is availablewith which to evaluate the Alexander technique asa therapy for arthritis-related problems.

alkaptonuria (ochronosis) This rare, inherited defi-ciency of the enzyme homogentisic acid oxidaseresults in homogentisic acid reaching high levels inthe body. This acid is excreted in the urine, whichwill then turn black if left to stand for a while becausethe acid oxidizes. The diagnosis of alkaptonuria issuspected if a person gives a history of passing darkurine or of urine that becomes dark after standing fora while. Pigmented or dark-colored deposits ofhomogentisic acid collect in tissues such as cartilagethat are rich in collagen, an important component ofjoints and soft tissues. These pigmented deposits are

4 adult-onset Still’s disease

called ochronosis. In early adult life, blue or blackdarkening of the ears or nose may occur. Homogen-tisic acid is also deposited in the cartilage of largejoints such as the knees, resulting in osteoarthritis. Itaffects the cartilaginous discs between vertebrae,resulting in pain and stiffness of the spine. On X raythese intervertebral discs are often heavily calcified.There is no specific treatment for the arthritis associ-ated with alkaptonuria. High doses of vitamin C mayslow the accumulation of pigment in tissues, but theeffects of this treatment on the long-term arthritisproblems are not known.

amyloidosis A rare group of illnesses caused byan insoluble protein complex (amyloid) beingdeposited between the cells of internal organs andeventually impairing their function. Amyloidosiscan rarely cause arthritis but is more often a com-plication of long-standing inflammatory arthritis.

Cause

Although amyloid was first described 150 years agoby the famous German pathologist R. Virchow, theproteins involved have been well characterizedonly in the last 30 years. The types of amyloid arenamed A for amyloidosis, followed by a letter orabbreviated name that represents the type of amy-loid protein. Three main types of amyloid proteincause different types of amyloidosis. In addition,there are also rare hereditary forms of amyloidosisand associations with rare diseases such as FAMILIAL

MEDITERRANEAN FEVER.

1. In AA amyloidosis, a protein called serum amy-loid A (SAA) is produced as part of the immuneresponse to chronic inflammation. The condi-tion is therefore sometimes called secondaryamyloidosis. This used to be a common compli-cation of chronic infections such as tuberculosis.However, with the development of more effec-tive antibiotics, it now usually results from long-standing inflammatory arthritis such asRHEUMATOID ARTHRITIS and ANKYLOSING SPONDYLI-

TIS and a chronic inflammatory disease, familialMediterranean fever. Genetic factors probablyaffect how often amyloidosis complicateschronic arthritis. For example, in Scandinaviancountries, amyloidosis complicating rheumatoid

arthritis, although uncommon, occurs signifi-cantly more often than in the United States.

2. AL amyloidosis is sometimes called primary amy-loidosis. It can be thought of as a type of malig-nancy of blood cells (plasma cells) thatoverproduce an amyloid protein composed of thelight (L) chains of an immunoglobulin protein.AL amyloid may also occur in patients with a typeof cancer called multiple myeloma that affects theplasma cells of the bone marrow. It can occur inpeople with benign monoclonal gammopathyand sometimes occurs in the absence of any asso-ciated illness. In all these conditions, a type ofwhite blood cell called plasma cells have escapedfrom their normal control mechanisms and pro-duce increased amounts of the amyloid proteins.

3. Ab2M amyloidosis, or beta2-microglobulin amy-loidosis, is the third type and is sometimes calleddialysis-associated amyloidosis. It occurs inpatients who have received hemodialysis for along time (see DIALYSIS) and can be detected inmost patients after 15 years of dialysis.

Symptoms

AA amyloidosis may not cause any symptoms andis sometimes diagnosed only after protein has beenfound in the urine and investigated. The amount ofprotein in the urine is often small initially, but itcan increase and result in nephrotic syndrome.This may progress to kidney failure. Amyloid pro-tein can be deposited in many tissues, including theheart, but heart failure is rare.

In AL amyloidosis the abnormal protein isdeposited in greater quantities in organs such asthe heart, liver, and tongue. Nephrotic syndromeand heart failure are common and usually have apoor outcome. The liver may enlarge, and gas-trointestinal involvement can lead to poor absorp-tion of nutrients and GI bleeding. Arthritis occursin less than 5 percent of patients and usually affectsshoulders, knees, wrists, metacarpophalangeal(MCP) joints, and proximal interphalangeal (PIP)joints. Amyloid can deposit in the soft tissues of thewrist and cause CARPAL TUNNEL SYNDROME.

Patients on long-term dialysis who have beta2-microglobulin amyloidosis develop arthritis, tendinitis,and carpal tunnel syndrome as well as destructivebony cysts that can sometimes cause fractures.

amyloidosis 5

Diagnosis

Biopsy of either an affected organ (e.g., heart orkidney) or of more easily accessible tissues (rectumor subcutaneous fat) will show the amyloid inapproximately 80 percent of patients. Aspiration offat, a test that involves drawing a small amount ofabdominal fat into a syringe, is often the most con-venient way to obtain a tissue sample. The type ofamyloid protein can be determined by staining thetissue with dyes that are specific for the differenttypes of protein. If the heart is affected, echocar-diography (an ultrasound of the heart) may showthickening of the walls of the ventricles and re-duced contractility of the heart. Nuclear medicinescans using various radiolabeled molecules havebeen useful when defining the extent of the diseaseand its response to treatment. However, they arenot used in routine clinical care. If myeloma is sus-pected, examination of the bone marrow will showincreased numbers of plasma cells.


Complications caused by amyloidosis such as heartand kidney failure are treated in the usual manner.Treatment of amyloidosis itself is directed at reduc-ing the production of amyloid protein so that less isdeposited in the tissues. A lot of research has beendirected toward developing methods to removeamyloid protein from tissues, but this is not cur-rently possible. In AA disease, the most importantaspect of treatment is to suppress the inflammationor, in chronic infections, to eliminate its cause. IfAA amyloidosis is caused by chronic inflammatoryarthritis, CORTICOSTEROIDS and drugs that suppressthe immune system are often used to control theinflammation. AL amyloidosis associated withmyeloma or a monoclonal gammopathy is usuallytreated with a combination of an anticancer drug,such as melphalan, and PREDNISONE. Some patientswith AL amyloidosis have been treated with bonemarrow transplantation. COLCHICINE may be helpfulfor patients with amyloidosis associated with famil-ial Mediterranean fever. In patients with beta2-microglobulin amyloidosis, renal transplantationenables them to stop hemodialysis and canimprove the symptoms.

ANA See ANTINUCLEAR ANTIBODY in Appendix II.

ANCA See ANTINEUTROPHIL CYTOPLASMIC ANTIBODY

in Appendix II.

angiokeratoma corporis diffusum A rare heredi-tary condition usually associated with a group ofgenetic conditions known as lysosomal storage dis-eases, for example Fabry’s disease. Angiokeratomasare small vascular lesions composed of one or moredilated blood vessels lying under the skin associ-ated with the proliferation of connective tissuecells. Affected children often have a degenerativearthritis affecting their distal interphalangeal jointsand characteristic dark red skin lesions are present.They also get episodic burning pain in the fingersand toes that is not due to the arthritis. Other man-ifestations include premature vascular disease, kid-ney failure, corneal opacities, and diarrhea. Thediagnosis is made by biopsy of affected tissue, forexample skin, liver, or bone marrow.

ankylosing spondylitis (AS) A chronic inflamma-tory arthritis that predominantly affects the spine.It has a strong genetic component, and over 95 per-cent of AS patients who are of Caucasian extractionhave a gene called HLA-B27. The disease affectsmainly young men and has a male to female ratioof 5:1. The frequency of AS in women may beunderestimated because they develop milder dis-ease. Symptoms almost always start before the ageof 40 years, usually in the 20- to 30-year age range.AS affects approximately 0.5–1 percent of people inthe U.S.

Cause

The association of AS with the HLA-B27 gene wasfirst described in the early 1970s and stimulatedconsiderable research into the causes of AS andassociated SPONDYLOARTHROPATHIES. The HLA-Bantigens are molecules that human cells express ontheir surface. In Caucasian populations, approxi-mately 10 percent of people have the HLA-B27gene. The frequency of this gene varies widely inother populations. It almost never occurs in theblack African population living south of the SaharaDesert but is found in as many as 50 percent ofHaida Indians in Canada. Generally AS is commonwhere the gene HLA-B27 is common and rarewhere HLA-B27 is rare. Experimental evidence

6 ANA

also suggests that the HLA-B27 molecule carries aparticular predisposition for AS. Experimentstransferring the human HLA-B27 gene to rodentsresulted in their developing an AS-like illness.

One role of the HLA molecules is to carry smallpeptide antigens processed in the cell to the surfacewhere they can be recognized by a subgroup oflymphocytes called CD8+ T cells. Less than 2 per-cent of all people with HLA-B27 have AS. How-ever, in families of patients with AS, nearly 20percent of people who carry HLA-B27 will developAS. These findings suggest that other genetic fac-tors in addition to HLA-B27 are important. Envi-ronmental factors may be needed to activate thedisease in people who carry the gene. HLA-B anti-gens are expressed on all cells in the body, so it isnot clear why the spine is particularly affected byAS. One popular theory is that of molecular mim-icry. Simply put, this theory suggests that animmune response is started against an infectingbacterium and that the response continues becauseantigenic determinants (small parts of an organismor other structure recognized by the immune sys-tem) are shared between the bacterium and theHLA-B27 molecule. Some bacteria and the HLA-B27 molecule do have identical antigenic deter-minants. That is, they look alike to the immunesystem. The related diseases REACTIVE ARTHRITIS

and REITER’S SYNDROME are known to occur afterinfection with such organisms. This lends supportto the theory that AS has a similar trigger. How-ever, we still do not understand exactly why ASdevelops.

Symptoms

Inflammation typically affects the large sacroiliac(SI) joints at the base of the spine and the smalljoints between vertebral bodies and between ribsand vertebral bodies (spondylitis). This leads to pain and stiffness, which is most severe in the morn-ings and tends to improve with exercise. The lowerback and neck are affected more than other parts ofthe spine. In many people this stiffness can progressto complete loss of movement as ligaments andjoints are gradually replaced by bone and fuse(ankylosis). This process takes many years, and therate at which it occurs varies in different people.Ankylosing spondylitis can also affect the peripheral

joints, usually large joints such as the hips, knees,and shoulders. The hips are more likely to be in-volved if the disease starts before the age of 20. If hiparthritis does not occur in the first 10 years afterdiagnosis, it is unlikely to do so.

Enthesitis, or inflammation where tendons orligaments join onto bone, is a hallmark of this dis-ease. This occurs particularly at the heel where theACHILLES TENDON joins the calcaneus (heel bone), inthe lower pelvis where the inner thigh musclesattach, and along the spine and the breastbonewhere the ribs join. Involvement of the jointswhere the ribs meet the breastbone and spine cancause severe chest pain and difficulty in breathing.Many patients have had tests performed to excludea myocardial infarction (heart attack) or lung dis-ease as a cause of unexplained chest pain beforethe diagnosis of AS was made. In teenagers a vari-ant of AS occurs. In this condition, enthesitis is themost common manifestation. The clinical presenta-tion of enthesitis and arthritis in a teenager issometimes called the SEA (seronegative enthesitisand arthropathy) syndrome. Not all teenagers withthe SEA syndrome develop the adult form of AS. Inmany with SEA, the arthritis lasts for a few monthsor years and then disappears.

In many patients, fusion of the joints in thespinal column causes increasing stiffness and even-tually a stooped posture that is typical of AS.Restricted movement in the neck makes it difficultfor patients with AS to turn their heads. As a con-sequence, activities such as reversing a car becomedifficult. Stiffness and restricted movement in thehips and knees can cause these joints to becomepermanently flexed, making walking difficult.Fusion of the rib joints reduces the ability of thechest to expand when a deep breath is taken.Reduced lung expansion can cause recurrent chestinfections and shortness of breath when the patientexercises. Scarring of the upper lobes of the lungsmay develop late in the disease and can becomeinfected with organisms that do not usually affecthealthy lungs (opportunistic infection).

Patients with AS can also develop several med-ical problems that are unrelated to their joints. Eyeinflammation is common, and anterior uveitis oriritis occurs in 25 percent of patients (see EYE PROB-

LEMS). Usually this presents with pain in one eye,

ankylosing spondylitis 7

blurred vision, discomfort in bright light (photo-phobia), and increased redness and watering of theeye. Attacks of iritis or uveitis usually subside with-in a few months but may recur later in either eye.The eye inflammation in AS seldom causes perma-nent loss of vision, but if treatment is delayed it can.

A number of cardiovascular complications mayoccur and are thought to be caused by chronicinflammation. Why the heart is a specific target inAS is not known. Cardiovascular complicationsinclude the following conditions:

• Inflammation of the first part of the aorta thatoriginates from the left ventricle (aortitis)

• Leaking of the aortic valve (aortic regurgitation),causing blood to flow back into the left ventricleafter it has been pumped out

• Heart block, in which electrical impulses fail to passnormally from specialized conducting tissue in theupper chambers of the heart, the atria, to the lowerchambers, the ventricles that pump blood

• Enlargement of the heart

• Pericarditis (inflammation of the lining layersaround the heart)

Aortic regurgitation and heart block are themost common cardiovascular complications. Theseare more likely to occur in patients who have hadAS for many years with involvement of peripheraljoints such as the wrists, shoulders, or knees.

Spinal fracture can occur after relatively minortrauma because the spine is rigid and less flexible.OSTEOPOROSIS is common and may occur early inthe disease, suggesting that it results from theinflammatory process rather than immobility. AMY-

LOIDOSIS, glomerulonephritis caused by depositionof immunoglobulin IgA, and cauda equina syn-drome are rare complications. In the cauda equinasyndrome, the fluid-filled membranes at the lower end of the spinal cord enlarge. This causespressure and damage to the lower spinal nerves,particularly those supplying function to the bladderand bowels.

Diagnosis

AS is often not diagnosed for several years after theonset of symptoms, especially in women. This is

because the onset of back pain and stiffness is grad-ual and in a young person is often ascribed to backstrain. Women develop AS less often than men andtherefore the diagnosis may not be considered inwomen.

A history of back pain with unusual morningstiffness and signs of enthesitis or arthritis thataffects large joints in a young adult should suggestthe diagnosis of AS. X-ray evidence of inflamma-tion of the sacroiliac joints is required to make adefinite diagnosis of AS. However, it is importantto recognize that X-ray changes can take up to 10years to develop. Therefore, in early disease, the Xrays can be normal. X rays of the SI joints are dif-ficult to interpret in teenagers and young adults.Radioisotope bone scans can show increaseduptake in the SI joints in the early stages of dis-ease before X-ray changes are visible. CT scans areboth sensitive and specific but have the disadvan-tage that they expose the reproductive organs tosignificant radiation. MRI of the SI joints is sensi-tive very early on, but its place in investigation isnot yet clear. Inflammatory markers in the bloodsuch as ESR may be raised but are not reliable,particularly in patients who have disease that islimited to the spine. Tests for RHEUMATOID FACTOR

and ANTINUCLEAR ANTIBODIES are negative. Thepresence of HLA-B27 increases the likelihood ofthe diagnosis of AS in patients of Caucasianextraction. However, because approximately 10percent of healthy people have the HLA-B27gene, this test is of limited value both in patientswith features typical of AS and in those withpoorly characterized back pain.


The aims of treatment are relief of symptoms (painand stiffness), improvement in flexibility, andmaintenance of posture thus enabling the individ-ual to continue his or her occupation and partakein leisure activities. Crucial to achieving these aimsis early diagnosis and patient education. Self-carethrough stretches, exercises, and appropriateknowledge and use of medications is essential for agood outcome. Learning a routine of stretches andexercises under the supervision of a physical ther-apist is very useful. Swimming is an excellent exer-cise for patients with AS because it exercises the

8 ankylosing spondylitis

heart and lungs and puts many joints through awide range of motion.

For most people with AS physical therapy,NSAIDs and occasional analgesics are sufficient. Asmall number of patients with severe diseaserequire more aggressive treatment with drugs thatattempt to control inflammation or slow down theprogression of disease. Most patients with estab-lished disease and fused joints or deformity willbenefit from occupational therapy, includingassessment for work environment alteration or useof ASSISTIVE DEVICES.

Many NSAIDs are used to treat AS. PHENYLBUTA-

ZONE is an NSAID that has a reputation amongolder rheumatologists for being particularly effec-tive in controlling the symptoms of AS. Because itoccasionally causes serious bone marrow damage,phenylbutazone is no longer available in manycountries. In surveys of patients with AS, INDO-

METHACIN was the preferred NSAID but it has a rel-atively high frequency of side effects, includingcentral nervous system effects such as dizziness.NAPROXEN was the next preferred NSAID. However,it is likely that most of these drugs can improvesymptoms, although individual patients may havepreferences for a particular NSAID. Some evidenceindicates that treatment with phenylbutazone andindomethacin may slow or prevent fusion of joints,but NSAIDs are used primarily to control symp-toms rather than to slow progression of disease.Among the drugs that are prescribed to controlinflammation if NSAIDs alone are insufficient, SUL-

FASALAZINE is safe and effective in some patients,particularly those with involvement of peripheraljoints. AZATHIOPRINE and METHOTREXATE have someeffect on both spinal and peripheral disease, butclinical trials are inadequate to assess the efficacy of these drugs. The newer anti-TNF drugs havebeen highly effective in patients with resistant dis-ease. Future trials will establish their role in treat-ment. Early reports suggest that a BISPHOSPHONATE

drug, pamidronate, may have useful effects. Thisgroup of drugs is more often used to treat osteo-porosis but is under investigation for the treatmentof AS.

Radiotherapy was used in the 1930s for spinaldisease with good responses. A report in 1950 thatAS patients who had received radiotherapy had a

higher than expected incidence of leukemiaresulted in a marked decline in this form of ther-apy. Although modern radiotherapy is probablymuch safer, it is still seldom used. However, it stillhas a role in intractable disease and has been usedin small doses to control local problems such asenthesitis of the Achilles tendon refractory to othertreatments. Local CORTICOSTEROID injections areuseful in treating swollen peripheral joints andenthesitis, but there is little role for long-term oralcorticosteroids in AS.

If the hip joint is severely damaged, total jointreplacement can dramatically improve a patient’squality of life. This is a common operation in AS.However, many patients are young at the time ofsurgery and are likely to need a second operationyears later to replace the artificial hip when itwears out. Patients with AS who undergo hip re-placement surgery have a greater chance of devel-oping heterotopic ossification, a condition wherenew bone grows around and into the new joint,thus restricting its motion. To prevent heterotopicossification, many orthopedic surgeons treat thehip with a low dose of radiotherapy before surgery.Surgery is also occasionally used to correct a severespinal deformity when the patient is bent so far for-ward that forward vision is impossible. The major-ity of patients with AS can lead an active life andcontinue to work. Indeed, some patients with milddisease who have had back pain but never soughtmedical advice for it are diagnosed only when aroutine X ray late in life shows the typical findingsof AS. A poorer prognosis is more likely if there isperipheral joint disease, a young age of onset, araised ESR, and a poor response to NSAIDs.

anticardiolipin antibody syndrome See ANTIPHOS-

PHOLIPID ANTIBODY SYNDROME.

antimalarials A class of drugs including HYDROXY-

CHLOROQUINE and CHLOROQUINE used to treatmalaria but also used to treat RHEUMATOID ARTHRITIS

and SYSTEMIC LUPUS ERYTHEMATOSUS.

antineutrophil cytoplasmic antibody (ANCA)See Appendix II.

antinuclear antibody (ANA) See Appendix II.

antinuclear antibody 9

antiphospholipid antibody syndrome This is alsoknown as anticardiolipin antibody syndrome orlupus anticoagulant syndrome. This syndrome ischaracterized by an increased risk of venous orarterial blood clots (thrombosis), recurrent mid- tolate-pregnancy loss, and thrombocytopenia in indi-viduals who have antibodies to phospholipids. Theantiphospholipid antibody syndrome may be pri-mary, when it occurs alone, or secondary, when itis found in association with another autoimmunedisease. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) is themost common cause of secondary antiphospholipidantibody syndrome, but less common causes areRHEUMATOID ARTHRITIS, SCLERODERMA,and SJÖGREN’S

SYNDROME.

Antiphospholipid antibodies were first recog-nized as causing a false-positive test result in earlyblood tests for syphilis. These antibodies do notalways result in complications. When complica-tions such as thrombosis do occur in patients whohave the antibodies, they are diagnosed withantiphospholipid antibody syndrome. Approxi-mately 3 percent of healthy people have antiphos-pholipid antibodies, but many never develop theantiphospholipid antibody syndrome. Treatmentwith some drugs, for example chlorpromazine,quinidine, and hydralazine, can induce antiphos-pholipid antibodies. These drug-induced antiphos-pholipid antibodies, and those found in associationwith HIV infection, are seldom associated withthrombosis.

The term lupus anticoagulant was coined whenit was recognized that some patients with SLE hadantibodies that acted as anticoagulants in the labo-ratory by prolonging tests of blood clotting such asthe Russell viper venom time or activated partialthromboplastin time. However, the term lupusanticoagulant turned out to be a misnomer. Theanticoagulant effects occur only in the test tube.These patients in fact have an increased risk ofblood clots, rather than excessive bleeding thatwould be expected if the antibody acted as an anti-coagulant. It was also a misnomer because manypeople who had a positive lupus anticoagulant testdid not have lupus. The antiphospholipid antibodysyndrome and the lupus anticoagulant syndromeare now known to be related, and some patientswho have an antiphospholipid antibody also have

a positive lupus anticoagulant test. However, theoverlap is not complete, and sometimes one test ispositive and the other negative. Both tests are asso-ciated with an increased risk of thrombosis. Inaddition to antiphospholipid antibodies, it is nowknown that other antibodies, for example beta2-glycoprotein antibodies, play an important role inthe development of the syndrome.

Cause

It is not clear how antiphospholipid antibodies thatdecrease blood clotting in laboratory tests increaseclotting in people. Several theories have been pro-posed. Normal endothelium (the thin layer of cellslining the inside of blood vessels) has complex pro-tective mechanisms to prevent thrombosis (i.e., hasan anticoagulant effect). Many of the antibodiesfound in this syndrome in fact bind to beta2-glyco-protein I and prothrombin. Beta2-glycoprotein I andprothrombin are proteins that bind to phospholipidson cell walls in the process of thrombus formation.One popular theory of how the antiphospholipidsyndrome occurs is that the antibodies interferewith these mechanisms and thereby allow throm-bosis to occur. The underlying trigger that results inthe formation of antiphospholipid antibodies is notknown. Indeed, the presence of the antiphos-pholipid syndrome simply seems to tip the body’snormal balance between thrombosis and anticoagu-lation in favor of thrombosis. A relatively minorevent can then cause damaging thrombosis.

Symptoms

Most individuals with antiphospholipid antibodiesdo not have symptoms unless a complicationoccurs. A thin, lacy, red-purple rash, LIVEDO RETICU-

LARIS, is common but does not cause symptoms.Patients with associated diseases such as SLE willhave the usual symptoms of that disease.

Pregnancy loss A common complication isrepeated miscarriage, often occurring in the secondhalf of pregnancy. Up to 50 percent of women withhigh levels of IgG antiphospholipid antibodies willhave some pregnancy loss. Lower levels and IgM orIgA antibodies are associated with a lower rate ofcomplications. Overall, the antiphospholipid syn-drome is not a common cause of pregnancy loss.Pregnancies that do not end in miscarriage have a

10 antiphospholipid antibody syndrome

greater chance of delivering prematurely, therebyplacing the immature infant at risk. In pregnanciesthat carry on to term, fetal growth is often poorbecause the placenta does not function well andthe supply of nutrients to the unborn baby is inad-equate.

Thrombosis The antiphospholipid antibodysyndrome is often diagnosed when someone spon-taneously develops blood clots in his or her arteriesor veins. Deep vein thrombosis (DVT) most oftenoccurs in the veins of the legs but can occur any-where. This can be dangerous if the clot breaks offand lodges in the blood vessels of the lungs (pul-monary embolus) since this is sometimes fatal.Arterial thrombosis reduces blood supply to theorgan affected and can result in stroke, myocardialinfarction (heart attack), or gangrene of a limb. Aswith other complications, the antiphospholipidsyndrome is not a common cause of these vascularproblems. It should be suspected when thrombosesoccur in young patients, nonsmokers, or inunusual sites.

Other complications These include leg ulcers,heart valve irregularities known as vegetations,and nervous system complications such as stroke.Thrombocytopenia is common but is usually mildand seldom leads to complications such as bleed-ing. Catastrophic antiphospholipid antibody syn-drome is rare but often fatal. It was given this namebecause in addition to clots occluding the bloodsupply to limbs, several organs such the lungs, kid-neys, and brain are affected.

Diagnosis

The diagnosis of antiphospholipid antibody syn-drome is difficult and requires a high index of suspicion. Recurrent thromboses, thrombosis in aperson for no apparent reason, or recurrent mid-trimester abortions usually trigger diagnostic test-ing. The tests performed include tests for bothanticardiolipin antibodies and lupus anticoagulant(see Appendix II). Because the antiphospholipidsyndrome is so common in patients with SLE,lupus patients are often screened to assess their riskof thrombosis. Antiphospholipid antibodies cancross-react with the antibodies detected by someblood tests for syphilis, resulting in a false-positivetest for that disease.


Most patients with significant levels of antiphos-pholipid antibodies who have not had a complica-tion take low-dose aspirin to decrease their chancesof developing a clot. Patients who have had athrombosis are very likely to have further prob-lems. Most patients with the antiphospholipid anti-body syndrome who have had one thrombosis aretherefore treated with a drug to prevent blood clotsforming (anticoagulant). Warfarin is the usual drugused and this is taken for a long time, sometimeslife. The dose of warfarin needs to be taken at thehigher end of the usual dose range to be effective.If there is a contraindication to treatment withwarfarin, then low-dose aspirin, which preventsplatelets from aggregating, is used, but it is not aseffective as full anticoagulation with warfarin. Inthis situation an injectable anticoagulant (aheparin) can be used for short periods to protectthe patient during high-risk periods such as surgeryor long flights. Treatment to prevent recurrence ofpregnancy loss is not standardized. However, goodresults are possible using the newer low-molecular-weight heparins given as daily or twice daily sub-cutaneous injections, often with aspirin, duringand after pregnancy. The patient is taught to do thisherself at home. Prolonged use of heparins cancause OSTEOPOROSIS, and some protection againstthis should also be used. High doses of corticos-teroids during pregnancy have been tried and areeffective, but the side effects outweigh the benefits.

arthritis Inflammation of joints that results inpain, heat, swelling, and loss of function. Arthritis isnot one condition but has many causes, and itaffects more than 40 million people in the UnitedStates. Arthritis in its many forms causes consider-able suffering to the affected individual and is costlyfor both the individual and society. Direct medicalcosts for patients with RHEUMATOID ARTHRITIS aver-aged $8,500 per year in the late 1990s. Half of thiswas in hospital costs, 26 percent in medicationcosts, and 8 percent for physician visits. Not only dopeople with arthritis have these direct costs, butthey may also suffer loss of earnings or requiremodification of their home or workplace. These areknown as indirect costs and average out at roughlytwo and a half times the direct costs.

arthritis 11

Approximately 5 percent of people of workingage in the United States have some form of arthritis.About 25 percent of workers with rheumatoid ar-thritis take early retirement because of their disease,as do 14 percent of those with osteoarthritis. Thiscontrasts with 3 percent of those without arthritistaking early retirement because of ill health. Al-though it is difficult to measure scientifically, severalstudies now show that effective treatment reducesthese costs as well as improves the quality of life.

Treatment of different types of arthritis varies,and classification aids the selection of rational ther-apy. Arthritis-related conditions can be classifiedinto the following categories:

1. Degenerative arthritis (osteoarthritis, OA) see OSTEO-

ARTHRITIS

2. Arthritis caused by crystal deposition see GOUT andCALCIUM PYROPHOSPHATE DIHYDRATE DEPOSITION

DISEASE

3. Rheumatoid arthritis (RA) see RHEUMATOID ARTHRITIS

4. Seronegative arthritis see ANKYLOSING SPONDYLITIS;

REITERS’ SYNDROME; PSORIASIS AND PSORIATIC

ARTHRITIS; INFLAMMATORY BOWEL DISEASE; andBEHÇET’S DISEASE

5. Connective tissue disorders see SYSTEMIC LUPUS

ERYTHEMATOSUS and SCLERODERMA

6. Infective arthritis see INFECTIVE ARTHRITIS

7. Arthritis caused by metabolic and systemic diseases seeHEMOPHILIA; ACROMEGALY; and SICKLE-CELL DISEASE

Diagnosis

A diagnosis of a particular type of arthritis is usu-ally made mainly on the symptoms and physicalfindings. Laboratory tests and X rays are sometimeshelpful but are seldom absolutely diagnostic (seeAppendix II). Examination of synovial fluid (seeJOINT ASPIRATION) is important in the diagnosis ofarthritis caused by infections and crystal deposi-tion, for example gout. For a few rheumatic prob-lems, for example VASCULITIS, a biopsy of tissue,often skin or a superficial nerve, can be diagnostic.

The following clinical features of arthritis aid thediagnosis.

1. Whether it is inflammatory or noninflammatory 2. Whether its onset is acute or chronic3. The number of joints involved and their dis-

tribution

4. The characteristics of the individual that predis-pose him or her to arthritis

5. The involvement of organs other than the joints

Inflammatory and noninflammatory arthritis

Inflammatory arthritis (RA, seronegative arthritis,crystal-induced arthritis, infective arthritis) causespain, often worse in the morning, swelling,warmth, redness, pain on movement, and severalhours of stiffness after arising. Noninflammatoryarthritis (degenerative arthritis) causes pain, oftenworse at night, and stiffness usually lasting only afew minutes after a joint has been in one positionfor a while. Soft tissue swelling, warmth, and red-ness are usually absent.

Acute and chronic arthritis Acute onset ofsevere symptoms occurring overnight is typical ofcrystal-induced and infective arthritis. Most othertypes of arthritis have a more gradual onset, anddegenerative arthritis typically becomes slowlymore noticeable over years.

The number and distribution of affected joints

Arthritis can affect many joints (polyarticular), afew joints (pauciarticular or oligoarticular), or onejoint (monarticular). The distribution of affectedjoints can be symmetrical, typically involving thesame joints on both sides of the body, or asymmet-rical, affecting scattered joints.

Individual characteristics Different types ofarthritis are more likely to affect people with certaincharacteristics at particular stages of their life. Forexample, gout most commonly affects middle-agedmen who are overweight and drink alcohol andelderly women who are on treatment for high bloodpressure or heart failure. Connective tissue diseaseslike Systemic lupus erythematosus (SLE) largelyaffect young women, and rheumatoid arthritis usu-ally starts between the ages of 40 and 60 years.

Organ involvement Connective tissue diseasestypically affect organs other than the joints, espe-cially the skin, blood, nervous system, kidneys,heart, lungs, and muscle. The organs involved maygive clues to which type of arthritis it is. For exam-ple, the skin changes in a patient with sclerodermapoint to that diagnosis. Other diseases such asacromegaly will usually be diagnosed because of theother organs involved before the arthritis becomes aproblem. The characteristics of various types of

12 arthritis

arthritis are summarized in the following table.There is, however, considerable overlap, and clinicalfeatures are only clues and are not diagnostic.


The aims of treatment are

1. Relief of pain and suffering 2. Maintenance and restoration of function3. Prevention of disease progression

The treatment of the various types of arthritisdepends on the diagnosis, the severity of disease,the individual patient’s response to different thera-pies, and a person’s needs. Treatment may involvea combination of physical therapy and exercises,lifestyle alterations, medications, and surgery. Thetreatment of specific types of arthritis is describedunder their individual entries but is summarized inthe table on the next page.

The prognosis of arthritis differs according to thediagnosis, severity of disease, and treatment and isdiscussed under individual entries. People with cer-tain forms of arthritis also develop related healthproblems such as lung, heart, and kidney diseasemore frequently than average. Paying carefulattention to these will also improve the patient’squality of life.

arthrocentesis See JOINT ASPIRATION in Appendix II.

arthrodesis A procedure in which a damagedjoint that cannot be replaced is surgically fused.The remains of the joint are removed and the endsof the two bones fixed in place by screws or by arod running through the bones until they haveunited. The advantages of arthrodesis are that itgives stability and excellent pain relief to severelydamaged joints. However, a disadvantage is that allmovement is lost. The procedure is most useful forjoints that are causing severe pain and where sta-bility is more important than movement such asthe distal interphalangeal joints and the proximalinterphalangeal joint of the index finger. Beforeproceeding with arthrodesis, the future implica-tions need to be considered with regard to the indi-vidual patient’s functional needs, the demands thatwill be put on the joint, and the state of the sur-rounding joints. For example, arthrodesis of onedisorganized wrist can improve grip strength con-siderably. However, if both wrists were fused, per-sonal hygiene would become very difficult.Although arthrodesis of the ankle leads to signifi-cant gait problems, it is still sometimes done forcrippling pain because JOINT REPLACEMENT surgeryat the ankle remains problematic.

arthroplasty See JOINT REPLACEMENT.

arthroscopy and arthroscopic surgery In its sim-plest form this involves direct visualization of thestructures inside a joint through a tube. Modernarthroscopes have improved sources of light, andthe image is magnified and transmitted to a videoscreen via a fiberoptic cable. Instruments can beinserted through separate entry points around ajoint, improving surgery by a technique known astriangulation. Arthroscopy is used both to obtain aclear view of anatomical abnormalities that may bethe cause of a patient’s symptoms and to performsurgery to correct the abnormalities. As recently asthe 1960s the value of arthroscopy was still beingdebated in the United States. However, withimprovements in instrumentation and video tech-nology as well as the diagnostic and therapeutictechniques, it has evolved into a widely used andvaluable procedure. Although arthroscopic diagno-sis has been partially displaced by MRI over the last

arthroscopy and arthroscopic surgery 13

CLINICAL FEATURES OF DIFFERENT TYPES OF ARTHRITIS

Poly-

Arthritis Inflammatory Acute Symmetrical articular

Osteoarthritis - - - ±

Crystal-induced + + - -

Rheumatoid arthritis + - + +

Seronegative + ± - ±

Connective tissue disorders ± ± ± ±

Infective + + - -

Metabolic/systemic ± + - -

14 arthroscopy and arthroscopic surgery

COMMON TYPES OF ARTHRITIS AND THEIR TREATMENT

Type of Arthritis Diagnosis Goals of Treatment Commonly Used Drugs*

Inflammatory Rheumatoid Decrease pain, maintain/ One or more of methotrexate,Arthritis arthritis (RA) improve function, RA remission sulfasalazine, hydroxychloroquine,

if possible; if remission is not leflunomide, cyclosporine possible, the goal is to control RA. azathioprine, gold, TNF antagonist,

± prednisone, ± an NSAID.

Gout Control the pain of acute gout attacks, NSAIDs or colchicine to controlcontrol the problem by decreasing acute attacks; allopurinol oruric acid levels in the blood and so uricosurics to decrease theprevent future gout. uric acid in the blood.

Pseudogout Control the pain of acute pseudogout NSAIDs, sometimes corticosteroids(CPPD) attacks, prevent attacks if possible. or colchicine.

Psoriatic arthritis, Decrease pain, maintain/improve An NSAID ± one or more ofreactive arthritis, function, remission if possible; methotrexate, sulfasalazine,arthritis of if remission is not possible, the hydroxychloroquine, gold,inflammatory goal is to control disease activity. cyclosporine, TNF antagonist.bowel disease

Ankylosing Decrease pain, maintain/improve An NSAID, sometimes with spondylitis function, and prevent deformity. methotrexate, sulfasalazine, or

TNF antagonist if the problem is detected early.

Degenerative Osteoarthritis (OA) Decrease pain, maintain/improve Acetaminophen; NSAID.joint disease function.

Connective tissue or Systemic lupus Prevent organ damage, improve Prednisone + one or more ofautoimmune diseases erythematosus (SLE) symptoms, control disease activity. hydroxychloroquine, azathioprine,

cyclophosphamide, methotrexate.

Scleroderma Prevent organ damage, improve Blood pressure treatment, symptoms, maintain joint mobility. antireflux treatment to improve

swallowing, treatment of Raynaud’s.

Dermatomyositis and Restore and maintain muscle Prednisone ± one or more ofpolymyositis strength, remission if possible; azathioprine, cyclophosphamide,

if not possible, control disease activity. methotrexate, cyclosporine.

Vasculitis Temporal arteritis Prevent organ damage (blindness), Prednisone, often alone, butremission if possible; if not possible, sometimes with azathioprinecontrol disease activity. or methotrexate.

Wegener’s Prevent organ damage, improve Prednisone + cyclophosphamide,granulomatosus and symptoms, remission if possible; if not or sometimes methotrexate,polyarteritis nodosa possible, control disease activity. leflunomide, or azathioprine, or

TNF antagonist.

Fibromyalgia Fibromyalgia Decrease pain, maintain/improve Aerobic exercise, antidepressants,function. muscle relaxers, sometimes NSAIDs.

Tendinitis/bursitis Tendinitis/bursitis Wait for it to get better, decrease pain, Rest, sometimes NSAIDs, sometimesmaintain/improve function. corticosteroid injections.

Osteoporosis Osteoporosis Prevent bone loss and prevent fractures. Adequate calcium and vitamin Dplus one of the following: Estrogens, SERMs, bisphosphonates,calcitonin.

*Medicines are only part of the treatment of arthritis problems. For many problems, exercise, physical therapy, or surgery can be very important.

decade, the role of arthroscopic surgery is continu-ally expanding. Advantages include precise diagno-sis, very small skin and joint capsule incisions,relatively brief disability and rapid rehabilitation, aswell as a better cosmetic outcome than opensurgery. Many arthroscopic procedures can be per-formed under regional anesthesia, and mostpatients are discharged home on the same day. Therisk of infection is lower than with open surgery.

The knee is a large accessible joint with complexinternal organization subject to large stresses thatfrequently lead to structural abnormalities. It isthus the ideal joint for this type of procedure. Thefirst arthroscopy was performed on the knee usinga modified cystoscope (used for looking into thebladder) in Japan in 1931. Lesions in the knee thatare amenable to arthroscopic surgery includemeniscal injury or degeneration (see MENISCAL

TEARS), ligament injury, OSTEOCHONDRITIS DISSECANS,

LOOSE BODIES, PATELLOFEMORAL DISORDERS, synovialdiseases, OSTEOARTHRITIS, and fractures of the sur-face of the tibia.

Although most arthroscopic surgery has beendone on the knee, several other joints are also suit-able. In the shoulder, tears of the glenoid labrum(the rim of supporting cartilage around the shoul-der joint—see SHOULDER PAIN), capsule, BICEPS TEN-

DON, or ROTATOR CUFF may be identified andrepaired. Loose bodies can be removed and syn-ovial or joint surface abnormalities repaired.Arthroscopic surgery is particularly useful in thesubacromial space just above the shoulder jointwhere the rotator cuff tendons can be repaired andthe undersurface of the acromion and acromioclav-icular joint can be smoothed without disrupting theoverlying muscles.

Arthroscopy is frequently used at the elbow toremove loose bodies and osteophytes. The cause ofchronic wrist pain can be very difficult to determine,and special arthroscopes have been developed toassist with this. In the ankle, arthroscopy is helpfulin diagnosing difficult ankle problems as well astreating synovial impingement, loose bodies, osteo-phytes, and irregularities caused by healed hairlinefractures. Although arthroscopy has been less fre-quently employed at the hip, the potential benefitsfrom avoiding open surgical exposure of this deepjoint suggest that it will continue to have a role

despite the disadvantages of limited maneuverability

and a small joint space.

assistive devices These include any device that

improves the functional capacity of someone with

a disability brought about by a rheumatic disease.

Disability in this context means the lack of ability

to perform an activity in the manner or within the

range considered normal for a human being. In the

assessment of the impact of rheumatic diseases,

these abilities or activities of daily living are often

grouped into functional classes or domains. Some

of the important domains are listed below, together

with examples of relevant assistive devices.

• Locomotion Many types of cane, crutch, or

walker may be used to unload a damaged or

painful joint. Manual or electric wheelchairs

may be used to cover distances that would oth-

erwise be impossible.

• Transport Spinner knobs on steering wheels

may enable someone with severe arthritis in the

hands to drive. Hand controls for the brakes and

the accelerator may do the same for those with

severely affected legs.

• Personal Hygiene Many aids, including hand-

held shower nozzles, grab rails to aid entry to

the bath or shower, long-handled combs, elec-

tric toothbrushes, glove-shaped washcloths with

soap pockets, and toothpaste squeezers, can

make life easier for those with painful joints or

loss of range of movement.

• Dressing Velcro closures for shoes and clothing

as well as modified clothing.

• Feeding Large-handled utensils, a rocker knife

that is used with a rocking rather than chopping

or cutting motion, jar openers, and many non-

slip items.

• Communication Rubber-tipped devices for typ-

ing, voice-activated tape recorders, and auto-

dial telephones.

• Housework Wheeled carts, long-handled reach-

ers, see-through pots, electric can openers and

food processors.

assistive devices 15

atrial myxoma A rare, benign heart tumor thatmost often occurs in the left atrium. The diagnosisis often difficult because the symptoms of atrialmyxoma can mimic other illnesses, includingrheumatological conditions such as VASCULITUS.

Symptoms include:

1. Systemic symptoms such as fever, weight loss,myalgia, and arthralgia.

2. Embolic symptoms that result from small frag-ments of the tumor, or small blood clots fromthe tumor surface, breaking off into the circula-tion and finally blocking blood vessels in otherorgans. These tumor emboli may cause stroke,blood in the urine, and a skin rash.

Blood tests may show nonspecific abnormalitiessuch as anemia and a raised ESR compatible withinflammation. The myxoma can be detected byechocardiography (ultrasound scan of the heart).Treatment by surgical removal is usually curativeand recurrence is unusual.

autoimmunity See IMMUNE RESPONSE.

avascular necrosis (AVN; also known as osteo-necrosis and aseptic necrosis) Death of an area ofbone marrow and bone resulting in loss of normalarchitecture. Avascular necrosis is not a specific dis-ease but is the end result of any condition thatdecreases the circulation to an area of bone to theextent that the bone dies. AVN can occur in almostany bone but does so more commonly at the endsof long bones. Thus it often affects bone that con-tributes to the normal architecture of the hip,shoulder, or knee joints. AVN is relatively commonand is the underlying cause of arthritis in approxi-mately 10 percent of people undergoing jointreplacement.

Cause

The cause of AVN is not well understood. However,a feature common to most theories is that theblood supply to an area of bone is inadequate,resulting in bone infarcts. Interruption of bloodsupply to bone can result from:

1. Mechanical factors, for example a fracture ordislocation that damages a blood vessel

2. Blockage of a blood vessel by clot (thrombosis orembolus), fat (fat embolus), or nitrogen bubbles(rapid decompression in divers)

3 Damage to a blood vessel, either directly, for exam-ple by VASCULITIS, or indirectly by neighboringinflammation causing swelling and pressure

Sometimes AVN occurs without any recognizedunderlying predisposing factor and is termed idio-pathic, but often it occurs in the presence of recog-nized risk factors. These include trauma, alcoholabuse, CORTICOSTEROID therapy, SYSTEMIC LUPUS ERY-

THEMATOSUS (SLE), SICKLE-CELL DISEASE, vasculitis,and rapid decompression in deep-sea divers.

Symptoms

Pain in the affected bone is common. The severityof the pain varies from a mild dull ache in chronicforms of AVN to incapacitating pain during acuteinfarction of bone. If the bone infarct is large, thisarea can weaken and partially collapse overmonths or years. If this occurs in bone that formspart of a joint, a relatively small alteration in struc-ture can alter the biomechanics of the joint sub-stantially and lead to severe degenerative arthritis.The symptoms during the late stages of AVN arethose of severe osteoarthritis, specifically pain thatincreases when the joint is used.

Diagnosis

The symptoms and clinical findings of AVN are notspecific. X-ray changes occur relatively late, and sev-eral months must pass before areas of increasedbone density are visible. In the early stages of AVN,magnetic resonance imaging or a radionuclide bonescan (see Appendix II) show characteristic featuresbefore X-ray changes occur and are useful for diag-nosis. AVN is often bilateral. Both hips should there-fore be scanned even if only one side is painful.


If AVN affects a weight-bearing bone, then avoid-ance of weight bearing by using crutches in theacute phase protects against loss of normal archi-tecture. If AVN affecting the hip joint is diagnosedbefore the bone has collapsed, some orthopedicsurgeons recommend a surgical approach knownas core decompression. The surgery involves drillinginto the head of the femur and removing a narrow

16 atrial myxoma

Ayurvedic medicine 17

core of bone and bone marrow. Research hasshown that the pressure in the bone marrow of ajoint affected by AVN is high. This increased pres-sure is thought to compromise the blood supply tothe affected area of bone. Removing a core of tissuereduces the pressure and may improve the bloodsupply to the area of bone undergoing AVN. Theefficacy of core decompression surgery to treat AVNof the hip has not been evaluated in rigorous con-trolled studies. Late in the evolution of AVN, jointreplacement surgery may be needed if the normalarchitecture of a joint such as the hip is destroyedand function is lost or pain is severe.

AVN See AVASCULAR NECROSIS.

Ayurvedic medicine A complementary, holisticapproach to health based on ancient Hindu texts. Itis traced back to the sages of ancient India. Theserishis are believed to have discovered the principlesof Ayurveda during deep meditation. These princi-ples were codified in the Vedas (knowledge) thatform the religious texts of Hinduism. The Atharva-

Veda is the source of Ayurveda. The basis of

Ayurveda is understanding a person’s dosha. Thereare three doshas or types that can be initiallyviewed as being similar to the common body types:Ectomorph (light and slim), endomorph (heavyand big boned), and mesomorph (muscular andmedium build). On top of these physical character-istics are layered information about learning styles,emotional tendencies, and spiritual inclinations.The three doshas are termed Vata, Pitta, andKapha. One is usually dominant and one sec-ondary.

These not only describe people but also deter-mine what foods they should eat and whatlifestyles are appropriate for them. According tothis model, arthritis is thought to result from weak-ened digestion, poor diet, and disturbed equilib-rium. Treatment of arthritis is not standardized.Individualized therapy can include steam baths,enemas, massage, bloodletting, herbs, exercises,yoga, fasting, and avoiding alcohol, meat, and cer-tain vegetables. Ayurvedic approaches to medicinehave not been adequately evaluated in well-designed studies.

B

back pain A surgeon in the United States canoperate on someone in the Middle East with aremote-controlled device. Scientists can build spe-cific proteins to block complex molecules secretedby white blood cells in the body or to deliver drugsto a specific subset of cells in the body. Researcherscan even predict the later development of certaincancers at the time individuals are born. However,we have no answer to the rising epidemic of simplelow-back pain. This does not mean that back painis new. There is a written description of sciatica dat-ing back to 1500 B.C. and back pain appears to havebeen a common problem in medical writings fromthe 1800s. In particular, the disability associatedwith back pain is on the increase rather than backpain itself. Studies in Scandinavian countries overthe last 40 years show no increase in the rate ofoccurrence of back pain over that time. There is noevidence to suggest that the pathology or nature ofthe problem is changing. However, the percentageof Swedish workers taking time off work becauseof back pain increased from 1 percent in 1970 to 8percent in 1992, and the average number of daysthey took off increased from 20 to 39 per year.Why, when people do less physical work and thetreatment possibilities are so much greater, shoulddisability increase? The answers may be as muchsociocultural as medical. Between 1991–93, theSwedish government progressively reduced sick-ness benefits (although they remain generous),and total sick leave for back pain fell from 28 mil-lion days in 1987 to 19.2 million days in 1995.Studies in less developed countries like Oman andNepal show that back pain is extremely common,but very few people are disabled because of it.Hardly anyone in these countries takes to their bedor stays off work because of back pain.

Population surveys show that around 60 percentof adults have experienced low-back pain at sometime, a figure confirmed in several developedcountries. In the 45- to 59-year-old age group, thisrises to about 70 percent. Many of these people willhave had short-lived back pain not requiring anytreatment. A third of the population has had backpain lasting more than a day in the previous 12months. About 6 percent have chronic disablingback pain. This can be compared with the 1 percentthat has the most common chronic inflammatoryarthritis, RHEUMATOID ARTHRITIS. In the UnitedStates, back pain is the commonest cause of activ-ity limitation in people under 45 years of age.There is no significant difference in the numbers ofmen and women reporting pain.

In any given year, 30 percent of adults who havenever experienced back pain will do so. For thosewho have had back pain previously, the figure isjust over 40 percent. In a 12-month study 10 per-cent of men and 7 percent of women between theages of 20–59 years had time off work because ofback pain. Back pain is conventionally divided intoacute or chronic by virtue of persisting for less thanor more than three months, respectively. This isbecause the three-month cutoff separates patientswith quite different characteristics and underlyingproblems. A third group of patients (recurrent)have had back pain for less than three months buthave also experienced previous attacks.

Cause

Much back pain is attributed to the abnormalitiesof the intervertebral disc, and sometimes the disc isindeed the culprit. In the adult, the top and bottomof each vertebral body is covered by a thin sheet ofCARTILAGE (as found in joints), the outer rim of

19

which is calcified (that is, bony). Attached to thisouter rim are concentric layers of tough fibrous tis-sue (the annulus fibrosis) that spiral round at anangle of 70º to the vertebral body to attach to thenext vertebral body. Each successive layer is atright angles to the previous one, thereby increasingthe ability to withstand torsion. Contained withinthese layers is a gelatinous substance called thenucleus pulposus. This allows for free movement aswell as providing a shock-absorbing ability. Impor-tant changes occur as we age. The nucleus pulpo-sus loses water, becoming smaller and stiffer.Cracks and tears start to develop in layers of theannulus fibrosis after the age of about 30 years.This occurs particularly in the inner two-thirds thathas no blood supply. These changes may lead tosignificant weaknesses and possibly bulging of theannulus fibrosis. The forces on the erect spine arealways tending to squeeze the nucleus out of itscontained space. Generally, it is most likely to beforced either upward or downward into the adja-cent vertebral body or outward through the retain-ing annulus fibrosis. It is likely that this actuallyoccurs only with a sudden increase in force. Apartfrom pain, such disc-bulging or protrusion can leadto several spinal problems. Spinal movement willbe reduced in the affected segments. Some forwardtilting of the spine occurs due to loss of height ofthe disc. Bony protrusions or osteophytes developaround and abnormal stresses are placed on theposterior spinal or facet joints that may thendevelop OSTEOARTHRITIS.

However, it is important to see back pain not asa disease entity but as a symptom that can arisefrom many different diseases or abnormalities.Approximately 90 percent of back pain patientshave mechanical back pain. This is defined as painfrom overuse of a normal structure or from traumato or deformity of an anatomic structure (includingthe disc). The exact source and nature of this painmay be extremely difficult to pinpoint, and specificdiagnoses vary between practitioners with differentspecial interests. Some diagnostic labels that areapplied to people in this group include discderangement or disruption, annular tear, spondy-losis, degenerative disc disease, disc syndrome,lumbar disc disease, back sprain or strain, facetjoint syndrome, spinal osteoarthritis, and sacroiliac

injury. While these are all potentially valid diag-noses it is just not possible to be sure of the precisecause of the pain in many people.

A small proportion of patients with mechanicalback pain will have nerve root impingement, usu-ally known as sciatica. This can be due to directpressure from disc material as the nerve leaves thespinal cord, a gradual narrowing of the canalthrough which the nerve exits the spine, interfer-ence with the nerve’s blood supply, or simplyswelling and inflammation close to the nerve.

The remaining 10 percent of patients with backpain have an underlying systemic disease, andthere are many such possible causes. Inflammatoryback pain is typified by ANKYLOSING SPONDYLITIS, butREACTIVE ARTHRITIS, psoriatic arthritis, and SAR-

COIDOSIS can all cause spinal inflammation (see PSO-

RIASIS AND PSORIATIC ARTHRITIS). Infective spondylitiscan be caused by any of the organisms causingINFECTIVE ARTHRITIS. It should be considered particu-larly in intravenous drug users (where staphylococ-cal species and gram-negative bacteria such asPseudomonas aeruginosa are common) as well asthose with lowered immunity due to cancer, HIVinfection, or other causes of chronic ill health. BRU-

CELLOSIS frequently involves the spine or sacroiliacjoints, and 50 percent of bone or joint TUBERCULOSIS

is in the spine.Tumors may arise in the spine (lymphoma, sar-

coma, giant cell tumor, osteoid osteoma, heman-gioma, chordoma) or metastasize there from aprimary cancer elsewhere (lung, breast, prostate,ovary, colon, and myeloma particularly). Bone dis-ease such as PAGET’S DISEASE, OSTEOMALACIA, andOSTEOPOROSIS can frequently cause back pain. Prob-lems outside the spine may occasionally first pre-sent as back pain. Such conditions affectinginternal organs include abdominal aortic aneu-rysm, kidney infection, pancreatitis, and colon can-cer. Herpes zoster (shingles) may give rise to severepain of uncertain cause for two or three days beforethe characteristic rash appears.

There are also well-described associations withback pain. While these might not physically causethe pain, the association is such that effective ther-apy will necessarily have to address them. Theseinclude obesity and smoking. Patients consultingtheir doctor for back pain are also more likely to

20 back pain

have consulted for stress or mental disorders.Depression is thought to be a consequence of backpain more often than a precedent.

Symptoms

Almost all patients with a back problem complain ofpain. Disability or restriction of activities is the mostimportant association with back pain. Disability andrestriction of activities are not the same, and thereis no close correlation between them. There is alsono close correlation between pain or disability andpathology or disease. Of note is that this means theseverity of pain does not provide any informationon the actual diagnosis. Some people with seriousspinal pathology will have little disability while oth-ers with minimal pathology are seriously disabled.Many people with low-back pain will have painelsewhere. This is most commonly in the neck butmay be widespread. It is important to note that painradiating into the leg does not necessarily indicatenerve root entrapment. The sacroiliac joint andassociated structures frequently refer pain into theupper leg. Pain with numbness or tingling that radi-ates down the leg to the foot usually does indicatenerve root irritation, though.

Diagnosis

Confusion has arisen because of the difficulty inmaking a precise anatomic diagnosis in many(some say up to 85 percent) patients with back painas well as the controversy surrounding variousdiagnoses. The anatomic diagnosis means identify-ing which structure the pain is coming from or inwhich the primary problem lies. Everyone present-ing with significant or persistent back pain shouldhave a detailed history taken followed by a thor-ough examination by a practitioner skilled in thisarea. The management of back pain is improved if,at this stage, a differentiation or triage into one ofthree groups is made. These are

• Simple low-back pain

• Nerve root pain

• Serious spinal pathology

Simple Low-Back Pain usually develops in patientsaged 20–55 years. The pain may be in the lowerback, buttock region, or thighs. It is mechanical in

that it varies with time and physical activity, andapart from the pain, the patient is well.

Nerve Root Pain generally radiates to the ankle orfoot. Frequently this unilateral leg pain is worse thanthe back pain. There is numbness or paresthesia inthe same area and signs of nerve irritation such asreduced straight-leg raising that reproduces the pain.There is loss of power, loss of sensation, or alteredreflexes in the area supplied by one nerve root.

Serious Spinal Pathology includes the inflammatoryconditions, infections, tumors, metabolic bone dis-ease, and other rare diseases mentioned above. Lessthan 5 percent of back pain is due to these. There isan increasing trend to use so-called red flags to iden-tify these. This requires the clinician to run througha validated list of signs and symptoms that signal thepossibility of serious pathology. Red flags include:

• Presentation younger than 20 years or olderthan 55 years

• Significant trauma such as a motor vehicle accident

• Constant, nonmechanical pain

• Thoracic back pain

• Previous history of cancer

• Steroid use

• Drug abuse or HIV infection

• Systemical unwellness, including weight loss or fever

• Widespread neurological abnormalities (morethan one nerve root)

• Deformity of the spine

• Bone destruction or collapse on X ray

• A raised ESR

Within the grouping simple low-back pain are ofcourse many different syndromes and a large num-ber of structures that may be giving rise to pain.However, most patients with simple back pain andno red flags do not need any diagnostic tests.Symptom-relieving treatment may be given in theexpectation of an early recovery. Many patientswith nerve root pain will also recover sponta-neously and special investigations will not berequired. All patients with positive red flags shouldhave further investigations done immediately. In

back pain 21

addition, those in the first two groups who do notimprove significantly within six weeks should havefurther investigations. These may include appropri-ate blood tests looking for an underlying systemiccondition and imaging. Blood tests may includethose indicating inflammation such as ESR, testsfor calcium and markers of bone turnover, as wellas tests looking for various forms of cancer such asprostate specific antigen. These will be dictated byeach individual’s circumstances. Plain X rays showbony lesions well but may take some time tobecome abnormal. Technetium bone scans on theother hand are very sensitive in showing abnor-malities early on but do not give very specific infor-mation. They are particularly useful if metastaticcancer (cancer that has spread) is suspected,although one particular cancer (multiple myeloma)may not be demonstrated in this way.

Magnetic resonance imaging (MRI) scans arethe investigation of choice for demonstrating nerveroot impingement and many other conditions suchas tumor or infection. Apart from expense, thechief drawback of MRI scans is the frequent findingof abnormalities in normal people. As MRI scansbecame widespread in the early 1990s, it wasfound that 40 percent of adults with no back painat the time had abnormalities on MRI of theirlower spine. It has therefore become important forradiologists reporting these scans to specify thedegree of the abnormality along internationallyagreed guidelines. In particular, it must be recog-nized that degenerative changes in the discs are anormal aging process. The MRI abnormalitiesshould also be in keeping with the clinician’sexpectations before they are accepted as the causeof the patient’s problem. CT scans may also be use-ful, although they show the soft tissues less well.There is very little place for traditional myelograms(injection of dye into the fluid space around thespinal cord), although they are very occasionallycombined with CT scanning to assist in the plan-ning of surgery. An electromyogram (EMG) may behelpful in a few instances where nerve lesions areatypical or difficult to interpret.


The treatment of back pain clearly depends on thediagnosis, and this discussion will be limited to

mechanical back pain. Many of the other causeswill be discussed elsewhere in this book. As indi-cated above, the vast majority of people with acuteback pain will recover spontaneously within a fewdays. Studies have shown that continuing withnormal activities (excluding heavy lifting) actuallyleads to a better outcome in acute back pain thaneither specifically designed back exercises or bedrest for a few days. Indeed, it has become apparentover the last 20 years that bed rest for more than aday or two leads to a much worse outcome. This isof course a dramatic change from an earlier erawhen rest was considered an important treatmentfor back pain.

Acute back pain For those people whose acuteback pain lasts more than a few days or in whomthe pain is very severe, treatment may be neces-sary. This group should first have serious diseaseexcluded as above and be reassured about this.Aggravating or initiating factors should be lookedfor, and ways of avoiding or modifying these dis-cussed. An explanation of the pain and possiblecauses is extremely important in enabling people tocontinue their normal activities while still havingpain. Pain relief is often necessary, and either painkillers or NSAIDs are helpful. Manipulation mayhelp reduce the pain more rapidly and improvemobility. Physical therapy as well as appropriateexercises may be prescribed or a referral made toan appropriate therapist to initiate these. Theexpected outcome should be discussed since manypeople have an overly negative view of back pain.Most patients seeking care for back pain (which isnot everybody with back pain) will improve con-siderably over the first four weeks, but only 30 per-cent will actually be painfree. After four weeks,about a third will continue to have moderate painand 25 percent will have marked limitation ofactivity. At 12 months, 70 percent will have hadsome recurrent back symptoms and 30 percent willhave had intermittent or persistent pain of moder-ate intensity. About 15 percent will still have sig-nificant activity limitation at this stage.

Chronic back pain The treatment of chronicback pain is much more difficult and complex. Psy-chosocial factors assume greater importance here.Treatment modalities include manual therapiessuch as massage and manipulation, soft tissue

22 back pain

injections, medication, exercise programs, corsetsand braces, back schools, COGNITIVE BEHAVIORAL

THERAPY, and work hardening (specific training toget fit for work activities). Most modern treatmentprograms for disabling chronic back pain wouldinclude cognitive behavioral therapy and exerciseas substantial elements. Factors such as job dissat-isfaction, relationship problems, and drug depen-dency that strongly impact on disability and illnessbehavior should be addressed. Work activities andthe individual’s fitness to undertake this must beassessed. Work-hardening programs analyze theindividual’s physical requirements at work anddesign a training program specifically to preparethem for this. Posture, both at work and duringdaily activities, frequently needs correction.Manipulation is less helpful than in acute backpain. Corsets and braces are generally best avoidedbut may provide some pain relief early in thecourse of treatment when used in conjunction withan exercise program. Analgesics, NSAIDs, andmuscle relaxants are often used with effect.

Evidence-based treatment Because back pain issuch a huge health care problem, the U.S. Agencyfor Health Care Policy and Research spent over twoyears and $1 million evaluating the scientific evi-dence for the effectiveness of the various treatmentsfor back pain in the early 1990s. This has since beenupdated by both Dutch and British researchers, andthe results are very briefly summarized here.

• Good evidence indicates that continuing ordi-nary activities leads to as good or better symp-tom re-lief and less disability than moretraditional approaches including specific exer-cises and short-term rest. Graded reactivationover days or weeks with behavioral manage-ment makes no difference initially but leads toless long-term disability.

• Manipulation results in a quicker reduction inpain and better mobility in the first six weeks ofback pain, but evidence for its value in chronicpain is inconclusive. When properly carried out,the risks of manipulation are very low. McKen-zie exercises (extension or flexion exercises)probably provide some benefit in acute backpain. However, it has not been shown that otherback-specific exercise programs are helpful in

acute back pain. On the other hand, strong evi-dence indicates that exercise therapy is beneficialin chronic back pain.

• Local therapies such as ice, heat, short-wavediathermy, massage, and ultrasound may pro-vide some short-term relief, but they do notalter the outcome. Traction is probably not effec-tive for either simple low-back pain or sciatica.There is no evidence that transcutaneous elec-trical nerve stimulation or TENS is effective foreither acute or chronic low-back pain.

• The use of orthotic shoe insoles in appropriatepatients is probably helpful, but correction of leglength differences of less than 2 cm is not. Thereis no evidence for the use of lumbar supports orcorsets. Biofeedback is probably not effective inchronic low-back pain.

• The evidence for soft tissue injections is equivo-cal. Evidence is contradictory regarding the useof acupuncture in chronic back pain. Reasonableevidence is available to support the use ofepidural steroid injections in both chronic low-back pain and specifically in sciatica. Facet jointinjections have not been shown to be effective.

• Back schools vary considerably in content, butthere is some evidence that this form of therapyis more effective than other types of conserva-tive treatment. There is also reasonable evidencein favor of behavior therapy.

• ACETAMINOPHEN, NSAIDs, and acetaminophen-opioid combinations are all effective in acuteand chronic back pain, but no one is better thanthe others. There is strong evidence that musclerelaxants are effective in acute low-back painand possibly in chronic, but they have signifi-cant side effects.

• There is good evidence that narcotics and benzo-diazepines for more than two weeks, COLCHICINE,systemic CORTICOSTEROIDS, bed rest with traction,manipulation under anesthesia, and the use ofplaster jackets are bad for the patient.

Surgery Patients with definite nerve rootimpingement in whom sciatica is severe, is dis-abling, and does not improve within four weeks orgets progressively worse will probably benefit from

back pain 23

nerve root decompression. Over 90 percent of thisgroup of patients with radiological imaging con-firming the clinical findings will have improvementin leg pain after surgery. However, many will con-tinue to suffer intermittent or persistent back pain.Back pain that does not travel into the leg does notusually respond to surgery. Reliable surgical proce-dures include complete laminectomy (removal ofthe bony sidewall of the spinal canal), fenestration(enlargement of the nerve root exit canal byremoval of some bone), and microdiscectomy (sim-ilar to fenestration but minimizing tissue destruc-tion by use of microscope). In all these procedures,as much of the offending disc material as possible isremoved. Indirect methods of removing the discsuch as chemonucleolysis (injection of an enzymeto dissolve the inner disc) or percutaneous discec-tomy (removal of inner disc material by insertionof the instrument into the side of the disc) are lesssuccessful, although they have all had periods ofpopularity.

SPINAL STENOSIS, which usually results from multi-ple factors including soft tissue and bony enlarge-ment and results in a very gradual encroachment onthe spinal canal and nerve roots, will usually requirecomplete laminectomy with or without spinalfusion. The cauda equina syndrome characterized byloss of or altered sensation in the saddle area, blad-der or bowel disturbance, and often gait disturbancerequires emergency surgical decompression.

bacterial arthritis See INFECTIVE ARTHRITIS.

Baker’s cyst (popliteal cyst) A pouch of synoviumextending behind the knee that is in communica-tion with the joint. It causes a cystic swelling deepin the tissue behind the knee and can extend intothe calf.

Cause

Any condition that causes arthritis of the knee, butmost often RHEUMATOID ARTHRITIS or OSTEOARTHRITIS,can cause a Baker’s cyst. The cyst is thought to formwhen there is a one-way connection between theknee joint and a pouch of synovium that hastracked behind the knee. When fluid develops in ajoint, very high pressures develop under loading.These pressures pump the fluid backward into the

lower-pressure cyst. The connection closes as thispressure is removed (when the foot is lifted) andtherefore functions as a one-way valve. Any condi-tion that increases the production of synovial fluidin the knee, such as arthritis, will cause fluid toaccumulate in the knee and track into the cyst,making it bigger. In children, Baker’s cysts canoccur rarely without any underlying arthritis of theknee. These cysts are thought to occur because ofvariations in anatomy present at birth.

Symptoms

A Baker’s cyst accumulates gradually and, if it issmall, may cause no symptoms apart from a feelingof fullness behind the knee. Some patients may feelit as a tightness behind the knee and, if very tense,complain of having a golf ball-like swelling there. Ifthe cyst enlarges, it can cause pain and a feeling offullness behind the knee and in the calf. If it rup-tures, synovial fluid tracks down into the muscles ofthe calf and causes a painful swollen calf—a clinicalpicture that is very similar to that seen when a clotdevelops in one of the deep veins in the leg (DVT ordeep vein thrombosis).

Diagnosis

Diagnostic tests are usually performed only forunexplained pain behind the knee or if a rupturedcyst is suspected. An ultrasound or magnetic reso-nance imaging (MRI) examination will show thecystic swelling behind the knee and fluid trackingdown the calf. If a deep vein thrombosis is sus-pected, an ultrasound is the appropriate investiga-tion and will usually provide the correct diagnosis.


Good control of the underlying knee arthritis willdecrease the production of synovial fluid and thusdecrease pressure in the cyst. Treatment withNSAIDs or injection of the knee with CORTICO-

STEROIDS often controls knee inflammation andreduces the swelling in a Baker’s cyst. Emptyingthe cysts by drawing the contents out through aneedle (aspiration) or removing the cyst surgicallyis seldom required unless conservative approacheshave failed. Surgical treatments may includearthroscopic (see ARTHROSCOPY AND ARTHROSCOPIC

SURGERY) repair of underlying mechanical problems in

24 bacterial arthritis

the knee, such as MENISCAL TEARS, or rarely removal ofthe synovial lining of the knee (SYNOVECTOMY). Mostcysts respond to an injection of intra-articular corti-costeroid, and although they can recur, surgery is sel-dom needed.

bee venom (apitherapy) An alternative therapythat uses bee venom to treat medical conditions,most often forms of arthritis and multiple sclerosis.The treatment usually involves allowing bees,often two or three, to sting the patient. The num-ber of bees used, the sites of the body they areencouraged to sting, and the frequency of treat-ment varies. Bee venom is also sold as tablets, oint-ments, and injections. In animal models of arthritis,several studies have shown that bee venomdecreases inflammation. However, its use inhumans is largely based on anecdotes and is notsupported by good clinical trials. Side effects arethose resulting from bee stings and include painand swelling at the site of the stings and, rarely,more serious generalized allergic reactions.

Behçet’s disease An inflammatory illness ofunknown cause that causes recurrent oral and gen-ital ulcers, eye inflammation, arthritis, rash, andgut and nervous system complications. Hippocratesmay have been first to describe Behçet’s disease,but it is named after a Turkish physician, HulusiBehçet, who is credited with the first moderndescription of the illness in 1937. There is a largevariation in the frequency of Behçet’s disease indifferent countries. The disease is common incountries along the ancient Silk Route such asTurkey (approximately 100 cases per 100,000 population), Japan, Korea, China, and Iran(approximately 15 cases per 100,000). However, isuncommon in the United Kingdom and UnitedStates (less than 1 case per 100,000).

Cause

The cause of Behçet’s disease is not known but isthought to involve both genetic and environmentalfactors. A genetic predisposition is suggested by theobservation that an inherited tissue type, HLA-B51, isstrongly associated with Behçet’s disease in Asiancountries. However, there is not a striking associationbetween HLA-B51 and Behçet’s disease in Western

countries. Many possible infectious causes such asherpes simplex and parvovirus have been investi-gated, but no infectious agent or environmental factorhas been shown to be the cause of Behçet’s disease.

Symptoms

The illness typically occurs in young adults in their30s or 40s, and the pattern of disease is most oftenone of intermittent attacks separated by periods ofgood health. The classical symptoms are oral andgenital ulcers with inflammation of the eyes, butmany other organs can be affected.

• Mouth and Genital Ulcers Recurrent, painfuloral ulcers that heal without scarring are oftenthe first symptom. The mouth ulcers are mostoften on the tongue or the mucosal lining of themouth on the inside of the cheeks and lips. Theytake about two weeks to heal. Recurrent,painful, deep genital ulcers that heal with scar-ring can affect the penis or scrotum in men orthe vulva or vagina in women.

• Eye Inflammation This usually affects deep tis-sues of the eye such as the uvea and causes red-ness of the eye, pain, and blurred vision (see EYE

PROBLEMS). If the retina is involved, sudden,painless loss of vision can occur.

• Skin Rash Rashes are common and can takemany forms, ranging from small, acnelike pus-tules to larger painful red nodules, known asERYTHEMA NODOSUM, that occur most often onthe front of the shin.

• Arthritis About half of patients have arthritisthat usually involves only one or a few joints,typically large joints such as knees, wrists, orankles.

• Gut Problems Inflammation of the small bloodvessels that supply the gut can cause pain,bleeding, ulcers, and perforation of the wall ofthe small or large bowel.

• Nervous System Complications Inflammation ofthe brain (encephalitis) or the thin tissue thatlines it (meningitis) can cause headache, stroke,seizures, and loss of memory.

• Vasculitis Inflammation of large and small bloodvessels (VASCULITIS) is common and is the under-lying cause of many of the clinical manifestations

Behçet’s disease 25

of Behçet’s disease. Inflammation of superficialveins that lie just under the skin can cause themto clot and form painful cords that can be felt(superficial thrombophlebitis). Inflammation oflarger, deep veins increases the risk of deep veinthrombosis. Inflammation of arteries can lead toformation of aneurysms or to narrowing andblockage of an artery. If the blood flow to anorgan is not adequate to supply oxygen andnutrients to the organ, then gangrene and deathof tissue will occur.

Diagnosis

There is no specific test for Behçet’s disease, and thediagnosis is based on the combination of symptomsand disease manifestations. Diagnostic criteria, suchas those set by the International Study Group forBehçet’s disease in 1990, define criteria that groupsof experts have generally agreed are needed to makethe diagnosis. According to these criteria, recurrentmouth ulcers must be present with at least anothertwo of the following symptoms: Recurrent genitalulcers, eye inflammation, a rash that is typical ofBehçet’s disease, or a positive pathergy test. Thepathergy test is positive when pustules form aroundareas of minor skin trauma, for example at siteswhere the skin has been punctured with a needle todraw a blood sample. A test for pathergy is done bypricking the skin on the forearm with a sterile nee-dle and seeing if a pustule forms at the puncture site.These diagnostic criteria have been establishedmainly for research protocols to make sure thatresearch studies of patients with Behçet’s disease areall discussing the same disease. The diagnostic crite-ria are not always helpful for an individual patientand do not have the same accuracy in different pop-ulations. For example, a positive pathergy test iscommon in Asian and Turkish patients but is lesscommon in American patients.


The treatment of Behçet’s disease depends on theorgans involved and the severity of disease. If thegut, nervous system, or eyes are involved, the ill-ness is treated aggressively with CORTICOSTEROIDS,usually prednisone, often combined with otherdrugs. COLCHICINE and topical corticosteroids may

also be helpful for oral and genital ulcers and eyeinflammation. If these drugs do not controlBehçet’s disease, then immunosuppressants such as CHLORAMBUCIL, AZATHIOPRINE, METHOTREXATE,

CYCLOPHOSPHAMIDE, and CYCLOSPORINE are added.There are good studies showing that azathioprine iseffective, but there are a few controlled trials com-paring different treatments. THALIDOMIDE is moder-ately effective for decreasing the frequency ofattacks of oral and genital ulcers but has many sideeffects and is absolutely contraindicated if there isany chance of the patient becoming pregnant.Recently, alpha-interferon and TUMOR NECROSIS FAC-

TOR (TNF) ANTAGONISTS have shown promise in earlystudies, but it is too early to tell what their role willbe. If venous or arterial thrombosis occur, thenanticoagulation, first with heparin and then withwarfarin, is used.

Behçet’s disease often has periods when the dis-ease is inactive, interspersed with periods when itflares. Complications include blindness, perforationof bowel wall, deep vein thrombosis, rupture of ananeurysm, and neurological damage, but death dueto Behçet’s is unusual.

biceps tendon rupture See SHOULDER PAIN.

biologicals (biologic agents) Broadly defined asdrugs manufactured using molecular biology tech-niques. Most biologic agents are antibodies to pro-teins such as CYTOKINES or their receptors. Forexample, INFLIXIMAB is an antibody to the cytokinetumor necrosis factor (TNF), and ANAKINRA is anantibody to the interleukin-1 receptor. Biologicagents can also act as decoy receptors. For example,ETANERCEPT mops up TNF produced by the body.Biologicals can be synthesized to mimic the actionof proteins normally made by the body to stimulateor inhibit the growth of cells. For example, ery-thropoeitin (trade names: Epogen; ProCrit) is agrowth factor that stimulates the production of redblood cells.

bisphosphonates A class of drugs that concen-trates in bone and decreases resorption (the removalof calcium from bone into the bloodstream). Bispho-sphonates are used to treat OSTEOPOROSIS and PAGET’S

DISEASE. They include ALENDRONATE (trade name:

26 biceps tendon rupture

Fosamax), RISEDRONATE (trade name: Actonel), andETIDRONATE (trade name: Didronel).

blood tests See Appendix II.

bone marrow transplantation An aggressivetherapy undergoing evaluation for a range ofautoimmune disorders. Bone marrow transplanta-tion (BMT) involves high-dose immunosuppressivetreatment followed by bone marrow replacement.BMT was developed as a treatment for severaltypes of cancer. Virtually all types of chemotherapyfor cancer suppress the bone marrow, which makesred and white blood cells and platelets. The theorybehind BMT was that much higher doses of anti-cancer drugs could be used to eradicate cancerthroughout the body, including the bone marrow,if physicians did not have to avoid suppressing thebone marrow. Isolated reports that autoimmunedisease improved in patients who received a bonemarrow transplant for cancer and studies in animalmodels showing benefits from BMT, have led towidespread interest in it as a potential treatmentfor autoimmune disease.

Autologous and allogeneic transplants Thereare two major types of BMT—autologous and allo-geneic. In autologous transplantation, patientsreceive their own marrow or stem cells. In allo-geneic transplantation, they receive the bone mar-row from a donor closely matched for tissue type(see HLA). The complications and mortality aremuch lower with autologous transplantationbecause rejection is not a problem. Virtually all thetransplants performed for autoimmune diseasehave been autologous stem cell transplants.

Autologous stem cell transplants A stem celltransplant involves three phases.

1. The patient receives CYCLOPHOSPHAMIDE andgranulocyte colony stimulating factor (G-CSF)to mobilize stem cells from the bone marrow.The cells are harvested by drawing the patient’sblood out of a vein, separating the stem cells,and returning the blood to the patient. The stemcells are stored for later use.

2. High doses of chemotherapy that are toxic to thebone marrow are administered. This is some-times called the conditioning regimen. There are

several different conditioning regimens, butmost are based on high-dose cyclophosphamide.The treatment causes severe bone marrow sup-pression, and white blood cell and plateletcounts decrease dramatically.

3. The stem cells are injected back into the patientthrough a vein and repopulate the bone marrow.The stem cells take about two weeks to establishthemselves and differentiate into cells that pro-duce white blood cells and platelets. During thesetwo weeks, the patient has almost no white bloodcell and platelets, and the risk of infection andbleeding is high. Patients who receive their ownstem cells do not need immunosuppressionbecause they will not reject their own cells.

As a Treatment for Autoimmune Disease

More than 500 patients have received high-dosechemotherapy with stem cell rescue for a range ofautoimmune diseases. There are no controlledCLINICAL TRIALS, so knowing how this treatmentcompares with more standard ones is difficult. Theeffectiveness of BMT may have been underesti-mated because patients who received a bone mar-row transplant were usually selected because theyhad not responded to standard treatments.

BMT has been tried in patients with RHEUMATOID

ARTHRITIS (RA), SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE), SCLERODERMA, and JUVENILE ARTHRITIS. Re-sponses to treatment have been variable, and physi-cians are not yet certain what the exact responserate will be for each disease. Approximately a thirdof patients have an impressive clinical response, an-other third a moderate response, and the final thirdno response. The treatment does not cure autoim-mune disease. Even patients who respond very wellinitially often relapse after months or sometimes afew years. Many centers are performing research todefine which patients are likely to respond to BMT.There have also been reports of patients with SLEresponding to high doses of cyclophosphamide with-out stem cell transplantation.

BMT is expensive and can have severe sideeffects. The risk of death varies from center to cen-ter. However, it is approximately 1–2 percent forpatients with RA but much higher, approximately10 percent, for those SLE and scleroderma. Thelong-term complications of the treatment may

bone marrow transplantation 27

include an increased risk of cancer. Overwhelminginfection is the most serious complication. BMT isan experimental treatment that is usually limited toresearch studies and should be performed only atcenters that are experienced with this technique.

bone scan See RADIONUCLIDE BONE SCAN inAppendix II.

bone spur A small outgrowth of new bone usu-ally caused by osteoarthritis. Most bone spurs donot cause symptoms and are not important. How-ever, if new bone is formed by the vertebrae andnarrows a canal that carries a nerve, it can causepressure on the nerve and pain and numbness inparts of the body served by that nerve (see SPINAL

STENOSIS). (See also HEEL SPUR.)

Bouchard’s nodes Bony nodules over the proxi-mal interphalangeal (PIP) joints of the fingers causedby osteoarthritis. The nodules can be painful if theyare bumped, and they decrease the flexibility of thePIP joint. No effective treatment is available.

brucellosis An infectious disease, uncommon inthe United States, that is a rare cause of arthritis.

Cause

Brucellosis in humans is caused by a bacterial infec-tion acquired from animals: Brucella abortus (cattle),Brucella suis (pigs), Brucella melitensis (goats), andBrucella canis (dogs). Humans usually acquire theinfection through eating or drinking unpasteurizeddairy produce from infected animals. Workers inclose contact with infected animals, for exampleslaughterhouse workers, can get infected by han-dling infected animals or carcasses.

Symptoms

The systemic symptoms of brucellosis dominate.The condition often presents as a fever of unknowncause with sweating, loss of weight, arthralgia(joint pains), myalgia (muscle pain), and headache.The arthritis can affect one or a few large jointssuch as the hip or knee but can also involve thevertebrae and sacroiliac joints (joining the lowerspine to the pelvis).

Diagnosis

The combination of a history of exposure toinfected animals or a diet that includes unpasteur-ized dairy produce, prominent systemic symptomsand culturing the organism from the blood of apatient, or a positive blood test for antibodiesagainst brucella are the basis for diagnosis.


A prolonged course of combination antibiotic ther-apy, most often a tetracycline such as doxycyclineand another antibiotic such as rifampin or strepto-mycin, effectively eradicates the infection.

Buerger’s disease (thombangiitis obliterans) Firstreported by von Winiwarter in 1879 and then fullydescribed by Leo Buerger in 1908, Buerger’s diseasein an illness that usually affects young or middle-aged men who smoke heavily. In this illness, smok-ing causes spasming and narrowing of the arteriesof the hands, legs, and feet, sometimes resulting ingangrene. Because there is no specific diagnostictest, researchers do not always agree on the diagno-sis and so the true frequency of Buerger’s disease iscontroversial. It is common in the Middle and FarEast but is not common in the United States, whereit affects about 1 in 10,000 people.

Cause

Although tobacco plays a key part in causingBuerger’s disease, why some smokers get it andothers do not is not clear. Some experts havereported that Buerger’s disease can occur in peoplewho never smoked or used other types of tobacco,but this is exceptional. In all smokers, the endothe-lium, a thin layer of cells that lines blood vessels, isdamaged by smoking so that the blood vessels donot dilate well and cannot increase the blood sup-ply to tissue when it is needed. It is possible thatthis damage to blood vessels caused by smoking isexaggerated in those smokers who developBuerger’s disease.

Symptoms

Buerger’s disease usually affects men in their 40s.The first symptom is often pain in an arm or legduring exercise (claudication). This symptomoccurs because tissues need more oxygen, and

28 bone scan

bursitis 29

therefore more blood, during exercise. In Buerger’sdisease, the arteries are narrow and the blood sup-ply is inadequate to meet the increased need. If thedisease gets worse, the pain can be present duringrest as well as during exercise and can lead to gan-grene. Buerger’s disease can also cause inflamma-tion of superficial veins that lie just under the skinso that they clot and form painful cords that can befelt (superficial thrombophlebitis).

Diagnosis

No test provides a certain diagnosis of Buerger’s dis-ease. In a patient with poor blood supply to a digitor limb, the diagnostic possibilities usually includeseveral conditions: Atherosclerosis, VASCULITIS, CHO-

LESTEROL EMBOLI SYNDROME, and Buerger’s disease.The patient’s symptoms and angiogram (X rays ofarteries) can help to separate these conditions. Theangiogram in Buerger’s disease, in contrast withwhat is found in atherosclerosis, does not usuallyshow narrowing of large arteries. Typically inBuerger’s disease, small- and medium-sized arteries,for example those around the wrist or ankle, havesome areas that are blocked and others that are not.These angiogram findings are not specific and aresimilar to those found in SCLERODERMA, SYSTEMIC

LUPUS ERYTHEMATOSUS, and RHEUMATOID ARTHRITIS

with vasculitis. To help make the diagnosis ofBuerger’s disease, diagnostic criteria composed ofcombinations of several clinical findings have beenproposed. Most classification criteria include the fol-lowing requirements: Male less than 50 years old,current or recent tobacco use, and unexplainedpoor blood supply to an arm or leg. These compos-ite clinical criteria are useful for research studies toensure patients with a similar disease are studiedbut are not always helpful in deciding whether anindividual patient has Buerger’s disease.


The only treatment that can reverse Buerger’s dis-ease and avoid amputation is to stop smoking.Smoking even a few cigarettes a day or chewingtobacco can keep the disease active. Drugs thatdilate the arteries can help avoid amputation in a

critical phase when a limb is almost gangrenous,but these vasodilator drugs do not affect the long-term outcome. Surgery to bypass blood vessels thatare blocked is not usually an option because thedisease affects many blood vessels and usuallyaffects medium-sized vessels that are not easilytreated with bypass surgery.

Ulcers and gangrene can develop at the tips ofthe fingers, toes, hands, or feet because of poorblood supply. Often more than one limb is affectedat the same time. If the blood supply to a tissue isnot adequate to supply the oxygen and nutrientsneeded, then the affected finger, toe, leg, or armcan develop gangrene. These often need to beamputated to prevent infection setting in andspreading from the dead tissue into the blood-stream and throughout the body. Buerger’s diseasewill progress unless the patient quits using tobacco.

bursitis Bursas are formed where there is signifi-cant movement between tissues. They consist of afibrous envelope lined with fat cells and synovialcells that secrete a thin film of collagen-rich fluid.This allows the tissues on either side of the bursa tomove freely with minimal friction. Bursas betweendeep tissues are formed before birth, but many bur-sas just under the skin are formed after birth inresponse to the friction at those areas. These areasinclude over the elbow, heel, around the big toe,and in certain areas over the spine. Deep bursasexist at most sites where tendons run over bone orcross a joint. Specific bursae that are commonlyinvolved in disease processes are mentioned in theappropriate sections.

Superficial bursas in particular are subject todirect trauma, and bleeding can cause significantpain and inflammation. Some scarring and loss ofthe synovial cells may result. Any disease thatcauses synovitis (inflammation of the lining mem-brane of joints) can cause bursal inflammation.RHEUMATOID ARTHRITIS and GOUT are common causes.Bursitis can result from frequent minor trauma, andinfection can occur, especially in the superficial bursae. (See also SOFT TISSUE ARTHRITIS–RELATED

PROBLEMS.)

C

calcium pyrophosphate dihydrate deposition disease (CPPD, pseudogout) A degenerativearthritis associated with the presence of calciumpyrophosphate crystals in the synovial fluid andjoint structures. Two broad groups of peopledevelop the disease. The first includes people olderthan 60 years of age who have had OSTEOARTHRITIS

for some time. In this group, women are affected atleast twice as often as men. Second, people with anunderlying metabolic disorder may develop CPPDat a much younger age.

Cause

The cause of CPPD is not known, but it occurs inassociation with other conditions, most oftenOSTEOARTHRITIS (OA) and less often hypothy-roidism, HEMOCHROMATOSIS, and conditions thatalter normal calcium control. It has been arguedthat the CPP crystals merely coexist withosteoarthritis and do not actually do any harm.However, many studies now show that people withcrystals have a worse outcome than those without.Also, there are families who develop chondrocalci-nosis before any arthritis is apparent, suggestingthat crystal deposition precedes arthritis. Animalstudies have also shown that injection of CPPDcrystals into a joint can cause arthritis. Calciumcrystals have been shown to stimulate the releaseof inflammatory CYTOKINES and enzymes thatdegrade cartilage in models of inflammation. Thereare therefore a number of potential mechanismsfor these crystals either to cause or to worsenarthritis.

Some patients have rare familial or inheritedforms of CPPD. In many of these, including Amer-icans of European origin, the genetic abnormalityhas been linked to chromosome 5. Another largegroup in New England, however, shows linkage to

chromosome 8, and this is therefore unlikely to bedue to a single abnormality. The genetic abnormal-ity that leads to CPPD remains unknown.

Symptoms

The symptoms of CPPD usually fall into one of twopatterns. The first involves background symptomscaused by chronic degenerative arthritis. The secondinvolves attacks of acute arthritis that punctuate thechronic low-grade arthritis. During attacks ofpseudogout, the affected joints become red, hot,swollen, and very painful—symptoms very similarto those of an attack of gout. (The chronic degener-ative form of CPPD is indistinguishable from OA. Itoften affects the same joints that develop OA, suchas the knees and hips. However, it can also affectjoints that seldom develop OA, such as the wristsand metacharpophalangeal (MCP) joints of the sec-ond and third fingers.) These attacks, often in awrist, knee, or ankle, can develop overnight andusually settle over a few days or weeks, althoughthey can recur. Just as happens with gout, acuteattacks of pseudogout can be brought on by otherunrelated medical illnesses, such as pneumonia, orsurgery. Some patients with CPPD have symptomsresembling RHEUMATOID ARTHRITIS. This pseudorheu-matoid form may be very difficult to distinguishfrom rheumatoid arthritis. Often the presence ofchondrocalcinosis (see Diagnosis below) or an abnor-mality of calcium control suggests the diagnosis.

Diagnosis

The diagnosis of CPPD is often made clinicallybased on the symptoms, but X-ray findings can behelpful. Many of the X-ray findings of CPPD aresimilar to those of OA and include narrowing of thejoint and formation of bone spurs. The new boneformation around joints that usually occurs with

31

OA (osteophytes) is more florid in CPPD. Anotherclue to the diagnosis of CPPD is that fibrous cartilagein joints such as the knees and wrists often calcifies(chondrocalcinosis) and can be seen on the X ray.The joints involved are also not quite typical of OA(see Symptoms). No blood test is available to helpmake the diagnosis. The most specific test is whenrhomboid-shaped calcium pyrophosphate crystalsare seen in the synovial fluid when it is examinedunder polarized-light microscopy. However, jointfluid is not always examined under polarized lightand the crystals may therefore be missed. Also, verysmall crystals may be too small to see under a lightmicroscope and other techniques are too expensiveto be used other than for research purposes.


No specific treatment is available for chronic CPPD.The usual management is similar to that of OA andincludes options such as weight loss to take the loadoff weight-bearing joints, exercise to strengthenmuscles around joints, and analgesics such as aceta-minophen or NSAIDs to decrease pain. In an acuteattack of pseudogout, it is often helpful for a physi-cian to drain a little of the synovial fluid through aneedle so that it can be cultured to make sure theacute inflammation is not caused by an infection inthe joint. The synovial fluid can also be examinedunder a polarizing microscope to see if calciumpyrophosphate crystals are present. NSAIDs arehelpful in reducing pain and swelling. Occasionallya short course of CORTICOSTEROIDS by mouth or anintra-articular injection of a corticosteroid areneeded to control the attack. Based on clinical expe-rience rather than evidence from clinical studies,COLCHICINE is sometimes used to prevent recurrentattacks of pseudogout in patients who have had fre-quent attacks.

Acute attacks of pseudogout can be incapacitat-ing but usually settle, either spontaneously or withtreatment, over a few weeks and do not cause per-manent joint damage. The outcomes of chronicCPPD are similar to those of OA and vary amongpatients. Some have mild intermittent or chronicarthritis symptoms that can be easily controlledwith painkillers such as acetaminophen or NSAIDs.Others have a more severe arthritis that sometimesrequires joint replacement surgery.

camptodactyly An inherited condition in whichthe little finger slowly becomes more and morebent at the PIP. It affects girls twice as often as boysand starts within the first 10 years of life. Bothhands are affected in 70 percent of patients. It mustbe distinguished from DUPUYTREN’S CONTRACTURE,and no treatment is required.

carpal tunnel syndrome This is the most com-mon entrapment neuropathy. An entrapment neu-ropathy occurs when there is damage or justimpaired function of nerves where they passthrough a confining tunnel or are close to the skinand are therefore susceptible to pressure. At thewrist the median nerve passes through the carpaltunnel. This is formed by an arch of four wrist orcarpal bones, the ends of which are joined bystrong fascia or connective tissue (flexor retinacu-lum) in the manner of a strung bow. Also passingthrough this tunnel are nine tendons from musclesthat predominantly close the hand, each coveredby a tenosynovial sheath.

Cause

The many causes of carpal tunnel syndrome (CTS)may be divided into inflammatory, noninflamma-tory, and idiopathic. This last term is used whenthere is no apparent cause. Inflammatory causesinclude all types of inflammatory ARTHRITIS, partic-ularly RHEUMATOID ARTHRITIS and psoriatic arthritis(see PSORIASIS AND PSORIATIC ARTHRITIS). Rheuma-toid arthritis is one of the most common causes ofCTS, causing 12 percent of cases in one large study.The connective tissue diseases such as SYSTEMIC

LUPUS ERYTHEMATOSUS and SCLERODERMA are less fre-quent causes, and GOUT and CALCIUM PYROPHOSPATE

DIHYDRATE DEPOSITION DISEASE (CPPD) are rare.Other rare inflammatory causes include gonococcaltenosynovitis, PIGMENTED VILLONODULAR SYNOVITIS,

EOSINOPHILIC FASCIITIS, LYME DISEASE, and infectionsincluding TUBERCULOSIS. Repetitive wrist move-ments may cause CTS as a form of occupationaloveruse syndrome, although the frequency of thisis debated.

Noninflammatory causes include metabolic disor-ders such as hypothyroidism, diabetes, AMYLOIDOSIS,

and ACROMEGALY. Others include hemodialysis forkidney failure, lipomas, or ganglions on the tendons

32 camptodactyly

passing through the carpal tunnel, pregnancy, frac-tures, or contusions close to the carpal tunnel.OSTEOARTHRITIS is a surprisingly common association.Women develop idiopathic CTS more frequentlythan men.

Symptoms

Typically the person is woken at night by a burningor bursting pain in the hand that is relieved byshaking it or getting up and moving about. Clumsi-ness such as dropping cups and plates is common,and the hand is often felt to be weak even in theabsence of detectable changes in the affected mus-cles. The pain is usually intermittent and worse atnight but may be persistent when severe. Classi-cally, it is felt in the three and a half fingers on thethumb side of the hand because this is the areasupplied by the median nerve. Often, people feelthat the whole hand or at least the ends of all thefingers are affected. Sometimes there is also anaching discomfort in the forearm. Activities thatinvolve alternating wrist movements or holdingthe wrist in a flexed position (turned to the palmarside) usually make the symptoms worse or bringthem on.

Diagnosis

CTS is usually diagnosed on the basis of a typicalhistory with one or more confirmatory signs onexamination. These include reduced feeling in theradial (thumb-sided) three and a half fingers, a lossof bulk in the bunch of muscles at the base of thethumb (severe cases only), swelling over the pal-mar aspect of the wrist (especially with inflamma-tory causes), and positive Tinel’s or Phalen’s signs.Tinel’s sign is positive if tapping over the carpaltunnel sends tingling or painful feelings into theaffected fingers. Phalen’s is positive if holding thehands completely flexed for a minute causes the individual’s usual symptoms to come on.

In mild or atypical cases it is best to obtain electrodiagnostic confirmation before embarkingon invasive treatment. This is a test that uses low-voltage electric current to measure how well andhow fast the median nerve conducts. This is com-pared with the opposite hand and with conductionin other forearm nerves such as the ulnar. Slowingof sensory transmission (that is, from fingers to

elbow) occurs before motor (movement) pathwaysare affected. The operator needs to be experiencedsince there is variation between individuals and theresults require interpretation. The test is not pleas-ant for the patient but remains the gold standard.Plain X rays are sometimes done but seldom giveuseful information. MRI scans may show distortionof the nerve and swelling of the tendon sheaths ininflammatory conditions. Except in extreme cases,however, they do not give any information abouthow the nerve is functioning. If both hands areaffected or the problem is recurrent or there areother features of a systemic disorder, blood andother tests should be done to look for the causesdiscussed above.


This is conservative or surgical. Mild or intermit-tent symptoms may respond to splinting alone. Alightweight forearm resting splint that holds thewrist in a neutral position is worn at night and forvariable periods during the day. A diuretic is some-times helpful in idiopathic cases when symptomsare worse just before menstruation. NSAIDs arenot very effective but may help when the cause isinflammatory. A one-month course of PREDNISONE

has recently been shown to be an effective treat-ment. Highly effective with inflammatory causes isa CORTICOSTEROID injection into the carpal tunnel.When given by an experienced operator, this is avery safe procedure, although there is a small riskof nerve or tendon damage. Control of inflamma-tion by systemically given medication is essentialwhen the underlying cause is an inflammatoryarthritis such as rheumatoid arthritis. Often asteroid injection with splinting is used to give tem-porary relief while medication changes are made togain control of the inflammation. Newer treat-ments such as ultrasound and laser neurolysis arestill being tested.

Consideration must be given to precipitatingactivities, either occupational or recreational, andchanges made where possible. Temporarily stop-ping activities such as meat cutting or pluckingchickens is usually necessary to allow resolution ofthe problem. Typing style may need to be altered.Many people can minimize the everyday stresses tothe carpal tunnel once they are made aware of

carpal tunnel syndrome 33

what these are. Wearing a working splint with arigid bar to maintain a relatively fixed wrist posi-tion is a good way to become more aware of wristposition during activities.

Surgical release of the flexor retinaculum is avery effective treatment of CTS. It is indicatedwhen the response to conservative treatment is in-adequate, when symptoms are recurrent or whenprogressive nerve or muscle damage exists. Occa-sionally the inflammatory synovial lining of ten-dons has to be stripped off in rheumatoid arthritis.Biopsy is indicated when inflammatory tissue isfound during surgery since this is often how rarecauses such as tuberculosis, fungal infections, oramyloidosis are first diagnosed. The surgery is notdifficult and can be done under local anaesthetic.

cartilage Specialized connective tissue formed bycells called chondrocytes that synthesize a matrixcomprised of collagen and proteoglycans. Cartilagecovers the bony ends of most moving joints andhas two main functions. It provides a low-frictiongliding surface that enables joints to movesmoothly, and it also acts as a shock absorber. Ashumans age, cartilage retains less water andbecomes less pliable and resilient so that small tearsdevelop in the surface that is usually smooth. Theaging cartilage is also less effective as a shockabsorber. These degenerative changes in cartilageare thought to play an important part in the devel-opment of OSTEOARTHRITIS.

celiac disease This sensitivity to gluten is verycommon, especially in people with Celtic ancestry.For example, it affects 1 in 1,200 people in theUnited Kingdom as a whole, but this rises to 1 in300 in parts of Ireland. Women are affected moreoften than men, and the main effect is reducedabsorption of important dietary elements.

Cause

Well over 90 percent of people in western Europewith celiac disease have the HLA-B8, DR3, DQ2genetic haplotype (see HLA), although other haplo-types are also common around the Mediterranean.There is often a history of a Celtic ancestor and10–20 percent of first-degree relatives are affected.All this indicates a strong genetic predisposition to

the disease, although the exact abnormality inher-ited is not yet known. The genetic haplotype aboveis associated with a number of autoimmune dis-eases. Celiac disease patients become sensitive tothe gluten in wheat. This damages the lining cellsof their small intestine, reducing the absorbingcapacity. The cause of the arthritis sometimes asso-ciated with gluten sensitivity is unknown. Possiblythe damaged gut allows antigenic material thatwould normally be kept in the gut to cross into thebody where it sets up an immune reaction (seeENTEROPATHIC ARTHRITIS).

Symptoms

Some patients have diarrhea, loss of weight, poorgrowth (in children), and anemia, but often thepresentation is less obvious. Only 50 percent ofpatients have diarrhea. Children may be diagnosedwhen investigated for short stature, infants forvomiting and weight loss, and women when theybecome severely anemic during pregnancy. Associ-ated autoimmune diseases may lead to the diagno-sis. These include thyroid disease, DIABETES, andarthritis. The arthritis is quite variable, but mostoften the spine, hips, knees, and shoulders areaffected. Elbows, wrists, and ankles are affected lessfrequently. The arthritis is fairly symmetrical andinflammatory with swelling and early morningstiffness but does not often cause damage visible onX ray.

Diagnosis

The diagnosis should be suspected in arthritispatients who have symptoms of bowel disease, areunusually anemic, or have a low serum calciumconcentration. Tests for iron, calcium, folate, andvitamin B12 often show low blood levels. Theamount of fat passed in the stools is increased, andthis can be measured. The diagnosis has recentlybecome much easier with the availability of a testfor antiendomysial antibodies that is extremelysensitive in picking up patients with celiac disease.Antibodies to gluten can also be measured but areless often positive. Before these antibody tests wereavailable, it was necessary to biopsy the gut wall,show that the typical changes were present, andthen rebiopsy after three months of a gluten-freediet to show that it had recovered. This is still done

34 cartilage

where the diagnosis is not clear. There is nothingdiagnostic about the arthritis other than its coexis-tence with celiac disease.

Treatment

Adopting a diet free of gluten not only restoresbowel function to normal but also causes resolu-tion of the arthritis. This form of diet should betaken on with the help of a dietician so that thepatient can become aware of the many productsthat contain gluten and learn how to substitutegluten free alternatives. One generally unsuspectedsource of gluten is many vitamin pills, and so theproduct label should be carefully read.

central nervous system vasculitis A rare form ofVASCULITIS (inflammation of blood vessels) affectingthe central nervous system, most often the brain.Central nervous system (CNS) vasculitis is classi-fied as primary or secondary. Several illnessesmimic the symptoms and complications of CNSvasculitis. Primary CNS vasculitis affects only theCNS and is also called primary angiitis of the ner-vous system, isolated angiitis of the nervous sys-tem, and granulomatous angiitis of the nervoussystem. In secondary CNS vasculitis, vasculitisaffecting many organs (systemic vasculitis) alsoaffects the CNS.

Cause

Primary CNS vasculitis The cause of primaryCNS vasculitis is not known. However, viral ill-nesses and drugs that suppress the immune systemare thought to play a role in some patients.

Secondary CNS vasculitis May be associatedwith the following conditions:

• Infections (a) Viral infections caused by herpesviruses, cytomegalovirus, human immunodefi-ciency virus (HIV), varicella virus that causeschickenpox or shingles, and many other viruses (b) Other infections such as syphilis, Lyme dis-ease, tuberculosis, and many other bacterial andfungal infections

• Systemic vasculitis Most types of systemic vas-culitis such as WEGENER’S GRANULOMATOSIS, POLY-

ARTERITIS NODOSA, BEHÇET’S DISEASE, andCHURG-STRAUSS SYNDROME can affect the CNS.

• Other rheumatic diseases Several other rheumaticconditions, for example systemic lupus erythe-matosus and SJÖGREN’S SYNDROME, can sometimescause CNS vasculitis.

• Lymphoma CNS vasculitis can occur withHodgkin’s and non-Hodgkin’s lymphoma, typesof cancers that affect the lymph nodes, bonemarrow, and other organs such as the spleen.

Conditions That Can Mimic

CNS Vasculitis

• Lymphoma A rare type of lymphoma thatoccurs inside blood vessels called intravascularlymphoma (also known as malignant angioen-dotheliomatosis) can mimic CNS vasculitis. Abrain biopsy is often needed to differentiatebetween the two.

• Drugs Many drugs, usually ones that constrictblood vessels, have rarely been associated withnervous system complications such as stroke.These vasoconstricting drugs can also causeabnormal angiograms in that the blood vessels inthe brain show irregular areas and spasm thatlook identical to the angiograms of patients withCNS vasculitis. Drugs that have caused strokeand abnormal angiograms include cocaine,amphetamines, heroin, and cold remedies, par-ticularly those containing phenylpropanolamine,a drug that was removed from the market by theFDA in 2000 because it increased the chances ofhaving a stroke. Vasoconstrictors do not seem tocause a true CNS vasculitis. However, they cancause clinical findings, for example stroke and anabnormal angiogram, that mimic those of CNSvasculitis.

• Strokes Any condition that causes many smallstrokes, for example atherosclerosis or bloodclots showered off an abnormal heart valve, canbe difficult to differentiate from CNS vasculitis.

Symptoms

The first symptom of primary CNS vasculitis is usu-ally a gradual and progressive, diffuse decrease inbrain function over many months. This oftenshows as memory loss, a change in personality, anda decrease in intellectual ability. Headaches occurin just over 50 percent of patients. Symptoms that

central nervous system vasculitis 35

usually indicate that there is a problem in a local-ized area of the brain, for example a stroke, occurin 10–20 percent of patients at presentation but inup to 40 percent throughout the illness. A carefulexamination (as well as MRI scanning) sometimesshows that two or more different areas of the brainare affected, and this is very useful in suggestingvasculitis as the cause of the stroke. Seizures occurat some stage in a quarter of patients. Rarely, vas-culitis can affect the spinal cord and result in paral-ysis of the legs or arms. Secondary CNS vasculitiscan cause symptoms identical to those of primaryCNS vasculitis. Making a definite diagnosis of pri-mary CNS vasculitis can sometimes be very diffi-cult. Systemic symptoms such as fever, sweats, lossof weight, anemia, and an elevated ESR are absentor mild in patients with primary CNS vasculitis,and if prominent, they usually indicate a secondarycause.

Diagnosis

No diagnostic test is always positive in CNS vas-culitis or is able to discriminate between primaryCNS vasculitis and diseases that mimic it. The diag-nosis is based on information from several sources,including the clinical findings, analysis of cere-brospinal fluid (see LUMBAR PUNCTURE in AppendixII), imaging tests such as MRI or angiogram, andsometimes a brain biopsy.

Cerebrospinal fluid (CSF), obtained by lumbarpuncture, is abnormal in 80–90 percent of patientswith primary CNS vasculitis. It often shows a smallincrease in the number of white blood cells andprotein concentration, findings that usually indi-cate inflammation or infection in or around thebrain. Examining CSF is useful to exclude an infec-tion because in CNS vasculitis all the bacterial andfungal cultures and tests for viruses in the CSF arenegative.

The most common MRI findings, many smallinfarcts deep in the tissue of the brain, are not spe-cific for CNS vasculitis. However, if the MRI andCSF examinations are completely normal, it ishelpful because that combination virtually ex-cludes the diagnosis of CNS vasculitis. The MRIprovides images of the brain tissue, but anangiogram is often done because it provides imagesof the arteries in the brain. The angiogram can be

normal. However, it is abnormal in more than 60percent of patients with CNS vasculitis and showsirregular arteries with patchy areas of narrowingand dilation. These angiogram abnormalities arenot specific for primary CNS vasculitis but canoccur with conditions that mimic it or cause sec-ondary CNS vasculitis.

Because there are no specific CSF and X-rayfindings that make the diagnosis of CNS vasculitis,a biopsy of the brain and meninges (the thin layerthat lines the brain) is sometimes needed to ruleout infections or lymphoma. The biopsy, whichsamples only a minute area of brain, is also not aperfect test and can be negative in about 25 percentof patients who eventually turn out to have CNSvasculitis.


Because CNS vasculitis is so rare, no clinical trialshave compared responses to different treatments.Treatment is with high doses of CORTICOSTEROIDS,often combined with an immunosuppressive drugsuch as CYCLOPHOSPHAMIDE, and usually continuesfor at least six to 12 months after the illness hasgone into remission.

If CNS vasculitis is not treated, it slowly pro-gresses and causes memory loss, dementia, stroke,and death. Drug treatment usually arrests theprocess and often improves some neurologicalsymptoms, although some symptoms can be per-manent. High doses of corticosteroids and otherdrugs that suppress the immune system often causeside effects, for example an increased chance ofdeveloping a serious infection. Treatment requirescareful monitoring.

Charcot’s joint See NEUROPATHIC ARTHRITIS.

chemokines Movement of white blood cells(leukocytes) into tissues and into areas where thereis inflammation is controlled by a subgroup ofCYTOKINES called chemokines. The synthesis andrelease of chemokines is stimulated by interleukin-1 (IL-1) and tumor necrosis factor (TNF), cytokinesthat act to promote inflammation. More than 40chemokines have been discovered and classifiedinto several families. Chemokines are classifiedbased on their structure. The two largest families

36 Charcot’s joint

are named CC and CXC. The CC family has twocysteine amino acids (designated C) that are alwaysnext to each other, and the CXC family has the twocysteines separated by other amino acids (desig-nated X). The nomenclature of chemokines can beconfusing because when they were discovered, dif-ferent researchers often gave the same chemokinedifferent names. Chemokines are often referred to,and are better known, by their abbreviated oldernames that describe function rather than theirnewer, official names. For example, the officialname of IL-8 (interleukin-8) is CXCL8, MCP(monocyte chemoattractant protein) is CCL2, andRANTES (regulated upon activation normal T cellexpressed and secreted) is CCL5.

Chemokines exert their effects by binding tospecific chemokine receptors that are found on tar-get cells. The receptors (R) for the CC chemokinesare named CCR1, CCR2, and so on, and those forthe CXC chemokine family are CXCR1, CXCR2,and so on. Different tissues have differentchemokine receptors, and this explains why thesame chemokine can have different effects in dif-ferent parts of the body. There are some inheritedvariations in the structure of chemokine receptorsthat affect how well they work. For example, it wasdiscovered that people with a particular geneticvariant of the chemokine receptor CCR5 are rela-tively resistant to HIV infection. This is because thevirus enters cells by binding to receptors for thischemokine, but people with the variant CCR5receptor are less likely to be infected by HIVbecause their receptors do not bind HIV well.

Chemokines modify several processes that regu-late inflammation and growth of cells and tumors.To fight infection in a particular part of the body,cells must move out of the bloodstream and con-centrate around the infection so that the inflam-matory response can be focused where it is needed.The number and type of white blood cells that areattracted to the area of inflammation is regulatedby chemokines. For example, in patients withpneumonia caused by bacteria, the infected tissuesof the lungs are infiltrated by many neutrophils, aprocess that is partly regulated by IL-8, a chemo-kine that acts as a powerful attractant for neu-trophils. Other chemokines, for example MIP(macrophage inflammatory protein) and eotaxin,

regulate the movement of macrophages and eosi-nophils into tissues. Apart from regulating in-flammation, chemokines also affect the growth ofcancers. Two factors that determine how big andhow fast a tumor grows are the ability of its cells todivide rapidly and the speed at which the tumorcan make new blood vessels (angiogenesis) andthus provide itself with more nutrition as it growslarger. Some chemokines, for example platelet fac-tor 4, reduce angiogenesis and tumor growth butothers, for example IL-8, do the opposite.

The role that chemokines play in regulating in-flammation and cell growth in autoimmune dis-ease, infections, and cancer is an area of activeresearch that is likely to produce drugs that willtreat these diseases by stimulating or inhibitingspecific chemokines.

chiropractic medicine About a third of the visitspatients make to alternative health practitionersare to chiropractors, making this the largest alter-native medicine profession in the United States.Chiropractic is a profession that specializes in themanipulation of bones, joints, and muscles to treatmedical disorders. Chiropractic has moved frombeing part of alternative medicine to become main-stream with practitioners licensed in all 50 states.Many health care insurance companies now reim-burse for visits to chiropractors, just as they do forvisits to mainstream physicians.

Chiropractic was founded in Davenport, Iowa,in 1895 by Daniel David (D. D.) Palmer, a grocerystore owner who cured deafness in a man bymanipulating his spine. The theory underlying chi-ropractic was that pressure on nerves irritatedthem and caused illness that could be corrected bymanipulation to relieve the pressure. Palmer devel-oped a school with its name derived from theGreek words cheir (hand) and praxis (use). His son,B. J. Palmer, developed and popularized the prac-tice further. As it developed, chiropractic attractedpractitioners with many different philosophies.Some have believed that all illness is the result ofspinal irritation and can be cured by manipulation,but others have restricted their interest to problemsaffecting muscles and joints. Some chiropractorsrestrict their treatment to manipulation, but othershave incorporated other alternative treatments

chiropractic medicine 37

such as herbal remedies. More recently chiroprac-tic has evolved into a practice that mostly restrictsitself to using manipulation to treat problems ofmuscles and joints.

Osteopathy (see OSTEOPATH), which like chiro-practic was based on the concept that manipulationof bones and soft tissues could alleviate symptomsand was also originally thought to be useful fortreating most types of illness, has evolved differ-ently. Over the years many osteopaths haveincreasingly incorporated traditional medicine intotheir practice. Now many patients treated byosteopaths do not receive manipulation but aretreated with medications identical to those pre-scribed by traditional physicians.

Chiropractic manipulation involves several dif-ferent techniques. One of the best known is thehigh-velocity thrust, a sudden, sharp thrust applied tothe spine, either directly by the practitioner’s handsor indirectly by using another part of the patient’sbody, for example a leg, as a lever to twist thespine. Other techniques involve the relief of mus-cle spasm through gentle stretching.

Chiropractic has fought a long battle with ortho-dox medicine that has included hunger strikes byimprisoned practitioners and prolonged legal bat-tles, but it is now generally accepted as a form oftherapy. Strong scientific evidence supporting theefficacy of chiropractic is limited to a few condi-tions. Many studies have compared chiropracticmanipulation with other forms of treatment forback pain. An overall synthesis of the many stud-ies, often with conflicting conclusions and inter-pretations, is that chiropractic treatment improveslow back pain and neck pain in the short term butis not useful for other medical problems such asasthma.

cholesterol emboli syndrome First reported inthe autopsy of a Danish sculptor, Thorwaldsen,cholesterol embolism is caused by clumps of cho-lesterol breaking off from a cholesterol plaque in anartery. They float downstream until they reachsmall arterioles where they lodge, block the arteri-ole, and cause small infarcts (areas of tissue death)in the organ. Although thought to be rare, choles-terol emboli have been found in 2–8 percent ofautopsies.

Cause

Atherosclerosis is the underlying cause of choles-terol embolism. Therefore conditions such as dia-betes, high blood cholesterol, smoking, and agingthat increase atherosclerosis also increase thechances of developing cholesterol emboli. In addi-tion to conditions that increase atherosclerosis, anyevent that makes the cholesterol plaque lining thewalls of arteries less stable can trigger cholesterolembolism. For example, cholesterol plaques can bedisturbed by medical procedures, such as angiogra-phy when a needle is placed in an artery or whensurgery is performed on an artery. If a person istreated with an anticoagulant such as heparin orwarfarin to prevent blood clots forming, this canincrease the risk of cholesterol embolism. In somepatients with atherosclerosis, cholesterol embolismoccurs without anticoagulation or any predisposingevent.

Symptoms

Cholesterol embolism can cause systemic symp-toms such as fever and affect many differentorgans, depending on where the showers of cho-lesterol crystals finally lodge. Organs often affectedare the skin, brain, and kidneys.

• Skin The commonest skin rash is LIVEDO RETIC-

ULARIS, a lacy reddish-purplish rash on the frontof the legs. This rash is faint, does not itch, andcan be difficult to see. Other common skinrashes are small purple or black spots thatresemble VASCULITIS and larger purplish nodules.A whole toe or finger can turn blue because itsblood supply is inadequate.

• Kidneys Worsening of high blood pressure anda decrease in kidney function, shown as a risinglevel of CREATININE (see Appendix II), in theblood are common.

• Central Nervous System If the emboli deposit inthe blood vessels of the eye, they can cause sud-den blindness or loss of vision. If a physicianexamines the retina with an ophthalmoscope,shiny yellow cholesterol plugs are sometimesvisible. Plugging of small arteries in the braincan cause a stroke, either permanent or lasting ashort time (transient ischemic attacks or TIAs).

38 cholesterol emboli syndrome

Diagnosis

Cholesterol embolism can be difficult to diagnosebecause it mimics vasculitis, and the clinical patternvaries according to which organs are involved. Thediagnosis is often missed because it is not consid-ered. Although the damage to organs in cholesterolembolism is caused by blocked arterioles, the pulsein an affected arm or leg is usually normal becausethe plugs are in small arteries, not the large onesthat form the pulse. Blood tests are not very usefuland can be misleading. The white blood cell countand ESR are often elevated and misleadingly sug-gest a diagnosis of infection or vasculitis. A higheosinophil count and low COMPLEMENT level canmisleadingly suggest a drug allergy or vasculitis.The most helpful diagnostic test is a biopsy of aninvolved organ (usually the skin is the most conve-nient site to biopsy) that shows needle-shaped cho-lesterol crystals blocking small arterioles.


There is no specific treatment for cholesterolemboli. Usually anticoagulants are avoided becauseof the concern that they may make the atheroscle-rotic plaque even more unstable and worsen theillness. There are a few reports in the medical liter-ature of patients responding to treatment with oneof the statin group of drugs that lowers cholesterol.Because the statins (examples are lovastatin,pravastatin, and simvastatin) are relatively safe andbecause almost all patients with cholesterol embolineed a drug to lower their cholesterol, many physi-cians start treatment with a statin.

Ulcers and gangrene can develop at the tips ofthe fingers, toes, hands, or feet if they do not getenough blood and oxygen. Often more than onedigit is affected at the same time. Toes are affectedmore often than fingers because atherosclerosis ismore common in the legs than the arms. If theblood supply to tissue is not enough to supply itsneeds, then gangrene in a finger, toe, leg, or armcan occur. If this happens, amputation is oftenneeded to prevent infection spreading from thegangrenous tissue into the bloodstream andthroughout the body. More often the gangrenoustissue slowly shrivels and falls off. The decrease inkidney function caused by cholesterol embolismoften plateaus after a few days or weeks and then

slowly improves. However, kidney function maydeteriorate to the level where a patient needs dial-ysis. TIAs resolve quickly, but strokes can be per-manent. Another serious complication is infarctionof the bowel. This can require surgery to removethe gangrenous part of the bowel.

Cholesterol embolism is serious and reported tobe fatal in as many as 80 percent of patients, butthis figure likely represents the outcome in patientswith the most severe form of the disease. Manypatients who have a milder form with just a bluetoe or a moderate decrease in their kidney functionafter an angiogram get completely better.

chronic fatigue syndrome A condition, of un-known cause, characterized by severe, sometimesdisabling fatigue and many other symptoms thataffect different organ systems. Many people in thepopulation suffer from fatigue at some time, andapproximately 25 percent of patients seen by pri-mary care physicians have fatigue that has lastedlonger than a month. However, only about 0.2–2.6percent of people meet the criteria used to define thechronic fatigue syndrome.

Cause

The cause of chronic fatigue syndrome is notknown and is controversial. Some experts believethat a physical cause exists but has not yet beenidentified. Others believe that chronic fatigue syn-drome does not exist as a separate entity but con-sists of many physical symptoms that are the resultof psychological stress, a process known as somati-zation. An argument against the theory thatchronic fatigue syndrome is the result of a particu-lar personality that responds to stress by develop-ing physical symptoms is the fact that chronicfatigue syndrome often starts suddenly in peoplewho, up until then, have been in relatively goodphysical and psychological health. However, inspite of intensive research, no clear cause ofchronic fatigue syndrome has been found.

Viral infection was first thought to be the causeof chronic fatigue syndrome because many patientshave a low-grade fever, sore throat, and enlargedlymph nodes. Epstein-Barr virus, the cause ofinfectious mononucleosis, was suspected, but stud-ies did not support this suggestion. Several other

chronic fatigue syndrome 39

viruses have been investigated, but none has beenfound to be consistently associated with thechronic fatigue syndrome.

Many studies have found that psychological dis-tress and psychiatric problems are more commonin patients with chronic fatigue syndrome than inthe general population. However, clearly separat-ing cause and effect has not been possible. In otherwords, is psychological distress more common inpeople with chronic fatigue syndrome because theyare feeling sick, or are the psychological symptomsthe cause of chronic fatigue syndrome?

An interesting study found that many patientswith chronic fatigue syndrome developed lowblood pressure and became dizzy when they wereplaced on a tilt table—a test performed to evaluatewhy people become dizzy or faint. During a tilttest, people are placed on a table that supportsthem so that they do not move or use their mus-cles. Then the table is tilted so that they are stand-ing upright but supported by the table, not theirmuscles. This test allows blood to pool in the veinsand is used to test the body’s ability to react tochanges in posture. In the initial studies, peoplewith chronic fatigue syndrome could not toleratethe tilt test. However, several later studies, someof which compared people with chronic fatiguesyndrome with people who were also out of shapebut otherwise healthy, did not confirm the sugges-tion that altered responses to changes in posturewere the cause of chronic fatigue syndrome. Asmall number of people have a condition knownas orthostatic intolerance—symptoms of a veryfast heart rate and dizziness after they have beenstanding for a while. Many of these people alsohave symptoms similar to those of chronic fatiguesyndrome. Most likely chronic fatigue syndromehas several causes and orthostatic intolerance isjust one.

Chronic fatigue syndrome often overlaps withthe symptoms of several other conditions thatcause chronic pain or fatigue and whose cause isnot understood. For example, many patients withfibromyalgia have chronic fatigue and vice versa. Itis not clear if fibromyalgia and chronic fatigue syn-drome are variations of the same condition thathave an overlapping spectrum of symptoms or ifthey are separate problems that sometimes causesimilar symptoms.

Symptoms

Chronic fatigue, often worse after a physical activ-ity at an intensity that was previously no problemand that is not caused by another medical problem,is the most common symptom. The onset of fatiguemay be sudden and can sometimes be dated from aviral infection. Many other symptoms can occur,including dizziness, poor concentration, unrefresh-ing sleep, poor memory, tender lymph nodes, mus-cle and joint pain, headaches, lack of energy, andlow-grade fever. Many of these symptoms overlapwith fibromyalgia, and some patients fulfill thediagnostic criteria for both conditions.

Diagnosis

No laboratory tests are available to help make thediagnosis. Laboratory tests are helpful because they areusually normal. If they are abnormal, these resultsmay be a clue to some other diagnosis. The diagnosisis made only after other medical causes of chronicfatigue such as anemia, thyroid problems, cancer,hepatitis, autoimmune diseases, and SLEEP APNEA havebeen excluded. The Centers for Disease Control (CDC)criteria are widely used to define patients with chronicfatigue syndrome for research studies. This definitionhas the following requirements:

1. Other medical, psychiatric, and substance abuseproblems must have been excluded.

2. The unexplained fatigue must be somethingnew (it cannot have been lifelong), is not helpedby rest, is not explained by hobbies or activities,and has a big effect on the person’s ability tolead a normal life.

3. Unexplained chronic fatigue must be accompa-nied by at least four of the following symptomsto meet the CDC definition of chronic fatiguesyndrome:

• Poor memory or concentration to the extentthat it affects the person’s personal activities

• Sore throat

• Tender lymph nodes in the neck or armpit

• Muscle or joint pain without joint swelling orredness

• Headaches that have a different characterfrom previous headaches

• Unrefreshing sleep

40 chronic fatigue syndrome

• Poor energy level for more than 24 hoursafter exercising

The fatigue and other symptoms must havebeen present for at least six months or haverecurred over that time.


Many of the studies that have examined treat-ments for chronic fatigue syndrome have includedonly a small number of patients, perhaps one of thereasons that the results have not always beenreproducible. The strongest evidence supports twotherapies, COGNITIVE BEHAVIORAL THERAPY and EXER-

CISE. In clinical trials, cognitive behavioral therapywas usually administered by experts for severalmonths, usually as six to 16 sessions each lasting30–60 minutes, and improved symptoms in morethan half the patients. The usefulness of aerobicexercise and flexibility training in chronic fatiguesyndrome have been studied, usually involvingsessions that built up to 20–30 minutes at leastthree times a week. Aerobic exercise was moreeffective than flexibility training, and about halfthe patients improved. Bed rest has not been ben-eficial and may be harmful. No drug therapy hasbeen consistently helpful.

Several antidepressants have been studied butthe results have been inconsistent, although somesymptoms, for example poor sleep, have oftenimproved. One promising study suggested thatsome patients with chronic fatigue syndrome hadan alteration of their blood pressure reflexes whenthey stood up and that treating them with fludro-cortisone, a drug that makes the kidneys absorb saltand water and increases the volume of the blood,improved symptoms. A later, more rigorousplacebo-controlled study did not confirm thesefindings. Corticosteroids, such as prednisone, havegenerally not been effective. Although some trialshave found a modest benefit with hydrocortisone,the results have been conflicting.

Chronic fatigue syndrome does not increase therisk of death and it does not cause structural damageto muscles or joints. However, it can have a majoreffect on quality of life, earning capacity, and activitylevels. The outcome of chronic fatigue syndrome hasnot been clearly defined because most studies havebeen performed in groups of patients who have been

treated by specialists and are likely to have been themost severely affected people. Generally, between 20and 50 percent of people have some improvement oftheir symptoms, but only 6 percent reach their previ-ous level of activity and well-being. The personalityand beliefs of the patient seem to affect the outcome.A positive outlook and the belief that symptoms canbe overcome are associated with a better outcome.(See also FIBROMYALGIA.)

Churg-Strauss syndrome A rare type of vasculitisdescribed by Churg and Strauss in 1951 that isprobably a variant of WEGENER’S GRANULOMATOSIS

and causes asthma, eosinophilia, and vasculitis.

Cause

The cause of Churg-Strauss syndrome is notknown but it seems to be associated with allergy.Most patients have a history of preceding nasalallergy. Eosinophils, which are prominent inChurg-Strauss syndrome, are also often elevated inpeople with allergic asthma and nasal or skinallergy. Immunoglobulin E (IgE), which is alsooften elevated in patients with allergic conditions,is usually raised in Churg-Strauss syndrome. Howallergy proceeds to vasculitis is unclear.

A few patients have developed Churg-Strausssyndrome after starting treatment with a class ofdrugs called leukotriene receptor antagonists. Thisincludes zafirlukast (trade name: Accolate) andmontelukast (trade name: Singulair). Several ex-planations have been put forward to explain whyChurg-Strauss syndrome seems to occur moreoften in people taking these drugs. One possibilityis that the patients with asthma who developedChurg-Strauss had it all along, but it was not diagnosed because the symptoms were suppressedby corticosteroids. Then, when they started treat-ment with a leukotriene receptor antagonist andwere able to decrease or stop their corticosteroids,the symptoms of Churg-Strauss that were previ-ously suppressed became obvious. However, anumber of patients not on corticosteroids have de-veloped Churg-Strauss syndrome after starting aleukotriene receptor antagonist. Another possibil-ity, therefore, is that this class of drugs may rarelycause the Churg-Strauss syndrome in a few peoplethrough mechanisms that are not clear.

Churg-Strauss syndrome 41

Symptoms

Many patients have allergic symptoms such asasthma or rhinitis (runny nose) for months oryears before the diagnosis. It is not clear if thesesymptoms are caused by Churg-Strauss that hasnot been diagnosed or if, at some point, Churg-Strauss develops on top of the allergic symptoms.Eosinophilia does not cause symptoms, but in apatient with vasculitis or unexplained illness, it isoften the first clue to the diagnosis. Symptoms canvary a lot and depend on the organs involved.

• Lung Asthma, resulting in wheezing and short-ness of breath, is usually episodic but can besevere and present much of the time. Vasculitiscan affect the lungs causing infiltrates and short-ness of breath that resemble pneumonia. Rarelyvasculitis can cause bleeding into the lung tissue.

• Nervous System Typically vasculitis involvesperipheral nerves affecting both sensation andthe ability to move. For example, if a nerve tothe foot is affected, the patient may lose or havealtered feeling in part of the foot and may not beable to pull it up so that it drags while walking,a symptom called foot drop. The nerves affectedare usually in different parts of the body, andthis symptom complex is called mononeuritismultiplex. The brain and nerves to muscles ofthe face and eyes are seldom affected.

• Kidney The kidneys can be affected, but this isless common than in Wegener’s granulomatosis.Kidney involvement cause’s blood and proteinin the urine but does not usually cause symp-toms unless the kidneys fail.

• Others All types of serious vasculitis can affectvirtually any organ. The skin is often affected,and rashes are common. Vasculitis typicallycauses purple spots that are raised and can befelt (palpable purpura), but almost any type ofrash can occur. Vasculitis affecting the blood ves-sels to the bowels is uncommon but can causebleeding, infarction, and perforation.

Diagnosis

The diagnosis is clinical and based on three featuresthat are key to the diagnosis: asthma, eosinophilia,and vasculitis. The differential diagnosis usually

includes asthma, Wegener’s granulomatosis, andother causes of vasculitis such as POLYARTERITIS

NODOSA. Asthma is a common disorder, and manypatients with asthma also have a mild eosinophilia.Churg-Strauss is differentiated from asthma by thepresence of vasculitis and a more pronouncedeosinophilia, often more than 1500 cells/mm3. Sim-ilarly, marked eosinophilia is uncommon inWegener’s granulomatosis and other types of vasculitis. There are unusual types of pneumoniasuch as eosinophilic pneumonia that can causeeosinophilia and respiratory symptoms, but vasculi-tis does not occur.

Laboratory tests provide useful information butare seldom diagnostic. Eosinophilia is often the firstclue to the diagnosis but is not specific.Eosinophilia can be caused by several conditionsincluding asthma, allergies, reactions to drugs, par-asitic infection, cancer, and vasculitis. If the kidneysare affected, the creatinine level in the blood maybe elevated and blood, protein, and white bloodcells are likely to be present in the urine. Nonspe-cific tests that go up with infection and inflamma-tion such as the ESR and C-reactive protein arelikely to be elevated. The antineutrophil cytoplas-mic antibody (ANCA) blood test (see Appendix II)is elevated in about 70 percent of patients and ismore likely to be a P-ANCA than the C-ANCA thatis more typical of Wegener’s granulomatosis. Anegative ANCA test does not exclude the diagnosisof Churg-Strauss. A chest X ray may show infil-trates. These can be of different shapes and sizesand can change rapidly.

A biopsy of affected tissue, often lung, typicallyshows eosinophils destroying the walls of medium-sized arteries (vasculitis), eosinophils in deep tis-sues, and formation of clusters of inflammatorycells around a center, called granulomas.


The treatment is as for any severe vasculitis andusually consists of a combination of corticosteroidsand an immunosuppressant such as CYCLOPHOS-

PHAMIDE (see Treatment under VASCULITIS). BecauseChurg-Strauss syndrome is uncommon, there isvery little guidance on its treatment from controlledstudies (see CLINICAL TRIAL). From the informationavailable, however, many patients apparently do

42 Churg-Strauss syndrome

well on corticosteroids alone and drugs likecyclophosphamide should be used only for moresevere disease, for example when there is involve-ment of heart or kidneys. About 80 percent ofpatients survive five years or more after diagnosis,but there is a wide range of disease severity thataffects the prognosis. Kidney involvement and vas-culitis affecting the heart or bowels indicate moresevere disease and a potentially worse outcome.

clinical trial An experiment performed on hu-mans to determine the safety and efficacy of atreatment. The clinical trial is a relatively recentand important scientific advance that has allowedscientists to measure and compare responses to atreatment objectively. Before clinical trials becamethe standard method for evaluating new treat-ments, these were introduced into clinical practiceempirically, using a trial and error approach, andwere then propagated among practitioners basedon word of mouth and anecdotal experience. Thissituation is similar to the approach currently usedto evaluate many herbal and other nontraditionaltherapies that are not classified as drugs and there-fore do not require proof of efficacy and safetybefore they are marketed.

Unscientific, anecdotal approaches to the evalu-ation of new therapies led to the introduction ofmany ineffective or toxic drugs. The controlledclinical trial with its unbiased design and objectivemeasurements revolutionized modern medicine.Anecdotal evidence is based on the responses ofone or a few patients and is a seriously flawedmethod for evaluating a treatment. Anecdotal evi-dence is similar to testimonials from customers—there is a bias to report only the positive responses.A second major problem with the anecdotalapproach to evaluating a treatment is that there isa natural tendency for people taking a new treat-ment to feel better, even if the treatment is an inef-fective dummy called a placebo. This positiveresponse to a new treatment, whatever it is, iscalled a placebo response. Clinical trial design hasevolved to overcome these problems. There areseveral different types of clinical trials.

Uncontrolled, placebo-control, and active-

control trials If a new treatment is studied alone,with no comparison group, it is called an uncontrolled

study. Uncontrolled studies are difficult to interpretbecause telling if any response is due to a true drugeffect or to the placebo response is impossible.Uncontrolled studies, although they can provideuseful preliminary information, are not strong evi-dence in favor of a new treatment, even if the resultsof the trial are positive.

To decide if a treatment is effective, it is best tocompare it with another treatment, and this iscalled a controlled trial. Controlled studies usuallycompare the new treatment against an inactivesubstance, like a dummy sugar pill, called a placebo

control, or else against some treatment that isknown to be effective, called an active control. Com-paring the results of the new treatment with theresults of the control treatment makes it much eas-ier to determine if the new treatment is effective.

A placebo-controlled study is generally more effi-cient in finding out whether a new treatment iseffective, but for ethical reasons this design is notalways appropriate. Most medical ethicists agree thatit is not ethical to treat a patient in a clinical trialwith a placebo if an effective treatment is availablefor that particular condition and if treatment withplacebo could result in irreversible, preventableproblems for a patient. For example, it is generallyconsidered ethical to evaluate a new drug for paincaused by osteoarthritis against placebo, providedpatients have access to adequate pain control if theirtreatment fails. However, if active rheumatoidarthritis (RA) is not adequately treated for severalmonths it can result in irreversible joint erosions.Therefore, determining how to perform ethical,placebo-controlled studies in RA is more difficult.

Randomized trials If the researchers in charge ofa study could choose to allocate patients to either thetreatment or the control groups, there could be a ten-dency for them to allocate those with the worst prob-lems into one or another of the groups. Then, becausethe patients in one group were sicker, that groupcould have a worse outcome, even if their treatmentwas effective. To prevent this happening, everyoneenrolled into a study should have an equal chance ofbeing allocated to receive the new treatment or thecontrol treatment—this is called a randomized study.Patients can be randomized into groups in differentways. One is a simple flip of a coin, but generally acomputer generates random numbers.

clinical trial 43

Open-label trials In an open-label studydesign, both the individuals in the study and theresearch staff know which treatment a patient isreceiving. This is a scientifically weak designbecause, even if the study is randomized and con-trolled, the open-label design allows the enthusiasmof patients and researchers for any new treatmentto bias their collection and interpretation of infor-mation. Most new arthritis treatments that havebeen evaluated in exploratory, open-label studieswere initially thought to be effective, but manywere later found to be ineffective when more rigor-ous double-blind clinical trials were performed.

Double-blind trials The opposite of an open-label study is a double-blind study. With this designneither the people in the study nor the researchersperforming the study know who has been allocatedto treatment or control. This means that neitherthe expectations of patients nor those ofresearchers can influence the interpretation of theresults. To keep a study double-blind is not alwayseasy. For example, the placebo and active drughave to be identical in appearance and taste. A ran-domized double-blind, placebo-controlled study isthe most scientifically rigorous design to evaluate anew treatment but is not always ethical or practi-cal. For example, a placebo-controlled study is notappropriate for evaluating a new treatment for acancer that already has an effective treatment, andperforming a double-blind study to compare a sur-gical treatment with a drug is very difficult.

Limitations of clinical trials Although clinicaltrials have been a major scientific advance, theyhave some limitations.

• Most clinical trials are performed by drug com-panies and usually compare a new drug with aplacebo. Most physicians and patients would bemuch more interested in how the new drug per-forms compared with the best-available treat-ment. Once the new drug is marketed, unless itappears to be better than the standard treat-ment, there is often no incentive for a drug com-pany to sponsor a study to compare it withstandard treatments.

• Most clinical trials study highly selectedpatients. Typically patients in clinical trials arerelatively healthy and are not taking many other

medicines. For example, patients with liver orkidney disease, recurrent infections, or recenthospitalizations are excluded from most trials.This means that when a new drug is approvedby the FDA and marketed, many types ofpatients not studied in clinical trials will take thedrug.

• Most clinical trials last for only a few months.Knowing the long-term effects of different drugsis more important because many types of arthri-tis are chronic. Clinical trials cannot provide thisinformation, and it is obtained from observa-tional studies that record the responses ofgroups of patients followed over many years.Such studies have their own problems becausepatients are not randomized to a particular drug.Therefore differences in outcome could be dueto differences in disease rather than differencesin response to drugs.

• Clinical trials determine the average response ina group of patients but do not predict what theresponse of an individual will be. Thus, althoughthe average response to drug A may be betterthan drug B in a clinical trial, an individualpatient may respond better to drug B.

Cogan’s syndrome A very rare type of VASCULITIS

described by Cogan in 1945 that affects the eyes,ears, and other organs.

Cause

The cause of Cogan’s syndrome is not known. Anassociation with smallpox vaccination and upperrespiratory tract infections has been reported, butthis could be coincidental and no infective causehas been identified. Cogan’s syndrome affectsyounger people, often in their twenties. Recently,researchers identified antibodies against sensorycells of the inner ear in patients with Cogan’s syn-drome, suggesting that it is an autoimmune illness.

Symptoms

The usual onset is with eye or ear symptoms. Vas-culitis can affect the inner ear and cause suddendeafness, dizziness with a sensation of spinning (ver-tigo), and unsteadiness or poor balance. The eyesymptoms are a red, watery eye that feels scratchy

44 Cogan’s syndrome

and is sensitive to light. The commonest type of eyeinflammation is known as interstitial keratitis. Thiscan be diagnosed by an ophthalmologist using a slit-lamp microscope to examine the eye. In addition toeye and ear symptoms, Cogan’s syndrome oftencauses systemic symptoms such as fever and weightloss. Vasculitis can also affect the aorta and causeleaking of the aortic valve or an aneurysm.

Diagnosis

There is no diagnostic test for Cogan’s syndrome.The diagnosis is made entirely on the clinical man-ifestations.


Because of its rarity there are no good studies thatdefine the best treatment for Cogan’s syndrome. Itis usually treated as a systemic vasculitis with highdoses of CORTICOSTEROIDS often combined with animmunosuppressant such as METHOTREXATE,

CYCLOPHOSPHAMIDE or CYCLOSPORINE. Vertigo usuallyimproves but deafness (40 percent of patients),blindness (8 percent), and leaking aortic valve (14percent) can be permanent.

cognitive behavioral therapy A type of therapymost often used to treat chronic pain such as thatresulting from FIBROMYALGIA or BACK PAIN or fatiguefrom CHRONIC FATIGUE SYNDROME. Cognitive behav-ioral therapy is used with other medical therapyand is not a replacement. It is based on the conceptthat beliefs about an illness and the strategies peo-ple use to cope with illness and other stresses athome or work can affect the outcomes of an illness.

Cognitive behavioral therapy helps patientsunderstand the techniques they are using to copewith illness and substitutes positive coping skills fornegative ones. The therapy starts with the patientdescribing the effect that various symptoms have onactivities such as work and hobbies and on attitudesand feelings, for example anxiety, depression, andhelplessness. This helps people recognize that whatthey do is affected by how they feel and think andvice versa. The basis of cognitive behavioral ther-apy is that by learning positive ways of coping andavoiding negative ones, someone can take anactive part in controlling symptoms and improvetheir quality of life. Therapy focuses on practical

strategies to deal with negative attitudes andbehavior and to improve physical activity and psy-chological health. Therapists are usually psycholo-gists or other health professionals with training incognitive behavioral therapy. A directory of trainedprofessionals is available from the Association for the Advancement of Behavioral Therapyhttp://www.aabt.org/ (see Appendix III).

Cognitive behavioral therapy techniques

Therapists teach several coping techniques. Afterthe patient has mastered and applied them, theprogram usually also involves a plan to maintainthese skills.

Relaxation The technique taught most ofteninvolves tensing and relaxing different muscleswhile resting quietly and focusing the mind onfeelings and thoughts of relaxation. After master-ing relaxation at rest, the patient learns how toidentify muscles that are sources of tension and torelax them during daily activities such as driving,sitting, or standing.

Pleasant imagery Placing pleasant and positiveimages in the mind’s eye helps relaxation and focusesthoughts away from unpleasant sensations such aspain. The patient chooses an image that is peacefuland pleasant, for example a beautiful mountain, andthen uses all the senses, smelling the mountain airand feeling the breeze, to make the image more real.The patient chooses images that have personal signif-icance, and the therapist works with the patient tomake the image as real as possible.

Alternating rest and activity Many patientsoverexert themselves on one activity and thenhave difficulty completing other tasks. Cognitivebehavioral therapy teaches patients to break activ-ities down into manageable pieces and plan theirdays around alternating periods of rest and activity.

Removing negative thoughts Therapists teachpatients to identify negative thoughts and feelingsand to substitute positive ones. For example, “I amfeeling terrible and will never get better” can bereplaced with “I have had bad times like this beforeand I can work through it.”

These skills are taught and reinforced by thetherapist using several techniques. One technique,cognitive rehearsal, consists of patients imaginingsituations and their responses. The therapist andpatient rehearse healthy responses so that when a

cognitive behavioral therapy 45

similar situation arises in real life, the patient isprepared for it. Role-playing is a similar technique.Therapists also ask patients to keep a journal andthen use it as a tool to identify unhealthy attitudesso that these can be redirected.

Results of cognitive behavioral therapy Clinicaltrials have studied the effect of cognitive behavioraltherapy in RA, rheumatoid arthritis, osteoarthritis,back pain, and fibromyalgia. In most studies, therapywas added to other medical treatment and improvedoutcomes such as pain, depression, anxiety, andquality of life.

complement More than 100 years ago scientistsnoticed that the cell walls of some bacteria rup-tured after they had been exposed to an antibodyand placed in fresh serum. As science advanced itwas discovered that complement was responsiblefor this. The activity of complement is the endresult of a cascade of interactions between a groupof proteins in the blood that forms the complementpathway. The complement cascade has severalfunctions. Two of the most important are defenseagainst bacteria and mopping up antigen/antibodycomplexes that could otherwise be harmful. Thereare two main complement pathways, the classicalpathway and the alternative pathway. Both workthrough a series of proteins called components thatare numbered C1, C2, and so on. The classicalpathway is usually activated by a reaction betweenan antibody and an antigen, but the alternativepathway can be activated without antibody. Thetwo pathways proceed by activating different com-ponents initially, then both activate C3. The finalsteps from then on are identical and result in theformation of a group of proteins, called the mem-brane attack complex, that can damage foreigncells like bacteria.

There are several inherited abnormalities of the complement cascade that can cause illness.Deficiencies of the early components of the cas-cade, for example C1, C2, and C4, increase the riskof developing an illness similar to systemic lupuserythematosus (SLE). Most complement deficien-cies are rare. The commonest is C2 deficiency, butonly about 1 in 10,000 people have a completedeficiency of it. Half of these develop an illness thatresembles SLE. Unlike typical SLE, people with C2

deficiency often develop an illness with a negativeANA blood test (see ANTINUCLEAR ANTIBODY inAppendix II). Why a complement deficiencyshould cause SLE is not clear. However, becausecomplement has the important function of clearingthe body of immune complexes, a deficiency in thecomplement cascade would likely allow immunecomplexes to accumulate. This would increase thechances of developing an autoimmune diseasesuch as SLE. Deficiencies of the later componentsof the complement cascade, for example C5, C6,C8, and C9 increase the risk of developing bacterialinfections, particularly those caused by Neisseria

meningitidis, a cause of bacterial meningitis. Another hereditary abnormality of the comple-

ment pathway results in increased rather thandecreased activity. Some forms of hereditaryangioedema are caused by a deficiency of theenzyme inhibitor that inhibits C1 in the early partof the complement cascade.

copper bracelet Copper worn in contact with theskin, either as a bracelet or a disc, is an alternativeremedy that many people use to treat arthritis. Itappears to be safe, but there is no good evidenceshowing that it is effective.

corticosteroids (glucocorticoids, steroids) Agroup of drugs with actions similar to those of theendogenous hormone cortisol that suppresses theimmune response.

COX-2–selective drugs See CYCLOOXYGENASE andNONSTEROIDAL ANTI-INFLAMMATORY DRUGS.

CPPD See CALCIUM PYROPHOSPHATE DIHYDRATE

DEPOSITION DISEASE.

CREST syndrome See SCLERODERMA.

Crohn’s disease See ENTEROPATHIC ARTHRITIS.

cryoglobulinemia The group of diseases termedcryoglobulinemia all share the laboratory finding ofhaving cryoglobulins on blood testing. When bloodplasma is cooled to less than 37°C, one or moreimmunoglobulin type precipitates out but redis-solves on warming. These immunoglobulins are

46 complement

termed cryoglobulins. Immunoglobulins (antibod-ies) are classified into five major types according totheir properties: IgA, IgG, IgM, IgD, and IgE. Withineach class of immunoglobulin, particular antibodiesmay be produced by one B lymphocyte and itsprogeny (monoclonal) or many lymphocytes andtheir progeny (polyclonal). The normal response toan infection would always be polyclonal.

Cryoglobulinemia is classified into three sub-groups. In type I, there is one monoclonal immuno-globulin, usually IgM. In type II, there are bothpolyclonal IgG and monoclonal IgM. Type IIIincludes both polyclonal IgG and polyclonal IgM.

Cause

Type I cryoglobulinemia is usually caused byWaldenstrom’s macroglobulinemia, lymphoma, ormultiple myeloma. In these diseases white bloodcells called plasma cells have become autonomous,multiplied greatly, and produced excessive amountsof immunoglobulins. In Waldenstrom’s macroglobu-linemia this is of IgM type, and in multiple myelomait may be IgG, IgM, or IgA. These immunoglobulinsor antibodies have no useful activity in the body. Astheir concentration in the blood increases, they havea natural tendency to precipitate in the colder partsof the body such as the hands, nose, and feet.

Type II and III cryoglobulinemia, togetherreferred to as mixed cryoglobulinemia, have largeamounts of IgG antibodies together with eithermonoclonal or polyclonal IgM that is directedagainst part of the IgG molecule. This type of IgMantibody is called rheumatoid factor (see AppendixII). When the IgM attaches to IgG molecules toform large complexes, they become liable to pre-cipitate. These may be associated with chronicinfection caused by HEPATITIS B, HEPATITIS C, lym-phoma, chronic lymphocytic leukemia, myeloma,and autoimmune diseases such as RHEUMATOID

ARTHRITIS, SJÖGREN’S SYNDROME, SCLERODERMA, andSYSTEMIC LUPUS ERYTHEMATOSUS. In a few patientsthere is no apparent cause, and this is termed essen-

tial mixed cryoglobulinemia.In 1989 the hepatitis C virus (HCV) was discov-

ered, and soon it was possible to do blood tests tolook for HCV infection. As these blood testsimproved, it became clear that HCV was the causeof 80–90 percent of mixed cryoglobulinemia. These

patients would previously have been said to haveessential mixed cryoglobulinemia.

Whatever the cause, the end result is that cryo-globulins form complexes and precipitate out whenthe blood temperature drops below 37°C. This isusually just below the skin, especially in the hands,ears, nose, and lower legs. It may form a gel, pre-cipitate, or actual crystals, depending on how muchabnormal protein there is and how cold the bloodbecomes. As a gel it may just cause sludging andpoor blood flow. When it precipitates onto theinner lining cells of the blood vessel (endothelium),an inflammatory reaction occurs with damage tothe blood vessel (VASCULITIS).

Symptoms

RAYNAUD’S PHENOMENON is common, as are jointpains and mild fever. The typical event that oftenleads to the diagnosis is leukocytoclastic vasculitisfollowing exposure to cold. This can lead to smallpurple-black lesions on the lower legs (purpura),larger black crusting lesions that may develop intoulcers, or even dry gangrene of fingers or toes.Occasionally there is inflammation of the filteringpart of the kidneys (glomerulonephritis). In type Icryoglobulinemia the protein level can become sohigh that the hyperviscosity syndrome develops.This is when the blood is so thick that it does notflow through small blood vessels very well. Hyper-viscosity syndrome may cause breathlessness, afainting feeling, headaches, difficulty in concentrat-ing, and aching in the legs. In addition there may besymptoms of the associated disease. In HCV infec-tion there is usually some inflammation of the liver,but generally this is less severe than in hepatitis B.

Diagnosis

There are two aspects to the diagnostic process,first the diagnosis of cryoglobulinemia and, sec-ond, the search for an underlying cause. Cryoglob-ulinemia may be diagnosed when an at-riskindividual, for example someone known to haveHCV infection or Waldenstrom’s macroglobuline-mia, complains of typical symptoms and theappropriate investigations are done. On the otherhand, someone may, for example, present withpurple-black lesions on the legs and have theappropriate investigations done when the biopsy

cryoglobulinemia 47

shows leukocytoclastic vasculitis. Blood should betaken in prewarmed syringes and given directly tothe laboratory to test for cryoglobulins. Theimmunoglobulins involved can then be typed andshown to be either monoclonal or polyclonal. Theplasma viscosity is measured by seeing how fastthe plasma can pass through a very fine tube.

If there is a single monoclonal cryoglobulin,then Waldenstrom’s macroglobulinemia or multi-ple myeloma is likely. Patients with Waldenstrom’smacroglobulinemia will have an IgM monoclonalimmunoglobulin; may have an enlarged liver,spleen, and lymph nodes; and their bone marrowbiopsy will show abnormal collections of lympho-cytes and plasma cells. Multiple myeloma patientsare less likely to have enlarged livers and spleensbut often have bone pain and X rays show verytypical punched-out lesions in the bone or a generalthinning of bone. The bone marrow biopsy willshow an excessive number of plasma cells.

The diagnosis of the autoimmune conditionslisted under “Cause” is discussed in the relevantsections of this book. Hepatitis B infection is associ-ated with a small number of cases of cryoglobu-linemia. The blood tests reliably show infection anddifferentiate between past exposure with immunityand current active infection. Blood tests for HCVhave proven more difficult. Currently, a secondgeneration ELISA (enzyme-linked immunosorbentassay) is usually done as a screening test and con-firmed by a RIBA (recombinant-based immunoblotassay) test. Most doctors would then go on torequest an HCV RNA test before starting treatment.This confirms the actual presence of the virus inthe blood being tested rather than just the body’sreaction to the virus, which the first two tests lookat. Because the HCV is present in the blood in verylow numbers, it was difficult to find before modernmolecular biology techniques became available.


Because cryoglobulinemia is an unusual manifesta-tion of a number of diverse diseases, the treatmentmay need to be directed at reducing the cryoglobu-lins as well as treating the underlying disease. Inthe noninfectious cases treating the underlyingcondition is usually all that is required. However, inemergencies it is sometimes necessary to deplete

the cryoglobulins rapidly. PLASMAPHERESIS is a tech-nique using automated blood cell separators inwhich 50 percent of the protein in blood can beremoved in a couple of hours. This has a temporaryeffect only. Immunosuppressive treatment withCYCLOPHOSPHAMIDE or high-dose CORTICOSTEROIDS

effectively shut down the production of the abnor-mal immunoglobulins although their effect willtake a week or more to become evident.

When the hepatitis B or C viruses are the under-lying cause, there is concern that immunosuppres-sive treatment may worsen the infection. Since thetreatment for these infections stimulates theimmune system (and may occasionally provokeautoimmune disorders), there is likewise concernthat this treatment may worsen the cryoglobuline-mia and/or the vasculitis. The best way to approachthis dilemma is not known at present. With mild orincomplete cryoglobulinemia, it is probably best tocommence antiviral therapy if the patient wishes tohave this. If a mild vasculitis is present, it may bebest to cover the antiviral treatment with a moder-ate dose of corticosteroid. If there is limb-threaten-ing vasculitis or renal involvement, this should beadequately settled with immunosuppressive treat-ment before starting antiviral medication (seeHEPATITIS B and HEPATITIS C). Hepatitis B is treatedwith alpha interferon, an immunostimulatoryCYTOKINE. Only about 35 percent of patients willrespond to this, and there are considerable sideeffects. Hepatitis C is treated by a combination ofalpha interferon and ribavirin, again with onlymoderate success. In this difficult situation treat-ment needs to be tailored to each individual withparticular regard to his or her wishes.

crystal-induced arthritis See GOUT and CALCIUM

PYROPHOSPHATE DIHYDRATE DEPOSITION DISEASE.

cyclooxygenase (COX) There are two COX en-zymes, COX-1 and the more recently discoveredCOX-2, that increase the formation of prosta-glandins and thromboxane from a precursor, arachi-donic acid. Prostaglandins are a family of chemicalsthat have many effects on tissues, including somethat increase inflammation. An important effect of thromboxane is that it causes platelets to becomesticky, clump together, and form blood clots.

48 crystal-induced arthritis

COX-1 is found in many different tissues, butCOX-2 is usually found only in tissues that havebecome inflamed. Older NSAIDs, such as aspirin,ibuprofen, naproxen, and many others, inhibitboth COX-1 and COX-2 enzymes. Decreasing theamount of prostaglandins made by COX-2 ininflamed tissues is anti-inflammatory and is usefulfor treating the symptoms of arthritis. OlderNSAIDs inhibit COX-2 but also inhibit COX-1 andthus decrease the amount of thromboxane madeby platelets. Decreasing thromboxane and makingplatelets less sticky can be helpful for preventingheart attacks, strokes, and illnesses caused byblood clots, but it can also increase the risk ofbleeding. Aspirin is a unique NSAID because it hasvery long-lasting effects on the platelet COX-1enzyme, and this is why aspirin is used to preventheart attacks and strokes. COX-1, in addition tobeing found on platelets, is also found in the stom-ach where the prostaglandins it makes protectagainst ulcers. The result is that older NSAIDs thatblock COX-1 and COX-2 are more likely to causepeptic ulcers as a side effect. To overcome thisincreased risk of peptic ulcer, scientists developeddrugs that blocked COX-2 and did not have mucheffect on COX-1. These drugs are sometimes calledCOX-2 selective NSAIDs (see ROFECOXIB, CELE-

COXIB, and VALDECOXIB).COX-2 selective drugs are no more effective in

decreasing pain and inflammation than nonselec-tive NSAIDs but cause GI side effects less often.Other common side effects of NSAIDs such ashypertension and decreased kidney function dooccur with COX-2 selective drugs, perhaps becausesome COX-2 is present in normal kidneys. COX-2selective drugs have no effect on COX-1 and there-fore do not decrease platelet stickiness and cannotbe used to prevent heart attacks. In fact, in oneclinical trial a few more heart attacks occurred inpeople taking high doses of the COX-2 selectivedrug rofecoxib than in those taking an older, non-selective NSAID, naproxen. It is not clear if this wasa chance finding, or if naproxen decreased the fre-quency of heart attack because of its effects onCOX-1 in platelets, or if rofecoxib increased thechance of heart attack. Standard doses of COX-2selective drugs have not been associated with anincreased risk of heart attack.

cystic fibrosis The most common lethal geneticdisorder in western Caucasian populations, cysticfibrosis is the result of an abnormality in the genefor the CFTR or cystic fibrosis transmembrane reg-ulator and affects about 1 in every 3,000 births inCaucasian Americans and 1 in every 15,000 birthsin African Americans. Cystic fibrosis affects manydifferent glands, including those lining the walls ofthe intestines, lungs, and sinuses. Symptoms of thedisease often start in childhood. A common symp-tom is poor absorption of food because the intesti-nal glands that are important for digesting food arenot functional. Repeated attacks of pneumonia arecommon because the glands in the layer lining thepassages of the lungs are not able to stop the nor-mal lung secretions from plugging up the airwaysand causing infections. Antibiotics and other med-ical advances have improved the prognosis and,perhaps because more patients with cystic fibrosisare surviving into their thirties, arthritis-relatedproblems are now recognized more often.

Cystic fibrosis arthritis A few patients withcystic fibrosis have developed a type of arthritisthat seems to be specifically associated with the ill-ness. This arthritis comes in acute attacks lastingdays or weeks, can affect one or several joints, andis often accompanied by a skin rash, usually ERY-

THEMA NODOSUM. Tests for rheumatoid factor andantinuclear antibodies (see Appendix II) and X raysare usually negative. The cause is not known, butbecause patients with cystic fibrosis suffer fromrecurrent infections, several investigators havesearched for an infectious cause. Infection couldcause arthritis either directly or indirectly. Accord-ing to one theory, infection could trigger anautoimmune response and cause arthritis becausethe molecular structure of parts of some infectiousorganisms is similar to that of parts of the humangenome. Researchers have not consistently foundparticular infections to be associated with arthritisin cystic fibrosis. Another possibility is that geneticvariability in people with cystic fibrosis mayexplain why only some get arthritis. Thus, theactual genetic variant of cystic fibrosis a person has,as well as his or her individual immune responsegenes, may be important. So far there is little infor-mation to support this suggestion. A plausibleexplanation is that because patients with cystic

cystic fibrosis 49

fibrosis have poor pancreatic function and there-fore do not absorb food well, they are more likelyto develop ENTEROPATHIC ARTHRITIS, a condition thatcauses a similar type of arthritis. Information aboutresponses to different treatments is limited. NSAIDscan improve symptoms, and some studies showthat they may also help the respiratory problems. Ifpossible, immunosuppressive drugs are avoidedbecause patients with cystic fibrosis are alreadypredisposed to developing infections.

Hypertrophic pulmonary osteoarthropathy

Any chronic lung problem, including cystic fibrosisthat causes clubbing (swelling of the tips of the fin-gers), can cause HYPERTROPHIC PULMONARY OSTEO-

ARTHROPATHY. The treatment of this condition isbased on decreasing the underlying infections, usu-ally with rotating courses of antibiotics.

Osteoporosis Patients with cystic fibrosis oftenhave a low absorption of vitamin D and calcium,two essential requirements for healthy bones. Also,because of chronic illness they are often not veryactive and therefore have a greater chance ofdeveloping OSTEOPOROSIS. The treatment of osteo-porosis in patients with cystic fibrosis is similar tothat of other patients with osteoporosis, but partic-ular attention is needed to ensure that enough vit-amin D and calcium is absorbed.

Vasculitis A few patients with cystic fibrosishave developed VASCULITIS affecting the skin, inter-nal organs, or both. No other cause was found, andtherefore cystic fibrosis is thought perhaps toincrease the risk of vasculitis.

Amyloidosis Patients with chronic infection orinflammation have an increased chance of devel-oping secondary AMYLOIDOSIS, and a few cases haveoccurred in patients with cystic fibrosis.

cytokines Small molecules that act as messengersbetween cells, particularly cells that regulate theimmune response. Cytokines are important forlocal communication between cells, in contrast tohormones, which circulate in the bloodstream andexert their effects on distant organs or tissues. Lowlevels of some cytokines can be detected in the cir-culating blood of healthy people, but they exerttheir main action over the very short distancesbetween cells in the same locality. The first localmessenger proteins discovered in 1969 were pro-

duced by lymphocytes and so were called lym-phokines. The name cytokine soon replaced thename lymphokine because other types of whiteblood cell also produced these messengers. Cyto-kines are produced mainly by white blood cells thathave been activated. The cytokine is then releasedinto the space between cells. If it comes into con-tact with its specific receptor on neighboring cells,it binds to the receptor and activates responses inthe target cell. These may either increase ordecrease inflammation and growth. More than 150cytokines are currently known. However, theinformation made available by the human genomeproject will allow scientists to identify many newmolecules that have a cytokine-like structure andthen to work forward and discover their biologicalfunction. Many cytokines share functions so thatoften several cytokines can cause the same effectson target cells. Cytokines can be divided accordingto whether their main effect is to increase ordecrease inflammation.

Cytokines that Increase Inflammation

Tumor necrosis factor alpha (TNF-a) Tumornecrosis factor got its name from the observationthat if scientists produced inflammation in ani-mals that had experimental tumors, then the ani-mals produced a substance, later called TNF, thatcould cause necrosis (death) of part of the tumors.TNF-a is produced mainly by monocytes andmacrophages but can be produced by activated Band T cells and fibroblasts. It stimulates cells to pro-duce other cytokines that increase inflammationsuch as interleukin-1 and interleukin-6. If TNF isinjected into animals, it causes fever, loss of weight,and shock. TNF-a seems to be particularly impor-tant in rheumatoid arthritis because mice that havebeen genetically engineered to make too muchTNF-a develop an illness similar to rheumatoidarthritis (RA). In humans, TNF-a is found in thesynovial fluid of patients with RA, and blockingTNF-a with an antibody, or mopping it up with adecoy protein, is an effective treatment for RA (seeADALIMUMAB, ETANERCEPT, INFLIXIMAB). TNF binds totwo receptors called p55 and p75. Some of thesereceptors are bound to cells, but others are not andare called soluble receptors. The soluble receptorscan act as a sump to mop up TNF and stop it from

50 cytokines

cytokines 51

reaching receptors bound to cells and activatingthem.

Interleukin-1 (IL-1) IL-1 is produced mainly bymonocytes and macrophages but can be producedby endothelial cells that line blood vessels and byactivated B and T cells. A lot of evidence suggeststhat IL-1 is important in RA. When IL-1 was injectedinto the knee joints of rabbits, it caused damage. Inanimal models of arthritis, blocking IL-1 with anti-bodies decreased the amount of joint damage. Inhumans, IL-1 is present in the synovial fluid ofpatients with RA.

IL-1 acts through two types of IL-1 receptors.Type I receptors are linked to cells so that the cellsrespond if this receptor is activated, but type IIreceptors are not linked to a signaling system andact as decoy receptors. Another mechanism used bythe body to control IL-1 activity is to produce a pro-tein that acts as an antagonist. This protein is calledIL-1 receptor antagonist (IL-1ra) and binds to the

same receptor site that IL-1 binds to but does notactivate the cell. If IL-1ra has bound to the sitewhere IL-1 would otherwise bind, the binding site isblocked and IL-1 cannot bind and activate the cell.This naturally occurring antagonist of IL-1 turnedout to be therapeutically useful because it was man-ufactured and has been developed as a drug that isan effective treatment for RA (see ANAKINRA.)

Interleukin-6 (IL-6) IL-6 is produced by mono-cytes, macrophages, activated T cells, and synovialfibroblasts that line joints and promotes inflammation.

Cytokines that Decrease Inflammation

Interleukin-10 (IL-10) IL-10 is produced bymonocytes, macrophages, and B and T cells. IL-10acts on cells to stop them from producing IL-1 andTNF-a, cytokines that increase inflammation.

Interleukin-4 (IL-4) IL-4 is produced by T cellsand acts on them so that they produce less IL-1 andTNF-a.

D

de Quervain’s tenosynovitis Inflammation of thesheath of tissue that lines the tendons of two mus-cles that pull the thumb away from the other fin-gers and up away from the palm (abductor pollicislongus and extensor pollicis brevis). This usuallyoccurs as a result of repetitive wrist and thumbmovement at work, home, or during recreationalactivities. Women aged 30 to 50 years are mostcommonly affected. De Quervain’s tenosynovitismay also occur in RHEUMATOID ARTHRITIS, psoriaticarthritis (see PSORIASIS AND PSORIATIC ARTHRITIS),other forms of inflammatory arthritis, followingtrauma or during pregnancy, and just after delivery.

The maximal inflammation is usually just abovethe level of the wrist, and the tendon appears hot,swollen, red, and tender. Moving the thumb or wristis painful. The tendons may be heard to creak asthey pass through the tight, inflamed tenosynovialtissue. Finkelstein’s test is positive. This involvesplacing the thumb across the palm, closing the fin-gers over it, and then turning the wrist away fromthe thumb side. This reproduces the patient’s pain.

Stopping the causative action and splinting isimportant in treatment. Lightweight splints thathold the thumb slightly up and out while allowingfull movement of the fingers and the end joint ofthe thumb are used. ICE and NSAIDs can relievepain. Careful injection of CORTICOSTEROIDS along thetendon sheath gives an excellent result in about 70percent of patients and may be repeated if symp-toms do not resolve or recur. If it has not resolvedin six months, surgery can be performed to releasethe tendons from the fibrous pulley that holds themdown at the wrist (extensor retinaculum) andremove some of the inflamed tenosynovium.

dermatomyositis and polymyositis Dermato-myositis is an autoimmune disease causing muscle

inflammation and weakness together with a num-ber of skin rashes. A very closely related disease,polymyositis, causes muscle inflammation andweakness but no rash. Both conditions will be dis-cussed in this section. There is an association withmalignancy in some adults with dermatomyositisand polymyositis. They are rare conditions, affectingonly three to five out of a million people. Womenare affected twice as often as men, and AfricanAmericans three times as often as Caucasians.

Cause

In these diseases the immune system behaves as ifthere is something in the muscle, skin, and otherorgans that it needs to attack and destroy. Lympho-cytes and other immune cells travel to theseorgans, leave the bloodstream, and cause inflam-mation. There are differences between the twoconditions. Immune cells, particularly lympho-cytes, directly attack muscle cells in polymyositis.In dermatomyositis they seem to cause most of thedamage by attacking the blood vessels that supplythe muscle fibers. In both the attack damages themuscle and other cells, causing them first to mal-function and then ultimately to die. The reason forthis immune attack remains unknown, althoughcertain people seem more prone to it than others.

In 1953 a pair of twins both developed dermato-myositis within a year of each other. Since then anumber of families have been found in which morethan one person has developed dermatomyositis orpolymyositis. In addition other autoimmune dis-eases have been found in the families of patientswith myositis more often than expected. Thesefindings could mean that either hereditary factorsor something in the environment shared by thesefamily members influenced the development of thedisease. To date no environmental factors have been

53

found to be important. A number of genetic varia-tions (alleles) have been found that predispose peo-ple to developing dermatomyositis and polymyositisas well as autoimmune diseases in general. Theassociations, however, are fairly weak. Likely morethan one allele is important in any one person.Also, these genetic factors only predispose people togetting the disease, they do not cause it.

In addition to occurring on its own, polymyositiscan occur as a complication of other autoimmunediseases such as SYSTEMIC LUPUS ERYTHEMATOSUS

(SLE) and SCLERODERMA and, rarely, as a side effectof treatment with PENICILLAMINE. It is also a commonmanifestation of the OVERLAP SYNDROME. Hydrox-yurea, a drug used to treat certain blood conditions,can occasionally cause dermatomyositis-like skinproblems.

Symptoms

Most adults first see their doctor with painlessweakness of upper arm, shoulder, buttock, andthigh muscles coming on over three to six months.Children and younger adults may have a morerapid onset and often have fever and fatigue aswell. A few people also have muscle aches. Thispattern of muscle involvement causes difficultydoing things above shoulder height, such as brush-ing hair, as well as lower limb activities like run-ning or climbing stairs. The muscles involved inspeech or swallowing are affected 10–20 percent ofthe time, leading to hoarseness, abnormal voice,difficulty swallowing, or food and fluids going upinto the back of the nose. There is some tendernessof the muscles in 50 percent of people.

Skin problems may start well before the muscleinvolvement in dermatomyositis. Occasionally thedisease is confined to the skin with no obvious mus-cle involvement, although sophisticated testing maystill show some muscle abnormalities. This condi-tion is called amyopathic dermatomyositis and mayconstitute up to 10–20 percent of dermatomyositispatients. The skin lesions are typically flat and pur-ple red and are found on the upper eyelids, cheeks,nose, neck, upper chest and back (shawl area),elbows, knees, and knuckles. A number of otherareas are less frequently involved. Quite a lot ofswelling may occur early on, and later the lesionsbecome thinner and lose their color. The skin of the

hands may become thickened, dry, and cracked, acondition known as mechanic’s hands. Gottron’spapules are typical raised lesions found overlyingthe outside of the finger joints and are found onlyin this condition. The small blood vessels in the nailfold become larger and fewer in number so thatthey can be seen with the naked eye. There is some-times bleeding in this area. Skin ulcers may occur,and occasionally troublesome itching or sensitivityto the Sun is found.

Many patients get joint pain or arthritis early on,but this is seldom severe. Calcification or bone for-mation under the skin or in the soft tissues especiallyaround muscles can be a serious problem. This usu-ally affects children who have had dermatomyositisfor some time and is rare in adults. It particularlyoccurs at sites of trauma and may cause ulceration ofthe overlying skin. RAYNAUD’S PHENOMENON is com-mon, especially in dermatomyositis and the overlapsyndrome.

Shortness of breath in someone with polymyosi-tis or dermatomyositis may be a symptom of a seri-ous problem, signaling heart, lung, or respiratorymuscle involvement. Both the diaphragm and themuscles between the ribs may be affected by theinflammation. This needs vigorous treatment andpossibly hospitalization until it can be shown thatmuscle strength is improving. About 30 percent ofpatients get inflammation of the gas-exchangingparts of the lung (alveolitis). This starts with acough and breathlessness when exercising andmay progress very rapidly. Patients with weakswallowing muscles or abnormal function of theesophagus are prone to getting chest infectionsbecause food or liquids go down the trachea intothe lungs.

Mild heart involvement is probably quite com-mon, but it is usually diagnosed only when severe.Abnormalities of heart rhythm are the commonestproblem and can be life threatening. Heart failuremay occur because of inflammation of the heartmuscle or as a complication of severe lung disease.

Adults with dermatomyositis develop an un-usual number of malignancies both in the fouryears before diagnosis and subsequently. The timeof greatest risk is the first five years after diagnosisof dermatomyositis. Many different types of malig-nancy occur, but ovarian cancer is particularly com-

54 dermatomyositis and polymyositis

mon. The risk of those with amyopathic dermato-

myositis is the same as those with muscle involve-ment. Children with dermatomyositis are not at anincreased risk of cancer. Although adults withpolymyositis do seem to have a slightly higher-than-usual risk, it is not as great as for those withdermatomyositis.

Diagnosis

The diagnosis must first be suspected because of theclinical findings and then confirmed by specialtests, ideally including a positive muscle biopsy.Special investigations may be required to identifyinvolvement of other organs. The finding of certainautoantibodies may give further information onthe type of disease. Depending on the patient’s riskprofile and treatment, further tests may need to bedone to look for cancer or to monitor the safety ofthe medications.

Confirming the diagnosis The first step indiagnosis is usually to confirm muscle damage.Enzymes leak from damaged muscle cells and maybe measured in the blood. These include creatinekinase (also called creatine phosphokinase),aldolase, and lactate dehydrogenase. Their levelsare useful in judging the response to treatment.Creatine kinase is the most useful of these and israised in over 95 percent of patients. Myoglobin isanother protein released into the blood from dam-aged muscle and can be useful in followingprogress, although it is less often used. An elec-tromyogram is useful in confirming muscle disease(as opposed to nerve problems) and for showingwhich muscles are involved. This involves insertinga very fine needle into a muscle and measuring theelectrical activity, both spontaneous and onattempted contraction of the muscle. Typical find-ings of muscle irritability and low-amplitude disor-dered impulses are found in 90 percent of patientsearly on but less frequently later on in severelyaffected muscles.

Trying to obtain confirmation of the diagnosiswith a muscle biopsy is important in all patients. Inthese biopsies, lymphocytes and other chronicinflammatory cells will be seen to be invading mus-cle cells that will be in varying states of damage ordeath. Not all the typical findings are seen in allbiopsies, and up to 20 percent are normal in definite

cases. This is because the disease affects muscle in apatchy manner. Even if an affected patch is biop-sied, the changes may still be developing so that itdoes not look typical. For this reason fairly largebiopsies should be taken from muscles with activeinflammation. Identifying the best muscle to biopsymay not be easy since weak muscles are not neces-sarily inflamed. The electromyogram has been usedfor this purpose, although it may cause musclechanges itself. MRI scanning is more useful, beingpainless, not causing any muscle changes, and giv-ing information about whole groups of musclesrather than just a small segment of a muscle. TheMRI needs to be done carefully since previous dam-age or simply disuse changes can look very likeinflammation on the scan. Special fat suppression T2weighted images need to be taken to avoid thisproblem. The skin changes of dermatomyositis areusually sufficiently characteristic not to requirebiopsy. However if there is doubt, biopsy will differ-entiate them from other autoimmune diseases.

Other organ involvement Spirometry mea-sures the mechanical ability to move air in and outof the lungs and should be done early on and at subsequent intervals to monitor progress. High-resolution CT scans are excellent at showinginflammation and scarring of the lungs that do notshow up on plain X rays until moderately ad-vanced. Occasionally, a bronchoscope is passed intothe main airways and washings taken to count thenumber of inflammatory cells, or a radioisotopescan (gallium scan) can be done. Both these proce-dures give information on how much inflamma-tion is going on in the lungs. However withincreasing experience using CT scans, they are sel-dom required.

An electrocardiogram (ECG or EKG), ultrasoundscan of the heart, and continuous monitoring ofthe heart rhythm for a period of time will be usedto evaluate the heart if the individual suffers frombreathlessness or palpitations and sometimes as ascreening investigation. Although the heart is mus-cle, it does contain slightly different enzymes thatcan be measured to see if it is affected. Theseinclude troponin I, troponin T, and the MB fractionof creatine kinase. Barium X-ray studies are used toidentify problems in the gut, including swallowingdifficulties.

dermatomyositis and polymyositis 55

Autoantibodies A number of patients have pos-itive blood tests for autoantibodies that are alsofound in patients with other diseases. These includeanti-U1-RNP (also found in MIXED CONNECTIVE TISSUE

DISEASE), anti-PM-Scl (also found in scleroderma),anti-Ro (found in SJÖGREN’S SYNDROME, SLE, andothers), and other nonspecific autoantibodies. Theseare sometimes called myositis-associated antibodies.

Other autoantibodies are found only in patientswith inflammatory myositis, so-called myositis spe-cific antibodies. It has been hoped that these anti-bodies would enable patients to be subdivided intogroups with very similar symptoms and complica-tions. In this way it would be possible, by knowingwhat specific autoantibody a patient had at theoutset, to anticipate what complications the indi-vidual might develop and even his or her responseto treatment. For example, patients with antisyn-thetase antibodies often have Raynaud’s phenome-non, fever, mechanic’s hands, more severearthritis, and inflammatory lung disease. Theyhave an average response to treatment. Antisyn-thetase antibodies are the commonest autoantibod-ies found and, of the six known at present,anti-Jo-1 is the most frequent. A second group hasantibodies to signal recognition particle (anti-SRP).They have a rapid onset of disease, the heart isoften affected, and there is a poorer response totreatment. A third group has anti-Mi-2 antibodies.They frequently have a severe dermatomyositisrash and include children with this condition. Theyrespond well to treatment. How useful theseautoantibodies will prove to be in predicting thecourse of the disease is not yet clear.

Associated malignancy All adults with der-matomyositis should be screened for malignancy atthe time of diagnosis. The tests done will vary fromperson to person but would likely include a chest X ray, ultrasound scan of the abdomen and pelvis,examination of the stool for blood, and blood teststo look for markers of malignancy, especially ovar-ian cancer (a CA-125 blood test). Other tests will bedone if there are suggestive symptoms or particularrisk factors such as a family history of breast orbowel cancer. Although the risk is less inpolymyositis, it is still reasonable to screen for thecommonest associated malignancies (lung andovarian cancer) and follow up any suspicious

symptoms. A relapse after successful treatment is awarning sign that a malignancy might have devel-oped, and the appropriate tests should be repeated.Screening tests are not necessary in children.


Because polymyositis and dermatomyositis are raredisorders, information about their treatment isbased on a relatively small number of patients andvery few controlled trials (see CLINICAL TRIAL.) Corti-costeroids are the mainstay of therapy in these dis-eases. This is usually given orally as PREDNISONE, butin severe disease and particularly in children it mayinitially be given intravenously as methylpred-nisolone. It has recently been shown that in somepatients lower doses of prednisone (30 mg per dayor less as a starting dose) result in as good an out-come as the higher doses traditionally used but withmuch fewer corticosteroid side effects. These sideeffects are related to both the dose taken and thelength of time the drug is used. Management of theside effects becomes one of the major problems withongoing treatment. To enhance the effectiveness ofcorticosteroids and allow lower doses to be used,most polymyositis and dermatomyositis patientsneed an additional medication to suppress theimmune system. AZATHIOPRINE or METHOTREXATE isusually used for this purpose, and both are effective.

When the disease cannot be controlled withthese medications or is initially controlled but thenreturns, it is termed refractory. Treatment of refrac-tory disease is difficult. A combination of azathio-prine and methotrexate has been shown to beeffective, as has INTRAVENOUS IMMUNOGLOBULIN. Thepowerful immunosuppressive drugs TACROLIMUS

and CYCLOSPORINE have both been shown to beeffective in small numbers of patients. Althoughcyclosporine might theoretically be expected to bemore effective in polymyositis than dermatomyosi-tis, this does not seem to be the case in practice.Fludarabine, a drug used to treat certain forms ofleukemia, has been used with moderate success.

Alveolitis or inflammation of the gas-exchangingpart of the lung is a very serious complication ofpolymyositis and dermatomyositis and needs to betreated vigorously before there is too much scarringin the lungs since this is not treatable. CYCLOPHOS-

PHAMIDE, cyclosporine, and tacrolimus have all

56 dermatomyositis and polymyositis

proven reasonably effective in this situation. Theskin lesions of dermatomyositis can be resistant totreatment with corticosteroids, and HYDROXY-

CHLOROQUINE is very effective in treating them. Aswell as improving the muscle inflammation, intra-venous immunoglobulin is effective in healing theskin lesions and may be used if hydroxychloroquinedoes not work.

As the muscle inflammation settles (usually indi-cated by the creatine kinase returning toward nor-mal), it is very important for the patient to begin agentle stretching routine and progress to a gradu-ated exercise program. This is because inflammationheals by fibrosis or scarring. This shortens musclesthat will also have lost a proportion of their musclecells. Although muscle cells can enlarge with train-ing and exert a greater force, no new muscle cellswill develop. The timing of stretching and exercis-ing is important and should be started in consulta-tion with the patient’s treating physician.

Polymyositis and dermatomyositis are very seri-ous illnesses. Before corticosteroids were discov-ered 50 percent of patients died from their disease.With modern treatment, nearly 90 percent ofpatients can be expected to be alive five years afterthe onset of the disease, excluding those with amalignancy. There are differences in outcomebetween the subgroups of disease. The outcome isbest for those whose myositis is associated withanother autoimmune disease (85 percent alive atfive years), second best for dermatomyositis (80percent), and worst for cancer associated myositis(55 percent). As mentioned, particular autoanti-bodies give some information on response to treat-ment and outcome. Patients with anti-Mi-2 oranti-PM-Scl have a 95 percent chance of beingalive at five years, those with antisynthetase anti-bodies a 65 percent chance, and those with anti-SRP, a 30 percent chance.

One-third of long-term survivors will haveenough weakness to interfere with their dailyactivities, and a few will be left with lung or heartproblems. Between 20 and 40 percent will havesignificant ongoing problems as a result of the sideeffects of the corticosteroids. There is concern thatthe powerful immunosuppressive medications maylead to later development of malignancy, and theymay also cause bone marrow damage.

DEXA (dual-energy X-ray absorptiometry) SeeAppendix II.

diabetes mellitus An illness caused by decreasedproduction of insulin or by decreased responsive-ness of tissues to it. Insulin, produced by the pan-creas, lowers blood glucose levels, and diabetes ischaracterized by high blood sugar levels. Type I dia-betes, also called insulin-dependent diabetes orjuvenile-onset diabetes, affects younger peoplewho need insulin injections to control it. Type IIdiabetes, also called noninsulin-dependent diabetesor maturity-onset diabetes, usually affects middle-aged, overweight people and can often be con-trolled by a special diet and tablets to lower theblood sugar. Well-known complications of diabetesinclude blindness caused by damage to blood ves-sels of the retina, kidney failure caused by damageto the glomeruli that filter urine, and an increasedchance of developing infections. Diabetes is alsoassociated with less well-known complications thatcan affect muscles, joints, and soft tissues.

Muscle, Joint, and Soft Tissue

Complications of Diabetes

Peripheral vascular disease Diabetes acceler-ates hardening of the arteries (atherosclerosis). Thevessels that supply the legs can become so nar-rowed that they do not carry enough blood. If thishappens it can cause pain when the person walksor exercises. This type of pain is called intermittentclaudication because the symptoms are intermit-tent and get better with rest but recur after exer-cise. Intermittent claudication is caused by a bloodvessel problem and is not a type of arthritis.Because it causes pain in the legs while walking,patients can be incorrectly diagnosed and treatedfor arthritis.

Hand contractures Patients who have had dia-betes for many years can develop fibrous tissue inthe tendons of their fingers so that they cannotstraighten them completely. This is called diabeticcheirarthropathy or diabetic contracture. It causesclumsiness and tightness of the fingers, and otherthan good control of the blood sugar, there is noeffective treatment for it. Diabetes increases thechances of developing DUPUYTREN’S CONTRACTURE andcan also cause tight skin on the fingers. An increase

diabetes mellitus 57

in the fibrous tissue of the finger tendons can causethem to catch and then suddenly release when anaffected finger is flexed, called TRIGGER FINGER.

Shoulder tendinitis Patients with diabeteshave an increased chance of developing shouldertendinitis that causes pain in the shoulder whenlifting the arm and can lead to a frozen shoulder.

Neuropathic arthritis Diabetes can damagethe nerves in the feet and legs so that the personcannot feel exactly where his or her ankles and feetare, and the individual walks awkwardly. The per-son does not feel that the ankle or foot joints arebeing damaged (see NEUROPATHIC ARTHRITIS).

Diabetic nerve and muscle damage Damage tonerves of the hands and feet (peripheral neuropa-thy) can cause numbness, tingling, and pain in theglove and stocking areas. It can also affect muscles sothat they shrink (atrophy) and become weak.

Other conditions DIFFUSE IDIOPATHIC SKELETAL

HYPEROSTOSIS (DISH), CARPAL TUNNEL SYNDROME, andinfections of bone (OSTEOMYELITIS) and joints(INFECTIVE ARTHRITIS) are more common in patientswith diabetes.

dialysis A process used to filter waste productsand toxins out of blood and replace the function ofthe kidneys. There are two common types of dialy-sis, hemodialysis and peritoneal dialysis. Withhemodialysis blood is removed from a patient, fil-tered through a membrane in a machine, and thenreturned. Peritoneal dialysis removes waste prod-ucts from the bloodstream by running clear fluidinto a space in the abdomen called the peritonealcavity and then later removing the fluid after wasteproducts have passed into it. Patients who havebeen on dialysis for a long time have a greaterchance of developing some arthritis problems.

One of the commonest rheumatic problems ispain in the bones caused by increased activity ofthe parathyroid glands. This is called secondaryhyperparathyroidism and is a natural response tothe low calcium and high phosphate levels foundin the blood of patients with poor kidney function.Secondary hyperparathyroidism is treated with alow-phosphate diet and drugs such as calcium saltsthat lower the concentrations of phosphate bybinding it in the gut and preventing it from beingabsorbed into the body.

Patients who have been on hemodialysis for along time have an increased chance of developingarthritis caused by the accumulation of a protein,beta2-microglobulin, that is not removed from thebloodstream by hemodialysis. This substance, a typeof AMYLOID, can collect in the carpal tunnel, causingCARPAL TUNNEL SYNDROME, and in the synovial cavitycausing arthritis. The diagnosis of this type of arthri-tis is usually suspected when a patient who has beenon hemodialysis for many years develops arthritis,most often affecting the shoulders, wrists, hips, andsmall joints of the hands. The X rays show cysts thathave occurred because small pieces of bone havebeen eroded. Some experts believe that the accumu-lation of beta2-microglobulin by itself is not the entirecause and that secondary hyperparathyroidism, boneproblems resulting from aluminum accumulationand deposits of hydroxyapatite crystals, may alsocontribute. There is no specific treatment for this typeof arthritis. However, it can be improved if a patientwho has been on dialysis receives a renal transplantand can discontinue dialysis.

The kidneys excrete uric acid in the urine so thatpoor kidney function causes uric acid levels in theblood to rise and increases that chance that crystalswill accumulate in the joints and cause an attack ofacute GOUT.

diet Many people believe that diet affects theirarthritis or that dietary supplements or vitaminsimprove their symptoms. A lot has been publishedabout the effects of diet on arthritis. Other than thefact that uric acid levels are elevated in people whodrink large amounts of alcohol or eat a lot of redmeat or organ meats (see GOUT), the results havenot been consistent. Many of the studies have beenuncontrolled and open label (see CLINICAL TRIAL),and their results may therefore be biased towardshowing a positive effect.

Several studies have shown that total fastingimproves the symptoms of rheumatoid arthritis(RA) in some patients, but the effects are tempo-rary. Because it was possible that food allergyaggravated arthritis, researchers have studied theeffects of elemental and exclusion diets. Elementaldiets contain minerals and amino acids rather thancomplex proteins and have resulted in a modestimprovement in symptoms in some patients but

58 dialysis

are impractical. Exclusion diets eliminate certainfood types and have identified a few patientswhose arthritis is consistently worsened by a cer-tain food type, for example milk products. Thesepatients appear to benefit by avoiding certain foodtypes, but overall, exclusion diets have not beensuccessful in patients with arthritis.

Several studies have found that a vegan or vege-tarian diet resulted in a modest improvement in RA,but the scientific evidence is not strong enough torecommend this as a useful component of routinetreatment. Many dietary supplements such as yeast,cider vinegar, honey, copper, zinc, magnesium, gar-lic, ginger, alfalfa, and shark cartilage have beenused to treat arthritis without adequate evidenceavailable to support or refute claims for their effi-cacy. Oxidative stress resulting in increased produc-tion of free radicals appears to be increased in manytypes of arthritis. Antioxidant vitamins, particularlyvitamin E and vitamin C, have therefore been sug-gested as treatments for arthritis. In some studies,high doses of vitamin E improved the symptoms ofRA. Vitamin C did not appear to improve symptomsof RA or osteoarthritis (OA) but was associated witha slower progression of OA in one study.

Some unsaturated fatty acids, particularly thosefound in fatty fish such as cod and in some plantssuch as evening primrose oil, decrease the produc-tion of inflammatory prostaglandins. Many studieshave examined the effects of fish oil and eveningprimrose oil in arthritis, and some have foundmodest benefits in RA.

Overall, there are not enough high-quality studiesof the effects of dietary supplements in arthritis to becertain of their effects. Most experts recommend ahealthy balanced diet without any specific exclusionsor supplements for patients with arthritis. If patientsdo become aware of a foodstuff that appears to maketheir arthritis worse, it is best to consult a dietician todesign an exclusion diet to test whether their impres-sion is really true. The dietician can then advise themon healthy eating with the exclusion of an implicatedfood. Processed food today is so complex it can bevery difficult for the individual to do this.

diffuse idiopathic skeletal hyperostosis (DISH)Also known as Forestier’s disease, DISH is a condi-tion in which there is exuberant bone growth at

characteristic sites. It is very common, being foundin approximately 10 percent of people over the ageof 65 years. It is found twice as often in men as inwomen and becomes increasingly common withage. DISH is found in all parts of the world. Typicalchanges of DISH have been found in the spines ofdinosaur skeletons, Egyptian mummies, and otherancient skeletons.

Cause

Although there are well-known associations, theprecise cause is not known. The condition starts atentheses. This is where ligaments, tendons, or jointcapsules attach to bone. There is initially a thicken-ing in this area followed by a gradual transforma-tion of the ligament or tendon to bone withincreased blood flow to the area. An associationwith obesity has been recognized for many years,and later a strong association with noninsulin-dependent diabetes (see DIABETES) was shown. Boththese conditions have high levels of insulin togetherwith resistance to its action in many tissues. Sinceinsulin acts as a growth factor to many tissues, thereis interest in whether this could be one of the fac-tors driving the excessive bone growth.

Symptoms

The powerful ligaments joining the spinal vertebraeare most commonly affected, and in advanced dis-ease, bony bridges can link four to five vertebrae,dramatically reducing spinal flexibility. It is likelythat the mechanical disturbance of movement cangive rise to intermittent spinal pain, but the processof DISH itself is rarely painful. Most patients haveno symptoms, and DISH is discovered only inciden-tally when an X ray is taken for some other reason.Spinal DISH may very occasionally cause difficultyswallowing when the bony protuberances press onthe esophagus. It can also cause narrowing of thespinal canal and pressure on either the spinal cordor the nerve roots as they exit the spine.

Outside of the spine DISH can cause HEEL SPURS,extra bony growth at the tips of the fingers, thicken-ing of tubular bones, and an increased tendency toform bone in the area of scarring after surgery. Heelspurs in particular can be painful, but again it isprobably the disturbance they cause to surroundingtissues that is painful rather than the DISH process.

diffuse idiopathic skeletal hyperostosis 59

Diagnosis

An X ray of the spine showing at least four adjacentvertebrae joined by newly formed bone is essentialfor the diagnosis. Other conditions that can causesimilar appearances should be excluded. These areparticularly ANKYLOSING SPONDYLITIS and degenera-tive disc disease (see BACK PAIN). The X-ray changesin DISH are usually quite distinctive, with the extrabone growth appearing to flow from vertebrae tovertebrae like candle wax, affect mainly the rightside of the spine and lacking severe changes in thedisc or any damage to the vertebral body.


Most people with DISH do not have symptoms anddo not need any treatment. Those with spinal stiff-ness need to understand what the problem is anduse occasional painkillers as needed. A very fewmay need surgical removal of a spur or decompres-sion of the spine or nerve root. Injection of a smallamount of CORTICOSTEROIDS around a painful heelspur may be very helpful. Those who are over-weight should lose weight and exercise more, but ithas not been shown that this will beneficially affectthe DISH. More importantly, in these patients thediagnosis of DISH may prove the trigger for themand their physician to recognize that they have themetabolic syndrome. These patients often have highinsulin levels, insulin resistance, obesity, hyperten-sion, gout, and high lipid levels as well as a highrisk of coronary artery disease.

disease-modifying antirheumatic drugs (DMARDs)A name that has evolved to mean drugs that alterthe course of rheumatoid arthritis by preventingjoint damage (see RHEUMATOID ARTHRITIS). DMARDs(pronounced “dee-mards”) do not belong to a singleclass of drug and can be classified as follows.

Anticancer drugs Although these drugs are alsoused to treat cancer, much lower doses are used toalter the immune response in rheumatic problems.Side effects are much milder and less common thanwith cancer chemotherapy. Established DMARDs are

METHOTREXATE (trade name: Rheumatrex)AZATHIOPRINE (trade name: Imuran)

Antirejection drugs These can be used to pre-vent organ rejection in people who receive an organ

transplant. However, because they suppress theimmune system, they are also useful for somearthritis-related problems. Established DMARDs are

LEFLUNOMIDE (trade name: Arava)CYCLOSPORINE (trade names: Sandimmune, Neoral)

Biologicals These are used to treat RA. Theyare antibodies or cytokines that are similar or iden-tical, to those the body makes and can manipulatethe immune response. Established DMARDs are

ETANERCEPT (trade name: Enbrel) REMICADE (trade name: Infliximab)ADALIMUMAB (trade name: Humira)ANAKINRA (trade name: Kineret)

Other DMARDs Several DMARDs have differentmechanisms of action that are not thought to alterthe immune response and do not fit neatly into a cat-egory. This category includes the following drugs:

AURANOFIN (trade name: Ridaura) oral gold pillsAurothioglucose (trade name: Solganal) intramus-

cular gold injection HYDROXYCHLOROQUINE (trade name: Plaquenil) an

antimalarialCHLOROQUINE (trade name: Aralen) an antimalarialMINOCYCLINE (trade name: Minocin) an antibioticPENICILLAMINE (trade name: Cuprimine) a drug

that binds metals like copper and leadSULFASALAZINE (trade name: Azulfidine) a combi-

nation of a sulfa antibiotic and a salicylate

DISH See DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS.

DMARDs See DISEASE-MODIFYING ANTIRHEUMATIC

DRUGS.

drug-induced lupus This diagnosis is made ifsomeone with no symptoms of SYSTEMIC LUPUS

ERYTHEMATOSUS (SLE) before taking a drug developsclinical SLE while taking a drug and this resolveson stopping the drug. The criteria for diagnosingSLE as well as a detailed description of the clinicalmanifestations and investigation will be discussedunder SLE. This section will discuss how drug-induced lupus differs from idiopathic SLE, thedrugs involved, some possible mechanisms, andtreatment of this condition.

60 disease-modifying antirheumatic drugs

Cause

The antihypertensive drug hydralazine was first rec-ognized to induce SLE 50 years ago. Since thenthere have been many reports of drugs inducinglupus and even more of drugs inducing the charac-teristic autoantibodies. It can be very difficult to besure that the drug did cause the disease in an indi-vidual case. Only two drugs, hydralazine and pro-cainamide, have been scientifically proven toinduce lupus. With many others the reports of anassociation are frequent enough to make a reason-able assumption that there is a real association.However, when there are only one or two reports oflupus occurring after use of a drug that has beenavailable for some years, then it is likely to havehappened by chance. Rare occurrences with new

drugs are always viewed with more suspicion. The

table below includes all drugs in use today, by cate-

gory of use, that have more than a couple of reports

of possibly inducing lupus. The risk associated with

their use is approximate for most of them. The risk

of developing lupus after taking procainamide for

one year is 20 percent and that for hydralazine is 8

percent, although this varies with the dose. The risk

for all the other drugs in the table is very much less

than 1 percent.

Many of these drugs can cause a positive

ANTINUCLEAR ANTIBODY (ANA) test without causing

any clinical manifestations of lupus, and this is

thought to be harmless. Drug-induced lupus usually

develops only after the drug has been taken for

months or years, unlike drug-induced flares (see

drug-induced lupus 61

POSSIBLE LUPUS-INDUCING DRUGS LISTED BY CATEGORY OF USE

Agent Risk Agent Risk

Antiarrhythmics Anticonvulsantsprocainamide high carbamazepine lowquinidine moderate phenytoin very lowdisopyramide very low ethosuximide very lowpropafenone very low primidone very low

Antihypertensives Antithyroid drugshydralazine high propylthiouracil lowmethyldopa lowcaptopril low Antirheumatic drugsacebutalol low penicillamine lowenalapril very low sulfasalazine lowclonidine very low phenylbutazone very lowatenolol very low minocycline lowlabetalol very low anti-TNF drugs very lowpindolol very lowminoxidil very low Diureticsprazocin very low chlorthalidone very low

hydrochlorothiazide very low

Antipsychoticschlorpromazine low Miscellaneousperphenazine very low statins (cholesterol-lowering drugs) very lowphenelzine very low levodopa very lowchlorprothixene very low aminoglutethimide very lowlithium carbonate very low alpha-interferon very low

timolol eye drops very low

Antibioticsisoniazid lowminocycline lownitrofurantoin very low

Symptoms). Evaluating some of these associationscan be very difficult. For example, penicillaminewas a commonly used DMARD for RHEUMATOID

ARTHRITIS 10–20 years ago, and a significant numberof rheumatoid patients will have a positive ANAanyway. A worsening of arthritis pain and feelinggenerally unwell in such a patient could thereforebe due either to a flare of the rheumatoid disease orto the onset of penicillamine-induced lupus.

As will be seen from the table, these drugs arevery different compounds acting on a wide rangeof tissues in the body. There seems no obvious rea-son why they should all induce a particularimmunological disease. One important finding isthat many drugs with the ability to induce lupusundergo breakdown within a class of white cellscalled neutrophils. This breakdown is through theformation of oxygen radicals and results in a formof the drug (metabolite) that has a high capacityfor reacting with other tissues. Because this takesplace in white cells (rather than the liver wheremost drugs are broken down), it suggests a way inwhich these metabolites may be concentrated inthe lymph nodes where they could act on theimmune cells that pass through there. Traditionalresearch has looked at ways in which these drugscould stimulate the immune system to attack theindividual’s own tissues. Recent research, how-ever, suggests that these drugs may interfere withthe immune system’s ability to recognize what isself and what is not. There is much that remainsunknown, however.

Symptoms

Drug-induced lupus differs from idiopathic SLEmainly in that the kidneys and central nervous sys-tem are very seldom affected. The commonest man-ifestations are arthritis, inflammation of the liningmembranes of the heart or lungs (serositis), fever,and feeling generally unwell. The patient will usu-ally have been taking the medication for manymonths or even years. Several drug-inducedautoimmune diseases that can sometimes also be amanifestation of SLE can occur in isolation in theabsence of other drug-induced lupus problems.These include autoimmune hemolytic anemia,thrombocytopenia, and skin rashes. Autoimmunehemolytic anemia is the destruction of the person’s

own red blood cells by their immune system. Like-wise immune thrombocytopenia is the destructionof the small blood cells involved in clotting calledplatelets. Drugs that are known to cause these twoproblems include penicillin, methyldopa, quinidine,levodopa, chlorpromazine, nomifensine, and alpha-interferon. The antifungal drugs griseofulvin andterbinafine may induce chronic lupus skin rashes.

Another group of drugs is able to cause flares oflupus. This is a completely different situation thanthat discussed above but is mentioned here becauseit frequently causes confusion. These patientsalready have SLE, although it may be very wellcontrolled. It is also different in that the flare typi-cally occurs within a week or two of taking thedrug and does not necessarily improve on stoppingit. Most frequently the flare is in the form of a rash.These reactions are better seen as drug allergiesrather than disease induction. SLE patients havelong been known to be particularly prone to drugallergies. Antibiotics are commonly involved inthese reactions, including sulfonamides, penicillins,cephalosporins, erythromycin, and ciprofloxacin.

Diagnosis

Patients with drug-induced lupus often do not ful-fill the criteria used to classify disease as SLE. Thediagnosis needs to be suspected in someone takingone of the drugs listed in the table for at least onemonth but usually longer. Some drugs tend toinduce particular problems, for example pro-cainamide often induces serositis, quinidine andminocycline induce arthritis, and minocyclineoften causes hepatitis.

Most patients will have a positive ANA test, butthis may be found in the absence of any disease andmay have been present before the drug was started. Aspecific type of ANA test, the anti-(H2A-H2B-DNA)antihistone autoantibody is often found in drug-induced lupus and very seldom in other situationsapart from true SLE and SCLERODERMA. However, thistest is not routinely available. Many patients withminocycline-induced lupus or VASCULITIS do not havea positive ANA test but may have a positive ANTINEU-

TROPHIL CYTOPLASMIC ANTIBODY test.Although it may seem difficult to be sure of the

diagnosis, the almost invariable improvementwithin weeks of stopping the drug is very useful.

62 drug-induced lupus


Once the diagnosis has been made or strongly sus-pected, the treatment is to stop the drug. Alterna-tive means of managing the condition being treatedshould obviously be made. A short course of CORTI-

COSTEROIDS is occasionally required for severe prob-lems, but usually they can be managed withsimpler medications such as NSAIDs or painkillersuntil symptoms settle.

drug-induced rheumatic disease In addition toDRUG-INDUCED LUPUS, there are several other mus-culoskeletal side effects of drugs.

Arthralgia, Arthritis, and Tendinitis

Quinolones A class of antibiotics, fluoro-quinolones, more commonly known as quinolones,can rarely cause musculoskeletal side effects. Exam-ples of quinolone antibiotics are ciprofloxacin, lev-ofloxacin, and norfloxacin. Arthralgia and myalgiaoccur in less than 1 percent of patients treated withthis class of antibiotics. More severe adverse effectssuch as arthritis, tendinitis, and rupture of a tendonare much less common. In animal studies,quinolones are harmful to cartilage, particularly ingrowing bones. Therefore quinolones are con-traindicated in children and adolescents and preg-nant women. Reversible arthritis, most oftenaffecting the knees, has occurred most often inpatients who received treatment with a quinolonefor several months to suppress chronic or recurrentinfection. Tendinitis, resulting in pain in theinvolved tendon, affects approximately 20 per100,000 patients treated with a quinolone. TheACHILLES TENDON is affected most often, but otherssuch as the quadriceps (in the area of the knee) orROTATOR CUFF (in the area of the shoulder) can beinvolved. Rupture of a tendon is rare, but the risk ishigher with prolonged quinolone treatment and inpeople who have other risk factors that weakentendons such as being older than 65 years or treat-ment with corticosteroids.

Vaccines Just as RUBELLA (German measles)can cause arthralgia and rarely arthritis, so too canthe vaccine used to prevent it. Arthralgia andarthritis after rubella vaccination are more com-mon in adults than children but usually resolvewithout treatment. Chronic arthritis is rare.

There have been a few reports of inflammatoryarthritis similar to rheumatoid arthritis (RA) devel-oping after vaccination for hepatitis B. One theoryis that the vaccine acts as a trigger for RA in peoplewho are already genetically predisposed. Anotheris that the association is coincidental. RA is a com-mon illness and the onset of RA symptoms and theadministration of a vaccine will occasionally occurat the same time coincidentally.

A vaccine called BCG (bacillus Calmette-Guérin)is used to prevent tuberculosis in many countries.More recently it has been used to treat bladder can-cer by placing it into the bladder to stimulate theimmune response. Arthralgia (0.5–5 percent) andarthritis (less than 1 percent) can develop in patientstreated for cancer using this vaccine. The arthritis isoften asymmetrical and affects large joints such asthe knee. This pattern resembles that of REITER’S SYN-

DROME, and other features typical of that conditionsuch as conjunctivitis and urethritis can occur. Theseclinical features and the fact that people who areHLA-B27 positive have a greater chance of develop-ing arthritis after treatment with BCG vaccine sug-gest that this type of arthritis may be a variant ofReiter’s syndrome. However, BCG may also initiatea RHEUMATOID ARTHRITIS–like disease.

Corticosteroids Inflammatory arthritis oftenresponds dramatically to treatment with corticos-teroids. However, if therapy is suddenly discontin-ued or if doses are decreased rapidly, patients maydevelop a flare of their original symptoms or an ill-defined syndrome of arthralgia and fatigue that im-proves when corticosteroid treatment is resumedor the dosage increased.

Cytokines Several CYTOKINES that are used totreat illness can themselves rarely cause arthritis,often associated with a positive blood test forautoantibodies such as ANTINUCLEAR ANTIBODY andRHEUMATOID FACTOR. Interferon-a, used to treat he-patitis B and C, and interleukin-2, used to treatsome malignancies, can rarely cause inflammatoryarthritis affecting small joints.

Gout and Hyperuricemia

Several drugs increase the concentration of uricacid in the blood (hyperuricemia) and thereforeincrease the risk of GOUT. Diuretics, such asfurosemide, bumetanide, and thiazides, which are

drug-induced rheumatic disease 63

used to increase the amount of sodium and waterexcreted by patients with high blood pressure orfluid retention due to problems such as heart fail-ure, often increase the concentration of uric acid inthe blood. Other drugs that do this are CYCLOSPORINE,an immunosuppressant, and pyrazinamide andethambutol, two drugs used to treat tuberculosis.

Osteoporosis

A common cause of OSTEOPOROSIS is treatment withhigh doses of corticosteroids. Osteoporosis associ-ated with corticosteroid therapy is more severe ifhigh doses are administered for a long time but canoccur even with low doses, such as 5–7.5 mg ofprednisone a day. Corticosteroids cause osteoporosisin several ways: They increase the loss of calciumfrom the body, reduce calcium absorption from thegut, and also decrease the activity of cells calledosteoblasts that form new bone. Individual patientstreated with corticosteroids vary in their susceptibil-ity to osteoporosis. Many patients treated with alow daily dose of prednisone, for example 5 mg orless, will not develop osteoporosis, while others do.The reasons for these variations in individual sus-ceptibility are not known. However, there are dif-ferences in the way the drug is absorbed and brokendown and in the glucocorticoid receptors throughwhich it acts. However, virtually every patienttreated with high doses, say more than 20 mg ofprednisone a day for more than a few weeks, willlose a significant amount of bone. The risk of osteo-porosis caused by corticosteroids can be decreasedbut not eliminated by taking calcium and vitamin Dsupplements. Osteoporosis in patients taking corti-costeroids is most often treated with a BISPHOSPHO-

NATE or, if the patient cannot take any of the drugsin this group, with other drugs used to treat patientswho have osteoporosis not associated with corticos-teroid treatment.

Prolonged treatment with heparin, an anticoag-ulant used to prevent blood clots from forming, cancause osteoporosis. Heparin has to be administeredby injection, so few people receive it for more thana week or two. However, because it does not crossthe placenta and therefore does not affect bloodclotting in the developing baby, heparin is the anti-coagulant most often used during pregnancy. Ifsomeone is pregnant and needs to be anticoagu-

lated, then heparin given by subcutaneous injec-tion is often administered during and immediatelyafter pregnancy. These patients have an increasedrisk of developing osteoporosis. This usuallyresolves slowly when heparin treatment is stopped.

Osteomalacia

Several drugs such as rifampin, phenobarbitone,and phenytoin stimulate the activity of liverenzymes that inactivate vitamin D. This impairs thebody’s ability to calcify new bone and can causeOSTEOMALACIA.

Osteonecrosis

Corticosteroids increase the risk of osteonecrosis(see AVASCULAR NECROSIS).

Vasculitis

Several drugs or classes of drug such as penicillins,sulfonamides, cephalosporins, thiazides, pheny-toin, and captopril can cause vasculitis that mostoften affects small blood vessels in the skin andcauses a rash that typically consists of purple spots.If a skin biopsy is done, it shows white blood cellsinvading the walls of blood vessels (leukocytoclas-tic vasculitis). Propylthiouracil, a drug used to treathyperthyroidism, can rarely cause vasculitis associ-ated with a positive antineutrophil cytoplasmicantibody blood test (see Appendix II). Vasculitisassociated with propylthiouracil treatment hasbeen complicated by glomerulonephritis and occa-sionally features of WEGENER’S GRANULOMATOSIS.Drug-induced vasculitis usually resolves when theoffending drug is stopped.

Myositis and Myopathy

Drugs can cause inflammation or degeneration ofmuscle, resulting in weakness, pain, and sometimeselevated blood levels of muscle enzymes such ascreatine kinase. A class of drugs used to lower cholesterol known as the statins or HMG coenzymereductase inhibitors, for example lovastatin andsimvastatin, occasionally causes myositis. Myalgiaoccurs in approximately 2 percent of patientstreated with a statin, but less than five in 1,000develop significant myositis with symptoms andlevels of muscle enzymes elevated 10 times or moreabove the normal range. Rarely, muscle inflamma-tion is so severe that death of large amounts of mus-

64 drug-induced rheumatic disease

cle occurs, a condition known as RHABDOMYOLYSIS.The risk of developing muscle inflammation washigher with cerivastatin than other statins, and thedrug was withdrawn from the market in 2001. Thechances of developing myositis on a statin drug arehigher in the first few months of treatment and aregreater in patients taking combinations of differentdrugs to lower their cholesterol. Myositis with astatin is more common in patients who are also tak-ing drugs, for example ketoconazole, an antifungaldrug, or cyclosporine, an immunosuppressant, thatslow the breakdown or elimination of many statins.

Colchicine, a drug used to prevent and treatattacks of gout, can damage nerves and muscles.This is a rare side effect even in people who havetaken an overdose of colchicine or taken it formany years. The first symptoms are usually weak-ness of the thigh, shoulder, and ankle muscles. Lev-els of muscle enzymes are usually increased.Muscle weakness is often accompanied by evidenceof nerve damage such as loss of sensation in thefeet and absent ankle reflexes. Muscle symptomsresolve soon after colchicine treatment is stopped,but neurological symptoms recover more slowly.

Hydroxychloroquine and chloroquine, anti-malarial drugs that are also used to treat systemiclupus erythematosus and RA, can rarely causemuscle disease, but this is not usually associatedwith much inflammation. The commonest symp-tom is weakness affecting proximal muscles such asthe thigh and shoulder, without elevation of mus-cle enzymes. Even less common is inflammation ofthe muscles of the heart, cardiomyopathy, which ifsevere can cause heart failure.

High doses of corticosteroids cause atrophy andweakness of muscles, particularly those around thehip and shoulder, which is therefore called a prox-imal myopathy. It causes symptoms such as diffi-culty standing from a seated position or liftingobjects above the head. The myopathy caused bycorticosteroids is gradual, not associated with painor elevated muscle enzymes, and more likely tooccur in patients who receive moderate or highdoses for a long time. Low doses of corticosteroids,for example less than 10 mg a day, seldom causemuscle problems. Corticosteroids are used to treatinflammatory muscle disease such as polymyositisand dermatomyositis, conditions that cause muscle

weakness. It is therefore sometimes difficult toknow if increased weakness is caused by the dis-ease or the treatment. If there are no clinical or lab-oratory signs of disease reactivation, such as anincrease in creatine kinase, a muscle enzyme thatincreases in inflammatory muscle diseases but notin corticosteroid myopathy, then the drug ratherthan the disease is likely to be responsible.

Alcohol can cause acute and chronic muscleproblems. Acute myopathy usually occurs in alco-holics after a heavy binge. It causes symptoms ofmuscle pain, weakness, and elevated enzyme lev-els. Most muscles are involved, enzyme levels areoften very high, and rhabdomyolysis can occur.Usually, unless rhabdomyolysis leads to kidney fail-ure, recovery is complete. Alcohol can also causemuscle atrophy and a chronic, painless proximalmyopathy. The onset of symptoms is gradual, andmuscle enzymes are normal or elevated only a lit-tle. The cause of alcoholic myopathy is not known,but direct toxic effects of alcohol on the musclecombined with the effects of poor nutrition maycontribute. Also, many alcoholics have diarrhea orvomiting and thus lose potassium and magnesium.This can increase the severity of muscle symptoms.Patients with chronic alcoholic myopathy are morelikely to have alcohol-induced heart muscle disease(cardiomyopathy), a condition that can lead toheart failure and death. Stopping alcohol can leadto improvement in muscle symptoms, but thisoccurs gradually over many months.

Penicillamine, a drug occasionally still used totreat RA and scleroderma, can cause inflammatorymyositis that can be difficult to differentiate fromDERMATOMYOSITIS AND POLYMYOSITIS. The risk ofdeveloping myositis does not seem to be related tothe dose or duration of treatment. Affected patientsmost often complain of proximal muscle weakness,but features thought to be typical of autoimmunedisease such as a rash and difficulty swallowing canoccur. Elevated muscle enzymes and symptomsrapidly revert to normal when the drug is stopped.

Cocaine, one of the commonest causes of dis-ease induced by an illegal drug, can cause muscleproblems ranging from small, asymptomaticincreases in muscle enzymes to rhabdomyolysiswith dramatic increases. Cocaine can cause muscledamage in several ways. Not only is it a powerful

drug-induced rheumatic disease 65

vasoconstrictor that decreases blood supply toorgans such as muscle, but it also increases the tis-sue concentrations of epinephrine and norepi-nephrine, fight or flight stress hormones, that candamage muscle. Muscle disease can be the mainsymptom of cocaine use, but more often it is part ofa clinical presentation that can include agitation,coma, confusion, seizures, and chest pain.

drug metabolism After a drug has entered thebody, it can be processed in several ways. Somedrugs, for example penicillin antibiotics, areabsorbed and then eliminated unchanged by thekidneys. Others, for example codeine, are absorbedas poorly active pro-drugs that are biotransformedby the liver to a more active metabolite, in the caseof codeine into morphine. The liver, in addition toactivating pro-drugs, biotransforms drugs intometabolites that are less active or toxic than theparent drug. These chemical reactions are classifiedinto Phase I and II reactions and are carried out byenzymes. Many Phase I reactions are mediated byenzymes belonging to a group called the cyto-chrome P450 (CYP) superfamily. This is classifiedinto families such as CYP1, 2, and 3 and furtherdivided into subfamilies such as CYP1A, 2D, and3A. Many drugs are metabolized by more than oneCYP enzyme, but some depend on a single path-way. Drugs eliminated by a single metabolic path-way are particularly likely to cause side effects ifthey are administered with another drug thatblocks that pathway. For example, CYCLOSPORINE,an immunosuppressant, is metabolized mainly byCYP3A4. If a drug that inhibits this enzyme, forexample the antifungal drug ketoconazole, is takenat the same time, the metabolism of cyclosporinewill be inhibited and blood levels will increase.Although the liver is considered the primary site ofdrug biotransformation, Phase I enzymes are alsofound in other sites and can affect drug levels. Forexample, CYP3A is found on the surface of the lin-ing cells of the small intestine and acts locally ondrugs as they are absorbed. Drug interactions canalso occur here. Grapefruit juice, for example, is astrong inhibitor of CYP3A in the gut but not theliver. Several studies have shown that the absorp-tion of drugs that are metabolized by CYP3A suchas cyclosporine and statin cholesterol, lowering

drugs is increased when they are taken with grape-fruit juice.

Phase II reactions make drugs more water solu-ble and therefore easier to excrete in the urine. Thisis achieved by adding a water-soluble moleculesuch as acetate (acetylation), sulfate (sulfation), orglucuronide (glucuronidation) to the drug.

There are several genetic variants of drug-metabolizing enzymes that affect how active theyare. For example, approximately 5–10 percent ofmost Caucasian populations have a variant ofCYP2D6 that is either inactive or poorly functional.This means that these people poorly metabolizedrugs that are substrates for this enzyme. Forexample, the activation of codeine to the activemorphine metabolite is carried out by CYP2D6.Therefore people with an enzyme that functionspoorly do not activate codeine well and do notreceive the analgesic benefits of codeine when theytake it. The older antidepressants such as amitripty-line and nortriptyline are also metabolized byCYP2D6, but in this case they are inactivated.Therefore people with the inactive enzyme havehigher blood levels of these antidepressants and aremore likely to have side effects if they are givenstandard doses of the drugs. The ability to predicthow an individual will respond to a drug based onhis or her genetic makeup, termed PHARMACOGE-

NETICS, is an area of intense medical research.

drug transport Drugs can cross biological mem-branes is several ways. One of the commonest issimple diffusion. This process is affected by the sizeof the molecules and whether they are water orlipid soluble. Drugs that cross membranes well tendto be smaller and lipid soluble. Recently severalactive pathways that pump drugs across cell mem-branes have been identified. These drug transportpathways are usually specific for a small number ofdrugs and are termed uptake or efflux transporters,depending on whether they pump drugs into orout of the cell. The best-known transporter is P-glycoprotein (PgP), the product of the multidrugresistance gene. This efflux transporter was inten-sively studied when it was discovered that sometumors are resistant to chemotherapy drugsbecause they are able to make this transporter andprotect themselves by pumping drug out of their

66 drug metabolism

Dupuytren’s contracture 67

cells. Scientists then discovered that PgP is foundnot only in some tumors but also in many normalcells, for example those lining the intestine, liver,and the blood vessels that act as a barrier betweenthe brain and the circulation (the blood-brain bar-rier). Also, in addition to chemotherapy drugs, sev-eral other drugs such as CYCLOSPORINE, digoxin,erythromycin, and protease inhibitors are PgP sub-strates. This means that absorption of these drugscan be affected by the amount and activity of PgP.Some drugs such as the protease inhibitors that are used to treat HIV infection do not cross theblood-brain barrier well. Some scientists believethat the reason HIV infection cannot be cured isbecause the virus hides from drugs in sanctuarysites such as the brain. Using drugs that inhibit PgPto allow protease inhibitors to penetrate the brainbetter is an interesting research area that mayimprove HIV therapy.

Dupuytren’s contracture A fibrosing diseaseleading to clawing of one or more fingers. The soft-tissue layer just beneath the skin in the palm of thehand has many fibroblasts. These are cells thatform the fascia or connective tissue here andthroughout the body. In Dupuytren’s contracture,the fibroblasts multiply and produce fibrosis in thepalm of the hand that first causes nodules andthen, as the fibrosis contracts, starts to dimple andtether the overlying skin and later to draw the fin-ger into a fixed curved position. It is fairly commonas people age, is found mainly in Caucasians, andaffects men five times as often as women.

Cause

Although the cause of Dupuytren’s contracture isnot known, there are associations. It is more com-

mon in association with epilepsy, DIABETES MELLITUS,excessive alcohol consumption, chronic lung dis-ease, REFLEX SYMPATHETIC DYSTROPHY, and probablysmoking. In some families it appears to be inherited.A few patients also have fibrosing problems in otherparts of the body, and this form is inherited.

Symptoms

The dimpling and tethering of the skin on the palmof the hand causes few problems. With progressivedisease the fingers become bent at the metacar-pophalangeals (MCPs) with an inability tostraighten them. The fourth finger is usuallyaffected first, then the fifth, and less commonly thethird and second. The fingers may become drawnback right into the palm when they not onlybecome useless themselves but also interfere withthe grasping of objects by the other fingers. Thisprocess usually takes many years and may stabilizeat any stage without further progression. Occasion-ally there may be fairly rapid progression. Althoughit may start on one side, both hands are usuallyaffected. Pain seldom occurs.


In the early stages warmth, moisturizing creamsand stretching are appropriate. The use of protec-tive gloves for manual work is recommended.When there is pain or rapid progression, injec-tions of CORTICOSTEROIDS into the affected areamay be helpful. If the deformity interferes signifi-cantly with daily activities, either just the affectedfascia or the whole of the fascia on the palm of thehand can be removed surgically. Sometimes a skingraft is used. Unfortunately, recurrences may stillhappen.

E

endocarditis See INFECTIVE ENDOCARDITIS.

enteropathic arthritis Inflammatory arthritisassociated with bowel disease, most often Crohn’sdisease and ulcerative colitis (see INFLAMMATORY

BOWEL DISEASE). The gut harbors many bacteria andother microorganisms but is also rich in lymphatictissue that protects the body against invasion.Enteropathic arthritis is thought to occur wheninfection or inflammation of the bowel allowsorganisms that would not usually enter the body todo so. Certain bacteria, or even parts of their cellwalls, can trigger arthritis in susceptible individu-als. Several conditions may cause enteropathicarthritis. These include infectious diarrhea (seeREACTIVE ARTHRITIS), inflammatory bowel disease,and bowel surgery that creates a loop of bowel witha dead end that allows overgrowth of bacteria (seeINTESTINAL BYPASS ARTHRITIS, WHIPPLE’S DISEASE, andCELIAC DISEASE). The type of bowel surgery creatinga loop of bowel used to be done to help people whowere extremely overweight lose weight. Because offrequent GI side effects, it has been replaced byother surgical procedures, including stapling of thestomach, that cause fewer problems.

eosinophilia myalgia syndrome This is a rare ill-ness, similar to scleroderma that usually occurredin people who used the health food supplement, L-tryptophan. There was an outbreak of the diseasein the United States in the late summer of 1989,and additional cases were also reported fromEurope. The initial group of patients was identifiedin New Mexico in 1989. Case-control studies sug-gested that the outbreak was associated with theuse of L-tryptophan. This product, an essentialamino acid, was marketed over-the-counter as ahealth food supplement for 20 years for the treat-

ment of insomnia and depression, although the sci-entific evidence supporting its efficacy was limited.Approximately 1,500 patients, including 26 whodied, were reported to the Centers for Disease Con-trol (CDC) in the 1989–90 outbreak, but it is esti-mated that between 5,000 and 10,000 people wereaffected. The disease almost disappeared after L-tryptophan was removed from the market.

Cause

The outbreak was traced to L-tryptophan and mostoften to L-tryptophan manufactured by a singlecompany, suggesting that a contaminant wasresponsible, but the exact cause is not known.Many people who used L-tryptophan from thesame batch that caused disease were not affected,suggesting that the risk to individuals exposed tothe same toxic chemical varied. Occasional caseshave been reported after L-tryptophan wasremoved from the market and are thought to becaused by unidentified chemicals that result in thesame syndrome. In support of this theory is that aclinical syndrome similar to eosinophilia myalgiasyndrome was seen during an outbreak of an ill-ness called toxic oil syndrome that occurred in Spainin the 1980s in people exposed to contaminatedrapeseed oil. An alternative theory to explain thefew cases of eosinophilia myalgia syndrome thatstill occur is that some people metabolize the natu-rally occurring L-tryptophan abnormally and actu-ally produce a toxic chemical themselves.

Symptoms

The symptoms of eosinophilia myalgia syndromecan affect almost any organ system. Typically themost characteristic early symptom is severe andsometimes disabling muscle pain (myalgia). Themuscles are tender and later in the illness canbecome weak. Fatigue, arthralgia (joint pain),

69

fever, cough, edema (swelling), poor memory andconcentration, and shortness of breath are com-mon. Most patients have a rash that can be itchyand urticarial initially (wheals) but that laterbecomes SCLERODERMA-like and can cause contrac-tures. Neuropathy affecting the nerves to the handsand feet can cause numbness and the sensation ofpins and needles in the glove and stocking areas.The brain can be affected, resulting in impairmentof memory and thinking.

Diagnosis

Blood tests show a marked eosinophilia in allpatients. Other blood tests are often abnormal, butthe findings are not specific. The white blood cellcount and ESR can be elevated and liver functiontests are abnormal in approximately 50 percent ofpatients. Despite severe muscle pain, muscleenzymes such as creatine kinase (CK) are usuallynormal. A biopsy of skin and muscle is abnormaland shows fibrosis and inflammation, findings thatcan be similar to those seen in EOSINOPHILIC FASCIITIS.The CDC criteria for classification as eosinophiliamyalgia syndrome are

• An eosinophil count more than 1,000 cells/mm3

• Generalized myalgia severe enough to affect thepatient’s ability to perform daily activities

• Absence of an infection or malignancy thatcould account for the first two criteria


CORTICOSTEROIDS are used to treat the acute illnessand the rash. Eosinophilia and swelling usuallyrespond rapidly. Fibrosis in the lungs, thickening ofthe skin, and neurological damage do not improvewith therapy. A range of immunosuppressive ther-apies has been tried, with little evidence of success.

In some patients the illness has a short durationwith complete resolution of symptoms, but approx-imately 40 percent of patients have chronic symp-toms. The central nervous system symptoms ofpoor memory and concentration are most likely topersist or worsen. Approximately 2–6 percent ofaffected patients have died, most often from pro-gressive neurological complications.

eosinophilic fasciitis A rare SCLERODERMA-likeillness that causes inflammation and thickening of

the fascia and is associated with eosinophilia. Firstdescribed by Dr L. E. Shulman in 1974, more than200 cases have now been reported in the medicalliterature. Eosinophilic fasciitis has occurred inpeople of all ages but is more common in adults.

Cause

The cause is unknown. However, because a similarillness called toxic oil syndrome occurred in peopleexposed to contaminated rapeseed oil and becauseisolated cases have been associated with exposureto organic chemicals and solvents such as tri-chloroethylene, an unidentified environmentaltoxin is thought to be responsible. In patients pre-senting with eosinophilic fasciitis, a history of recentstrenuous physical exertion is common, but the sig-nificance of this observation is not known. A syn-drome that has some similar features, EOSINOPHILIA

MYALGIA SYNDROME, was recognized after eosino-philic fasciitis. Some authorities believe that some ofthe early cases of eosinophilic fasciitis were in fact alate stage of eosinophilia myalgia syndrome.

Symptoms

Pain and swelling in the deep tissues below the skinare the first symptoms. Over weeks or months thetissue becomes thick and immobile, and dimplingof the skin can result in a characteristic orange peelappearance. The arms and legs are affected mostoften, but occasionally, the face and trunk can beinvolved. The thickening of deep connective tissuereduces the mobility of muscles, tendons, andjoints, resulting in contractures. Systemic symp-toms include low-grade fever and loss of weight.

Diagnosis

The clinical findings and the presence of eosinophiliaare clues to diagnosis, but a biopsy of skin anddeeper tissues is usually needed. Other thaneosinophilia, which is not always present, blood testsare not useful, and tests such as rheumatoid factorand antinuclear antibody are usually normal.


CORTICOSTEROIDS usually control the disease. Occa-sionally immunosuppressive drugs are added if theresponse to corticosteroids alone is inadequate. Con-tractures can limit the mobility of joints. Internalorgans are not usually involved, and the prognosis isgood in most patients.

70 eosinophilic fasciitis

eosinophilic myositis A rare inflammatory muscle disease associated with an increased num-ber of eosinophils in the blood (eosinophilia) ormuscle. Up to 1993, only 31 cases had beendescribed in the medical literature. No specificcause has been identified, but some cases havebeen associated with an allergic response to adrug. Muscle inflammation can affect several mus-cle groups diffusely or, less often, can cause focal,nodular lesions. The average age of onset in areview of published cases was 43 years but rangedfrom 14 to 70 years. Men were affected twice asoften as women. Most patients had eosinophiliaand increased muscle enzymes such as creatinekinase. The most common symptoms were musclepain, cramping, and swelling. Weakness was un-common. Treatment with CORTICOSTEROIDS im-proved symptoms in most patients and the overallprognosis was good.

epicondylitis (tennis elbow, golfer’s elbow)The bony prominences on the inner and outerside of the elbow are known as the epicondyles.They are the lower part of the humerus (upperarm bone) and form the attachment of musclesthat move the wrist. Muscles that move the handaway from the palm (as in a backhand stroke intennis) attach to the outer or lateral epicondyle.Those that move the hand in the palmar direction(as in a forehand stroke) attach to the inner ormedial epicondyle. When these attachmentsbecome inflamed, the condition is called epi-condylitis. In common usage they are often calledtennis (outer epicondyle) or golfer’s (inner epi-condyle) elbow, although less than 5 percent oflateral epicondylitis is found in tennis players andan even smaller percentage of medial epicondyli-tis in golfers.

Lateral epicondylitis is quite common, withbetween 1 and 3 percent of the population havingit at some stage. Although most patients are nottennis players, nearly 50 percent of tennis playerswill suffer from it at some time. It is most frequentbetween the ages of 40 and 60 years. Manypatients are manual workers, while in others thereis no obvious cause. Medial epicondylitis or golfer’selbow is a very similar condition on the oppositeepicondyle but is not common.

Cause

Small tears develop where the muscle joins thetendon close to the epicondyle. With repeated tearsand scarring, chronic or ongoing inflammationdevelops, and the individual feels a persistent achewith more severe pain on use of the involved mus-cles. The grip will often weaken. In lateral epi-condylitis, there will be marked tenderness overthe bony prominence on the outside of the elbowor close to it and the pain will be most severe onflexing the wrist up (as in a backhand stroke).Stretching these muscles (tuck the thumb into thepalm of the hand, flex the wrist down, and thenslowly straighten the elbow) may also producesome pain but is important in rehabilitation aftertreatment. The opposite movement of the wristwill bring out the pain of medial epicondylitis thatis usually less severe and spread over a wider area.

Symptoms

The chief symptom is pain felt in the upper fore-arm. The pain is made much worse by use of thehand and forearm, particularly with gripping orrepetitive movements. Most patients will complainof some weakness of the grip as well. The pain isnot confined to the same, usually quite small, areathat the tenderness is but will be around theaffected epicondyle.

Diagnosis

The diagnosis is made based on the history andexamination, but an X ray may be done to excludeOSTEOARTHRITIS of the elbow joint. When the con-dition does not respond to usual therapy, othercauses should be considered, particularly arthritisof the elbow joint, inflammation of the ligamentthat holds the head of the radius (forearm bone)in place, and nerve entrapments. Compression ofthe posterior interosseus nerve (a branch of theradial nerve) as it passes backward just below theelbow may be particularly difficult to diagnosewhile giving rise to complaints very similar to thefar more common tennis elbow. Electrical stimula-tion studies can be helpful in diagnosing nerveentrapments.


Many treatments have been and are still used forepicondylitis. The three most frequently used are

epicondylitis 71

• Rest with some immobilization

• Ultrasound

• Local corticosteroid injection

Rest of the involved muscles certainly helpshealing, but it needs to be for at least six weeks.Since it is bad for joints and muscles to be completelyimmobilized for this length of time, a variety of mov-able elbow splints have been developed. It is alsopossible to use a wrist splint that prevents the wristfrom flexing toward the palm and thereby stretchingthe muscles in lateral epicondylitis. Ultrasound iseffective but takes longer and is more expensivethan a corticosteroid injection. It has a lower relapserate, however. Usually a combination of either ultra-sound or injection plus rest (or at the very leastavoidance of aggravating activities) is used. Strap-ping of the forearm muscles an inch or two belowthe elbow reduces the tension on the injured mus-cle/tendon junction and can be helpful in allowingpatients to recommence activities. At this stage gen-tle stretching should also be undertaken. Similartreatment is used for medial epicondylitis.

Despite such a combined approach to lateral epi-condylitis and an excellent initial response rate,about a third of patients will have had a recurrenceof their symptoms by six months. Often conserva-tive treatment is repeated with stricter immobiliza-tion. However, with repeated relapses and if thediagnosis is certain, surgery may be considered.Many surgical procedures have been done over theyears, depending on what the surgeon consideredthe essential problem to be. However, the mostcommon and least invasive is simply to cut the ten-dons close to their attachment to the epicondyle.They will heal by fibrosis or scarring, and the effectwill be to lengthen them. This approach is success-ful in nearly 90 percent of cases.

erythema nodosum An inflammatory skin rashthat causes red, painful nodules in the deep tissuesunder the skin, most often on the shin. It occurs atall ages and in both genders but affects youngwomen more often.

Cause

The exact mechanism is not known, but it isthought to result from an immune reaction to an

underlying infection or drug. Several conditionsare associated with erythema nodosum. Theseinclude streptococcal upper respiratory tract infec-tions, SARCOIDOSIS; INFLAMMATORY BOWEL DISEASE;

BEHÇET’S DISEASE; pregnancy; infections such as TU-

BERCULOSIS, coccidiomycosis, histoplasmosis, blas-tomycosis, and leprosy; and reactions to drugs suchas penicillins, estrogen, iodine, and sulfonamides.In approximately one-third of patients no underly-ing cause can be found.

Symptoms

The first symptom is the development of painful,shiny, red raised lumps on the shin. The lesions areoften 1 inch or more in diameter and can occur inother parts of the body such as the thighs or arms.Over four to eight weeks the nodules change colorand resemble a bruise slowly turning from red toblue and then to brown. The nodules do not usu-ally ulcerate. Systemic symptoms such as fever,fatigue, and arthralgia (joint pain) are common.Less often there is mild arthritis, most often affect-ing the knees. The symptoms can be severe andlimit walking and other day-to-day activities.

In patients with erythema nodosum associatedwith sarcoidosis, there may be arthritis of the anklesand enlarged lymph nodes on chest X ray. This com-bination of findings is called Löfgren’s syndrome.

Diagnosis

The diagnosis is usually made clinically from thetypical rash. Occasionally if the rash is not typical, askin biopsy is done. This shows inflammationaround the blood vessels in deep subcutaneous tis-sues, particularly fat (panniculitis). The white bloodcell count and the ESR are often elevated, but labo-ratory tests are not helpful in making the diagnosis.They are, however, helpful in diagnosing theunderlying cause. For example, a throat culturemay detect the presence of a streptococcal infection,or a chest X ray may show signs of sarcoidosis or aninfection such as tuberculosis or histoplasmosis.


If there is an underlying associated illness, it shouldbe treated. For example, antibiotic therapy, mostoften penicillin, is the usual treatment for strepto-coccal infection. If a drug is the cause, it should bediscontinued. Treatment of the symptoms may in-

72 erythema nodosum

clude analgesics to control pain or NSAIDs todecrease inflammation. Occasionally if symptomsare not responding to these drugs, a CORTICOSTEROID

is used. A potential disadvantage of corticosteroidtherapy is that because it suppresses the immuneresponse, it can aggravate an unrecognized under-lying chronic infection such as tuberculosis.

The course is usually self-limited. Symptomsslowly improve and resolve completely over a fewweeks or months, even without any specific treat-ment. A few patients have a more protractedcourse and the condition can recur.

erythrocyte sedimentation rate (ESR) SeeAppendix II.

exercise Views on exercise range from thoseenthusiasts who point to its importance in manag-ing obesity, diabetes, hypertension, and arthritisand suggest that it can prevent cancer to the “whenI feel the urge to exercise I quickly lie down till itpasses” brigade. For people with musculoskeletaldisorders, exercise becomes more difficult and atthe same time more important. It is important forpain relief, maintaining independence, recreationand quality of life, recovering from surgery orsevere bouts of arthritis, improving sleep, manag-ing body weight, and feeling better. Specific prob-lems require specific exercises, and exercises needto be done correctly. Many people will require thehelp of a physical therapist or personal trainer toachieve this. Specific exercises that may be re-quired, for example those to restore normal scapu-lohumeral rhythm in a patient with shoulder pain,are beyond the scope of this book. This section willfirst address some general principles of rehabilita-tion exercises and then aspects of exercise in gen-eral as they apply to people with arthritis.

Rehabilitation Exercise

Rehabilitation is defined as “restoration to a formercapacity.” In patients with chronic arthritis, restor-ing or improving functional level may be a moreappropriate definition. Rehabilitation may berequired in a patient with severe inflammatoryarthritis such as RHEUMATOID ARTHRITIS once theinflammation has been controlled, in a patient whohas gradually lost functional ability, following an

acute injury, and always following surgery. Every-body has different goals and abilities as well as different forms of arthritis at various stages. Reha-bilitation programs should be tailored to each indi-vidual’s needs and abilities. The goals should berealistically achievable and the time frame appro-priate. Important aspects of rehabilitation includethe following.

• Muscle Conditioning When a joint is painful andswollen, the muscles that normally move itweaken rapidly. This is worsened by inactivity,particularly if the muscles are habitually held ina shortened position. So, for example, when anathlete injures a knee or someone with ANKY-

LOSING SPONDYLITIS develops an inflammatoryeffusion at the knee, the quadriceps muscles(the large muscles in front of the knee) thatextend and stabilize the knee will rapidly decon-dition. Although this is easily seen as a reduc-tion in size, the weakening is always greaterthan the size change would suggest. This isbecause there is an increase in fatty tissue in themuscle with deconditioning. Following resolu-tion of such an event it is therefore necessary tocondition the muscle again.

Muscle conditioning requires overload andactivity-specific exercises. The latter is most rele-vant to athletes and indicates that different types ofexercise will produce different conditioning effects.The individual’s goals must be known when devis-ing an exercise program. In order to increase mus-cle strength, power, and endurance, it is necessaryto overload it. This means that if a patient witharthritis just wants to be able to walk reasonablywell after a knee replacement, walking by itself isnot adequate muscle conditioning for the quadri-ceps muscles that have become small and weakprior to surgery. There are several ways in whichoverload training is achieved:

(a) Increasing speed of movement, e.g., forquadriceps doing leg extensions (straightening theknee from a sitting position) or climbing stairs faster

(b) Increasing the number of times the exerciseis repeated, e.g., more leg extensions or stairs

(c) Exercising more frequently, e.g., from once aday to twice then three times a day

exercise 73

(d) Exercising against resistance, e.g., attachinga weight to the shoe before doing leg extensions.

(e) Decreasing the rest time between exercises

(f) Altering the range through which the muscleis exercised

This final method is a very specialized area andshould be done only under expert guidance. Usu-ally a muscle is best exercised through its full nor-mal range of movement.

The four components of muscle conditioningthat need to be considered in planning rehabilita-tion exercise are strength, power, endurance, andmotor reeducation.

1. Strength is the muscle’s ability to exert force.This can improve before any noticeable increasein muscle size. This improvement is thought tobe due to the improved blood supply and meta-bolic efficiency that occur with training. Threemain types of exercise are used.

(a) Isometric exercises are when a muscle is con-tracted without moving the joint. These can bestarted before a joint has completely settleddown as they cause very little pain and will notcause an inflamed joint to flare. They can pre-vent a lot of the wasting that occurs with apainful joint and perhaps some of the loss ofproprioception (see below). The muscle is usu-ally contracted for six seconds followed by a 20-second rest. Ten to 20 contractions are per-formed many times a day at increasing intensitywith the joint in various positions.

(b) Isotonic exercises involve moving a jointthrough its range of movement with a constantresistance, e.g., doing a biceps curl holding adumbbell. These can be concentric (when themuscle shortens) or eccentric (when the musclelengthens). Eccentric exercise is particularlyimportant in rehabilitation, especially if therehas been a tendon or musculotendinous injury.It should be started very gradually, however,since too rapid an increase can damage a decon-ditioned muscle. The use of free weights isalmost always better than using exercisemachines. Free weights provide appropriatestress to all the involved tendons and ligaments.They require activation of not only the muscle

group being trained but also all the stabilizingand postural muscles and in this way preparesthe individual for real-world activity. Exercisemachines cut out all postural and supportingmuscle action and should be used only toachieve specific, short-term goals.

(c) Isokinetic exercises are when the speed ofmovement is constant throughout the fullrange. Because the force that a muscle is capableof exerting is different when the muscle is at dif-ferent lengths, isokinetic exercises are doneagainst a machine that is capable of varying itsresistance in response to the force applied. It ispossible to perform more muscle work with thisform of exercise than isometric or isotonic exer-cise, but there is maximal loading at the weak-est points of the range of movement. Isokineticexercise is used mainly for testing rather thanfor rehabilitation itself.

2. Power is the speed at which muscles can performwork or explosive strength. A standing high jump,for example, is a measure of power in the legmuscles. It is important in sports such as sprint-ing and the jumping and landing of basketballplayers. Power exercises come later in a rehabil-itation program. Plyometric exercises such as hop-ping and bounding are often used before anathlete attempts actual sport-specific maneuvers.

3. Endurance is the ability of muscle to performrepeated contractions. Most marathon runnerswill have highly developed endurance, althoughthey may have relatively little power comparedwith a tennis player. Endurance is improved byperforming many repetitions of an exercise withrelatively little resistance, e.g., walking, jogging,cycling.

4. Motor reeducation is important because musclesdo not act in isolation. Rather, the prime moverworks with the help of synergistic or supportingmuscles on the background of stabilizing muscleaction. In addition, human action usuallyinvolves a chain of movements (the kineticchain) rather than one group of muscles movinga joint. For example, a right-handed baseballpitcher’s throw (excluding the windup) beginswith pressure being exerted onto the ground bythe right foot and is then followed by a chain ofmovements through the body until the right

74 exercise

wrist and fingers apply the final acceleration andcurve to the ball. Following a significant injuryor flare of arthritis it is not uncommon for thesechain movements to become relatively uncoupled

or for stabilizing muscles to become inactivated.This is a frequent cause, for example, of shoul-der injuries or tendinitis to fail to settle afterwhat appears to be adequate treatment. Musclereeducation is required to restore the normalpatterns of movement, and this is as importantin elderly patients with rheumatoid arthritis as itis in elite athletes. The first step toward musclereeducation is an analysis of faulty movementpatterns by a skilled examiner.

• Flexibility The pain of an inflamed arthritic orinjured joint causes the person to restrict itsmovement. The swelling in the joint also reducesthe amount of movement possible and there isspasm of the muscles around the joint that causea variable degree of splinting. The joint capsule,ligaments, and other soft tissues can in a shortwhile start to contract so that once the originalinflammation has been successfully treated, thejoint may be stiff with a limited range of move-ment and tight muscles and tendons. Joint mobi-lization is used to free up the joints andstretching to relax the muscles and lengthen ten-dons. Mobilization should be started as soon aspossible before severe restriction develops. Thereare many mobilization and stretching techniquestaught by physical therapists that are appropriateat different stages of rehabilitation.

• Proprioception Normally our joints, muscles,and tendons are continuously sending nerveimpulses to the spinal cord and brain carryinginformation about the position of our limbs andjoints in space. This is called proprioception. Fol-lowing injury or surgery these nerve pathwaysare damaged, leading to poor balance, poorcoordination, and reduced sense of joint posi-tion. This can lead to reinjury. Proprioceptivetraining involves retraining these nerve path-ways. Following an ankle injury, for example, apatient might start by standing on one leg,progress to standing on an unstable surface suchas a wobble board, and then progress to one-legtrampoline jumping.

• Functional Exercise Rehabilitation progressesfrom the conditioning of muscle groups andretraining faulty movement patterns to activitiesthat the individual intends doing for work orrecreation. These latter are broadly termed func-tional exercises. Although basic functional activ-ities such as walking and jogging are startedearly on in rehabilitation, more advanced activ-ities such as would be required for a soccerplayer or manual worker to return to sport andwork will start only once muscle conditioning,flexibility, and proprioception are progressingwell. Initially functional exercises that simulatethe individual’s desired activity are done in acontrolled setting. The intensity is graduallyincreased with careful monitoring before spe-cific sport or work activities are started. Eventhen it is advisable to return to previous levels ofactivity in a graduated fashion.

• Biomechanical Abnormalities These may haveproduced the injury or be the result of eitherinjury or progressive arthritis. They may presentas muscle tightness or weakness or actual jointabnormalities. Clearly, successful rehabilitationwill depend on identifying them and correcting orameliorating them. This can be achieved by mus-cle stretching, conditioning, proprioceptive train-ing, taping, and orthotics and shoe modification.

Exercise for Arthritis

One of the major advances in treating muscu-loskeletal conditions over the past 25 years hasbeen the realization of the dangers of rest, espe-cially bed rest, and the importance of exercise.Much pain and disability suffered by arthritispatients is due to poor posture and muscle functionthat results from inactivity and muscle imbalancerather than active arthritis itself, although thearthritis may have initiated these problems. Mostpeople with arthritis who take up exercise find ithelpful. Benefits that they report include moreflexibility, less pain, and improved general health.People find controlling their weight easier if theyexercise regularly. They sleep better, have moreenergy, and find the exercise helps in dealing withstress. In general, exercise should involve somecombination of aerobic activities for endurance,stretching or range of movement exercises, and

exercise 75

strengthening exercises for muscle conditioning(see Rehabilitation Exercise section above).

For those with severe arthritis, it is advisable totake advice before starting an exercise program.This may be from the patient’s doctor, a physicaltherapist, or both. The Arthritis Foundation inmost areas is likely to have appropriate exerciseclasses or be able to advise on what is availablelocally. There are also a number of very good self-help exercise books for patients with arthritis.Exercise should be enjoyable, although this willvary among individuals. Many people enjoy exer-cising to music (in a gym, at home, or with a Walk-man), some like exercising in a group, othersalone, some in the morning, and others later in theday. Warming up before vigorous exercise orstretching is important. Gentle exercise is the usualway to warm up, but this can be helped by havinga warm environment, using heat rubs, or simplydressing warmly.

Relaxation techniques are a very rewarding wayto end an exercise session. Progressive relaxationwhere each part of the body is first moved (usuallycontracted) and then relaxed before moving on tothe next part is a commonly used technique. Thereare many others, however, including breathingtechniques, imagery, and meditation. Many tapesare available to assist with relaxation. People withmuscular pain find this particularly helpful. Walk-ing is the most readily available form of aerobicexercise and can be fun (e.g., with a pet or friend),uplifting (in a beautiful park), educational (listen-ing to a lecture on a Walkman), or incorporatedinto daily life (walk to a friend’s house rather thandriving). Cycling is also a good aerobic exercise thatavoids much of the impact of walking or jogging,especially when using a stationary bike or modernmountain bike.

Two forms of exercise are particularly usefulwhile joints are inflamed or very painful. Exercisingin water, especially warm water, can give pain reliefas well as useful exercise even when hips, knees, orankles are too painful to walk any distance on. Notonly is the water and the warmth relaxing but italso unloads the weight-bearing joints while pro-viding good resistance to muscle action. The otheruseful form of exercise is isometric exercises, as dis-cussed above under Rehabilitation Exercise.

Although recreational exercise is generally morefun, activities such as housework and gardeningcan be turned into therapeutic exercise. It is impor-tant to be aware of doing tasks with a good postureand alternating activities frequently. If weeding forexample, weed for 10 minutes and then get up andcarry the weeds to the compost heap rather thanremaining kneeling for 40 minutes. Consider theuse of gardening stools, wheelbarrows, high chairsin the kitchen, and ergonomic tools so as not tocause strain. It is clear, however, that the benefit ofhousework as exercise is less than enjoyable recre-ational exercise.

eye problems Several rheumatic illnesses canhave associated eye problems. All parts of the eyecan be involved, but different illnesses are morelikely to affect particular parts of the eye.

Conjunctivitis

The conjunctiva is the most superficial layer of theeye. When it is inflamed the superficial blood ves-sels become dilated and the eye turns red, becomesitchy, and feels painful. Vision is not affected butcan be blurred if the eye waters. The most commoncauses of conjunctivitis are allergy and viral or bac-terial infection. Patients with any rheumatic dis-ease that causes SICCA SYNDROME, for exampleSJÖGREN’S SYNDROME, SYSTEMIC LUPUS ERYTHEMATO-

SUS, and RHEUMATOID ARTHRITIS, are more likely todevelop conjunctivitis. Sicca syndrome causes dryeyes that are easily irritated by minor trauma, andthe resulting inflammation causes conjunctivitis.The treatment of conjunctivitis associated withsicca syndrome includes measures to prevent theeye from drying out, for example glasses with sideshields, eye drops or lubricant eye ointment tocounteract dryness, and antibiotic drops if a bacte-rial infection is present. Some patients with siccasyndrome get problems because of the mucouslayer drying out and forming a crusty materialrather than an absolute lack of tears. These patientsmay be helped by the use of drops that containacetylcysteine that dissolve mucus.

Episcleritis

The episclera is a layer lining the eye that lies belowthe conjuctiva and above the sclera. It is superficial.

76 eye problems

When it is inflamed, the eye becomes red butvision is not affected. Oral or topical NONSTEROIDAL

ANTI-INFLAMMATORY DRUGS may relieve symptoms,but often no specific treatment is prescribed andsymptoms resolve spontaneously. Rheumatoidarthritis is often associated with episcleritis.

Scleritis

Inflammation of the sclera, the layer below theepisclera, causes a red, painful eye. The pain is deep,severe, and aching in character compared with thesuperficial scratchiness caused by conjunctivitis orepiscleritis. A few patients get an associated uveitis.Vision can be affected, and scleritis should betreated by an ophthalmologist. Treatment involvesmanagement of the underlying condition and mayrequire CORTICOSTEROIDS and immunosuppressivedrugs. Approximately 60 percent of patients withscleritis have no associated systemic disease, 30 per-cent have rheumatoid arthritis, and the remainderhave one of a variety of less common diseases.These include, systemic lupus erythematosus, VAS-

CULITIS (particularly WEGENER’S GRANULOMATOSIS),INFLAMMATORY BOWEL DISEASE, ANKYLOSING SPONDYLI-

TIS, and RELAPSING POLYCHONDRITIS. In patients withsevere rheumatoid arthritis, nodules can occur inthe sclera and inflammation can cause the sclera tobecome thin. If scleral inflammation in rheumatoidarthritis is not controlled, the sclera can become sothin that the globe of the eye perforates and blind-ness results. This is, fortunately, very rare.

Uveitis

Inflammation of the uveal tract, the tissues liningthe inside of the eye, can occur with severalrheumatic diseases. Uveitis is usually classified asanterior uveitis affecting the tissues in the front ofthe eye such as the iris (iritis) or posterior uveitisaffecting tissues at the back of the eye such as theretina (retinitis and choroiditis). Approximately 40percent of people with uveitis have an underlyingrheumatic illness.

Anterior uveitis This often causes a red,painful eye with disturbance of vision and dis-

comfort in bright light (photophobia). Some typesof anterior uveitis, particularly the type associatedwith JUVENILE RHEUMATOID ARTHRITIS, can be rela-tively asymptomatic and if not diagnosed andtreated can cause gradually progressive, irre-versible loss of vision. The diagnosis of uveitis ismade by an ophthalmologist using an instrumentcalled a slitlamp microscope that provides a clearand enlarged view of the interior of the eye.Anterior uveitis increases the amount of cells pre-sent in the anterior chamber of the eye, and thisis visible as a flare on slitlamp examination.Approximately 25 percent of patients withspondyloarthropathies such as REITER’S SYNDROME

or ankylosing spondylitis will develop anterioruveitis at some time during the course of the ill-ness. Typically this uveitis has an acute onset andaffects one eye, although if recurrent attacksoccur, the other eye can be affected. Anterioruveitis associated with spondyloarthropathies isusually a self-limiting problem and settles overweeks or a few months. Recurrent attacks arecommon, but the prognosis is good and perma-nent visual loss is rare. Anterior uveitis usuallyresponds to treatment with local corticosteroids.

Posterior uveitis The most prominent symp-tom is often loss of vision. Unless there is associatedanterior uveitis, the eye may not be red or painful.It is important to differentiate infectious causes ofposterior uveitis such as toxoplasmosis andcytomegalovirus from rheumatic disorders such asBEHÇET’S DISEASE and SARCOIDOSIS. If an infectiouscause has been excluded and vision is threatened,posterior uveitis is often treated with systemic cor-ticosteroids and immunosuppressive drugs. Inmany patients no definite cause for uveitis isfound.

Other Eye Disorders

Vasculitis of large- and medium-sized vessels asoccurs with TEMPORAL ARTERITIS (giant cell arteritis)can affect the artery supplying the retina and causesudden, irreversible blindness. Cataracts occur morecommonly in patients treated with corticosteroids.

eye problems 77

F

familial Mediterranean fever (FMF) An inher-ited disorder that causes acute attacks of fever,arthritis, pleurisy, and peritonitis. An illness char-acterized by paroxysmal peritonitis was firstdescribed by T. C. Janeway and H. O. Mosenthal in1908 and was termed periodic disease until the1950s, when the name familial Mediterraneanfever was used to describe the illness. FMF occursmost commonly in populations of Mediterraneanorigin such as Sephardic Jews, Arabs, Armenians,and Turks. It also occurs sporadically in individualsin other populations.

Cause

FMF is the first rheumatic disease for which a cleargenetic cause has been found. The gene responsiblefor FMF was cloned in 1997 and designated MEFV.In 1998, Eisenberg and colleagues reported threemutations in this gene that were found in manypatients with FMF. Subsequent work has shownthat five mutations, designated V762A, M694V,M694I, M680I, and E148Q, account for approxi-mately 75 percent of patients with FMF. Thesemutations likely derive from single individuals orfounders who lived long ago. Other mutations cancause FMF, and so far 29 mutations in the MEFVgene have been described. In American popula-tions in whom FMF is not endemic, not all themutations responsible for the illness have beenidentified. The ability to identify the genetic causesof FMF has enabled researchers to study popula-tions in whom the disease is common. In thesepopulations where about 1 in 500 people areaffected, the carrier rate for an abnormal MEFVgene is as high as one in six people. The high fre-quency of abnormal MEFV genes in healthy peoplehas led to the suggestion that it may impart a bio-logical survival advantage, but this is speculative.

The MEFV gene codes for a single protein namedboth pyrin and marenostrin by different researchgroups. This protein suppresses the inflammatoryresponses of granulocytes (polymorphonuclearwhite blood cells). Individuals with FMF producean abnormal protein that does not efficiently sup-press inflammation. It is not clear why some partsof the body such as the pleura and peritoneum areparticularly likely to be affected in people withFMF or what triggers acute attacks.

Symptoms

The onset of symptoms occurs before the age of 10years in 50 percent of patients, and only 5 percenthave their first attack after the age of 30 years.Attacks start suddenly and last one to four days.The frequency of attacks varies, but often theyoccur several months apart. As patients get olderthe frequency and severity of attacks tend todecline.

Fever occurs with every attack and is often sucha prominent symptom that it is not unusual for apatient to have been extensively evaluated forsevere recurrent fevers before the diagnosis of FMFis made. Another common symptom is abdominalpain, present in more than 90 percent of patients.The pain has features of peritonitis and can mimicother causes such as appendicitis. Again, it is notunusual for patients to have had emergencysurgery performed for suspected peritonitis beforethe diagnosis of FMF is made. Pleurisy occurs inmore than half of patients, but pericarditis is rare,affecting less than 1 percent. Arthritis occurs inmost patients and is typically acute and asymmet-rical, affecting large joints such as the knee, ankle,and wrist, often at the same time as the acuteattack. Arthritis resolves spontaneously and com-pletely. A less common, more chronic arthritis

79

affecting the sacroiliac joints has been described.Other symptoms include myalgia and a red rashthat resembles a bacterial infection of the skin, butlike the acute attack, these resolve spontaneously.

Diagnosis

Common laboratory tests are not helpful for mak-ing the diagnosis. During an acute attack, tests thatreflect inflammation such as the ESR, CRP, andwhite blood cell count are often raised (see Appen-dix II). The symptoms of FMF together with abnor-mal blood tests are often interpreted by physiciansas indicating the presence of a serious infection orsurgical problem in the abdomen. The correct diag-nosis is often not made until other causes for thesymptoms have been excluded. Genetic testing forthe common variants of the MEFV gene associatedwith FMF is now widely available and is helpful inmaking the diagnosis.


The most effective treatment is COLCHICINE, a drugthat prevents white blood cells from leaving thebloodstream to set up inflammation at the affectedsite. While taking colchicine more than 50 percentof patients have no further attacks, and in theremainder, the attacks are less frequent and severe.Colchicine also decreases the risk of AMYLOIDOSIS

and slows progression in patients who develop it. The most serious complication of FMF is AA

amyloidosis. This commonly affects the kidneysand causes protein to leak into the urine and kid-ney failure. The frequency of amyloidosis variesamong different ethnic groups. Preliminary evi-dence indicates that the different genetic variantsassociated with FMF impart different risks fordeveloping amyloidosis. The risk of amyloidosis indifferent populations is also affected by treatmentwith colchicine. Zemer and colleagues reportedtheir findings in a large series of 1,070 patients inIsrael and found that less than 2 percent of patientswho took colchicine regularly developed amyloido-sis compared with 50 percent who did not.

Felty’s syndrome Patients with RHEUMATOID

ARTHRITIS occasionally develop an enlarged spleenand an abnormally low white cell count (leukope-nia). This is known as Felty’s syndrome. It is quite

rare and occurs in less than 1 percent of patientswith rheumatoid arthritis. All Felty’s syndromepatients are positive for RHEUMATOID FACTOR.

Cause

The fact that Felty’s syndrome sometimes occurs inmembers of the same family suggests that there maybe genetic factors in its development. This is sup-ported by the very strong association with the HLA-DR4 gene (see GENETIC FACTORS). This association isstronger than with other rheumatoid arthritispatients. There is also an association with a gene thatresults in less-than-normal amounts of COMPLEMENT

factor 4 being produced. Different factors may bemore important in different patients with Felty’ssyndrome, but two main abnormalities are found inall patients to a degree. First, these patients havevery high levels of antibodies in the blood that stickboth to each other and to the surfaces of white cells.This has three effects on the white cells: They are lesseffective at attacking invading organisms; they tendto clump on the walls of the blood vessels ratherthan circulating in the blood as usual; they areremoved from the bloodstream and destroyed by thespleen, which enlarges as a result. Second, the bonemarrow does not respond to a low white cell countby producing many new cells as it would normally.

Symptoms

The arthritis may not be severe or even active atthe time Felty’s syndrome develops. It is always anerosive arthritis but in a third of patients is quies-cent when Felty’s syndrome starts. An enlargedspleen is necessary to make the diagnosis, but thiscan be difficult to detect early on. If suspected, anultrasound scan of the abdomen is a good way toshow splenic enlargement. The size of the spleendoes not predict the severity of the other problems.

Weight loss is common and may be marked. Legulcers are frequent and may be very difficult toheal. They are presumed to result from low-gradeVASCULITIS or inflammation along the blood vesselsof the legs. The most dangerous complication ofFelty’s syndrome is the frequent infections towhich these patients are prone. Infections aremostly with common organisms especially thosenormally found on human skin, and occur 10 to 20times more often in Felty’s patients than in other

80 Felty’s syndrome

rheumatoid arthritis patients. Mild anemia thatmay be due to more rapid breakdown of red bloodcells and a low platelet count are common.Platelets are small blood cells involved in the clot-ting of blood.

Diagnosis

Felty’s syndrome is diagnosed when a patient withrheumatoid factor-positive rheumatoid arthritisdevelops an enlarged spleen and a white cell countof less than 2000 cells/mL of blood. It should be dif-ferentiated from a low-grade leukemia of largegranular lymphocytes (a small subset of whiteblood cells), which can give rise to a very similarpicture. A quarter of these patients also haverheumatoid arthritis. These large granular lympho-cytes have a very typical appearance and, if sus-pected, can be recognized on examination of ablood sample or a bone marrow biopsy.


The arthritis should be treated along the usual linesfor rheumatoid arthritis. Often good control of therheumatoid inflammation will lead to a rise in thewhite cell count. Pulse intravenous CYCLOPHOS-

PHAMIDE is effective in healing ulcers but carries significant risks, especially in blunting the immuneresponse to infection. Growth factors such as granulocyte-macrophage colony-stimulating factor(GM-CSF) can dramatically increase the white cellcount and may be useful in managing overwhelm-ing infections but have no role in long-term treat-ment. Androgenic steroids (similar to testosterone)and drugs like lithium may also increase the whitecell count but do not have an established role intreatment.

Splenectomy (surgically removing the spleen) iseffective at raising the white cell count in allpatients. In a quarter, however, it will drop to lowlevels again. The anemia and low platelet countalso improve as do some leg ulcers. Splenectomyincreases the risk of infection with certain types ofbacteria. It is possible to vaccinate against some ofthese before removing the spleen, thereby givingpartial protection. Vaccines are available for Pneu-

mococcus, Haemophilus, and Meningococci. Splenec-tomy is generally used only in those with severedisease in whom other therapies are ineffective.

People with Felty’s syndrome have a shorter lifeexpectancy than others with rheumatoid arthritis.This usually results from infections.

fibromyalgia A syndrome characterized by wide-spread musculoskeletal pain, poor sleep, fatigue,and a number of tender points on physical exami-nation. A syndrome is a grouping of symptoms thatare characteristic enough to be used to describe agroup of patients. It does not imply a disease entity,although some syndromes subsequently becomeknown as diseases as more knowledge accumu-lates. This point is worth laboring because of theconsiderable debate still surrounding the termfibromyalgia. The debate is not about whether thepain and suffering are real but rather about whatfibromyalgia is and whether it should be separatedfrom other chronic pain syndromes. Surveys showthat between 1 and 2 percent of the population indeveloped countries fit current criteria forfibromyalgia. It is more common in Caucasians,and in women and there is a trend for patients tohave slightly higher-than-average social class.

Cause

There is no agreement on the cause, and there isunlikely any one specific cause. A proportion ofpatients describe a traumatic event of some sortbefore the symptoms first start. These includeinfections, accidents, emotional trauma, or corti-costeroid withdrawal. Women who have been sex-ually abused as children appear to be prone todeveloping chronic pain problems in later lifeincluding fibromyalgia. Five factors are believed toinfluence the development of this syndrome.

First, early studies suggested abnormalities inthe painful muscles, but more recent controlledstudies have shown these to be no different fromnormal individuals. There are differences in energyutilization and oxygen levels in the affected mus-cles, but it is not possible to say whether this is aprimary (causative) problem or simply the result ofmuscle deconditioning. More than 80 percent offibromyalgia patients are deconditioned or unfit bya variety of measurements. Deconditioned muscleis more likely to develop very small areas of traumathat result in pain. Because of this pain the muscleis not used normally, and reflexes in the brain may

fibromyalgia 81

actually reduce blood circulation in that muscle.Deconditioning therefore worsens, there is moreminor trauma to muscle fibers, and the conditionescalates. In keeping with this, nervous control ofblood flow to the hand has been shown to beabnormal in fibromyalgia patients, and this may bewhy some patients develop RAYNAUD’S PHENOMENON-like symptoms.

Second, although the absence of any recogniz-able disease might once have led people to think offibromyalgia as a psychological problem (“it is all inyour head”), this is no longer tenable. Indeed, thecomplex interaction and indivisibility of mind andbody mean that very few doctors would find thistype of thinking useful, although it may still beencountered in neighbors, workmates, and the like.There are, however, some clear psychological differ-ences when fibromyalgia patients are comparedwith healthy control groups (see CLINICAL TRIAL foran explanation of controlled studies). Fibromyalgiapatients have more psychological symptoms, and aquarter have clinical depression. About 50 percenthave had clinical depression at some time in thepast, and there is also more depression in their fam-ilies. There is no personality type, however. Differ-entiating whether the depression preceded thefibromyalgia or was in part caused by the chronicpain of fibromyalgia is difficult. Nevertheless, it isimportant that the fibromyalgia be identified andtreated appropriately.

Third, about 80 percent of fibromyalgia patientsreport that they awake in the morning not feelingrefreshed, and many will be aware of several night-time awakenings. By studying brain waves using anelectroencephalogram (EEG), it has been shownthat people with painful conditions have manymore wakings at night than they are aware of. EEGsshow that fibromyalgia patients have frequentinterruption of stage 3–4 sleep, which is believed tobe the most restorative. Normal individuals whohave their stage 3–4 sleep experimentally inter-rupted fairly soon develop fibromyalgia-like symp-toms. Furthermore, people with other conditionscharacterized by interrupted sleep patterns, such asthose with SLEEP APNEA, frequently developfibromyalgia. While disturbed sleep is likely impor-tant in the development and maintenance offibromyalgia, the manner in which it acts is

unknown and there remain unresolved difficultiesin some of the experimental findings.

Fourth, fibromyalgia is a chronic pain syn-drome, and there are physicochemical changes thatoccur in the pain-processing pathways in chronicpain. These changes occur in the nerves that carrysignals from skin, muscle, and joints to the spinalcord as well in areas in the spinal cord where theseinputs are processed. In the spinal cord there arenerve networks that allow interaction with mes-sages coming down the spinal cord that can eitherblock or encourage transmission of the peripheralsignals upward. It should be remembered that painis felt only if these signals reach the upper levels ofthe brain where people become conscious of pain.It is possible for the pain signals from very dramaticinjuries to be completely blocked for long periodsof time. There are many examples of this in sportand war situations. Initially in chronic pain theconstant bombardment of signals coming into thespinal cord produces changes in the ion channels ofnerve cells that make it easier for these signals to betransmitted. Later on there are probably perma-nent changes in these cells. Along with this is thespreading of nerve activity so that a wider area isfelt to be painful than was initially the case. Thesechanges are important in understanding the wide-spread pain and tenderness that can occur withstimuli that would not ordinarily cause pain.

In fibromyalgia, particular interest has focusedon high substance P levels in the CSF (fluid sur-rounding the brain and spinal cord) and low levelsof serotonin in the blood. Substance P stimulatesnerve endings that initiate pain impulses (i.e., itinduces a pain signal) and is also known to play arole in pain transmission in the spinal cord. Sero-tonin is a substance that is released by nerves inorder to stimulate other nerves (a neurotransmittersubstance). It also has important effects on bloodvessels. The systems in the brain that particularlyuse serotonin as a transmitter have to do withsleep, mood, and pain experience. Some studieshave suggested that levels may be low infibromyalgia patients as well as in depressedpatients.

Fifth, many patients who fulfill the diagnosticcriteria for fibromyalgia have segmental spinal dys-function. Simply put, this means there are areas

82 fibromyalgia

where two or more vertebrae have a restrictedrange of movement relative to each other in one ormore directions. This can result from many condi-tions, including a disc prolapse or protrusion,osteoarthritis of the spine, poor posture, obesity, orany injury or condition that results in asymmetri-cal spinal movement. People with segmental spinaldysfunction frequently develop changes in tissuesaway from the spine but in the affected segment(the areas supplied by nerves from that level of thespinal cord). The whole body is divided up intothese segments according to what level of thespinal cord the nerve supply comes from. If thespinal dysfunction is ongoing, they are at risk ofdeveloping a chronic pain syndrome.

Symptoms

Pain described as muscular or around joints is themost frequent complaint. Stiffness often occurs thattends to be worse in the mornings. The pain mayvary from day to day and is often made worse bystress, physical activity, poor sleep, and humidweather. Studies have shown that fibromyalgiapatients report pain as being similar in severity tothose with rheumatoid arthritis (pain is a private,subjective experience; there is no absolute measure)and that the effect on the household’s earning ca-pacity is nearly as bad as someone getting rheuma-toid arthritis. Patients frequently wake unrefreshed,and fatigue is a significant problem. Sleep is oftendisturbed even when the patient is unaware of it.This usually takes the form of frequent waking ornear waking after which the patient drops off tosleep again. Waking in the early hours of the morn-ing and not being able to get back to sleep again istypical of depression, not fibromyalgia.

Fibromyalgia patients often suffer from othercomplaints such as frequent headaches, peculiarfeelings in different parts of the body (such as tin-gling or burning in part of the hand), and a feelingof swelling, particularly of the hands (when noswelling can be seen). An increased sensitivity tocold and occasionally Raynaud’s phenomenon-likesymptoms occur. Dry eyes and mouth, palpitations,dizziness, difficulty in concentrating, and multipleallergies may occur. Anxiety is common. Moodswings and irritability occur. There is an overlapwith migraine and irritable bowel syndrome.

Although patients may feel weak, there is noactual loss of muscle strength other than mightoccur from reduced use. The characteristic findingsare numerous tender points mainly around theneck and shoulders but also around the hips andknees together with an absence of signs of otherdiseases that could cause the same symptoms.

Diagnosis

The American College of Rheumatology has issuedcriteria for the classification of fibromyalgia, andthese are widely used as the basis of diagnosis. Thepatient should have suffered widespread pain for atleast three months. Widespread means pain in bothleft and right side of the body, both above andbelow the waist, and relating to the spine. In addi-tion, there should be at least 11 out of 18 desig-nated points around the neck, shoulders, hips, andknees that are felt as painful when pressed on witha force of about 4 kg. In practice, not all these cri-teria need to be met at one time in order for thediagnosis to be made.

Blood tests, X rays, and scans are all normal infibromyalgia. Blood tests may be done to excludeother difficult-to-diagnose conditions that can giverise to widespread aching and fatigue. Such illnessesinclude POLYMYALGIA RHEUMATICA, reduced thyroidfunction, autoimmune forms of HEPATITIS, multiplesclerosis, and autoimmune forms of arthritis such asSYSTEMIC LUPUS ERYTHEMATOSUS. It is considered pos-sible to have fibromyalgia and another painful con-dition such as rheumatoid arthritis (then known assecondary fibromyalgia). As long as this other con-dition is recognized and treated appropriately, thentreatment of fibromyalgia can improve the patient’ssense of well-being. The danger lies in diagnosingfibromyalgia and not recognizing the presence ofthese other conditions (see also the related CHRONIC

FATIGUE SYNDROME). Many patients with fibromyal-gia will meet diagnostic criteria for chronic fatiguesyndrome and vice versa. Some patients with eitherof these conditions will also meet criteria for irrita-ble bowel syndrome and migraine.


Treatment is aimed at improving the contributingfactors discussed under Cause above. General com-monsense measures include avoiding sitting for

fibromyalgia 83

long periods, avoiding awkward postures, doingregular stretches, and taking a hot shower in themorning. All these can significantly prevent orrelieve the pain and stiffness. Patients should avoidoverexertion when they feel well since this is likelyto bring on a period of increased pain. More spe-cific treatment should be tailored to the individualpatient and might include the following.

• Education about the condition gives the patientsome understanding of what may have seemed astrange and frightening condition. It may alsoallay some of the fears people have such as end-ing up in a wheelchair or dying young. An un-derstanding of the state of the muscles andmusculoskeletal system is necessary before thepatient will work through the pain and fatigue toimprove matters. Relatives and significant othersshould also have a reasonable understanding ofthe condition. This is particularly importantbecause fibromyalgic patients look well and it is counterproductive if they constantly or fre-quently have to prove that they are suffering.Relatives and workmates should not, however,make a fuss over the patient unnecessarily andshould still expect him or her to contribute tofamily life or the workplace. Education mayinclude information about pacing activities andmini and micro rest techniques at work.

• Supervised general aerobic exercise has beenshown not only to improve fitness but also toreduce pain levels and improve the patient’s well-being. Unfortunately, unsupervised home exer-cise programs appear less successful, and manyfibromyalgia patients are reluctant to join groupexercise classes. The increase in pain after exer-cise is one reason that patients do not maintainregular exercise programs. They should startexercising slowly, do low-impact exercise, and tryto tolerate some increase in pain. Sleep does notappear to be improved by exercise. Specificstrengthening exercises and stretches to correctpostural problems and spinal dysfunction areimportant but have not been subjected to con-trolled study.

• Some evidence indicates that biofeedback, hyp-notherapy, and acupuncture all improve pain

and some other symptoms, although there arevery few controlled trials.

• Good evidence shows that COGNITIVE BEHA-

VIORAL THERAPY, either alone or as part of a mul-timodal pain therapy program, is effective inimproving fibromyalgic symptoms. In addition,self-management programs emphasizing eithercoping skills training or exercise provide benefitto some but not all patients.

• Many medications may be used. Most fibro-myalgia patients will have tried variouspainkillers such as ACETAMINOPHEN and NSAIDssuch as DICLOFENAC and IBUPROFEN and possiblyeven oral CORTICOSTEROIDS without much bene-fit. There does not appear to be any value inusing these medications long-term to managethe condition. However, most patients will findthem intermittently useful for headaches orflares of pain. Surveys show that fibromyalgiapatients find NSAIDs more helpful than pureanalgesics (painkillers).

The most commonly used medications are thoseto improve the quality of sleep. Low doses of tri-cyclic antidepressants such as amitriptyline,imipramine, and cyclobenzaprine have consistentlyshown improvements in sleep, pain, and generalwell-being in controlled trials. The tricyclics notonly promote stage 4 sleep but also act on painpathways. Not all patients benefit, however, andmany do not tolerate these medications even atlow doses. There is little information on the bene-fit of the newer antidepressants, and the benzodi-azepines should be avoided because of theiraddictive potential.

Ketamine works on the central pain mechanismsbelieved to be operative in chronic pain syndromes.It has been shown experimentally to relieve musclepain and referred pain as well as to lower pain sensitivity in fibromyalgia patients. Using ketamineas a regular medication is not possible, but thereis a lot of interest in developing a drug with similaractions that could be taken regularly.

Clinical depression should be treated in theusual way if present. Many fibromyalgia patientsare reluctant to consider the possibility that theymay be depressed. This probably reflects a societal

84 fibromyalgia

view that mental illness is somehow bad or evi-dence of weakness of character combined with arigid separation of mind and body. While neither ofthese views has any medical validity, they willlikely continue to be prevalent in society for sometime. Frank discussion between the clinician andpatient is the best way to bring these concerns outinto the open.

While fibromyalgia is not a life- or limb-threaten-ing condition, it is a long-term problem in manypatients. Over two-thirds of patients still have somesymptoms 10 years after diagnosis, and 10 to 20 per-cent receive disability payments at some timebecause of the fibromyalgia. For many patients,however, the symptoms are controllable and are at anuisance level rather than being disabling. Men andthose who are depressed or single tend to do lesswell. Children, in whom fibromyalgia is less com-mon, seem to do very well, with 75 percent havingfully recovered within 12 months in one study.

fibrositis See FIBROMYALGIA.

foot pain Since the feet bear the body’s entireweight, abnormalities and lesions, whether severeor minor, frequently cause pain and disability. Forproblems affecting the heel area, see HEEL PAIN andACHILLES TENDON. Many forms of inflammatoryarthritis such as RHEUMATOID ARTHRITIS, psoriaticarthritis (see PSORIASIS AND PSORIATIC ARTHRITIS),REACTIVE ARTHRITIS, SARCOIDOSIS, and GOUT affect theankle and foot, and these are discussed in the rele-vant sections. There is a considerable differencebetween adults and children as to the causes of footpain. This section will discuss foot pain under thefollowing headings:

Musculoskeletal foot pain in childrenMusculoskeletal foot pain in the adultNerve lesions causing foot pain

Musculoskeletal foot pain in children Footpain in children usually results from developmen-tal problems.

• Flat feet may be congenital (the child is born likethat) or acquired (it develops only after weightbearing is established at around two years of

age). Congenital flat feet may be flexible or rigid.Note that infants are naturally flat-footed andonly when this is severe is treatment required.Flexible flat feet are treated with exercises andinsoles that hold the feet in the correct positionuntil there is sufficient maturity and strength. Inseverely affected children, hinged casts that canbe easily applied and removed are used intermit-tently to promote soft tissue maturation in anappropriate position. While casts and insoles areuseful, they merely provide support. Only exer-cise will strengthen muscles sufficiently to holdthe correct position. Good exercises includewalking on tiptoes and picking up marbles andmoving them with the toes. The Achilles tendonmay need stretching to achieve a good foot posi-tion. Acquired flat feet in children are often amanifestation of HYPERMOBILITY. Treatment issimilar. Rigid flat feet are more difficult to treat.Here the heel bone (calcaneus) is semifixed in aturned-out position and the talus (the bone atthe heart of the ankle that acts as a universaljoint) points in and down, almost reversing thenormal arch along the inner border of the foot. Aseries of casts that progressively correct this mal-position are used. In severely affected children,though, some surgical correction is oftenrequired as well. Fusing of the affected joints(ARTHRODESIS) may be necessary later in life.

• Claw foot or pes cavus is the opposite of flat feet,with an exaggerated arch and sometimes a shortfoot. It is usually inherited but can also occur inother conditions such as polio, Friedreich’sataxia, and spina bifida. The foot is very stiff andtherefore has little shock-absorbing capacity.Athletes and people who do a lot of walkingtherefore frequently develop pain. Stretchingthe muscles that pull the toes up and wearingmodified shoes helps. It is also possible tolengthen the tissues that support the arch of thefoot while removing slices of bone to lower thearch toward normal surgically.

• Metatarsus varus refers to a condition in whichthe feet turn inward toward each other midwayalong the length of the foot. This can lead to anawkward gait and tripping. This should be dif-ferentiated from an intoeing gait, which may

foot pain 85

have many causes, and clubfeet. The diagnosis isbest made by a foot specialist. Mild degrees ofmetatarsus varus can sometimes be corrected bywearing the shoes on the opposite feet. Morecommonly, though, progressive corrective castsare required. Good results are obtained withearly treatment.

• Congenital clubfoot or talipes equinovarusoccurs in about one in 1,000 births and affectsboth feet in half the affected infants. The foot isturned in and down and the heel is also turnedin (unlike metatarsus varus above). It cannot bebrought up to 90° because of a very tightAchilles tendon. Gentle stretching followed bytaping or use of a cast is begun early and maycorrect the milder 30–40 percent. In those thatcannot be adequately corrected in this way,surgery is usually performed between three andsix months of age.

• Although tarsal coalition may cause a rigid flat-foot, it is usually unsuspected until it causes footpain in adult life. In tarsal coalition, a bony barlinks two of the mid- or hindfoot bones and doesnot allow any movement at that joint. This lossof movement causes increased stress on theother midfoot joints, which eventually give riseto pain. This commonly begins after someincreased stress such as weight gain or suddenincrease in the amount of walking or time spentstanding. The diagnosis is evident on plain X rayand in difficult cases can be confirmed by a CTscan. The bony bar can be removed surgically,but pain may continue because of establishedOSTEOARTHRITIS in the adjacent joints.

Musculoskeletal foot pain in the adult Mostmusculoskeletal foot pain that is not due to aninflammatory arthritis (see ARTHRITIS for classifica-tion) results from abnormal stresses on normal tissues, normal stresses on structurally abnormaltissues, or highly repetitive stresses on normal tissues.

• Acute foot strain may result from a sudden unac-customed increase in walking or other activity.This could include walking on unusually roughsurfaces or in poor footwear. The pain may arise

from muscles, ligaments, tendons, joint capsules,or a combination of these. Treatment, if required,is with rest, ice, massage, or NSAIDs. If the activ-ity is repeated before adequate recovery of thetissues, damage may occur and result in chronic(ongoing) foot strain. This not only takes longerfor the pain to subside but may lead to perma-nent alterations in the tissues and, in the longterm, osteoarthritis of the joints. An example ofchronic foot strain is PLANTAR FASCIITIS.

• Metatarsalgia refers to a condition in which painis felt under the balls of the feet. It is oftendescribed as walking barefoot on pebbles. Nor-mally most of the weight is borne on the ends ofthe first and fifth metatarsal bones (the bonyenlargements just before the toes start). The endsof the second, third, and fourth metatarsals forman arch between these two at toe off and there-fore do not normally take as much weight. Toeoff is that point in the stride just before the footleaves the ground when only the metatarsalheads and toes are in contact with the ground.However, if the arch flattens (splaying of thefoot), they then take as much weight as the firstand fifth but without as good padding as thesetwo. As a result they become painful anddevelop calluses. There are many reasons for thisanterior arch to flatten. The most common is lossof tone in the supporting muscles as people growolder, together with increasing weight. Alongwith the flattened arch the toes tend to ride upand become curved in shape (cock-up toes).Exercises to strengthen the small muscles of thefoot, weight loss, and orthoses to prevent theheel bone from turning out too much and to takethe pressure off the ends of the metatarsal bonesare all helpful. Surgery is useful in relieving painbut will not restore normal foot biomechanics.

• In hallux valgus the first metatarsal (the longerbone on the inner border of the foot that runsdown to the big toe) moves toward the other footand away from its neighboring metatarsals. As aresult the big toe deviates the other way, oftenpushing the second toe out of position. A bunionthen develops at the base of the big toe. The causeof this abnormality has been debated for sometime and there is still little agreement on it. Even

86 foot pain

if high-heeled shoes that constrict the toes are notthe cause, they will undoubtedly make a mildhallux valgus worse. Most patients are olderwomen with a broad front part of the foot and aflat arch. Many of these women will rememberdeviation of the big toe occurring when theywere quite young, but generally, they seek treat-ment only when the condition becomes painful.This is usually when BURSITIS develops over thebunion. If hallux valgus develops before the ageof 20 years, it should be treated prophylacticallyto prevent or delay progression. Appropriatefootwear is important, especially flat heels and abroad front end. Corrective insoles for the flatfoot are used, and splints that hold the foot in thedesired position can be worn at night. In olderpatients, molding the shoe to accommodate thebunion helps relieve pain. Many surgical proce-dures are established for hallux valgus that workreasonably well. Two of the commonly used onesare known as Keller’s and McBride’s procedures.Surgical correction is reasonably successful,although it does not restore normality and manypatients continue to have some pain and oftensome stiffness. It should be done for pain and dis-ability, therefore, not appearances.

• Bunions may develop anywhere there is exces-sive pressure against a person’s shoe. This iscommonly on the inside of the big toe associatedwith splaying of the foot or hallux valgus. Theyare also common on the outside of the base ofthe little toe where there is often an underlyingbursitis. This is known as a Tailor’s bunion fromthe days when tailors used to sit cross-legged.They can also result from poorly fitting shoes.Shoe modification and bunion pads are helpful.Surgical correction of the underlying bonyprominence may be indicated.

• Two small bones called sesamoids are found inthe tendons beneath the end of the firstmetatarsal bone. Inflammation can occur here,termed sesamoiditis. Temporary rest with a shoeinsert to relieve pressure is the usual treatment.Occasionally in resistant cases the sesamoid issurgically removed.

• Hallux rigidus refers to stiffness of the joint atthe base of the big toe such that it no longer

bends enough to allow normal walking. Thisusually results from osteoarthritis in older indi-viduals but can occur in younger people as aresult of trauma or following recurrent attacksof gout. If mild, the wearing of a stiff-soled shoerelieves pain. CORTICOSTEROID injection may givetemporary relief. If severe, surgery can be doneeither to fix the joint in a usable position (seeARTHRODESIS) or to put in a joint replacement.

• Morton’s syndrome describes a condition inwhich the first metatarsal bone is congenitallyshort. This is different from Morton’s neuralgia(see below). Morton’s syndrome causes prob-lems around the joint at the base of the secondtoe because the second metatarsal bone, beinglonger than the abnormal first, takes an unusualamount of weight and stress during walking andrunning.

• A march fracture is a STRESS FRACTURE of the sec-ond metatarsal bone. This occurs as a result ofoveruse stress, as for example new army recruitsmarching on the parade ground. Initial X raysmay be normal and should be repeated twoweeks later if the diagnosis is considered likely.Treatment is with initial immobilization andthen more gradual conditioning.

Nerve Lesions Causing Foot Pain

• Lesions in the lower spinal cord that irritate orpress on the L5 or S1 nerve roots can give rise topain in the foot. In young people, this is usuallydue to a lumbar disc prolapse and in older peo-ple to osteoarthritic changes in the lower spine(see BACK PAIN). Especially in younger peoplethere may be little or no back pain, and if thereis no muscle weakness, the foot pain can be bothpuzzling and distressing.

• The common peroneal nerve is a branch of thesciatic nerve that winds around the fibula bonejust below its head that can be felt as a bonyprominence just below the outside of the knee.Because the nerve is close to the skin here, it canbe easily damaged by trauma in this area. Thiscan cause pain over the top of the foot and frontof the ankle. However, there is usually clearcutweakness in raising the foot and turning it out-ward so the diagnosis is relatively easy. In addi-

foot pain 87

tion, numbness is more common than pain. Thenature of the trauma should also point to thediagnosis.

• The superficial peroneal nerve is a branch of thecommon peroneal. It can become trapped as itcomes up through the fascia in front of the ankleand cause a similar unpleasant burning pain onthe top of the foot. Because it supplies only rela-tively small muscles, the weakness is less obvi-ous. The diagnosis can therefore be puzzling. Theclue is that the web space of the big toe and theinside of the second toe are not affected sincethey are supplied by the deep peroneal nerve.

• The deep peroneal nerve (also called the ante-rior tibial nerve) enters the foot running acrossthe front of the ankle toward the inside. Here itpasses underneath a retinaculum known as thecruciate crural ligament, where it can becomecompressed. This is the equivalent of CARPAL

TUNNEL SYNDROME in the hand and is known asthe anterior tarsal tunnel syndrome. It causespain in the web space of the big toe and innersurface of the second toe. Runners, skiers,dancers, and people who repeatedly sprain theirankle are at particular risk.

• The posterior tibial nerve passes down andacross the inner surface of the ankle and heel

bone and is covered by a ligament. It canbecome compressed here and cause pain in thesole of the foot.

• The small nerves supplying sensation to the toes,the interdigital nerves, can become stretched bycock-up toes or suffer direct pressure, especiallyin patients with rheumatoid arthritis. Occasion-ally these nerves enlarge, and this is known asMorton’s neuroma.

• REFLEX SYMPATHETIC DYSTROPHY is a complex dis-order that most often affects the foot or hand.

frostbite Damage to peripheral tissues (especiallytoes, fingers, nose, and ears) caused by prolongedexposure to extreme cold. Frostbite affects theextremities, particularly the hands and feet. If theacute injury is severe, tissue death occurs and dig-its may need to be amputated. The cold injury canalso damage blood vessels and cartilage in joints,resulting in OSTEOARTHRITIS many years later. Theproblem of frostbite arthritis is a late complication.No treatment will alter the course if appliedbetween the cold injury and the development ofarthritis. Other than the usual treatments forosteoarthritis, no specific treatment is available forarthritis caused by frostbite.

88 frostbite

G

ganglion A small cystic lump found close to jointsor tendons. Ganglia occur more often in peoplewith arthritis but also occur in people with healthyjoints. Any type of arthritis, injury, or overuse isbelieved to increase the chances of developing aganglion. They occur most often in the area of thewrist and do not usually cause symptoms. Usually,a patient will report finding a small lump that feelsas if it contains fluid in the area of a wrist, ankle, orknee. Some ganglia can become painful if they arebumped or injured. However, most ganglia do notcause symptoms and many patients notice a gan-glion because they are concerned about the devel-opment of a new lump. Ganglia that have formedrecently feel soft and can be compressed like asmall balloon that is filled with water, but as theyage, they develop a thicker wall of fibrous tissueand feel much more solid.

Treatment

Some ganglia resolve by themselves or after theapplication of firm compression. Many ganglia donot cause symptoms and do not require specifictreatment. The traditional treatment for a ganglionwas to strike it firmly with a heavy book such asthe family Bible. As a consequence of this, gangliahave sometimes been called Bible cysts. A firm blowwill rupture a newly formed ganglion, causing theswelling to disappear when its mucus-like contentsescape into the surrounding tissues. However,many ganglia treated in this way recur. An alterna-tive treatment is for a physician to empty the cystby aspirating its contents through a needle. Again,recurrence is common. An injection of a CORTICO-

STEROID into the cyst after aspiration may decreasethe chances of recurrence. Ganglia that recur afterconservative treatment and cause symptoms mayrequire surgical removal.

genetic factors Most rheumatic problems arethought to have a genetic component. Some condi-tions such as FAMILIAL MEDITERRANEAN FEVER,

HEMOCHROMATOSIS, and HEMOPHILIA are entirely dueto a defined mutation in a single gene. For mostconditions, though, the genetic component is likelyto be smaller and to involve many genes.

The sequencing of the human genetic code(genome) has greatly increased the ability ofresearchers to identify genetic variability that maybe associated with an increased risk of disease. Thegenetic code of most humans is almost identical,but occasional changes result in the genetic differ-ences known to exist among individuals. Many ofthese changes are the result of single nucleotidepolymorphisms or SNPs (pronounced “snips”)—achange in one of the millions of bases that make upthe genetic code. Two common approaches havebeen used to identify genetic variations related todisease. The first is called a genome wide scan. Withthis technique, investigators have no preconceivedidea of which genes are likely to be involved butuse markers to screen the entire genome for differ-ences among affected and nonaffected people. Thegenome wide-scan approach requires a large num-ber of subjects and is more powerful if it is per-formed using affected and nonaffected members inthe same family. The second technique is called acandidate gene approach. This strategy examines vari-ability in genes that are thought to play a key rolein the cause of a disease. There are many largestudies using both of these approaches to identifygenetic variants that are important in rheumaticdiseases.

A strong association between the HLA-B27 tissuetype (see HLA), an inherited factor, and ANKYLOSING

SPONDYLITIS (AS) is well-known. Approximately 95percent of Caucasian patients with AS carry the

89

HLA-B27 gene. However, approximately 10 per-cent of healthy people also carry this gene and themajority do not develop AS. The implications ofthese observations are that the HLA-B27 geneincreases the risk of developing AS significantly,but other factors that have not been identified arealso required before the illness occurs.

Many rheumatic illnesses occur more frequentlyin some families, but for most, no reproduciblegenetic causes have been identified. Genetic varia-tion in the collagen gene has been associated witha rare familial type of OSTEOARTHRITIS, but thegenetic factors underlying the common form ofosteoarthritis in the general population are notclear. RHEUMATOID ARTHRITIS (RA) has been knownto be associated with HLA tissue types (DR4) sincethe 1970s. The risk of RA is increased fourfold inindividuals with HLA-DR4 tissue type (newnomenclature HLA-DRB1 0401, 0402, and so onfor the different variants of the 04 tissue type). Thestrength of the association varies in different popu-lations and has been weaker in African Americansthan in Caucasians. In SYSTEMIC LUPUS ERYTHEMATO-

SUS, several studies have reported associationsbetween SNPs in the gene coding for tumor necro-sis factor, but the association has been variable.

Considerable genetic variability occurs amongindividuals and populations affecting both the metab-olism and efficacy of drugs (see PHARMACOGENETICS).

German measles See RUBELLA.

giant cell arteritis See TEMPORAL ARTERITIS.

glucocorticoids See CORTICOSTEROIDS.

golfer’s elbow See EPICONDYLITIS.

Goodpasture’s syndrome This is a rare, life-threatening autoimmune illness that causes lunghemorrhage and kidney failure. Ernest W. Goodpas-ture (1886–1960) first described the illness in 1919when he was examining the lungs of patients whohad died in the 1918–19 influenza epidemic andnoted a new illness that affected the lungs and kid-neys of one patient. In 1958, almost 40 years later,M. C. Stanton and J. D. Tange attached the nameGoodpasture’s syndrome to an illness that causedsevere lung and kidney disease. In subsequent years

scientists discovered that Goodpasture’s syndromewas a unique illness caused by antibodies directedagainst a component of the kidney and lung. In ret-rospect, the original patient Goodpasture describedmay have had a systemic vasculitis affecting thelungs and kidneys rather than the autoimmune con-dition that now bears his name.

Goodpasture’s syndrome is rare, affecting aboutone person per million per year. It affects Cau-casians more than other races and men more oftenthan women. It can occur at any age but most oftenaffects people in their 30s.

Cause

Goodpasture’s syndrome is caused by antibodiesagainst type IV collagen, a component of the cellsthat line the lungs and the glomeruli of the kid-neys. The glomeruli are lined by a thin layer calledthe basement membrane that is rich in type IV col-lagen. Because it produces antibodies directedagainst the basement membrane, Goodpasture’ssyndrome is sometimes known as antiglomerularbasement membrane disease. The underlying causethat turns on the production of autoantibodies isnot known. In some patients the disease is pre-ceded by a respiratory tract infection or some otherillness that could damage the lungs. Often there isno preceding event, and no specific infectious ortoxic cause has been identified.

Symptoms

In most patients, symptoms start suddenly withcoughing, often producing blood-stained sputum,and shortness of breath. A chest X ray shows wide-spread shadowing. Hemorrhaging into the lungscan cause severe shortness of breath and thecoughing up of large amounts of blood. Lung hem-orrhage is more common in smokers. Kidney fail-ure can progress rapidly and cause symptoms ofnausea, fluid retention, and poor appetite. In mostpatients both the kidneys and the lungs areaffected, but in a few the lungs are spared. Bloodtests show an elevated creatinine concentration,indicating poor kidney function, and the urine usu-ally contains protein, blood, and cells.

Diagnosis

Several different illnesses, including WEGENER’S

GRANULOMATOSIS and SYSTEMIC LUPUS ERYTHEMATOSUS,

90 German measles

can cause sudden lung and kidney failure. Goodpas-ture’s syndrome is diagnosed from the clinical pic-ture and a positive blood test for antiglomerularbasement membrane antibodies. The test is positivein more than 95 percent of patients with Goodpas-ture’s syndrome. A tissue biopsy, most often fromthe kidney, is usually obtained to confirm the diag-nosis. The biopsy shows inflammation in andaround the glomeruli and deposits of antiglomerularbasement membrane antibodies.


Patients are often critically ill when the disease isdiagnosed and need aggressive therapy not only tosuppress the production of antibodies but also tosupport lung and kidney function. High doses ofCORTICOSTEROIDS combined with CYCLOPHOSPHAMIDE

are used to suppress the production of antibodies,and PLASMAPHERESIS is used to remove antibodiesfrom the bloodstream. Many patients require DIAL-

YSIS to support kidney function during the acutephase of the illness. If treatment is started earlythough, kidney function can recover and long-term dialysis be avoided.

Before effective treatment was available, Good-pasture’s syndrome was usually fatal. If treatment isstarted early, before kidney failure is established,more than 90 percent of patients survive. If severelung hemorrhage is present, oxygen transport fromthe air to the bloodstream in the lungs is oftendecreased and a patient may need to be treated in anintensive care unit on a ventilator (a machine thatbreathes for the patient). With time and immuno-suppressive therapy, lung function improves and thepatient can be weaned from the ventilator. If kidneyfailure has set in before treatment is started, kidneyfunction may not recover and the patient willrequire permanent dialysis.

gout Described by Hippocrates in 500 B.C., gout isone of the oldest forms of arthritis known. The uratecrystals that start an attack were discovered morethan 400 years ago. One of the medications still usedtoday, COLCHICINE, was isolated from its herbal ori-gins nearly 200 years ago. Once known as the “kingof diseases and disease of kings,” gout became asso-ciated with excessive eating and drinking. Althoughthere is some truth to this, there are many other rea-

sons that people get gout. About eight in every 1,000people suffer from gout, making it one of the morecommon forms of arthritis. This translates to 2.1 mil-lion people in the United States having gout, withmen being affected three times as often as women.

Uric acid is the final breakdown product ofpurines in humans. Purines are essential for man-ufacturing DNA and RNA and are therefore presentin all animal cells. Humans have higher uric acidlevels than most other animals because the animalsproduce an enzyme called uricase that breaks uricacid down further. Humans actually have the genefor uricase but have inactivated it at some stageduring evolution. Uric acid is a powerful antioxi-dant. It is believed that the uricase gene was inac-tivated because of the advantages of having apowerful antioxidant. Given the current enthusi-asm for taking antioxidants such as vitamin C andvitamin E as well as a host of others marketed ashealth supplements, it is interesting to look at howmuch trouble one of our natural inbuilt antioxi-dants has caused the human race.

Cause

Although hyperuricemia (high blood levels ofurate) is not the same as gout, it is the major riskfactor for gout. Generally speaking, anything thattends to raise the blood urate level is a risk factorfor gout. However, not everyone with raised uratelevels will get gout. About 95 percent of uric acid inthe blood combines with sodium to form moleculesof monosodium urate, which is much more solublethan uric acid in both blood and joints. Many peo-ple use the terms uric acid and urate interchange-ably. Although they have different chemicalstructures, for everyday purposes, it does not reallymatter. At levels up to about 0.35 mmol/L (5.8mg/dL) urate dissolves well in body fluids, and lev-els are similar in joints and blood most of the time.Above that level it can form a stable supersaturatedsolution. The higher the concentration, the morelikely it is to crystallize out of solution. When itcrystallizes out into joints and soft tissues, it mayinitiate an intense inflammation called gout. Theeasiest way to view the relationship between bloodurate levels and gout is to look at the risk of devel-oping gout in either one year or five years given acertain urate level as in the table on the next page.

gout 91

In males, there is a significant rise in urate lev-els at puberty. Although this rise is less marked inwomen, they have a further rise after menopause.Since most people probably have raised urate lev-els for 10 to 20 years before getting gout, this mayexplain the typical age of onset in men in their 30sand 40s and in women in their 60s.

Causes of hyperuricemia Either the formation oftoo much urate or not getting rid of it quicklyenough can lead to a buildup. Two-thirds of a per-son’s urate is eliminated in the urine. In most peo-ple there will be a variety of factors operating tocause significant hyperuricemia.

• Enzyme deficiencies can lead to overproductionof uric acid. The best-known one (that of anenzyme abbreviated as HGPRT) is extremely rareand when severe, also results in mental retarda-tion (the Lesch-Nyhan syndrome). Minor abnor-malities in this enzyme can cause high uric acidproduction without mental problems. Manyother enzyme abnormalities have recently beendiscovered, but at present these account for onlyan extremely small number of people with gout.People developing gout under the age of 20 yearsare very likely to have an enzyme abnormalitypredisposing them to hyperuricemia.

• Many Polynesian groups of people have geneti-cally determined hyperuricemia as well as fre-quent gout. Chinese and Filipino people livingtraditionally in their own lands have normalurate levels but are prone to hyperuricemia onmodern diets or when living in Western coun-tries. This is probably due to an interactionbetween diet and genetic makeup. Even in West-

ern populations the genetic contribution to theurate level has been calculated as 40 percent.

• Body bulk is the strongest predictor of uratelevel in the vast majority of people. This is truefor straightforward weight measurements aswell as for weight corrected for height. This isnot just related to dietary intake, because weightloss will actually increase the amount of uricacid passed in the urine.

• Dietary intake of foods high in purines is impor-tant (see later under Treatment and Outcome).Regular alcohol intake (not necessarily exces-sive) increases urate levels in a number of ways.It slows down uric acid excretion in the urine aswell as speeding up the breakdown of somepurines to form urate. In addition, beer containsa large amount of purine itself.

• Many drugs may increase urate levels. The mostcommon are the diuretics (water tablets), espe-cially the thiazides but also furosemide andbumetanide. Low-dose aspirin is now commonlyused for the prevention of heart disease and willslightly increase urate levels (although high doseslower it). Others include most cytotoxic (anti-cancer) drug regimens, levodopa, and the anti-tuberculous drugs ethambutol and pyrazinamide.

• Diseases such as PSORIASIS in which there is anincreased rate of cell turnover also lead to higherurate levels. An extreme degree of this happenswhen treatment for leukemia and lymphoma isbegun.

• Lead exposure can lead to kidney disease andhigh urate levels.

• Patients who have received an organ transplant,usually a kidney or heart, develop high urate

92 gout

RELATIONSHIP OF GOUT TO BLOOD URATE LEVELS IN MEN

Blood Urate Risk of Developing Gout

In One Year In Five Years

< 0.42mmol/L (7 mg/dL) <1 per 1,000 5 per 1,000

0.42–0.47 mmol/L (7–7.9 mg/dL) 1 per 1,000 6 per 1,000

0.48–0.53 mmol/L (8–8.9 mg/dL) 4 per 1,000 10 per 1,000

> 0.54 mmol/L (> 9.0 mg/dL) 49 per 1,000 220 per 1,000

levels, frequently get gout, and have particularproblems with its treatment.

Given a high urate level for many years, thereare many events that may precipitate an attack ofgout. These include any sudden illness, trauma(even minor), surgery, a large intake of alcohol orlarge purine-containing meal, or starting on one ofthe drugs listed above. Bleeding from the gut(which may be due to taking NSAIDs to settle theprevious attack) seems to be a particularly potentinitiator of gout.

Symptoms

Typically the patient awakes in the early hours ofthe morning with pain in the great toe, less com-monly the heel, ankle, or midfoot. This becomesprogressively worse and is often excruciating. Insevere attacks there may be fever and chills. Mostfirst attacks (90 percent) occur in the great toe. Thisis probably because of the frequent minor traumathis toe suffers as well as the fact that cold precipi-tates gout (the urate becomes less soluble) and feetare often the coolest part of the body. Only onejoint is affected in 90 percent of first attacks, but astime goes on, more and more joints are likely to beaffected during an attack. Somebody having a firstattack of gout has a 60 percent chance of havinganother within one year and a 90 percent chanceof having another within five years. Ankles, knees,and hands are commonly affected. Not all attacksare severe and may be put down to sprained anklesor bruised heels because they do not appear to be atypical gout attack.

Even if untreated, most attacks of gout will set-tle down after 10 to 14 days. Initially there are noabnormalities to see once the attack has settled.However, after years of gout with no treatment tolower the urate levels, it may become chronic; thatis, the gaps between attacks become shorter andshorter until it is continuous. When this happensthere are always many joints affected and it mayoccasionally look very like rheumatoid arthritis. Bythis time damage has occurred to the joints withloss of cartilage and cysts in the bone.

Tophi may also develop in longstanding gout.Tophi are collections of urate crystals that steadilygrow larger if the urate level remains high. If closeto the skin surface they may periodically break

open and discharge chalky, white material (theurate crystals). They may also cause pressuresymptoms on nerves and other deeper tissues. Thespine, heart, eyes, and voicebox are among theunusual places to be affected by tophi. Tophi sel-dom develop within 10 years of first developinggout and are becoming much less common withbetter treatment of hyperuricemia.

Gout may be difficult to diagnose when attacksare not typical. Women develop gout later thanmen (usually in their 60s), and it more frequentlyaffects more than one joint from the beginning. Inolder patients, attacks may be less severe but longerlasting, and frequently other forms of arthritis aresuspected. Gout has a tendency to develop in dam-aged joints and may not be suspected if these arejoints not commonly affected by gout. Gout in theshoulder and hip joints is particularly difficult todiagnose. Some people with OSTEOARTHRITIS of thehands develop gout there that causes intermittentpain and swelling that should be distinguishedfrom erosive osteoarthritis. In these situations thedanger is that the intermittent gout will acceleratethe damage to the joint if unrecognized. In severegout the joint is fiery red and hot, hugely swollen,and exquisitely painful. This is exactly what anacute joint infection looks like. In addition the suf-ferer is likely to have sweats and chills, and it is notsurprising, therefore, that they are frequentlytreated as infective arthritis initially.

High urate levels can lead to two kinds of kidneydisease, and these can occur in patients who havenot had gout as well. In the first, uric acid crystalsform in the small tubules of the kidney or theureters that drain urine from the kidney to thebladder and, often together with calcium crystals,form kidney stones. This can lead to intense pain(renal colic) as well as blockage of tubules orureter. In the second type, uric acid crystals form inthe tissues of the kidney and cause inflammationthere. These patients may go on to develop kidneyfailure.

A number of conditions are closely associatedwith gout and should be addressed or looked for aspart of the management plan:

Obesity Nearly 80 percent of people with goutare more than 10 percent overweight, and nearly60 percent are 30 percent overweight. Not only

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does this indicate a poor health outcome, butincreased weight has a direct effect on raising uratelevels.

Diabetes This association may simply bebecause of the obesity since there is some disagree-ment about the strength of the association in dif-ferent studies.

Hyperlipidemia A risk factor for heart disease,this is especially likely to be present in those whodrink alcohol. About 80 percent of gout patientshave hyperlipidemia.

Hypertension Approximately 30 percent ofgout patients are hypertensive, and nearly 30 per-cent of hypertensives have a high urate level.

Atherosclerosis Patients with gout developatherosclerotic problems (angina, heart attacks,strokes, and poor circulation to the legs) at ayounger age than others. However, the high uratelevels and gout do not cause this but probably acombination of the other associated conditionsmentioned above do.

Diagnosis

It is necessary to take fluid from a joint or materialfrom a tophus and see urate crystals under a po-larized-light microscope to diagnose gout defi-nitely. This not always possible, however, and intypical presentations not necessary. When the set-ting is not typical, however, every effort should bemade to find the crystals. In long-standing gout,the X rays show bony damage that is very typical ofgout and useful in the diagnosis.

The blood urate levels are not very useful inmaking the diagnosis during a sudden attack. First,many people with mildly raised urate levels willnever develop gout, and second 40 percent of peo-ple with acute gout will have a normal level duringthe attack. All of this second group will, however,have a raised urate level later on when the attackhas settled. Because the diagnosis may still some-times be difficult, the American College ofRheumatology has developed criteria for the diag-nosis that relies on at least three of 12 suggestivesymptoms, signs, and investigations being present.


There are several quite different aspects to thetreatment of gout:

• Treatment of the sudden painful attack of gout

• Prophylactic or preventative treatment of thegout

• Treatment to lower the urate levels

• Transplant gout

• Management of the associated conditions listedabove, which will not be discussed here

The acute attack Rest has been shown toshorten the sudden attack of gout. Cold compresseshelp relieve pain but do not shorten the attack.COLCHICINE has been used for 200 years and is stillan effective drug. The traditional high doses usedfor acute attacks are, however, not well toleratedmainly because of the severe diarrhea. In lowerdoses it also does not work as quickly as theNSAIDs and is therefore usually used only whenthese drugs cannot be used or for prophylaxis (seebelow). All the traditional NSAIDs work in gout.PHENYLBUTAZONE should not be used because of itssevere side effects, especially on the blood-formingparts of the bone marrow. INDOMETHACIN is oftenpreferred by gout patients because it is very power-ful. However, it also causes more side effects thanthe others. IBUPROFEN, DICLOFENAC, NAPROXEN, PIROX-

ICAM, tenoxicam, and SULINDAC have all been usedwith success. The most important factor in usingcolchicine or the NSAIDs is to take them as early aspossible in the attack. It is usual to start with a highdose and reduce it as the attack comes under con-trol. There is limited experience with the newerCOX-2 inhibitors, although one study with high-dose ROFECOXIB (Vioxx) shows that it is effective.

CORTICOSTEROIDS may be used when colchicineand the NSAIDs are contraindicated. They are mosteffective if injected directly into the affected jointbut can be taken orally as well. On average, anacute attack will get better in seven days. The morejoints involved, the longer before improvement.

Prophylactic treatment When there is a largeurate load in the body, urate-lowering therapy maytake some time to reduce this load sufficiently toprevent gout. The initial period of urate-loweringtherapy may also increase the frequency of attacksin a quarter of patients. For these reasons, manypatients are given prophylactic or preventativetreatment during the initial urate-lowering phase.

94 gout

Low-dose colchicine (one to two tablets a day) isvery effective, preventing attacks in 85 percent ofsuch patients. The NSAIDs may also be used. Typi-cally this therapy will be continued for six to 12months but possibly longer in those with numeroustophi. It is usual to continue this treatment until thepatient reaches the target urate level and remainsfree of attacks for three months at this level.

Urate-lowering treatment In severe or fre-quent gout or gout with complications, loweringthe urate level to less than 0.35 mmol/L (5.8mg/dL) is essential for good management. If thiscan be achieved, tophi will resolve and the risk of further attacks will be very small. There are drug and nondrug means to achieve this, and acombination of the two is usually required. Urate-lowering treatment has been shown to be cost-effective if an individual is having more than twoattacks of gout a year.

(a) Nondrug Urate-Lowering Therapy Weight losswill lower the urate level by 0.05 mmol/L (0.83mg/dL) for every 10 kg lost. It will also improve bloodpressure, diabetes, and hyperlipidemia if present. Alow-protein diet will reduce urate levels by 0.06mmol/L (1mg/dL). A high fluid intake assists urateloss in the urine and prevents kidney stone forma-tion. The urate-lowering effect is small, however.Reducing alcohol intake and giving up beer alto-gether is very effective at lowering urate levelsbecause of the mechanisms discussed under Causeabove. Avoiding foods high in purines should be partof every gout patient’s management plan. These arelisted below in three groups according to their purinecontent. The first two groups should be avoided alto-gether and the third eaten in moderation.

• Very high purines—heart, herring, meatextracts, mussels, yeast

• High purines—anchovies, bacon, liver, mutton,salmon, venison, wild fowl, cod, haddock

• Moderate purines—asparagus, brains, chicken,beef, eel, kidney beans, lentils, lima beans, lob-ster, mushroom, peas, spinach, oysters, otherfish, and meat products

(b) Drug Therapy ALLOPURINOL partially blocksthe enzyme that forms uric acid from xanthine.

This leads to higher levels of xanthines. However,these are more soluble than urate and do not causethe same problems. It is the most effective urate-lowering drug and is commonly used first whetherthe patient is forming too much urate or not get-ting rid of it quickly enough. It is important to startat low doses and slowly build up so as not to causeincreased attacks of gout during the early stages oftreatment (see Prophylactic Treatment above).Allopurinol is also used to treat patients about tostart chemotherapy for certain kinds of tumors(especially lymphomas and leukemias) since theycan get massive release of uric acid. Unfortunately,somewhere between 5 and 20 percent of patientsdevelop side effects on allopurinol that requiresstopping it. Allopurinol also interacts with severalother drugs, and patient and doctor need to beaware of these. This can be a particular problem intransplant patients.

If allopurinol is not tolerated, there are a num-ber of drugs that increase the amount of uric acidpassed in the urine. These are known as uricosuricdrugs. The most effective is benzbromarone, whichcauses a similar degree of urate lowering to allo-purinol. It is also a very useful drug in transplantpatients. Although used in Europe for many years,it is not available in the United States. PROBENECID

is somewhat less effective, although reasonablywell tolerated, with only 2 percent of patients stop-ping the drug because of side effects. It too has anumber of interactions with other drugs (mainly inblocking their excretion by the kidneys), which canlead to serious problems if not taken into account.SULFINPYRAZONE is probably more effective thanprobenecid, but more people have side effects withit. It also has an anticlotting effect by reducingplatelet function. This can be an advantage if some-one needs antiplatelet treatment because of heartdisease and the low-dose aspirin is being stoppedwhile the urate levels are being lowered. Onceurate levels are stable at the required level, low-dose aspirin can usually be restarted without anyproblems. Sulfinpyrazone and benzbromarone aremore effective than probenecid when there is poorkidney function.

Transplant gout Cyclosporine is used to pre-vent rejection in most transplant patients. Unfortu-nately, it causes high uric acid levels by altering

gout 95

blood flow through the kidneys, and many trans-plant patients get gout. There are several specialproblems in this situation. Allopurinol causes muchhigher-than-usual levels of AZATHIOPRINE, anothercommonly used transplant drug, and this combina-tion can lead to serious side effects. Colchicine veryrarely causes damage to nerves and muscles, butthis side effect becomes more frequent ifcyclosporine is also being used. In addition, some ofthe uricosuric drugs may not be effective if kidneyfunction is not adequate. Treatment of transplantgout is best undertaken in consultation with anexperienced rheumatologist. Some strategies toovercome these problems include:

• Reducing the dose of azathioprine to about athird and monitoring carefully when startingallopurinol

• Using urate oxidase to break uric acid down; thisneeds to be given into the veins once a monthand is still experimental

• Using MYCOPHENOLATE MOFETIL instead of aza-thioprine

• Using benzbromarone, which is an excellenturate-lowering drug in this situation

Gulf War syndrome A collection of symptomsoccurring in veterans of the Gulf War. In Januaryand February 1991, a coalition army led by theUnited States fought a war against Iraq. The warwas unusual in that the risk of exposure of soldiersto biological agents was thought to be high andbecause burning oil wells exposed soldiers to poten-tially toxic substances. Approximately 700,000 U.S.troops were deployed in the Gulf War. In January1992, reports appeared of an increased frequency ofunexplained, unusual illnesses in soldiers who hadreturned. The term Gulf War syndrome appeared tocome into usage more as a result of media attentionthan scientific definition of a unique constellationof symptoms that constituted a new syndrome.Much research has focused on the question ofwhether Gulf War syndrome exists as a unique ill-ness. Although the answers are not clear, theweight of scientific evidence does not indicate theexistence of a unique syndrome or illness.

Cause

The cause of Gulf War syndrome is not known.There are several conflicting opinions that can bedivided into three main camps.

First, Gulf War syndrome does not exist as a dis-crete entity and was created by the media, notmedical evidence. The term syndrome implies aunique grouping of symptoms, but no such group-ing has been found in Gulf War veterans. In moststudies of U.S., U.K., and Canadian soldiers, almostevery symptom studied occurred more frequentlyin veterans of the Gulf War than in soldiers whowere not deployed. There was no unique pattern tothe increased symptoms. Opponents of this posi-tion argue that the word syndrome is a semanticdefinition and that the absence of a defined syn-drome does not imply the absence of illness.Renaming the condition Gulf War illness wouldovercome the inability of researchers to definereproducibly a clear syndrome. However, the termillness also requires a definition, something thathas been difficult to establish.

Second, Gulf War syndrome is a poorly definedentity that is caused by psychological stress. Simi-lar syndromes have been reported after manywars and was variously named shell shock, sol-dier’s heart, and neurasthenia. The level of psy-chological stress resulting from the Gulf War maynot have been as great as in previous wars if oneconsiders the duration and intensity of fighting orthe numbers of casualties; however, the type ofstress was different. The risk of exposure to biological or chemical weapons was greater andmay have resulted in prolonged anxiety and psychological stress, particularly in those peoplewho believed they were exposed to harmful sub-stances.

Third, Gulf War syndrome was caused by expo-sure to infectious or toxic substances, either aloneor in combination. Several candidates have beenproposed and studied. There is no reproduciblerelationship between exposure to depleted ura-nium, smoke from oil fires, vaccines, insecticides,and chemicals such as pyridostigmine that wereused to protect against nerve gas and risk of devel-oping Gulf War illness. However, many studies,particularly those examining the role of multiple

96 Gulf War syndrome

vaccinations and exposure to potentially harmfulagents, are ongoing. No infectious agent has repro-ducibly been associated with the illness. Someresearchers reported finding an atypical myco-plasma and clinical response to treatment with anantibiotic, doxycyline, but others found no evi-dence of infection. Clinical trials with doxycyclineare being conducted.

Symptoms

Many symptoms have been reported, but the mostcommon are fatigue, poor memory, myalgia, arthral-gia, diarrhea, rash, weakness, and neuropathy.Many of the symptoms overlap with FIBROMYALGIA

and CHRONIC FATIGUE SYNDROME, and some patientsfulfill diagnostic criteria for these conditions.

Diagnosis

No diagnostic laboratory test is helpful. Laboratorytests are usually normal. The diagnosis was usuallyapplied to veterans of the Gulf War who developed

symptoms that were not explained by anothermedical diagnosis.


No specific treatment is available for Gulf War syn-drome. Treatment is symptomatic and similar to thatprescribed for fibromyalgia. Low doses of antidepres-sants are used to improve sleep and decrease fatigue.Clinicians often prescribe COGNITIVE BEHAVIORAL

THERAPY and EXERCISE. These treatments have beenfound to be effective in fibromyalgia. A large, ran-domized study of the efficacy of these interventionsin Gulf War syndrome is underway.

Veterans with Gulf War syndrome report moresymptoms and a poorer quality of life than thosewho were not affected. Studies that have examineddeaths and hospitalizations in Gulf War veteransand the frequency of birth abnormalities in theirchildren have found an increased risk of deathfrom accidents but no indications of more frequentcomplications of medical illnesses.

Gulf War syndrome 97

H

heat A therapy used to alleviate musculoskeletalsymptoms. Physical therapy often involves the appli-cation of heat or cold (see ICE) to relieve symptomsand improve function. Patients with inflammatoryarthritis often suffer from stiffness and decreasedmobility that is particularly severe in the morningafter arising and then slowly improves during theday. Many have noticed that these symptomsimprove more rapidly if they take a hot bath orshower. It is not known how heat relieves arthritissymptoms, but it increases blood flow in tissues. Thiscould either wash out chemicals that cause inflam-mation or, alternatively, deliver chemicals thatoppose inflammation. Some of the beneficial effectsof heat may occur because it changes the painthreshold. Heat and pain messages are transmittedthrough different nerve fibers, but traffic in onegroup of nerves could decrease transmissionthrough others. Also, if the sensation of superficialheat is strong, it can distract the brain from process-ing pain messages from joints. Heat could also act onmuscles and connective tissue to make them moreflexible. Superficial heat can be applied using hotwater, heating pads, or paraffin or wax baths. Heatthat reaches the deeper tissues is applied by a phys-ical therapist using ultrasound. Local application ofheat causes few side effects unless the temperature istoo hot or heat is applied for a long time, in whichcase burns can result. In most patients the painfulsensation caused by excessive heat prevents thisfrom happening. However, patients with nerve dam-age, such as peripheral neuropathy that decreasestheir ability to feel heat and pain, may sustain burnsby applying excessive heat without being aware of it.Regular application of heat such as hot-water bottlesto an area can lead to a mottled reddish brown dis-coloration of the skin known as erythema ab ignewithout actually causing a painful burn.

heel pain The heel is the first part of the body tostrike the ground while walking and, during slowor moderate speed running, does so with a forceseveral times that of the individual’s weight. Giventhese large forces operating on the heel, it is per-haps surprising that heel pain is not more common.However, sophisticated biomechanical factors areoperating to reduce the stress of foot impact on theground. These include movements of the pelvis,hips, knee, and rotation of the tibia (shinbone) thatsmooth out the gait. These will not be discussedhere. However, if their function is disturbed for anyreason, the stresses at the heel and ankle may begreatly increased and therefore more likely to giverise to painful conditions. The heel bone (calca-neus) itself has a special protective pad (see belowunder Painful Heel Pad), and the foot has a com-plex mechanism to help absorb the impact (seebelow under Plantar fasciitis). Needless to say, apainful heel will dramatically affect walking orrunning. The important causes of heel pain are dis-cussed below.

Plantar fasciitis This is the most commoncause of heel pain. People usually complain of painunderneath the foot just in front of the calcaneus(heel bone). The pain often comes on after unac-customed standing, walking, or athletic activity. Itis more common in the overweight and in thosewith flat feet.

Shortly after the heel strikes the ground in nor-mal walking, the foot goes into pronation to absorbthe force of impact. Pronation involves a looseningof the joints of the midfoot so there is more give,the arch of the foot drops and there is a slight turn-ing out of the forefoot while the calcaneus itselftilts over to the inside and dips its nose down. Thisresults in the force of impact and weight bearingbeing spread through a number of bones, joints,

99

ligaments, and muscles rather than just in a directline through the heel to the ground. One of theimportant structures in this mechanism is the plan-tar fascia. This is a tough, flat, fibrous tissue thatspans from the front lower edge of the calcaneus tothe base of the toes, supporting the long arch of thefoot like an unusually wide bowstring. It also sendsfurther slips along the toes that serve to tighten theplantar fascia when the toes are curled up (as whentaking off from that foot). As the foot goes intopronation, the long arch tends to collapse slightlyand the plantar fascia is stretched and stressed. Thisis a normal event. However, if the stresses are sud-denly increased by, for example, rapid weight gainor a large increase in the distance walked,microtears can develop in the plantar fascia. Thisresults in small areas of inflammation that canaccumulate and cause pain. This commonly affectsthe middle section of the plantar fascia or itsattachment to the calcaneus.

A similar process can occur with normal or min-imal stresses if the structures themselves are abnor-mal. This can occur in patients with inflammatoryarthritis such as RHEUMATOID ARTHRITIS who areprone to develop overpronation, or in people whoare naturally flat-footed. Patients with SPONDY-

LOARTHROPATHIES are also prone to develop inflam-mation at the attachment of the plantar fascia tothe calcaneus with relatively little stress.

Typically the pain is felt on walking or prolongedstanding and is worse after a rest or first thing inthe morning, easing a bit with continued activity.Tenderness can be produced by pressing on thefront end of the calcaneus toward the inner borderof the sole or toward the middle of the long arch ofthe foot. Pain will also be felt when the toes arepulled upward since this tightens the plantar fascia.X ray may show a HEEL SPUR, but this seldom affectstreatment.

Relieving the pressure over the attachment ofthe plantar fascia may improve pain on walking,especially if there is a spur. This is achieved byusing a heel pad either with a cutout below thetender area or a softer gel material in this area.However, this does not address the cause. Sincepronation is an important factor in most cases, aninsole that supports the long arch along the innerborder of the foot and acts to limit pronation is

often used. This can be combined with a pressure-relieving cutout. Weight loss and appropriatefootwear are important for some people. Injectionof a local anaesthetic and CORTICOSTEROID aroundthe attachment of the plantar fascia is helpful insettling down the inflammation quickly.

Subcalcaneal bursitis This may cause pain inthe same area as plantar fasciitis or heel spurs. Itdiffers from plantar fasciitis in that pulling the toesup does not make the pain worse. BURSITIS orinflammation of the bursa below the calcaneususually happens in older people following trauma(falls, prolonged walking, or badly fitting shoes).

Painful heel pad The thick elastic pad beneaththe calcaneus acts as a shock absorber. This is madeup of fatty and elastic tissues separated into numer-ous cells by tough, fibrous sheets. These maybecome damaged and sometimes burst, either bysevere trauma as when falling from a height or byrepetitive minor trauma as occurs in elderly over-weight individuals or martial arts practitioners.Treatment is by using a heel pad with or withoutraising the heel in order to shift weight forwardinto the foot. An injection of local anaesthetic canrelieve pain in severe cases. It is usually a short-lived condition.

Dupuytren’s contracture An exactly similarcondition to the DUPUYTREN’S CONTRACTURE seen inthe hand may affect the plantar fascia. It may beinherited and is also related to alcohol intake,epilepsy, and diabetes. The nodules are easily feltbeneath the skin, and treatment is similar to that ofthe hand.

Posterior calcaneal bursitis This bursitis affectsmainly women who wear high-heeled or narrow-counter shoes or people who play sport in inappro-priate footwear. The red swollen bursa may be seenbelow the skin surface behind the heel. Treatmentis to avoid the offending shoe. A triangle can be cutout of the counter of an old shoe to be worn untilthe bursitis has healed. Aspiration and injection ofa small amount of corticosteroid may be used inresistant cases.

Calcaneal apophysitis (Sever’s disease) This is apainful condition of the back of the heel usuallyaffecting active boys between the ages of eight and13 years. In growing children most of the bones ofthe body have large areas of cartilage that have yet

100 heel pain

to be converted to bone. This involves a gradualspreading of bone from both the middle of the boneand one or more areas near the ends of the bone, thesecondary epiphyses. The cartilaginous area wherethese two bone centers have not yet joined (the epi-physis) can become injured by the pull of a powerfultendon. In Sever’s disease, the epiphysis just belowthe attachment of the ACHILLES TENDON is involved. Itbecomes tender, mildly swollen, and causes painwhen standing on tiptoes or jumping. Only one sideis usually involved, but it may affect both sides.

Radioisotope bone scans will show up the areaas hot, and MRI scans can confirm the diagnosis. X rays will show differences between the two sideslater on. However, the diagnosis can be made clin-ically without these investigations. Treatment is toavoid activities that involve powerful contractionof the calf muscles such as sport and outdoor play.This can be difficult to achieve with young boys,and a slight heel raise is helpful in reducingAchilles strain. If very severe, crutches can be usedor an above-knee walking plaster applied for aperiod. Once the inflammation has settled, recov-ery is complete.

Subtalar arthritis The talus is an importantbone in the ankle that has a joint above with the twolower leg bones, two joints below with the calcaneusor heel bone, and in front with the bones of the mid-foot. Arthritis affecting its two joints with the calca-neus causes pain felt deep inside the heel. Whensevere this can cause disabling pain on walking. Itmay occur after significant trauma to the ankle andis a complication particularly of RHEUMATOID ARTHRI-

TIS and JUVENILE ARTHRITIS. If the foot is brought upwith the toes toward the head, the talus is locked inplace and the calcaneus can then be moved fromside to side to test this joint. This movement will bepainful in subtalar arthritis, and there will usually betenderness on the outside of the ankle just in frontof the prominent bone there, the lateral malleolus.Treatment is with relative rest and NSAIDs. Injectionof local anaesthetic and corticosteroid into the jointgives temporary relief. Molded orthotics may helplong term. When very severe an ARTHRODESIS willrelieve pain but reduce walking ability.

Calcaneal fractures The calcaneus or heelbone is strong and fractures only with considerableforce or when an individual’s bone is generally

weak, as might be found in OSTEOPOROSIS. Fracturesusually result from a fall from height onto the feet.Just over half the people suffering this fracturehave a good outcome. Surgical fixation of the frac-ture probably gives slightly better results than con-servative management. The outcome tends to beworse if the fracture involves the subtalar joint (seeSubtalar Arthritis above). Early range of motionexercises and non-weight-bearing for eight to 12weeks is important for a good recovery.

Pump bumps These are firm swellings near theattachment of the Achilles tendon. They are bonyenlargements on the calcaneus associated withwearing high-heeled shoes or other shoes with atightly fitting heel counter. They are usually pain-less unless there is an overlying bursitis.

Achilles bursitis Bursitis can occur betweenthe skin and the Achilles attachment at the heel orbetween the Achilles and the heel bone. Whenboots are worn and the bursitis is ongoing, it isknown as winter’s heel.

Rheumatoid nodules These are found on theAchilles tendon one or two inches up from its bonyattachment. They are intermittently painful, andtreatment is to prevent shoes from rubbing againstthe nodules either by use of padding or by wearingdifferent shoes.

Black heel Occasionally athletic teenagers oryoung adults develop a bluish black area under-neath the back of the heel. The shearing forces ofvigorous running and jumping cause minor bleed-ing into the skin, giving this appearance. No treat-ment is necessary. (See also ACHILLES TENDON.)

heel spur A spur is a small bony outgrowth thatoccurs where a tendon or ligament attaches to abone. This is commonly as a result of inflammationat that site (termed an enthesis) and may representa healing phase. The lower front edge of the heelbone or calcaneus is a common site for spurs toform. These usually develop because of plantarfasciitis (see HEEL PAIN). In ANKYLOSING SPONDYLITIS,

associated SPONDYLOARTHROPATHIES, and ACHILLES

tendinopathies, a spur may form at the back of theheel pointing up the leg. The heel spur by itself isseldom painful. When there is pain it is usually dueto the associated plantar fasciitis or enthesitis or anunrelated but nearby condition. However, if the

heel spur 101

biomechanics of the foot alters, with, for example,a lowering of the long arch of the foot, the alteredangle of the spur in relation to the foot and plantarfascia may set up inflammation and pain.

Treatment of a spur behind the heel may involvea local CORTICOSTEROID injection to reduce theinflammation and padding or alternative footwearto relieve the pressure until healed. The plantarspurs from the lower calcaneus are subject togreater pressures, and treatment is much the sameas for plantar fasciitis. Occasionally these spurs aresurgically removed together with release of theplantar fascia when there is a poor response toother treatments.

hemarthrosis Bleeding into a joint that causespain and swelling. There is often significant inflam-mation leading to pain, warmth, redness, and ten-derness. Depending on the cause, it will usuallysettle within a few weeks. Aspiration to remove asmuch blood as possible will speed resolution. Incases that do not resolve adequately, ARTHROSCOPY

may be done to wash out the joint thoroughly andpossibly remove inflamed synovium. The manycauses of hemarthrosis include HEMOPHILIA, heman-gioma (a benign tumor of the synovial joint lining),scurvy (vitamin C deficiency), trauma causing frac-ture or ligament rupture, surgery, leukemia andmalignant tumors of the adjacent bone, GOUT andCPPD, anticoagulant therapy, and PIGMENTED VILLON-

ODULAR SYNOVITIS.

hemochromatosis This is usually an inheriteddisease that leads to excessive buildup of iron in thebody and damage to a number of organs. A famousGerman pathologist, F. D. von Recklinghausen,described the disease in 1889, but it was only in1927 that Sheldon suggested it was due to aninborn error of metabolism. It was finally proven tobe genetically linked in 1975. The nature of thetwo most common abnormalities leading to hered-itary hemochromatosis (HHC) was discovered onlyas recently as 1996. This discovery by Feder and hiscoworkers has lead to an explosion of research andknowledge about the disease and huge benefit tocarriers of the abnormal gene.

The disease is most common in northwesternEurope and in populations that have migrated from

there. Between three and five people in every 1,000of such a population have the disease. It is thereforeone of the most common genetic diseases. Unlikemany hereditary diseases, it is relatively simple totreat in the early stages, and therefore early diagno-sis is crucial. Occasionally certain unrelated diseasescan lead to iron overload, which causes problemssimilar to the inherited disease.

Cause

Iron is both essential for the normal functioning ofthe human body and a poison in excess. Since ironis all around us, we have developed mechanismsfor keeping excess iron out of our bodies. In thissense the gut contents are outside of our bodies.The cells lining our gut are continually beingturned over. That is, they are lost into the gut asthey get older and replaced by new cells. The newcells start at the bottom of little folds in the gut wallcalled crypts and move toward the top, where theirfunction is to absorb all the nutrients we need. Asthey are being formed at the bottom of the crypts,they are programmed as to how much iron toabsorb according to the body’s iron need at thetime. This programming is achieved by altering theamount of a protein known as HFE. The more HFEprotein produced, the less iron absorbed. HFEtherefore acts to keep iron out of the body.

More than 90 percent of patients with HHC willhave two copies of a mutated (changed) gene thatcodes for the HFE protein (i.e., these genes carrythe information each cell needs in order to makethe protein). Since people normally inherit onegene from each parent, patients actually have tohave two mutated genes to be unable to make thenormal protein. The mutations are very minor dif-ferences but clearly alter the protein’s functionquite dramatically. The most common mutation isknown in shorthand as C282Y and the other asH63D. Some people have one copy of C282Y andone of H63D, and a proportion of them can alsodevelop the disease. The abnormal protein allowsexcessive amounts of iron to enter the bloodstreamand become stored throughout the body. An adultman needs to absorb about 1 mg of iron a day anda woman about 1.5 mg to remain healthy. TypicallyHHC patients absorb two to three times as muchiron as other people, i.e., 4 mg a day. After many

102 hemarthrosis

years the iron load can become enough to interferewith the function of a number of organs.

Because of a property of genes known as incom-plete penetrance, not everyone with two C282Ygenes will develop the disease. An even smallerpercentage of those with two H63D genes or oneC282Y plus one H63D gene will do so. A very smallnumber of patients with HHC will have neither ofthese mutations (and therefore presumably have asyet undiscovered mutations). One such disordercauses iron overload in children and is known asjuvenile hemochromatosis.

Many number of other diseases can lead to ironoverload without any known genetic tendency tooverabsorb iron. Black Africans who drink a tradi-tional beer brewed in nongalvanized iron potssometimes develop iron overload. This condition,previously known as Bantu siderosis, is especiallyseen in southern Africa, but a similar condition hasbeen rarely reported in African Americans. Becauseonly a minority of such beer drinkers are affected, itis thought that there is some as yet undiscoveredgenetic tendency involved as well as the high dietaryiron load. Blood contains a lot of iron, and patientsrequiring regular blood transfusions over a longperiod of time will develop iron overload as a result.This includes patients with severe thalassemia, com-plicated sickle-cell anemia (see SICKLE-CELL DISEASE),bone marrow failure, or following aggressive treat-ment of cancer. The pattern of iron loading in allthese patients is different than that in HHC, but theresulting organ damage is much the same.

Symptoms

Many years of iron accumulation are required tocause symptoms, and these usually start betweenthe ages of 40 and 60 years. This varies considerablyamong patients, however. Women tend to developproblems later than men because they lose modestamounts of iron with regular menstruation. Thesudden increase in iron accumulation aftermenopause probably causes the characteristic devel-opment of symptoms in women a few years aftermenopause. Liver and joint problems are common,together with weakness, tiredness, reduced sexualdrive, and skin discoloration. Heart failure, diabetes,and other hormone abnormalities tend to occurlater. The disease can be divided into four stages.

• Stage I is when someone is diagnosed as havingthe genetic predisposition to the disease. He orshe is perfectly healthy and may never developproblems related to HHC. However, there willstill be concerns related to screening other fam-ily members and getting insurance.

• Stage II is when iron stores reach two to fivetimes normal and blood tests begin to show ironoverload, although the patient still has no symp-toms. These stage II patients need regular bloodmonitoring, and some will need treatment.

• Stage III is when symptoms due to iron overloadstart.

• Stage IV is when one or more organs (usuallythe liver) have developed irreversible damage.

The liver is usually affected first and will beenlarged in most symptomatic patients. Blood testsof liver function may not be abnormal until verylate in the disease. Loss of body hair, blotchy red-ness of the palms, smaller testicles, and increasedbreast size in men can occur. Cirrhosis (widespreadand irreversible scarring of the liver) will developin the long term. This can lead to bleeding from theesophagus (gullet) due to high pressure in theveins taking blood to the liver. Of patients with cir-rhosis, 30 percent will develop cancer of the liver.These complications can be largely avoided by earlytreatment.

The joint disease is a form of OSTEOARTHRITIS

coming on prematurely. It typically affects the sec-ond and third metacarpophalangeal joints (andsometimes proximal interphalangeal joints) thatare seldom affected in the usual type of osteoarthri-tis. Wrists, shoulders, hips, knees, and ankles arealso affected. Some patients have an unusuallydestructive form of osteoarthritis. HHC is also oneof the possible underlying causes of CPPD duringwhich there may be episodes of quite intense jointinflammation. Unlike many of the other complica-tions of HHC, the joint disease is not muchimproved by treatment. The osteoarthritis in par-ticular progresses regardless of treatment once ithas developed.

Darkening of the skin used to be quite commonbut is becoming less so with the earlier diagnosis ofHHC following the development of genetic testing.

hemochromatosis 103

DIABETES MELLITUS used to affect 65 percent ofpatients but again should become increasingly pre-ventable with early diagnosis. Involvement of theheart occurs in 10–15 percent of symptomaticpatients and usually causes heart failure. The heartenlarges and abnormal rhythms (which may belife-threatening) are particularly common. Heartfailure is more common and develops earlier in thehemochromatosis caused by repeated blood trans-fusions.

Lower sex hormone production can occur inboth sexes. This may cause loss of body hair, low-ered sex drive, impotence, loss of menstrual peri-ods, and smaller testicles. Very occasionally theremay be dysfunction of the adrenal, thyroid, orparathyroid glands, all of which produce importanthormones. Patients with hemochromatosis are alsounusually prone to getting certain infections. Theseinclude Vibrio vulnificus, Listeria monocytogenes,

Yersinia enterocolitica, Salmonella sp., Klebsiella pneu-

moniae, Escherichia coli, and Rhizopus infections.

Diagnosis

The most important step is considering the diagno-sis. This is both because the onset of symptoms isusually very slow and subtle and because the vari-ous manifestations may be diagnosed as diseasesthemselves (osteoarthritis, diabetes, cirrhosis of theliver, etc.) without realizing that there is an under-lying disease causing these problems. Once sus-pected, confirming the diagnosis is easy. Iron iscarried around the body by a carrier protein calledtransferrin. The percentage saturation of transfer-rin can be measured. This rises with rising bodyiron, and levels over 55 percent in woman and 60percent in men strongly suggest iron overload. Fer-ritin is a protein involved in iron storage, and lev-els rise with iron overload although somewhatlater than transferrin saturation. In someone withHHC, the transferrin saturation will typically risebetween the ages of 20 and 30 and ferritin will risebetween 30 and 40 with symptoms beginning afterage 40. This is quite variable, however. Confirmingwhether someone carries one or both of the C282Yand H63D mutations has now become relativelysimple with a blood test. Thus stage I and II HHCcan be diagnosed with these three blood tests.Transferrin levels are less reliable in detecting theiron overload due to repeated blood transfusions.

Ferritin levels are a reasonable indicator in this sit-uation, but liver biopsy is still the most accuratemeasurement.

A liver biopsy has been the traditional way toconfirm iron overload and is still required to showthe degree of damage to the liver. This involvespassing a hollow needle into the liver and remov-ing it quickly with a core of liver tissue. There is avery small but measurable chance of bleeding afterthis, and it is not infrequently uncomfortable orpainful. It is therefore done less frequently nowthat improved blood tests are available. Sophisti-cated CT and MRI scanners can also measure theamount of iron in the liver, but this capability is notyet widespread.

Further tests may then need to be done to assessthe degree of organ damage depending on the stageof the disease. Hormone testing can evaluate thesex hormones, adrenal hormones, and thyroid andparathyroid function. An EKG and echocardiogram(ultrasound scan of the heart) should be done in allsymptomatic (grade III) patients, and continuouselectrical monitoring of the heart may be indicatedby the patient’s symptoms. X rays are useful inevaluating the arthritis and are sometimes diagnos-tic. Marked involvement of the second and thirdmetacarpophalangeal joints is characteristic. Thefinding of thin lines of calcification along the carti-lage in joints is suggestive of CPPD. MRI scans canalso be useful in evaluating the joints.

A number of features of this disease suggest thatroutine screening would be a good idea:

• HHC is common.

• There are relatively easy tests to determine car-rier status (the C282Y and H63D genes) and ironoverload (transferrin saturation and ferritin).

• Treatment is cheap, technically easy, and accept-able to most patients.

• Early treatment can prevent considerable dis-ability, suffering, and costly treatment of thecomplications of HHC.

Despite these arguments, most public healthbodies and governments are not recommendingscreening. Their arguments revolve around the factthat not everyone who has two copies of C282Ydevelops the disease (although the vast majority

104 hemochromatosis

do) and the ethical problems relating to predictionof disease. However, everyone agrees that once apatient has been diagnosed, his or her first-degreerelatives should be offered screening. This is doneby checking for the presence of the C282Y andH63D mutations on a blood test. If present, thetransferrin and ferritin should be measured to assessthe iron load. In younger stage I patients theseshould be repeated periodically. If the gene tests arenegative, it means that individual has not inheritedthe same susceptibility to develop HHC as his or herfamily member. As explained above, there is still atheoretical chance that the individual could developthe disease through some other as yet unknownmutation, but this risk is extremely small.


The treatment is to remove iron from the bodyuntil body stores are normal and then maintain thislevel. Blood contains about 0.5 mg of iron per mL.Removing a unit of blood (the normal amountgiven during a blood donation) therefore removes200 to 250 mg of iron. As long as the patient ishealthy, it is possible to remove a unit of bloodevery week or fortnight without any adverseeffects. In the presence of heart failure or otherchronic disease this may have to be slowed down.Frequent removal of blood (termed venesection orphlebotomy) is continued until the ferritin level isbelow 100 mg/L. This may take up to two years.Venesection is then continued just often enough tokeep the ferritin at this level. This is usually two tofour times a year.

Although patients do not have to limit theirdietary intake of iron strictly, which they may findunpleasant, they should take some precautions.Vitamin C and iron supplementation should beavoided. Vitamin C promotes iron absorption. Bothof these may be found in multivitamins or otherhealth supplements or health drinks. Red meat is apotent source of iron and should be limited. Alco-hol should be avoided in those with clinical liverinvolvement and limited in stage II. Raw shellfishare best avoided since there have been deaths inHHC patients from Vibrio vulnificus infections.

Complications of HHC such as diabetes, heartfailure, or endocrine deficiencies are treated as theywould be in any other patient. See the OSTEOARTHRI-

TIS and CPPD sections for treatment of these forms of

arthritis. In the past transfusion services generallydid not accept blood for transfusion into otherpatients if the donor suffered from a chronic illness.Many HHC patients are very healthy, however, andthere is nothing wrong with their blood. Increas-ingly, therefore, transfusion services are acceptingHHC blood, and many patients welcome the oppor-tunity to help provide this service.

Obviously, venesection is not an option forpatients who require regular transfusions to main-tain an adequate red cell level (thalassemia, sickle-cell anemia, etc.). Currently the only alternativefor these patients is desferrioxamine. Desferriox-amine is a chelating agent, which means that itbinds very tightly to iron and therefore removesfairly large amounts of iron from the body as it isexcreted. It is given as an infusion under the skinand can remove 10 to 20 mg of iron per day. Ifdone on a daily basis, this is just less than half theamount removed by weekly venesection.

Roughly a third of untreated HHC patients die ofheart failure, a third of liver failure or its complica-tions, and a third from liver cancer. Treatment hasbeen shown to improve the five year survival ofthese patients from only 33 percent to 89 percent.Since Feder and colleagues’ discovery of the twoimportant gene mutations and the development ofrelatively simple blood tests to aid the diagnosis,many more patients have been diagnosed at amuch earlier stage. It is hoped that this will bringtheir life expectancy very close to that of the nor-mal population. However, further long-term stud-ies of patients being currently diagnosed will beneeded to see if this in fact happens.

With successful treatment the liver and spleenget smaller, liver function improves (although anycirrhosis present remains), heart failure resolves,and diabetes improves in about half the patients.Reduced sex hormone production and the arthritisare not affected by treatment. If the disease istreated before cirrhosis develops, there is noincreased risk of liver cancer.

hemophilia An inherited disorder of the blood-clotting mechanism that increases the risk of bleed-ing. Hemophilia A, caused by a deficiency ofclotting factor VIII, affects about 80 percent ofhemophiliacs and is more common and more

hemophilia 105

severe than hemophilia B which is also known asChristmas disease and is caused by deficiency ofclotting factor IX.

Cause

Hemophilia results from mutations in the genes forfactor VIII and IX. These genes lie on the X chro-mosome, and males, because they carry only one Xchromosome, are affected by hemophilia if theyhave the abnormal chromosome. Women, on theother hand, because they have two X chromo-somes, one inherited from each parent, are unlikelyto have two abnormal chromosomes and are pro-tected from disease. However, if they have oneabnormal X chromosome they are carriers, andtheir children will have a 50 percent chance of hav-ing hemophilia if they are male and a 50 percentchance of being a carrier if they are female. Approx-imately one-third of patients with hemophilia donot have a history of affected family members, andthe disease is then thought to have arisen from anew mutation. Although hemophilia is thought ofas being a disorder of blood, one of the problems itcauses, bleeding into muscles and joints, can resultin acute and chronic musculoskeletal problems.

Symptoms

Patients with a very low level, less than 1 percentof normal, of factor VIII or IX activity are severelyaffected and often develop symptoms caused byspontaneous bleeding before they are two yearsold. Patients with less severe hemophilia oftenhave factor levels that are 5 percent or more of nor-mal and may develop symptoms only after surgeryor trauma.

The symptoms caused by bleeding depend onthe site affected. Bleeding into soft tissue and mus-cle causes pain and swelling in the area. A largecollection of blood (hematoma) can cause damageto nerves and other tissues directly through pres-sure and indirectly by cutting off the nerves’ bloodsupply. Hematomas slowly resorb but cause dam-age and scarring to the surrounding tissues and canresult in contractures that prevent a limb fromstraightening. Bleeding into a joint is calledHEMARTHROSIS and causes severe pain, swelling,and difficulty moving. Most patients with severehemophilia suffer spontaneous hemarthrosis inearly childhood, usually when they start to walk.

In later life, acute hemarthrosis can occur sponta-neously or after minor trauma. Acute hemarthrosisusually resolves over two weeks, but recurrentepisodes of bleeding into a joint damages it and cancause chronic inflammation resulting in swelling,deformity, pain, and loss of function. How blooddamages the joint is not known exactly. Activationof platelets and white blood cells and the release ofiron are all thought to play a role in damaging car-tilage and stimulating abnormal growth of the syn-ovium or joint lining.

Diagnosis

Hemophilia is diagnosed from the family history ofa bleeding problem, the clinical features, tests ofblood clotting ,and levels of factors VIII and IX. Bythe time musculoskeletal problems occur, the diag-nosis of hemophilia is often known.


Patients with hemophilia are usually treated byspecialized centers. The basis of treatment is avoid-ing medications, such as aspirin, and environmen-tal situations such as contact sports, that increasethe risk of bleeding and replacing the deficient clot-ting factors. The focus is on early and intensivehome administration of the appropriate clottingfactor by patients at the first symptom of a bleed.Factors VIII and IX are available as either a con-centrate made from human blood from manydonors and treated to inactivate viruses or as arecombinant product made using molecular biol-ogy techniques. In the early years of the HIV epi-demic many patients with hemophilia were treatedwith factor concentrates made from blood before itwas routinely screened for HIV infection. Many ofthese patients became infected by HIV and subse-quently developed AIDS. Because there is no riskof transmitting viral infections with recombinantclotting factors, they are often preferred.

The best treatment for hemophilia arthritis is toprevent it by adequate and early replacement ofclotting factors. Giving the appropriate clotting fac-tor as early as possible and drugs to control paintreats acute hemarthrosis. In the early stages ofhemarthrosis draining the blood by drawing it outof the joint through a needle (ARTHROCENTESIS) maydecrease the long-term damage to the joint.Chronic arthritis can be improved by intensive clot-

106 hemophilia

ting factor replacement, pain control, and physicaltherapy to prevent contractures and strengthenmuscles. A few patients do not respond to treat-ment and have recurrent, frequent bleeding into ajoint; some of these patients benefit from surgeryto remove the inflamed lining of the joint (SYN-

OVECTOMY). Joint replacement surgery has beenperformed in patients with end-stage hemophiliaarthritis with a severely damaged, painful joint.However, joint replacement surgery is avoided ifpossible because complications occur more often inpatients with hemophilia. Also, most of thepatients are young with a long life expectancy andwill therefore almost certainly need future surgeryto revise the replaced joint.

Henoch-Schönlein purpura (HSP) This is thecommonest form of VASCULITIS in children.Although it may affect anyone from six months to80 years old, the vast majority of patients are agedbetween two and 10 years. It occurs mostly in thefall and winter months and often follows an infec-tion. In this form of vasculitis, small blood vesselsbecome damaged by inflammation. Skin, bowel,joints, and kidneys are commonly affected.

Cause

The cause is not fully understood. IgA antibodiesclearly play an important role. Of the five classes ofimmunoglobulins or antibodies, IgA is mostinvolved with protection against infection and otherevents at mucosal surfaces, i.e., the inner lining ofthe nose, throat, lungs, gut, and genital areas. InHSP not only are IgA levels in blood raised, butthere is increased formation of chains of IgA mole-cules and complexes of IgA and other molecules.When these relatively heavy complexes settle outon the walls of small blood vessels, they causeinflammation. The white cells attracted to this areathen cause damage to the blood vessel wall, whichmay result in blood cells leaking out or the bloodvessel actually blocking off (thrombosis). On biopsythis appearance is called leukocytoclastic vasculitis, butHSP is only one of several causes of this.

It is well known that HSP often follows an infec-tion, usually of the throat or chest. Many organismshave been implicated, including streptococcal bacte-ria, Helicobacter pylori, hepatitis B virus, herpes sim-plex virus, human parvovirus B19, Coxsackie

viruses, and adenovirus (a cause of the commoncold). HSP has also followed the use of medications,but there do not seem to be any particular proper-ties of the drugs or infecting organisms that mightinitiate this abnormal immune response. Rather,there may be subtle abnormalities in the IgA ofsome people that predisposes them to develop HSP.A lot of research is being conducted in this area atthe moment.

Symptoms

HSP cannot be diagnosed without the characteristicskin rash. This comprises small 2–10 mm diameterblue-black spots on the legs and buttocks. Thesespots are easily felt to be lumpy. They may start asreddish lumps or wheals. About 75 percent ofpatients get arthritis, usually affecting the ankles orknees, that may start before the rash. A smallernumber develop gut problems, usually colickypain, vomiting, and passing of blood in the stools.A serious complication of gut involvement is intus-susception. This is where one section of bowelpushes through the next section so that the first liesinside the second. This double tube of bowel causesobstruction. If it does not resolve, it can lead to per-foration or bursting of the bowel wall. In HSP thisusually affects the small bowel.

About 40 percent of patients also get inflamma-tion of the kidneys. This is recognized by findingsmall amounts of blood and, less often, protein inthe urine. Kidney involvement usually starts a cou-ple of weeks after the rash and may last muchlonger than the other manifestations. A large num-ber of other complications rarely occur, includinginflammation of muscle, testes, bladder, eye, heartor pancreas, bleeding in the lungs, seizures,reduced level of consciousness, movement disor-ders, loss of nerve function, and paralysis. Theseare fortunately all very rare.

Diagnosis

In children, the clinical manifestations are charac-teristic and the diagnosis can be made without anyspecial tests. The urine should be tested to look forkidney involvement. Adults often have atypicaldisease and may require more intensive investiga-tions. A throat swab may grow streptococcus.Biopsy of the rash shows the picture of leukocyto-clastic vasculitis with destruction of small blood

Henoch-Schönlein purpura 107

vessel walls by white cells and the remains of broken-up white cells close by. Biopsy of the kid-ney is done occasionally and shows the presence ofIgA and varying degrees of damage to the filteringpart of the kidney (glomerulonephritis). Blood lev-els of IgA are often raised.


CORTICOSTEROIDS are very helpful in treating thearthritis and abdominal pain. In the absence ofsevere complications, HSP will resolve sponta-neously in about four weeks. Kidney involvementis the one manifestation that may not resolve, andthe outlook for most patients depends on howbadly their kidneys are affected. Although nearlyhalf of HSP patients continue to have minor abnor-malities on urine testing, only 1 percent go on todevelop end-stage renal failure. Adults with HSPare more likely to develop serious kidney problemsthan children. Those with a lot of blood or proteinin the urine initially or severe damage on kidneybiopsy have the worst outcome. These patientsshould therefore receive aggressive treatment withlarge doses of corticosteroids intravenously initiallyand then in tablet form together with AZATHIOPRINE

or CYCLOPHOSPHAMIDE.

hepatitis Inflammation of the liver resulting inelevated blood levels of alanine aminotransferase(ALT) and aspartate aminotransferase (AST)enzymes. Hepatitis can be acute and may resolvecompletely or may be chronic and can lead to liverscarring or cirrhosis. There are many causes ofhepatitis, the commonest being viral infection,drugs, alcohol, and autoimmune disease.

hepatitis, autoimmune A subset of hepatitis thatis thought to be caused by an autoimmune illness.Chronic autoimmune hepatitis can be divided intotwo subtypes:

1. An illness previously called lupoid hepatitis thataffects mainly young women and is associatedwith a positive antinuclear antibody (ANA) test

2. An illness that affects mainly children and isassociated with a positive test for antibodies toliver-kidney microsomal antigens (anti-LKM)and not with ANA

Cause

The cause is not known. However, it is thought thata genetic predisposition and an environmental trig-ger act in synergy to trigger and sustain an autoim-mune inflammatory process that targets liver cells.

Symptoms

The onset of symptoms varies and can be acute,with an illness similar to acute viral hepatitis, orinsidious. Fatigue, nausea, arthralgia, jaundice, anddecreased appetite are common. Less common arearthritis, pleurisy, SICCA SYNDROME symptoms, rash,and VASCULITIS.

Diagnosis

The diagnosis is based on the clinical presentation,elevated liver enzyme tests, a positive ANA or anti-LKM test, and negative tests for viral hepatitis. Aliver biopsy is often performed to assess the severityof the illness and to exclude other causes of hepati-tis. In addition to a positive ANA test, which usuallyhas a smooth or homogenous pattern, positive testsfor other autoantibodies such as RHEUMATOID FACTOR

and smooth-muscle antibodies are common.


The severity and course of autoimmune hepatitis ishighly variable. If severe and chronic with featuresthat on liver biopsy are called chronic activehepatitis, then treatment with CORTICOSTEROIDS isprescribed because cirrhosis and liver failure mayresult. Autoimmune hepatitis is one of the fewtypes of liver disease that responds to corticosteroidtreatment. Prednisone, initially in high and then indecreasing doses, will induce remission in 80 per-cent of patients. Some physicians add anotherimmunosuppressant drug such as AZATHIOPRINE orCYCLOSPORINE for patients who do not respond tocorticosteroids alone or who require high doses tomaintain remission. Studies have shown improve-ment in both symptoms and liver biopsy samples,and more than 90 percent of treated patients sur-vive longer than 10 years. Prolonged treatment,often for a year or longer, is required. Approxi-mately 50 percent of patients remain in remissionor have only mildly active disease for a time afterthe initial course of therapy is completed. However,most patients relapse within a few years of stopping

108 hepatitis

treatment and require further courses or oftenindefinite maintenance treatment.

hepatitis, drug-induced The liver is the organ pri-marily responsible for the metabolism and detoxifi-cation of most drugs, so it is not surprising thatseveral drugs can cause liver damage and result inhepatitis. Drugs can cause two major types of liverdamage, toxic hepatitis and idiosyncratic hepatitis.

Cause

Toxic Hepatitis is liver damage that is predictable andwill occur in most people exposed to a certain doseof the toxic chemical or drug. Examples are aceta-minophen overdose, carbon tetrachloride, and theAmanita species of mushroom. Often toxicityextends beyond the liver and other organs areaffected.

Idiosyncratic Hepatitis is unpredictable, does notdepend on the dose of drug taken, and occurs inonly a few people who have taken a particulardrug. Why a few people develop hepatitis afterexposure to a drug and others do not is not known.Affected individuals are thought to be more sus-ceptible to liver damage from a particular drugbecause either they develop an allergic response orthey metabolize the drug differently and form toxicby-products that damage liver cells. Idiosyncratichepatitis can be further subclassified according towhether the primary damage is to the liver cells(hepatitic) or to the system that excretes bile(cholestatic). However, there is often overlap, andmany drugs can cause a mixed hepatitic andcholestatic illness. Drugs that have caused ahepatitic pattern of liver damage include halo-thane, NSAIDs, LEFLUNOMIDE, METHOTREXATE, SUL-

FASALAZINE, and many others. Drugs that havecaused cholestatic liver damage include oral con-traceptives, erythromycin, anabolic steroids, andchlorpromazine.

Methotrexate and leflunomide, drugs used totreat RHEUMATOID ARTHRITIS, can rarely cause chronicliver damage resulting in scarring or cirrhosis.

Symptoms

Drug-induced hepatitis can result in symptoms andliver enzymes tests that are similar to those of viral

hepatitis. Unless severely affected, many patientshave no symptoms and hepatitis is suspected onlywhen routine blood tests are performed.

Diagnosis

No diagnostic test enables a particular drug to beidentified as the cause of hepatitis in an individualpatient. The usual clinical approach is to performblood tests for viral hepatitis and if these are nega-tive and drug-induced hepatitis is suspected to stopthe drug that is thought to be responsible. To be surethat a particular drug was the cause of a patient’shepatitis would require that once the hepatitis hadresolved, the patient be treated with the drug anddevelop hepatitis again. This rechallenge test wouldbe very helpful in pinning down a particular drug asthe cause of a patient’s hepatitis but is seldom per-formed because there is a risk that reexposure to thedrug could induce severe hepatitis.


Most types of drug-induced hepatitis are treated bystopping the offending drug. The outcome dependson how severe the liver injury is. It ranges fromrapid reversal of mildly abnormal liver functiontests to death from liver failure.

hepatitis B A common viral infection transmittedfrom person to person by blood or body fluids thatresults in acute and chronic liver inflammation, cir-rhosis, and liver cancer. In the United States,approximately 200,000 cases occur annually. Theliver complications of hepatitis B infection are themost frequent and serious ones, but musculoskele-tal symptoms can also occur.

Cause

Hepatitis B virus is found in blood, semen, andother body fluids, and like HIV, it is transmittedfrom person to person by blood or body fluids.Hepatitis B virus is more infectious than HIV and isable to survive for longer outside the body. There-fore, transmission of hepatitis B from person toperson can occur by sharing toothbrushes. How-ever, sexual contact and sharing of needles are thecommonest ways the virus is transmitted. Intra-venous drug users who use dirty or shared needleshave a very high risk of contracting HIV and

hepatitis B 109

hepatitis B and C. Needle exchange programs thatprovide clean needles have been started in somecountries to combat this form of transmission.Transmission of hepatitis B to patients by medicalprocedures is rare. Blood products are screened forviruses such as hepatitis B, and medical instru-ments are either disposable or sterilized betweenpatients. Health workers can be infected by acci-dentally pricking themselves with a needle used ona patient with hepatitis B. If this happens, thechance of getting hepatitis B can be as high as 30percent and is much higher than the chance of get-ting HIV infection from a needle stick (less than 1percent). Outbreaks of hepatitis B have occurredfrom contaminated equipment in tattoo parlors.Pregnant women who are infected with hepatitis Bcan transmit the infection to their babies.

Symptoms

Symptoms may not appear until several monthsafter transmission of the virus. Ones such asarthralgia, poor appetite, and fatigue are usuallymild and nonspecific, and approximately a third ofpeople have no symptoms. Some patients becomevisibly jaundiced, with the white parts of their eyesturning yellow and their urine becoming dark.Severe hepatitis resulting in liver failure is rare andoccurs in approximately five out of 1,000 infectedpeople. Most patients develop antibodies to thevirus and eliminate the acute infection, butapproximately 5 percent become chronic carriersand can transmit the infection to others. Carriersare at risk of long-term complications. Somechronic carriers seem to carry the virus without itcausing much liver inflammation, but others havechronic hepatitis that can lead to cirrhosis andeventually liver failure. Patients who carry thevirus, even those with ongoing liver inflammation,usually have no symptoms unless chronic liver dis-ease develops. This may cause jaundice, swelling ofthe abdomen due to fluid (ascites), swelling of thelegs, and symptoms of liver failure such as confu-sion and coma.

In addition to nonspecific musculoskeletal symp-toms such as fatigue and arthralgia that are commonduring acute hepatitis B infection, there are twowell-recognized rheumatic syndromes, the arthritis-dermatitis syndrome and hepatitis B vasculitis.

Hepatitis B arthritis-dermatitis syndrome

After infection has occurred and immediatelybefore hepatitis develops, approximately 20 per-cent of people develop symmetrical arthralgiaaffecting many joints, typically the small joints ofthe hands, and a rash that can be urticarial. Thesymmetrical involvement of the small joints of thehands can lead to an incorrect diagnosis ofrheumatoid arthritis. The joint pain is severe andoften out of proportion to the degree of swelling,which is usually minimal or absent. The arthritis-dermatitis symptoms seem to herald the hepatitis.As soon as it develops the musculoskeletal symp-toms settle without causing any permanent jointdamage. A similar pattern of arthralgia and arthri-tis resembling rheumatoid arthritis has occurred ina few patients after they were vaccinated againsthepatitis B (see DRUG-INDUCED RHEUMATIC DISEASE).

Hepatitis B vasculitis Approximately 25 per-cent of patients presenting with POLYARTERITIS

NODOSA have hepatitis B vasculitis. Unlike thehepatitis arthritis-dermatitis syndrome, whichoccurs just before hepatitis develops, hepatitis Bvasculitis can occur at any stage in the course ofhepatitis B infection. Polyarteritis nodosa andhepatitis B vasculitis have identical symptoms. Thesymptoms depend on the organs affected. Fever,loss of weight, rash, abdominal pain, neuropathy,glomerulonephritis, kidney failure, and hyperten-sion are common.

Diagnosis

Hepatitis B infection In many patients hepatitis Binfection does not cause symptoms and infection isnot diagnosed until blood tests, often performed foranother reason, suggest that infection has occurred.This usually happens in one of two ways. The firstis when an otherwise healthy person donates blood.All donated blood is routinely screened for HIV andhepatitis B and C. People whose blood tests are pos-itive for one of these infections are often advisedthat they should see their physicians for furthertests. The second is when an otherwise healthy per-son has a routine physical examination and bloodtests show elevated levels of alanine and aspartateaminotransferase enzymes (see LFTS in AppendixII). Specific blood tests for markers of hepatitis Band C infection are then performed to make the

110 hepatitis B

diagnosis. The hepatitis B surface antigen (HBsAg)test is positive in patients with acute infection butbecomes negative in the majority who develophepatitis B surface antibodies and eliminate thevirus. Chronic carriers who do not eliminate theinfection remain positive for HbsAg. In thosepatients in whom the virus is actively multiplying,another marker, hepatitis B e antigen (HBeAg), isalso positive. Viral DNA can also be measured inpatients in whom the virus is replicating. A liverbiopsy is not performed routinely to diagnosehepatitis B infection but can be useful for assessingthe activity and severity of chronic disease.

Hepatitis B arthritis-dermatitis syndrome Thesymptoms of arthritis and rash occur just before, orat the same time, as the first symptoms of hepatitis.Blood tests show elevated liver enzymes with apositive HBsAg test.

Hepatitis B vasculitis In patients with poly-arteritis nodosa or a similar type of systemic vas-culitis caused by hepatitis B, the tests for viralinfection and replication (HBsAg and HBeAg) arepositive. Other diagnostic tests are performed toestablish the diagnosis of vasculitis. These includean angiogram of the arteries to the kidneys andbowel that arise from the aorta. The findings onangiogram are identical to those of polyarteritisnodosa and show small aneurysms and irregularityof small and medium-sized arteries. A biopsy ofaffected tissue, usually muscle, nerve, or skin,shows vasculitis.


Hepatitis B A very effective vaccine prevents thedisease. In addition to vaccination, other measuresare used in developed countries to prevent peoplefrom becoming infected. These include testing allblood products for hepatitis B, sterilization of med-ical instruments, and educational programs toencourage drug users not to share needles. Indeveloping countries hepatitis B is a serious prob-lem, and in some countries as many as 10 percentof the population are chronic carriers. In peoplewho have been exposed by a needle stick, hepatitisB infection can be prevented by rapid injection ofimmune globulin and hepatitis B vaccination.

Acute hepatitis B infection is usually not treated,and more than 90 percent of people clear the infec-

tion without problems. Patients with chronichepatitis can be treated with antiviral drugs such asalpha-interferon and lamivudine. Liver transplanta-tion is reserved for patients with severe cirrhosisand deteriorating liver function. People whodevelop cirrhosis have an increased risk of develop-ing a type of liver cancer, hepatocellular carcinoma.

Hepatitis B arthritis-dermatitis syndrome

Most patients do not need any specific therapy. Theillness is short-lived and settles spontaneously.

Hepatitis B vasculitis Treating hepatitis B vas-culitis is difficult. The standard treatment for seriousvasculitis, CORTICOSTEROIDS combined with animmunosuppressant such as CYCLOPHOSPHAMIDE, isoften needed to control the vasculitis but has thenegative effect of promoting viral replication. Theapproach usually used is to control the vasculitis andthen to start treatment with antiviral drugs. Thelargest experience with this type of sequentialimmunosuppressant/antiviral therapy for hepatitis Bvasculitis is from a group in France headed by Dr. LucGuillevin. They report good results, with approxi-mately 80 percent of patients surviving five years.

hepatitis C The cause of an illness previouslycalled non-A, non-B hepatitis was identified in1989 and the illness renamed hepatitis C. Approx-imately 170 million people worldwide and 3 mil-lion in the United States are chronic carriers ofhepatitis C. In the United States, it is the common-est cause of chronic hepatitis and hepatocellularcarcinoma.

Cause

Hepatitis is caused by an RNA virus belonging tothe family of flaviviruses. There are many variantsof the hepatitis C virus (HCV) with minor differ-ences in their genetic structure that allow them tobe classified into six genotypes. Different genotypespredominate in different parts of the world. In theUnited States genotypes 1, 2, and 3 are common.The different genotypes vary in their response totherapy, with genotype 1 being the most resistant.

Before 1990 hepatitis C was often transmittedthrough transfusion of blood or blood products, butroutine testing of donors for hepatitis C has virtu-ally eliminated this route of transmission. How-ever, new infections still occur, and as is the case

hepatitis C 111

with hepatitis B, sexual contact and sharing of nee-dles are the most common ways the virus is trans-mitted. Intravenous drug users who use dirty orshared needles have a very high risk of contractingHIV and hepatitis B and C. Transmission of hepati-tis C to patients by medical procedures is nowextremely rare. Health workers can be infected byaccidentally pricking themselves with a needleused on a patient with hepatitis C. If this happens,the chance of getting hepatitis C is about 3 percent,much lower than the 30 percent risk of gettinghepatitis B in this way. A pregnant mother cantransmit the virus to her infant but it happens lessoften than with hepatitis B.

The cause of rheumatic problems associatedwith hepatitis C is not known. Autoantibodies suchas rheumatoid factor and antinuclear antibody(ANA) are often found, but it is not clear if they aredirectly implicated in the cause of musculoskeletaldisease.

Symptoms

Most people infected with hepatitis C do not knowthat they have been infected because the symptomsof the acute infection are usually trivial. In a fewpeople acute hepatitis develops and they have symp-toms of nausea, jaundice, and fatigue. Approxi-mately 20 percent of infected people clear the virusspontaneously and have no further problems, but inthe other 80 percent the infection persists. In thesepeople some liver inflammation occurs. The exactrisk of severe liver disease in hepatitis C carriers isnot known because it can develop 30 or more yearslater, but about 20 percent of infected people arethought to progress to severe liver disease. If thishappens it may cause symptoms of jaundice,swelling of the abdomen due to fluid (ascites),swelling of the legs, and symptoms of liver failuresuch as confusion and coma. Several conditions thataffect organs other than the liver can occur inpatients who carry hepatitis C. Because the viruswas discovered only in 1989, the range of clinicalconditions it may cause or be associated with is stillbeing defined. Hepatitis C is widely accepted as caus-ing two rheumatological conditions, CRYOGLOBULINE-

MIA and inflammatory polyarthritis, but severalother associated problems have been described.

Cryoglobulinemia Both hepatitis B and C cancause cryoglobulinemia, but hepatitis C is more

likely to do so. It is estimated that this develops inbetween 10 and 60 percent of HCV infected peoplewith large variations between different countries.Hepatitis C is one of the most common causes ofcryoglobulinemia, and in some studies 80 to 90percent of patients with this condition have hadhepatitis C.

Inflammatory polyarthritis Arthralgia is com-mon and is found in about a third of infectedpatients, but arthritis occurs in only about 4 per-cent. Some patients develop symmetrical inflam-matory polyarthritis that is very similar torheumatoid arthritis, with symptoms of pain andswelling that affect mainly the small joints of thehands. This type of arthritis is not a feature of acutehepatitis C infection but can occur at any time dur-ing the course of the illness. Unlike most types ofarthritis associated with viral infections, hepatitis Carthritis persists, often for years. Many patientshave symptoms of both cryoglobulinemia andarthritis. Hepatitis C and rheumatoid arthritis areboth relatively common illnesses and will thereforeoccur together in some patients by chance. Thearthritis associated with hepatitis C can be very dif-ficult to distinguish clinically from true rheumatoidarthritis. To add to the confusion, many patientswith hepatitis C, even those without arthritis, alsohave a positive blood test for rheumatoid factor.Hepatitis C arthritis differs from classical rheuma-toid arthritis because it is less likely to cause jointdeformities or erosions and tends to cause morepain than swelling in affected joints.

Other conditions SJÖGREN’S SYNDROME, POLY-

ARTERITIS NODOSA, VASCULITIS, NEUROPATHIC ARTHRITIS,

FIBROMYALGIA, and MYOSITIS have occurred in asso-ciation with hepatitis C infection.

Diagnosis

Because most patients who have acute hepatitis Cinfection or are chronic carriers have no symptoms,the diagnosis is often not made until blood tests,performed for some other reason, raise the possi-bility. This often happens in one of two ways. Thefirst is when an otherwise healthy person donatesblood. All blood is tested for HIV and hepatitis Band C. People whose blood tests are positive forone of these are often advised that they should seetheir physicians for further tests. The second iswhen an otherwise healthy person has a routine

112 hepatitis C

physical examination and blood tests show ele-vated levels of alanine and aspartate aminotrans-ferase enzymes suggesting some liver disturbance(see LFTS in Appendix II). Specific blood tests formarkers of hepatitis B and C infection are thenobtained to make the diagnosis.

The usual blood test performed to screen forhepatitis C infection is an ELISA test that detectsantibodies to viral protein. This test can be falselynegative but this is rare, occurring in less than 1percent of patients. A false negative ELISA is morelikely to occur in patients with a poor immuneresponse, for example those who also have HIVinfection and patients with cryoglobulinemia. Afalse positive ELISA test can also occur, and there-fore a positive (enzyme-linked immunosorbentassay) ELISA test is followed by a more specificconfirmatory test for hepatitis C. This is usually arecombinant-based immunoblot assay, also called aRIBA. In patients who are being treated for hepati-tis C, the amount of virus (viral load) can be mea-sured using polymerase chain reaction (PCR). Aliver biopsy is often performed to provide informa-tion about the activity of the disease and theamount of scarring.

All patients with cryoglobulinemia and poly-arteritis nodosa should be tested for hepatitis B andC infection. In patients with other rheumatic con-ditions, hepatitis C is usually diagnosed when rou-tine blood tests reveal elevated liver enzymes. Inpatients with rheumatoid arthritis, hepatitis Cinfection is sometimes discovered when screeningblood tests are performed before starting treatmentwith methotrexate or leflunomide, drugs that canrarely damage the liver.


Hepatitis C infection is treated to reduce the chanceof a person developing cirrhosis, liver failure, andhepatocellular carcinoma. Because an estimated 80percent of infected people do not develop seriousproblems, physicians have tried to treat thosepatients with the highest risk of long-term compli-cations selectively. Persistent elevation of liverenzymes is one clue to ongoing inflammation, butthe best indicator of liver damage is a liver biopsythat provides information about both the amountof old scarring and new inflammation.

Treatment for hepatitis C has advanced rapidly,and a combination of a long-acting form of inter-feron alpha (pegylated interferon) and anotherantiviral drug (ribavirin) has given the best resultsso far. Patients treated with this combination for 48weeks have a 40 percent chance of clearing theviral infection permanently. Preliminary informa-tion suggests that treatment decreases the risk oflong-term complications of hepatitis C even inpatients who relapse or do not clear the infection.

Inflammatory arthritis associated with hepatitisC infection is difficult to treat because many of thedrugs that could be used, such as methotrexate andleflunomide, are contraindicated in people withliver disease. There are no large studies to guidetherapy but most rheumatologists use NON-

STEROIDAL ANTI-INFLAMMATORY DRUGS, low doses ofCORTICOSTEROIDS, and DMARDS such as HYDROXY-

CHLOROQUINE, SULFASALAZINE, or GOLD. Treatment ofhepatitis C infection with antiviral drugs usuallyimproves cryoglobulinemia but is less effective incontrolling arthritis.

herpes zoster Also known as the varicella zostervirus, this is the cause of the common childhoodillness chicken pox. Once the individual is overchicken pox, the virus is able to stay alive but dor-mant in the dorsal root ganglia. These ganglia arenodes along the large sensory nerves just beforethey enter the spinal cord. Later in life the viruscan become reactivated, causing inflammation ofthat particular nerve (with severe pain) and a dayor two later a rash in the area that the nerveserves. This is known as zoster or shingles and ismost likely to occur when the individual’simmune system is suppressed. Common reasonsfor this are older age (over 60 years), malignancy(especially lymphomas and leukemias), andimmunosuppressive treatment. Both chicken poxand shingles can be very severe illnesses in thosewith poor immune function. The many clinicalmanifestations and treatment of this virus will notbe discussed here. As far as rheumatic diseases areconcerned, there are two main circumstances inwhich herpes zoster is important: immunosup-pressive therapy and vasculitis.

• Immunosuppressive Therapy Drugs such asCYCLOPHOSPHAMIDE, AZATHIOPRINE, METHOTREXATE,

herpes zoster 113

and CYCLOSPORINE are often used to treat severeVASCULITIS or resistant RHEUMATOID ARTHRITIS andother inflammatory arthritis. Use of these drugsalways requires a balance between suppressingthe immune system enough to stop the damageit is causing and not suppressing it so much thatthe patient becomes too susceptible to infections.With the above drugs, zoster or shingles is oftenthe first infection to occur and can serve as awarning that the immune system is oversup-pressed. The number of white cells in the blooddrops with immunosuppression, and shinglesbecomes more likely when the lymphocytecount drops below 0.6 x 109 per liter.

• Vasculitis Rarely, herpes zoster can cause a VAS-

CULITIS. Unlike many other infectious causes ofvasculitis, the zoster virus actually invades thelining cells of blood vessels, thereby provoking animmune response that damages the blood vessels.

hip pain The hip is a true ball-and-socket jointwith the head of the femur (thigh bone) fitting intoa round socket in the large pelvic bone. The joint iscrossed by very powerful muscles that work tomove the lower limb under the entire body weightor hold the body upright on one grounded leg whilethe other is in the air. It is also crossed by the nervesand blood vessels of the lower limb. Pain in the hipregion may arise from the joint itself, the bones, thetendons, muscles, ligaments, and the bursas in thearea or be referred there from elsewhere.

• Joint Disease Pain from the hip joint is usuallyfelt in the groin but also characteristically radi-ates down the front of the thigh to the front ofthe knee. If it is long-standing, then the gaitbecomes abnormal, muscles weaken, and painmay be felt in a wider area. All the inflammatoryforms of arthritis may affect the hip, especiallyANKYLOSING SPONDYLITIS (often early on), REAC-

TIVE ARTHRITIS, psoriatic arthritis (see PSORIASIS

AND PSORIATIC ARTHRITIS), and RHEUMATOID

ARTHRITIS (often quite late). These will usually bediagnosable by occurring in the context of dis-ease elsewhere. OSTEOARTHRITIS frequentlyaffects the hips, and farmers are at increased riskof this. If osteoarthritis of the hip is causing pain,X rays will confirm its presence. GOUT may occa-

sionally affect the hip joint, especially if there isalready some degree of osteoarthritis, but this isan unusual joint to be affected by gout. Pseudo-gout or CPPD may affect the hip joint. Althoughrare, INFECTIVE ARTHRITIS such as TUBERCULOSIS

can occur here. A fibrosing or scarring processaffecting the joint capsule that usually occurs atthe shoulder causing a frozen shoulder (seeSHOULDER PAIN) can also affect the hip joint occa-sionally. This is more common in DIABETES.

• Bone Disease Regional osteoporosis is anunusual, painful form of OSTEOPOROSIS that quitecommonly affects the head of the femur when itdoes occur. This is often during pregnancy. AVAS-

CULAR NECROSIS often affects the head of thefemur. PAGET’S DISEASE commonly affects thehead of the femur, the pelvis, or both. Pain canresult from the Paget’s disease itself or the arthri-tis that results from the softer bone deformingand losing its congruity. Cancers may occasion-ally spread to the pelvis or upper femur andcause pain there. In OSTEOMALACIA it is notuncommon to get a specific type of insufficiencyfracture called Looser’s zones at the upper end ofthe shaft of the femur. Especially since there isoften weakness of the surrounding muscles,osteomalacia can present as hip pain. Fracturesof the hip are usually easily diagnosed because ofthe trauma that causes them, the inability towalk, and the abnormal position of the leg. How-ever, in people with osteoporosis, they can some-times occur with minimal trauma, and becausethe bones are not displaced, the individual cancontinue to walk. In these unusual situations anX ray is required to make the diagnosis.

• Soft Tissue Disease A number of bursas aroundthe hip commonly cause pain. People withinflammatory arthritis such as rheumatoid dis-ease are more likely to get bursitis, but there aremany causes. Weakness of the hip-stabilizingmuscles leading to an abnormal gait is a com-mon cause. This may develop due to lack of fit-ness, an increase in weight, or following pain inor injury to the back or a leg. It may also be theresult of disease in the hip joint so that bursitisand hip arthritis not infrequently coexist. Themost common bursas involved (TROCHANTERIC

BURSITIS) are just above and below the greater

114 hip pain

trochanter. This is the bony point felt at the out-ermost part of the hip area. It is sometimes con-fused with the hip joint itself, which is actuallyseveral inches deeper than this point.

TENDINITIS may affect any tendon, but three spe-cific tendons are worth mentioning. The tendon ofthe gluteus medius muscle (one of the large buttockmuscles) is frequently stressed by the same condi-tions that cause bursitis around the greatertrochanter, and tendinitis here is often confusedwith bursitis. It is important to correct the causativeabnormality and strengthen the muscle to treat thistendinitis effectively. The other tendon in the hiparea that can cause confusion is that of the iliopsoasmuscle. The psoas muscle originates from the lowerspine and runs through the pelvis, where it joins upwith the iliac muscle coming off the inside of thepelvis. They form a common tendon that attaches tothe upper femur. Especially in sports enthusiastswith faulty technique, a tendinitis with or withoutan associated bursitis can develop and cause painthat is felt deep in the groin. A bursitis here is notinfrequent in rheumatoid arthritis. Since the painworsens with movement, it can be thought to bearthritis of the hip joint unless a very careful exam-ination is done. Adductor tendinitis causes pain atthe inner upper thigh and is worsened by stretchingthe adductor muscles that run down the inner thigh.Horse riders are particularly prone to this, as are bal-let dancers, martial arts practitioners, and othersportspeople.

• Referred Pain Pain referred from the lower backmay be felt at the back or side of the hip area.Pelvic abscesses or those at the back of theabdomen as well as some cases of appendicitismay refer pain to the hip, usually when theyirritate the psoas muscle.

HIV See HUMAN IMMUNODEFICIENCY VIRUS.

HLA A genetic region that codes for tissue typesand is important in determining whether a trans-planted organ is accepted or rejected was identifiedand called the major histocompatibility complex(MHC). The MHC area in humans is on chromosome6 and is called the HLA (human leukocyte antigen)region; it contains many genes involved in regulating

an individual’s immune response. The HLA region isdivided into three regions called class I, II, and III.

HLA class I antigens include HLA-A, B, and Cantigens. One of the best-known genetic markers ofa rheumatic disease is the HLA-B27 tissue type,which is strongly associated with ANKYLOSING

SPONDYLITIS. At each location (locus) in the map ofhuman genes are different possibilities (alleles) thatcan code for proteins that are virtually identical butdiffer in only a few amino acids. This slight differ-ence can, however, change their function. Advancesin molecular biology have led to the ability to sub-classify genetic variants. For example, the HLA-B27tissue type is now divided into subgroups such asHLA-B2701, HLA-B2702, and so on. More exactsubclassification allows clearer identification of thegenetic component of an illness. If we can obtaininformation about the differences in risk or severityof illness in people with different genetic variants, itwill allow us to understand and predict better whathaving a particular genetic makeup (genotype)means for an individual.

HLA class II antigens are divided into DR, DQ,and DP antigens that are usually found on B lym-phocytes and monocytes, although inflammationcan induce their expression on other cells. DR anti-gens are classified into subgroups that can impartrisks for different diseases. For example HLA-DRB1*0401 and *0404 are associated with rheuma-toid arthritis in many ethnic groups.

Just as HLA antigens determine whether anorgan transplanted from one person to another islikely to be accepted or rejected, so too they affectthe immune response to other stimuli and thus alterdisease susceptibility. HLA tissue type affects thedevelopment of T cells, the antigens they recognize,and the antigen peptides that are processed and pre-sented to the immune system. One theory to explainthe association between inherited HLA antigens anddisease susceptibility is that part of a foreign mole-cule, for example a bacterium, could have a similarDNA code to an HLA molecule. Via this molecularmimicry an infection could trigger an immune reaction that targets both the bacterium and self-antigens, in other words, an autoimmune disease.

homeopathy The name is derived from the Greek homoios meaning “like” and pathos meaning

homeopathy 115

“suffering.” This is taken to mean treating like withlike. Practitioners of homeopathy trace their rootsback to Theophrastus Bombastus von Hohenheim,otherwise known as Paracelsus, in the 16th centuryand Samuel Hahnemann in the 18th century.Despite studying medicine, Hahnemann became atranslator of texts. While translating a text on treat-ing malaria with quinine (still used), he began exper-imenting on himself with quinine and believed thiscaused the symptoms of malaria. He therefore devel-oped his theory that giving a patient a substance thatcaused symptoms similar to the disease the patientwas suffering from would bring about a cure.

Hahnemann then set about testing a wide vari-ety of remedies on himself, his family, and hisfriends. Since some of these made people feel quiteunwell, he started diluting his remedies until theside effects disappeared. At this point the effects dis-appeared as well. He is then said to have discoveredthat vigorous shaking of the by now extremelydilute remedy not only restored its effect but madeit even more effective. He called this potentisation.Potentisation and treating like with like remain thecornerstones of homeopathy. Another key conceptis that there is a vital force that was disturbed by ill-ness. There are now several thousand homeopathicremedies that are used in such dilute preparationsthat they are extremely unlikely to retain a singlemolecule of the original substance.

Hahnemann wrote a book explaining whyhomeopathic treatment was effective for acute ill-nesses but not chronic ones. Some would argue thatthis is because many acute illnesses are self-limitingand will get better with or without treatment (e.g.,most common viral infections), whereas chronicdiseases (e.g., most common forms of arthritis) bydefinition will not. James Kent was largely respon-sible for spreading homeopathy in the UnitedStates, and Edward Bach promoted it in the firstpart of the 20th century in London, England. Whilethere is no doubt that some homeopaths are andhave been remarkable healers in the broadest possi-ble sense of the word, there is nothing to suggestthat homeopathic remedies have any effect.

homocystinuria A rare group of inheritedenzyme deficiencies can lead to the accumulationof excessive amounts of the sulfur-containing

amino acid homocysteine. Amino acids are thebuilding blocks of proteins. High homocysteine lev-els interfere with the way collagen links together.Collagen is important in forming connective tis-sues, which include tendons, ligaments, support forskin and other structures, as well as being animportant constituent in bones and joints. Patientswith homocystinuria may therefore develop prob-lems from weakness of these structures.

The ligaments holding the eye lens in place areoften affected, and 80 percent of patients developdislocation of the lens. Half the patients have somereduction in intellectual capacity. OSTEOPOROSIS andHYPERMOBILITY SYNDROME are common. The vascu-lar problems associated with homocystinuria arelife-threatening. A quarter of patients die from vas-cular complications before the age of 30. Thesecomplications include blockage of arteries to theheart, kidneys, and brain, causing heart attack, kid-ney failure, and stroke, respectively.

The condition can be diagnosed by blood andurine tests, and some of the enzyme deficienciescan be identified from pieces of tissue. Successfultreatment depends on early diagnosis. Special dietscan then be introduced that restrict the amino acidmethionine and provide extra cystine. Half of allpatients respond partially to supplementation withpyridoxine, a B vitamin.

housewife’s knee See PREPATELLAR BURSITIS.

human immunodeficiency virus (HIV) A retro-virus that infects T lymphocytes, replicates, damagesthe immune system, and causes AIDS (acquiredimmunodeficiency syndrome). In addition to thewell-known infective complications of HIV infec-tion, several musculoskeletal problems occur.

Cause

HIV is found in many body fluids, but infection istransmitted from person to person by sexual con-tact, by injection of blood or blood products, or byan infected mother to her child during pregnancy.HIV is not highly infectious and is not spread fromperson to person by casual contact. The cause of therheumatic problems associated with HIV infection isnot known, but there are several theories. One isthat HIV itself triggers a local reaction that damages

116 homocystinuria

joints and muscles. In support of this idea, HIV canbe found in inflamed joints. However, it is not clearthat the presence of virus means that the HIV iscausing the arthritis because the virus can be foundin most parts of the body. Another theory is thatHIV, because it suppresses the immune system,increases the frequency of infections and that someof these cause a REACTIVE ARTHRITIS. A third possibil-ity is that the dysregulation of the immune systemthat occurs with HIV infection results in autoim-mune rheumatic problems.

Diagnosis

The diagnosis of HIV infection is usually suspectedwhen a patient develops an infection that wouldnot otherwise occur in a person with a healthyimmune system. There are several diagnostic bloodtests. The most common one is an ELISA screeningtest, but a western blot or detecting the virus itselfusing polymerase chain reaction (PCR) are morespecific. If a patient known to have HIV developsarthritis, few specific tests help diagnose its cause.If the clinical picture suggests that a direct infectionof the joint may be the cause of the arthritis, thenthe joint will need to be aspirated and the fluid sentfor culture. In patients suspected of having myosi-tis or vasculitis, a biopsy of muscle or skin confirmsthese diagnoses.

Symptoms, Treatment, and Outcome

Some patients have symptoms of acute HIV infec-tion within days or weeks after infection. Thesesymptoms are similar to those of many viral ill-nesses and include a nonspecific rash, fever, sorethroat, headache, cough, flulike symptoms, mouthulcers, diarrhea, enlarged lymph nodes, andarthralgia. The acute illness settles spontaneouslyover a few weeks and is followed by a period,which may last years, during which patients do nothave symptoms. As the immune system becomesmore severely affected, patients develop symptomsof AIDS such as loss of weight, diarrhea, enlargedlymph nodes, and opportunistic infections (infec-tions that are not common in healthy people).

HIV treatment has been revolutionized byhighly active antiretroviral therapy (HAART), andthe prognosis for affected patients has improvedfrom almost certain death to a five-year survival

rate of more than 90 percent. Treatment is pro-longed and usually lifelong. It consists of combina-tions of drugs from different classes such asnucleoside analogs, protease inhibitors, and reversetranscriptase inhibitors. Measuring the amount ofvirus in the blood (viral load) can monitor theresponse to therapy. Many patients respond well totherapy, and the viral load can decrease to anundetectable level. However, treatment does notcure the infection and the viral load rapidlyincreases if treatment is stopped.

Most patients with HIV infection have nonspe-cific rheumatic symptoms like joint or muscle painand fatigue over the course of their illness, but aminority also develops more specific musculoskele-tal problems. These often occur months or yearsafter the diagnosis of HIV infection but can some-times be the first symptom leading to the diagnosis.The following musculoskeletal symptoms or syn-dromes, all of which also occur in patients withoutHIV infection and are discussed in detail elsewhere,can occur.

• ARTHRITIS and REITER’S SYNDROME

• PSORIASIS AND PSORIATIC ARTHRITIS

• INFECTIVE ARTHRITIS

• AVASCULAR NECROSIS

• VASCULITIS

• SJÖGREN’S SYNDROME

• SLE and OVERLAP SYNDROME

• MYOSITIS and RHABDOMYOLYSIS

• FIBROMYALGIA

• HYPERTROPHIC PULMONARY OSTEOARTHROPATHY

Arthralgia, arthritis, and Reiter’s syndrome

Arthralgia is a common nonspecific symptom thatcan occur in any chronic illness, but some patientswith HIV develop attacks of acute severe joint painwithout any swelling. These attacks of acute arthral-gia often subside spontaneously over a few days.Several types of arthritis may occur. The most com-mon is a type of arthritis that overlaps with reactivearthritis and Reiter’s syndrome. Asymmetricalswelling of large joints such as knees and ankles andinflammation of tendons such as the Achilles ten-don and of sites where tendons join bone (enthesi-

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tis) may occur. These are sometimes accompaniedby other symptoms of Reiter’s syndrome such asurethritis and conjunctivitis. Experts disagreewhether the incidence of this type of arthritis isreally increased by HIV infection. Some believe thatHIV infection is often a marker for high-risk sexualbehavior, and therefore the incidence of Reiter’ssyndrome would be expected to be higher becauseof this and not because of the HIV infection. Thestrongest argument against this point of view comesfrom studies performed in Africa where Reiter’s syn-drome and reactive arthritis were uncommonbefore the HIV epidemic but are now common med-ical problems, almost always occurring in patientswith HIV infection. Reiter’s syndrome in patientswho do not have HIV infection is usually triggeredby a clearly diagnosed infection such as diarrheacaused by salmonella or urethritis caused bychlamydia. However, in HIV-associated arthritis aspecific trigger is seldom identified. HIV-associatedarthritis is usually treated with NONSTEROIDAL ANTI-

INFLAMMATORY DRUGS to control pain and swelling.In most patients the arthritis settles over a fewmonths, but in some it persists. There are no largescientific clinical trials to provide information howbest to treat this type of arthritis. Clinical experiencesuggests that some patients with persistent arthritisrespond to SULFASALAZINE, a drug also used to treatinflammatory bowel disease and rheumatoid arthri-tis, or to HYDROXYCHLOROQUINE. METHOTREXATE isavoided because some patients have developedKaposi’s sarcoma, a type of cancer that occurs moreoften in patients with HIV infection. If a single jointis particularly inflamed and bacterial infection of thejoint has been excluded, it may respond to an intra-articular corticosteroid injection.

A handful of patients have developed a type ofarthritis that is similar to rheumatoid arthritis withsymmetrical inflammation of the small joints of thehand. It is not clear if this is just coincidence andrheumatoid arthritis has developed in a personwho is also infected with HIV or if this is part of thespectrum of arthritis associated with HIV.

Psoriatic arthritis Severe psoriasis and psori-atic arthritis can occur for the first time after a per-son is infected with HIV. The rash is often pustular.The arthritis is typical of psoriatic arthritis withasymmetrical involvement of large joints such as

the knee or smaller joints of the fingers or toes,causing sausage digits. Psoriatic arthritis in patientswith HIV infection can be difficult to treat.Methotrexate, a drug that would usually be used totreat severe psoriatic arthritis, is avoided because itincreases the risk of infection and may increase therisk of Kaposi’s sarcoma.

Infective arthritis Joint infections are morecommon in patients with HIV infection and aremost commonly caused by a bacterium, Staphylo-

coccus areus, the same organism that is often thecause of infective arthritis in patients without HIVinfection. The symptoms and treatment are similar.Patients with HIV infection, because of immuno-suppression, can have joint infection caused byunusual organisms, including fungi and mycobac-teria. Intravenous drug users with HIV infectionare more likely to get infected joints.

Avascular necrosis Some people who areinfected with HIV get avascular necrosis (AVN) inbones, and this causes acute pain and eventuallyweakening of the bone. Scientists do not knowhow HIV causes AVN.

Vasculitis Most types of vasculitis haveoccurred in patients with HIV. Whether this is justcoincidence or in some way related to the virus isnot clear.

Sjögren’s syndrome Patients with HIV infec-tion can develop a condition similar to Sjögren’ssyndrome with enlargement of the salivary glandsand symptoms of dry mouth and eyes. Sjögren’ssyndrome is caused by proliferation of CD4 lym-phocytes in salivary glands and other tissues. Thesyndrome associated with HIV is caused by CD8lymphocytes and is sometimes called diffuse infil-trative lymphocytosis syndrome (DILS). It caninvolve the lungs and cause difficulty breathing.

SLE overlap syndrome HIV infection does notcause SLE. In fact, because of the immunosuppres-sion it causes, it may protect against it. Becausemany of the symptoms of HIV and SLE overlap, thetwo conditions can be mistaken. For example, fever,loss of weight, arthralgia, arthritis, facial rash, hairloss, glomerulonephritis, leukopenia, thrombocy-topenia, seizures, coma, pneumonia, and a positiveANA blood test can occur in both. A false positiveELISA HIV test can occur in patients with SLE, butmore specific tests for HIV are negative.

118 human immunodeficiency virus

Myositis and rhabdomyolysis HIV is associatedwith several types of muscle disease. Myalgia (mus-cle aching) is very common but occurs with manychronic conditions. Severe loss of muscle massoccurs with advanced AIDS and in some countrieswas called slim disease. An illness very similar toDERMATOMYOSITIS AND POLYMYOSITIS with weaknessof proximal muscles and elevated muscle enzymescan occur. Some of the drugs used to treat HIV canaffect muscles, for example zidovudine (AZT) cancause myositis. Muscles are remarkably resistant toinfection, but in patients with HIV infectionabscesses can occur in big muscles such as those ofthe thigh (pyomyositis). Rhabdomyolysis withsevere muscle damage, very high levels of muscleenzymes, dark urine caused by a protein calledmyoglobin (the result of muscle breakdown), andimpaired kidney function have occurred in approx-imately 20 patients with HIV. Sometimes recog-nized causes of rhabdomyolysis such as prolongedseizures or drug therapy have been present, but insome cases HIV infection has been the only predis-posing cause.

Fibromyalgia Chronic pain, fatigue, andfibromyalgia are symptoms that occur more oftenin HIV infection and many other chronic illnesses.

Hypertrophic pulmonary osteoarthropathy

(HPOA) Chronic bacterial infection, particularlylung infection, can cause swelling of the ends of thefingers (clubbing) and pain and swelling at the endof long bones close to joints like the knee and wrist.Treatment of the infection improves the rheumaticsymptoms.

hypermobility syndrome The occurrence ofmusculoskeletal symptoms in a hypermobilepatient who does not have another recognizablegeneralized rheumatic disease. The exclusion ofanother rheumatic disease is important becausemany of the manifestations of hypermobility canalso occur in people who do not have hypermobil-ity, and it is more the number and wide range ofproblems that typifies this syndrome. Despitehypermobility first being described by Hippocratesmore than 2,000 years ago, it is a difficult conceptfor many people and remains poorly understoodand underdiagnosed. Hypermobility is a feature ofmany inherited disorders of connective tissue such

as Marfan’s and Ehlers-Danlos syndromes. Theseare considered to be separate from what is some-times termed benign hypermobility syndrome.

Unusual looseness of the ligaments can be found,at least in one or two joints, in up to 10 percent ofthe population. It is particularly common in chil-dren and diminishes rapidly during childhood andthen more slowly in adulthood. In general, AfricanAmericans have a greater range of joint movementthan Caucasians, and Asians a greater range thanAfrican Americans. People with hypermobility willfrequently have been called double-jointed as chil-dren and may make career choices as a result oftheir condition. All contortionists are hypermobileas are many ballet dancers. It should be emphasizedthat not everyone with hypermobility will developproblems because of it (see definition above).

Cause

Patients with the inheritable connective tissue dis-eases Ehlers-Danlos and Marfan’s syndromes havereasonably clear-cut abnormalities in the makeupof their collagen or fibrillin (connective tissues).Very likely hypermobility syndrome has similar asyet undefined causes. Hypermobility syndromeoften runs in families, and some differences in themake up of collagen have been shown in thesefamilies. The connective tissues form most of thesubstance of tendons, ligaments, and cartilage aswell as supporting structures such as the skin,arteries, and heart valves. It is therefore theseorgans that show weakness or abnormal function ifthe connective tissue is slightly abnormal.

Symptoms

The problems experienced by people with hyper-mobility syndrome can be divided into four groups.

• More traumatic and overuse injuries occur thanaverage. These include partial or complete ten-don or ligament tears, especially around theshoulder and ankle, and injury with inflamma-tion at the attachment of ligaments and tendonsto bone (enthesitis). Back pain is also common.

• The ligaments are looser than normal, thusjoints may become unstable. This can lead todislocation, either complete or partial (known assubluxation). Commonly affected joints are the

hypermobility syndrome 119

shoulder, kneecaps, metacarpophalangeals, andjaw joint. Flat feet may be a manifestation ofsubluxed joints.

• A chronic arthritis develops. Usually this isOSTEOARTHRITIS, which is likely to develop earlierthan average. A few patients also develop a mildinflammatory arthritis (see ARTHRITIS for the dif-ference) that is secondary to the repeated traumabut is probably often misdiagnosed. Many peoplewith hypermobility syndrome suffer from jointand muscle pain with no obvious abnormali-ties to be found on examination. If the hyper-mobility is not recognized, these people may betold there is nothing wrong with them and frus-tration and depression is then understandablycommon.

• Organs outside the musculoskeletal system maybe affected. The skin may be thin and stretchyand develop striae (scarlike lines similar to thosethat women develop on their abdomens afterpregnancy). Prolapse of the mitral valve mayoccur. This allows blood to leak back from themain pumping chamber in the heart (the leftventricle) to the collecting chamber (left atrium).Individuals with hypermobility syndrome proba-bly have more abdominal hernias, rectal andvaginal prolapse, stress fractures, and the head ofthe thighbone pushing through the pelvic bone(protrusio acetabuli). A number of patients havea physical appearance similar to patients withMarfan’s syndrome (marfanoid habitus).

Diagnosis

Many different sets of criteria for diagnosing hyper-mobility syndrome are still used, although therehave been international efforts to form an agreedmethod. The commonly used major criteria are aBeighton score (see below) of 4/9 or greater andjoint pain in four or more joints for longer thanthree months. Marfan and Ehlers-Danlos syndromesmust be excluded first. Beighton described a series oftests that led to a scoring system for generalizedhypermobility. These are positive if the little fingerbends back more than 90°, the thumb can be bentback to touch the forearm, the elbows and kneesbend backward (hyperextend) excessively (score 1for each side), and if the hands can be placed flat onthe ground with the legs straight (score 1).

If either four out of nine Beighton criteria orpain in four joints are not present, minor criteriacan be used to make the diagnosis, but more areneeded. These include a Beighton score of less than4, more than one joint dislocation, skin striae,recurrent tendon and ligament injuries, Marfan-like body build, mitral valve prolapse, and herniasor rectal prolapse.


The first step in managing hypermobility syndromeis actually to make the diagnosis and provide infor-mation about it. Many patients have sufferedunexplained pain for some time, and understand-ing their condition can give considerable relief. Anassessment of the impact on the patient’s lifeshould be made and sensible advice concerningcareer and recreational choices given. Treatablecomplications such as tendinitis are identified andtreated as they occur. Special caution should betaken before embarking on surgical procedures dueto poor tissue healing and the frequently disap-pointing results from surgery.

Ideally, the patient should be referred to a phys-ical therapist with special experience in hyper-mobility, although such a person may not alwaysbe available. Physical therapy involves teaching thepatient to recognize his or her (greater-than-normal) range of movement and do regularstretches through this range. Muscle strengthening,with most exercises done in the middle of therange of movement, and proprioceptive exercises(such as standing on a wobble board) have beenshown to reduce pain in patients with hypermobil-ity syndrome. Many patients with generalizedhypermobility have flat feet, and appropriate use oforthotics is important. Acute pain is treated withanalgesics and NSAIDs, and chronic pain mayrequire use of low doses of antidepressants and/orCOGNITIVE BEHAVIORAL THERAPY.

The outcome for individual patients will varyconsiderably. Some people may be troubled by so-called growing pains as children and then grow outof it as their tissues tighten up with aging. Otherswith severe hypermobility may experience manyof the problems listed above; develop hip, knee,and back problems in early adulthood; and go on toget early osteoarthritis.

120 hypermobility syndrome

hypertrophic pulmonary osteoarthropathy (HPOA)This can lead to quite rapid onset of pain that usu-ally affects hands, wrists, and ankles but also occa-sionally the elbows and knees. Typically the areaaround the nail bed becomes swollen, giving the fin-gers a drumstick appearance, a finding called club-bing. The pain may be described as deep andburning, and there may be associated sweating inthe hands and feet. The affected areas are mildlyswollen, warm, and dusky red. A careful examina-tion may show that the swelling extends beyond thejoint margins and that the ends of the long bones areexquisitely tender.

HPOA is most frequently caused by lung cancerand may present some months before the cancerbecomes apparent. Other tumors in the chestregion, both benign and malignant, can cause it ascan chronic infections of the lung and heart valves.Occasionally inflammatory conditions affecting theliver or bowel are the cause. The diagnosis is usu-ally made on the characteristic findings on X ray oflifting of the outer layer of the affected bones,termed periostitis. The ESR is raised, but if fluid isremoved from a joint the appearances are notinflammatory.

Successful treatment of the underlying causeresults in prompt improvement in HPOA. Painkillersand NSAIDs are helpful. The outcome depends onwhether the underlying cause is treatable.

hypnosis During hypnosis the subject passes intoa trance. This is an altered state of consciousness inwhich the subject’s attention is intensely focusedwhile attention to other stimuli is reduced. It is nota deep sleep or unconsciousness. The subject isawake and can respond to the therapist. Percep-tion, memory, behavior, and suggestibility arealtered. In therapy the increased suggestibility canbe used to influence behavior and feelings. Hyp-notherapists claim benefit in chronic pain and

chronic fatigue syndrome among many other med-ical and psychological problems. About 85 percentof the population are hypnotizable. A typical ther-apeutic hypnosis session will go through six stages:

1. An introduction explaining what hypnosis isand is not and answering the patient’s questionsand concerns

2. Induction3. Deepening of the trance using two or three

deepening techniques4. The therapeutic work, which may include ego

strengthening, addressing a specific problem,and suggestions for behaviors following the hyp-nosis (posthypnotic suggestion)

5. Dehypnotizing6. Debriefing

Hypnosis should not be performed on peoplewith psychoses, severe depression, drug abuse, ifthe subject is opposed to it (for example on reli-gious grounds), or if the problem being addressed isbeyond the therapist’s competence.

hypophosphatemic rickets An inherited condi-tion in which the kidneys do not reabsorb phos-phate normally, resulting in an excessive loss in theurine. This leads to a condition similar to ricketsbut does not respond to vitamin D (as ricketswould). Patients are usually short with poor teethdevelopment and as adults develop OSTEOMALACIA

(weak bones). Hypophosphatemic rickets is one ofthe causes of CPPD and also results in calcificationof ligaments and new bone formation aroundjoints. Both calcium and phosphate levels in theblood are low, and urinary phosphate levels areinappropriately high. Treatment is with largeamounts of phosphate by mouth together with anactivated form of vitamin D.

hypophosphatemic rickets 121

I

ice A therapy used to alleviate musculoskeletalsymptoms. Physical therapy often involves theapplication of heat or cold (see HEAT) to relievesymptoms and improve function. The major symp-tom of arthritis, painful swollen joints, can some-times be improved by local application of icepacks.Ice can be applied directly, but this is messy. Manypatients prefer to use a packet of frozen vegetablesto apply the cold for 10 to 20 minutes. Somepatients with chronic arthritis find that applicationof cold makes their symptoms worse. Acute traumasuch as sporting injuries to joints, muscles, ten-dons, and ligaments are treated with rest, ice, com-pression, and elevation (RICE).

Cold and pain messages are transmitted throughdifferent nerve fibers, but traffic in one group ofnerves could decrease transmission through others,thus decreasing pain. Also, if the sensation of super-ficial cold is strong, it can distract the brain from pro-cessing pain messages from joints. Cold causes bloodvessels to constrict, decreasing blood flow to theinflamed area and thus decreasing swelling and heat.

Provided ice is not applied for too long, it is safe.A few patients develop urticaria after exposure tocold, but this usually resolves without treatment.Ice treatment is avoided in patients with RAYNAUD’S

PHENOMENON because it worsens their symptoms.

idiopathic thrombocytopenic purpura See THROM-

BOCYTOPENIA.

immune response A complex system of relateddefenses against foreign organisms. Immunity isinnate and acquired. The innate immune responsecan act immediately and does not require previousexposure to an organism or the production of anti-bodies. Innate immunity is provided by phagocytic

cells that engulf and digest invading organisms; aswell as a particular type of lymphocyte called thenatural killer or NK cell. Acquired immunity is tar-geted against specific parts of organisms called anti-gens that the immune system recognizes as beingforeign. It has two components, humoral and cel-lular immunity. The COMPLEMENT system is animportant part of the immune response. Comple-ment helps the process of ingestion and destructionof foreign organisms that have been coated withantibody as well as recruits inflammatory cells tosites of inflammation.

The cause of many rheumatological conditions,for example RA and SLE, is not known. However,because antibodies (rheumatoid factor and antinu-clear antibody (ANA), respectively) against normalcomponents of the body occur, they are consideredautoimmune diseases. The presence of autoanti-bodies does not automatically imply the presenceof an autoimmune disease, for example low levelsof ANA are common in healthy people. Someautoantibodies do not cause damage directly butmay do so when they bind to complement andlodge in tissues such as the kidney. Others directedagainst a patient’s cells can damage them. Forexample antiplatelet antibodies can cause THROM-

BOCYTOPENIA. Why autoantibodies develop andcause disease in some people is not clear. One the-ory is that autoreactive T cells that are normallydestroyed in the thymus gland escape destructionand trigger an autoimmune response. Another isthat the ability of the immune system to tolerateself-antigens is broken down.

Innate immunity Several different types ofphagocytic cells are important mediators of innateimmunity. Monocytes are a type of white blood cellthat circulate in the bloodstream and move into

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inflamed tissues where they change their structurea little and are called macrophages. These mononu-clear cells are important phagocytic cells, but theyalso serve another important function. They ingestand break up foreign proteins into smaller pieces.These pieces (antigens) are then carried to the surface of the cell where they may be recognized byT cells. Because of this function they are sometimescalled antigen-presenting cells. Neutrophils, alsocalled polymorphonuclear leukocytes or polysmake up 80 percent of the circulating white bloodcell population and are important phagocytic cellsthat also contain enzymes that are able to kill anddigest ingested cells. NK cells are also called largegranular lymphocytes and are T cells that are able tophagocytose invading cells. People with a deficiencyof NK cells have an increased risk of viral infection.

Humoral immunity B lymphocytes that pro-duce immunoglobulins mediate humoral immu-nity. These proteins are also called antibodies andare targeted at antigens on invading cells that thebody recognizes as foreign. There are five majorsubtypes of immunoglobulins, IgG, IgA, IgM, IgE,and IgD, that have different properties. For exam-ple, IgM is produced rapidly after an antigen is rec-ognized and IgA is produced mainly by lymphocytesin the gut and other mucosal surfaces.

When B cells are exposed to an antigen, theyproliferate and differentiate into activated B cellsthat produce antibodies that bind to the antigenand neutralize it. Some B cells become memorycells so that when they come across the same anti-gen at a later time, they are able to recognize itrapidly, multiply, and produce antibodies.

Cellular immunity T lymphocytes that pro-duce CYTOKINES and other mediators to inhibit orstimulate other immune cells to carry out theimmune response largely mediate cellular immu-nity. T and B lymphocytes look similar under amicroscope, but they can be differentiated bymarkers on their surface. These markers can bedetected by antibodies and cells categorized intosubtypes designated CD (cluster of differentiation)types. Most T cells are CD4 (helper cells) or CD8(cytotoxic/suppressor) cells. The importance ofCD4 cells in the body’s defense against infection isillustrated by the susceptibility of HIV patients withdepleted CD4 cell counts to a range of infections.

immunodeficiency A state in which the body’sability to fight infection is decreased. Immunodefi-ciency can be primary, caused by genetic abnor-malities, or secondary, due to drugs or infectionsthat affect the number or function of white bloodcells (see IMMUNE RESPONSE). The major complica-tion of immunodeficiency is increased susceptibil-ity to infection. Patients who are unable to makeantibodies efficiently (deficient B lymphocyte orhumoral immunity) are particularly susceptible torecurrent bacterial infections. Those with adecreased cellular immunity (deficient T lympho-cyte or cell-mediated immunity) have a greaterchance of getting viral or fungal infections.

Primary immunodeficiencies are a group of dis-orders caused by genetic defects that affect thefunction of the immune system. Many of the pri-mary immunodeficiencies are also associated withan increased risk of developing malignancy andautoimmune disease.

A drug, infection, or radiation usually causes sec-ondary immunodeficiency. This suppresses or dam-ages bone marrow and decreases the number ofwhite blood cells or affects their function. Humanimmunodeficiency virus (HIV) infection is the mostcommon cause of immunodeficiency worldwide. Incountries where HIV infection is less common, thecommon causes are cancer chemotherapy andimmunosuppressive treatment to prevent rejectionafter organ transplantation. Many serious rheu-matic diseases such as VASCULITIS are treated aggres-sively with drugs such as CORTICOSTEROIDS andCYCLOPHOSPHAMIDE that suppress the immune sys-tem and increase the risk of infection. Several otherconditions such as diabetes, decreased kidney orliver function, malnutrition, and severe burns alsosuppress the immune system.

Cause of Primary Immunodeficiencies

These rare inherited illnesses are subdivided intoseveral subgroups classified according to whethertheir main effect is on antibody production, cellu-lar immunity, or both.

Combined immunodeficiencies Patients havedefects that affect both cellular and antibody compo-nents of the immune response. Symptoms usuallystart in the first years of life with serious, recurrentinfections. Without treatment these diseases are

124 immunodeficiency

often fatal in infancy. Several different genetic con-ditions cause a similar clinical picture. For example,severe combined immunodeficiency (SCID) iscaused by mutations in the interleukin-2 receptor,and adenosine deaminase (ADA) deficiency iscaused by mutations in the gene coding for theenzyme adenosine deaminase.

Disorders in which antibody deficiency predom-

inates Patients can have defective antibody for-mation because B lymphocytes either do notdevelop or do not function normally. Immunoglob-ulin A (IgA) deficiency is the most common pri-mary immunodeficiency. It affects approximatelyone in 700 Caucasians and results in absent or verylow levels of IgA. The range of symptoms andseverity is wide. Some people are completelyhealthy, and others have recurrent sinus, lung, andgastrointestinal infections. Another disorder iscommon variable immunodeficiency (CVID), withan estimated incidence of between one in 50,000and one in 200,000. It affects men and women andis often diagnosed only in early adulthood. Thesymptoms are recurrent sinus and lung infections,diarrhea, and autoimmune disease. Infections withStreptococcus pneumoniae and Haemophilus influenzae

are frequent, but infections with other organismsoccur. In CVID levels of all antibodies aredecreased, but because another function of B cellsis to signal T cells, T cell responses (cell-mediatedimmunity) can also be affected. IgA deficiency isincreased in the families of people with CVID, andthere are families where some members have CVIDand others IgA deficiency.

Rheumatic Symptoms and Primary Immunodeficiencies

Autoantibodies occur more often in patients withprimary immunodeficiencies than in healthy peo-ple, and autoimmune illness can occur. This is mostcommon in CVID, affecting approximately 20 per-cent of patients. A range of autoimmune disorderscan occur, including thyroid disease, hematologicaldisease, polyarthritis resembling RHEUMATOID

ARTHRITIS, SYSTEMIC LUPUS ERYTHEMATOSUS, and SJÖ-

GREN’S SYNDROME. The arthritis associated withCVID is usually chronic and affects knees, wrists,ankles, and fingers but unlike rheumatoid arthritisdoes not cause erosions of bone. In the primary

immunodeficiencies there is an increased risk ofdeveloping lymphoma.

The treatment for the primary immunodeficien-cies associated with severe T cell or enzyme defects isbone marrow transplantation. In patients with defec-tive antibody production immunoglobulin replace-ment therapy with intravenous immunoglobulin(IVIG) decreases the risk of infections.

inclusion body myositis (IBM) This form of inflam-matory muscle disease (compare with DERMATO-

MYOSITIS AND POLYMYOSITIS) was discovered just over30 years ago. Since then it has been increasingly rec-ognized and is now the most common muscle dis-ease in people over the age of 50 years. It occursmostly in older people and is more frequent in men.

Cause

The cause is unknown. Biopsy of involved muscleshows characteristic pinkish-colored inclusions andrimmed vacuoles (cavities) under the ordinarymicroscope. There are also some lymphocytesinvading the muscle and wasting of some musclefibers. The electron microscope shows the inclu-sions to be filaments just like those found in thebrains of people with Alzheimer’s disease. Furtherinvestigations have shown that they contain beta-amyloid protein as in Alzheimer’s. While this doesnot identify what is causing the disease, it doesthrow light on the process of muscle damage. Itshould be stressed that patients with IBM are notmore likely to develop Alzheimer’s disease.

Symptoms

Weakness in affected muscle groups is the mainproblem. Unlike other inflammatory muscle dis-ease, the weakness of IBM comes on very slowly.Although, like polymyositis, it affects the musclesaround the hips and shoulders, IBM is distinct inalso affecting the muscles of the forearms andlower legs. Characteristic problems are weakness ingripping objects and in lifting the toes and feetupward. Weakness and thinning of the quadricepsmuscles (large muscle group in front of thigh) isalso very characteristic of IBM. Some patientsdevelop signs of nerve damage as well.

There is usually a slow increase in weakness overa period of years. The muscles used for swallowing

inclusion body myositis 125

are often affected later on, and this can cause notonly problems with getting adequate nutrition butalso recurrent chest infections.

Diagnosis

Because of the very gradual onset of weakness, thediagnosis is often delayed. Indeed, deciding whenthe disease actually started can be very difficult.When the disease is established, the characteristicdistribution of the muscles affected should suggestthe diagnosis in an older individual. A good musclebiopsy, examined by electron microscopy as well asroutine light microscopy, should confirm the diag-nosis, showing the changes described under Causeabove. The biopsy will also show the extent of scar-ring and replacement of muscle tissue with fat.

Other tests may give supportive evidence. Theenzymes released by damaged muscle can be mea-sured in the blood and are usually only slightlyraised. Creatine phosphokinase is the most useful ofthese. However, these tests are normal in 20 percentof patients. Very high levels, on the other hand,suggest a different diagnosis. Electromyography,involving measurement of electrical activity byputting very fine needles into muscle, may suggestthe diagnosis by showing abnormalities not usuallyfound in inflammatory muscle disease as well asevidence of nerve damage. Occasionally the antinu-clear antibody test is positive but this is not typical.


The treatment of IBM is difficult. One reason is thevery slow progression of the disease so that it cantake over a year to be sure that the treatment isworking or not. Another is that much of the weak-ness is degenerative (accelerated aging) in natureand not inflammatory, and only the inflammationcan be treated. Early attempts to treat the diseasewith CORTICOSTEROIDS (effective in other forms ofMYOSITIS) were not successful. In many patients theweakness actually seemed to get worse. Cortico-steroids are of course recognized to cause muscleweakness as a long-term side effect. In the 1990showever, it became clear that up to half of patientsshow some response to immunosuppressive treat-ment. In IBM response means that the deteriora-tion stops or slows down rather than the patientreturning to normal strength.

Because IBM is uncommon and the response totreatment not dramatic, doing good controlledCLINICAL TRIALS is difficult. Therefore, treatmentrecommendations are necessarily based on inade-quate information. Between 30 and 50 percent ofIBM patients respond to immunosuppression withAZATHIOPRINE or METHOTREXATE. Trying treatmentearly on in the course of the disease before toomuch muscle is damaged is best. Although peoplewith higher muscle enzyme levels (and thereforepresumably more inflammation) at the start oftreatment have a better response rate, the degree oftheir physical improvement is not related to theimprovement in enzyme levels. Responders shouldcontinue with therapy long term. If no response totreatment is seen, it is best withdrawn to preventpossible side effects. A progressive resistancestrength-training program is safe and effective.Very few patients have been treated for more thanfive to 10 years, and it remains to be seen how suc-cessful treatment is in prolonging the health andlife expectancy of those who respond.

A number of other immunosuppressive agentshave been tried in small numbers of patients with-out notable success. These include CYCLOSPORINE,

CYCLOPHOSPHAMIDE, and intravenous immunoglob-ulin. Most patients require assistance with normaldaily activities between five and 10 years afterdiagnosis. Eventually they become wheelchairdependent or bed bound. Progress is quite variable,however, and some patients remain independentafter 20 years.

infective arthritis (infectious arthritis) Arthritiscaused by a foreign organism infecting a joint. Sev-eral viral infections (see VIRAL ARTHRITIS) causearthritis. Whether this is caused by direct infectionof joints or by a reaction to the virus is not clear.Bacteria are the most frequent cause of infectivearthritis, but given the right conditions, virtuallyany organism can infect a joint. Bacterial arthritis issometimes called septic arthritis. Infection with thespirochete Borrelia burgdorferi can cause arthritis(see LYME DISEASE).

Cause

For an organism to infect a joint two things have tohappen. First, the organism has to reach the joint.

126 infective arthritis

Second, the organism has to multiply in the joint.Usually joints are sterile with no organisms presentand have excellent defenses to protect against thefew organisms that might settle there. Organismscan reach a joint by (1) direct penetration, forexample trauma such as surgery or an intra-articu-lar injection; (2) traveling in the bloodstream to thejoint from another infected site, for example pneu-monia, meningitis, and gonorrhea can be compli-cated by septic arthritis; and (3) spreading from anearby skin or bone infection into the closest joint.Several conditions increase the chance of a jointgetting infected.

• Immunosuppression Any condition that decreasesthe immune response (see IMMUNODEFICIENCY)will increase the risk of infective arthritis. This isbecause the body’s immune defenses and those inthe joints are suppressed, and therefore, organ-isms are more likely to gain access to the jointthrough the bloodstream and multiply.

• Trauma Joint damage from any cause increasesthe risk of infective arthritis, but injuries or pro-cedures that penetrate the joint are particularlyhigh risk. If something that is contaminatedwith bacteria penetrates the joint, infection islikely. Penetrating injuries of this type contami-nate the joint with a bacterial load that itsdefenses cannot overcome and occur most oftenin motor vehicle and other accidents and in war-fare. Penetration of the joint by a sterile medicalinstrument, for example as occurs in JOINT INJEC-

TION or ARTHROSCOPY, is very low risk.

• Arthritis Any type of arthritis damages a jointand increases the chances that bacteria circulat-ing in the bloodstream will be able to settle in ajoint and infect it. RHEUMATOID ARTHRITIS is themost common risk factor for developing infec-tive arthritis.

• Artificial Joint The metal and plastic hardwareused to replace a joint does not have naturaldefenses against infection, and prosthetic jointsare more likely to become infected than naturalones.

• Infection If someone has an infection inanother site, organisms will more likely circulatein the bloodstream, settle in a joint, and cause

infection. This can happen with virtually anyinfection, including pneumonia, urinary tractinfection, meningitis, diverticulitis, and INFECTIVE

ENDOCARDITIS. Intravenous drug users who injectdrugs that are not sterile have low levels of cir-culating bacteria that need not cause systemicinfection but can settle in joints and infect them.

Virtually any organism can infect a joint, butgram-positive bacterial infections occur most fre-quently. Staphylococcus aureus is the most commoncause of bacterial arthritis in both natural and pros-thetic joints in adults. Haemophilus influenzae is acommon cause of septic arthritis in children agedone to five years, but the introduction of routinevaccination of children in the United States againstthis infection has decreased the frequency. Infec-tions with gram-negative bacteria occur more oftenin the elderly, children, patients who are immuno-suppressed, and intravenous drug users. Neisseria

gonorrhoeae, the organism that causes gonorrhea, isa common cause of septic arthritis in young, sexu-ally active adults. Septic arthritis is usually causedby a single organism but about 10 percent of infec-tions are caused by several organisms. Such polymi-crobial infection is more likely after penetratinginjury or surgery to a joint and in patients who havepolymicrobial infection elsewhere, for example inthe abdomen after rupture of a diverticulum.

Mycobacterium tuberculosis, the organism thatcauses TUBERCULOSIS, is a common cause of infec-tive arthritis in countries with high rates of tuber-culosis infection. Arthritis caused by othermycobacteria and by fungi are rare and usuallyoccur only in patients with immunodeficiency.Other types of mycobacteria, called atypicalmycobacteria, can also cause arthritis.

Fungal arthritis Several types of fungi canrarely cause arthritis in immunosuppressedpatients. These include Coccidiodes immitis, Histo-

plasma capsulatum, Blastomyces, Aspergillus, Cryptococ-

cus, and Candida.

Symptoms

Bacterial arthritis Symptoms usually startsuddenly and are often severe. In 80–90 percent ofpatients only one joint is infected. The knee isinfected in 50 percent of patients, but hip, wrist,

infective arthritis 127

shoulder, and elbow infection are common. Infec-tion of the sternoclavicular joint, where the collar-bone joins the breastbone, is more likely inintravenous drug addicts. An infected joint throbsand becomes red, hot, swollen, and very painful. Itis difficult for the patient to bend or move the jointat all. There are often systemic symptoms such asfever, but elderly and immunosuppressed patientscan have septic arthritis with a normal temperature.

Gonococcal arthritis Gonococcal infection ofthe genital organs can spread to involve the jointsand causes somewhat different symptoms. Usuallyit infects the joint by spreading through the blood-stream; this is called disseminated gonococcal infec-tion. There is often a rash, which may range fromlarge purple spots to small inconspicuous blistersabout the size of the head of a match. Two types ofarthritis can occur. The first affects several joints,can migrate from one joint to another, and oftenoccurs with inflammation of tendons (tenosynovi-tis). The second is much more similar to classicalseptic arthritis and infects a single joint. Someexperts believe these types of arthritis are differentstages of one process that first affects many sites andthen localizes in one joint. The genital gonorrheainfection usually causes symptoms of urethritis(burning when urinating and a discharge at the endof the penis) in men, but women may carry aninfection without knowing it. Disseminated gono-coccal infection is more common in women and ismore frequent at the time of menstruation.

Tuberculous or fungal arthritis These types ofarthritis do not cause acute symptoms but, rather,slow and progressive arthritis with swelling,warmth, and pain in a single joint. Tuberculosis isparticularly likely to affect the spine, and then itcauses back pain localized to one area.

Diagnosis

If a patient develops a rapid onset of pain, redness,and swelling in a joint, there are only a few likelycauses. These include infective arthritis, trauma,and arthritis caused by crystals (see GOUT or CALCIUM

PYROPHOSPHATE CRYSTAL DEPOSITION DISEASE). Acutegout can be indistinguishable from septic arthritis.In both conditions a single joint is red, hot, swollen,and acutely tender, and the patient may have feverand an elevated white blood cell count and ery-

throcyte sedimentation rate. X rays are often nor-mal and unhelpful in the early stages, the timewhen making the correct diagnosis is most impor-tant. A bone scan will show increased concentrationof the radioisotope in the infected joint, but this alsooccurs with inflammation without infection so it isnot helpful in differentiating the two. MRI is help-ful to evaluate pain in deep joints such as the hip.

Clues to diagnosis of septic arthritis are a historythat the joint has been punctured, infection atanother site, a prosthetic joint, and preexistingarthritis. The diagnosis can be difficult in patientswith rheumatoid arthritis because in RA a singlejoint can sometimes become much more painfuland swollen than others, without being infected.The most reliable way to make the diagnosis of sep-tic arthritis, and the only way to exclude it, is for aphysician to aspirate synovial fluid (see JOINT ASPI-

RATION in Appendix II) and send it to be examinedand cultured. Synovial fluid in septic arthritis isoften white or yellow and looks like pus. Manypolymorphonuclear white blood cells are present. Ifthe fluid is stained and examined under a micro-scope, bacteria may be visible in 50 percent of cases.The bacteria may take one to five days to grow inculture, and therefore, antibiotic treatment is usu-ally started before the culture result is available ifseptic arthritis is strongly suspected. However, cul-ture is still the most accurate way to diagnose septicarthritis and identify the responsible organisms.Joint fluid should also be examined for crystals,because if these are present it suggests that the diag-nosis may be gout or pseudogout rather than septicarthritis. However, infection may occasionally coex-ist with gout.

The diagnosis of gonococcal arthritis is not asstraightforward. It may be suspected because of thepatient’s lifestyle and the presence of a rash. Some-times the diagnosis is confirmed when the gono-coccus is cultured from the blood or synovial fluid.However, in many patients synovial fluid culturesare negative, but the bacterium can be culturedfrom other sites such as the urethra, cervix, andvagina even though patients may not have symp-toms there. The organism can be difficult to cultureunless special techniques are used.

The diagnosis of tuberculous or fungal arthritis isusually suspected if there is a destructive arthritis in

128 infective arthritis

a single joint that progresses slowly over weeks. TheX rays are often abnormal by the time a patient con-sults a physician. In spinal tuberculosis there can bedestruction of the body of a vertebra, the discbetween two vertebrae, and an abscess alongsidethe spine. Diagnosis requires the culture of theorganism, sometimes from synovial fluid but moreoften from a synovial biopsy.


The principles of treatment are aggressive, appro-priate antibiotic therapy and drainage of theinfected synovial fluid. Antibiotics are usuallygiven intravenously for the first week or two toensure that blood levels are high. Once an infectionis under control oral antibiotics can be used. Thechoice of antibiotic ideally depends on the identityof the infecting organism. However, when treat-ment is started before the results of the joint fluidcultures are back from the laboratory, a choice ismade based on the most likely organism in that set-ting and the appearance of organisms seen underthe microscope. The initial antibiotic therapy isusually chosen to cover staphylococcal infectionand is often cephazolin for infections that started inthe community and vancomycin for infectionsacquired in a hospital. If a gram-negative infectionis suspected, different antibiotics are selected oranother antibiotic is added to broaden the spec-trum of organisms covered. Once an organism iscultured from the joint fluid, then the antibiotictreatment can be changed to target that organismspecifically. Antibiotics treatment often lasts four tosix weeks.

Joint fluid can usually be drained by aspiratingit through a needle. This may need to be repeatedif the fluid reaccumulates. The number of whiteblood cells in the synovial fluid decreases as theinfection responds to treatment. Completely drain-ing a joint using a needle can sometimes be difficultbecause the fluid is thick and accumulates in pock-ets. If this happens ARTHROSCOPY is often performedto drain the fluid. Because draining the hip jointthrough a needle is difficult, surgical drainage isusually performed, either directly or by arthros-copy. The outcome of septic arthritis varies a lotdepending on the causative organism, how longthe infection has been present, and the response to

antibiotic therapy. Gonococcal arthritis usuallyresponds rapidly and completely to treatment,while staphylococcal infection responds muchmore slowly and often causes permanent jointdamage. The outcome is worst in patients withother serious medical problems, immunosuppres-sion, and polymicrobial infection.

Prosthetic joints In patients with infected arti-ficial joints the joint often needs to be surgicallyremoved to allow the antibiotics to clear the infec-tion. Prolonged antibiotic therapy, often for manymonths, is required to clear such an infection. Ifthe infection clears, the surgeon may be able toreoperate and put in a new artificial joint.

Tuberculous or fungal arthritis Tuberculousarthritis requires standard treatment with a combi-nation of drugs used to treat tuberculosis. Fungalarthritis is treated with an antifungal drug that isselected according to the sensitivity of the organism.

infective endocarditis This is an infection of theinner lining of the heart, usually involving one ofthe valves that controls the flow of blood throughthe heart. Of people who develop infective endo-carditis, 75 percent have a previously damaged heartvalve. This can be following previous RHEUMATIC

FEVER, an aortic valve with two rather than the nor-mal three cusps, a leaking mitral valve (mitral valveprolapse), congenital heart disease, or an artificialheart valve. Others at risk of developing infectiveendocarditis include intravenous drug users andthose with long-standing intravenous lines for vari-ous reasons such as intravenous feeding andchemotherapy.

Cause

Subacute endocarditis is caused by organisms thatare usually not very effective at causing infections.However, if they are physically introduced into thebloodstream and land on an abnormal valve, theymay do so. Even in these circumstances infection israther unusual. The most common such organismis Streptococcus viridans, which may enter the blood-stream after dental work or because of infectedgums. Instrumentation or surgery on the bowel orgenitourinary system may introduce organismsthat live in those areas such as Escherichia coli, fae-

calis, and bovis. Other bacteria include Streptococcus

infective endocarditis 129

pyogenes, Haemophilus parainfluenza, Neisseria,

Pseudomonas, and Brucella. Acute endocarditis is caused by vigorous organ-

isms that cause severe infections and often affectpreviously normal heart valves. The most commonof these is S. aureus, which is frequently found onhuman skin and may be introduced by puttingneedles in veins or injections.

Culture-negative endocarditis refers to thosepatients in whom the blood cultures do not grow anyorganisms. This may be because the patient has beengiven antibiotics before being investigated (e.g.,when another doctor has not suspected the diagnosisof endocarditis) or because the infection is with anunusual organism that does not grow easily. Theseinclude chlamydiae, rickettsias, fungi, and Brucella.

Symptoms

Acute endocarditis is a dramatic life-threatening ill-ness with fever and rapidly worsening heart fail-ure. Subacute endocarditis comes on more slowly,often with a low-grade fever, loss of appetite,weight loss, feeling generally unwell, and short-ness of breath. Joint pain is common as the diseaseprogresses.

The infection causes little collections of cells anddebris on the valves (vegetations) that can breakoff and cause a stroke; gangrene of finger, toe, oreven limb; or block other important blood vessels.Anemia and heart failure develop, and smallamounts of blood in the urine are common.Changes in the hands such as flat red spots, tenderlumps at the ends of fingers, little black splinter-like bleeds under the fingernails, and a curvingover of the nails (clubbing) are very characteristicand, once present, lead to the diagnosis.

Arthralgia and back pain are common in infec-tive endocarditis, but arthritis occurs less often.Sometimes this is due to the organisms settling inthe joint as well as on the heart valve and causingseptic arthritis (see INFECTIVE ARTHRITIS). More oftenthe arthritis is not due to direct infection of jointsand the synovial fluid is sterile. Knees and anklesare most often affected.

Diagnosis

No diagnostic test is available. The diagnosis mustbe suspected in any patient with an unexplainedfever and a heart murmur and then as much evi-

dence as possible gathered, some of it before treat-ment is started. At least three separate lots of bloodshould be taken to try to grow the organism, andthis should be done before antibiotics are given.Blood tests show anemia and a raised white cellcount. The ESR and C-reactive protein (markers ofinflammation) are raised. Special antibody-basedtests may detect the presence of unusual infectionssuch as chlamydiae, rickettsias, and Brucella.Rheumatoid factor may become positive.

Examination of the urine may show smallamounts of blood and protein. The EKG may beabnormal or may just show a rapid heart rate.Echocardiography is a method of scanning the heartusing the echoes of sound waves (ultrasound) andmay show the vegetations on the valves, leakingvalves, or just the preexisting abnormalities. This isusually done by placing a probe on the chest wall.In difficult cases, though, better pictures can beobtained by passing a probe down the esophagus orgullet and scanning the heart from behind.


Once the diagnosis is made, best bet antibiotics arestarted until organisms are grown from the bloodand tested against specific antibiotics to indicate the optimal treatment. Successful treatment shouldlower the temperature in 10 days and the C-reactive protein within two weeks. Especially inacute endocarditis there may be severe damage tothe valve, and emergency surgery may be the onlyway to save the patient’s life. Despite the advancesin antibiotics and surgery, nearly one in fivepatients with infective endocarditis dies. Rapiddiagnosis, being able to grow the causative organ-ism, and access to urgent surgery when needed arethe most important ways of preventing death.

Following successful treatment, the risk of rein-fection should be assessed and reduced. For exam-ple, teeth may require removal if they are thesource of bacterial infection and preventive antibi-otics should be given at the time of minor surgery.

inflammatory bowel disease (IBD) A term thatdescribes two illnesses, ulcerative colitis andCrohn’s disease, both of which cause chronicinflammation of the bowel and sometimes associ-ated arthritis. There are ethnic and geographic dif-

130 inflammatory bowel disease

ferences in frequency. IBD is rare in most develop-ing countries and is more common in developedcountries where approximately four out of every10,000 people have Crohn’s disease and eight outof 10,000 have ulcerative colitis.

Cause

Despite a great deal of research, the precise cause isnot known. There is a genetic predisposition toIBD. Studies in identical twins suggest that this isstronger for Crohn’s disease than for ulcerative col-itis. If one identical twin has Crohn’s disease, therisk that the other will get it is approximately 50percent. For ulcerative colitis this risk is approxi-mately 10 percent. Genetic studies have linked IBDto a gene on chromosome 16 that codes for a pro-tein called NOD2, but the overall contribution ofthis gene to the risk of IBD is small and othergenetic factors are likely to be involved. The factthat if one identical twin has IBD the other oftendoes not suggests that environmental factors pre-dispose or protect against the disease. One suchenvironmental factor is infection. Infectious causeshave been suggested and sought, but no repro-ducible evidence implicates a particular agent.Studies performed in animal models suggest thatthe presence of bacteria in the bowel seems to beimportant. One theory is that ulcerative colitisresults when the body’s immune system becomesintolerant of the normal bacterial flora in thebowel. Many other environmental factors havebeen studied. Smoking may protect against ulcera-tive colitis but increase the risk of Crohn’s disease,and NSAIDs and psychological stress have alsobeen proposed as triggers by some researchers.

IBD is often regarded as an autoimmune disease,partly because symptoms outside of the gut such asarthritis occur and because treatment withimmunosuppressive drugs is often effective. Also,there is abnormal activation of immune cells withproduction of inflammatory cytokines; however,this often reverts to normal when the disease isquiescent. The cause of arthritis is not known, butthe observation that IBD and several other types ofgut problems are associated with arthritis (seeENTEROPATHIC ARTHRITIS) suggest that perhaps bacte-ria, their cell walls, or toxins they produce leakthrough the inflamed bowel wall into the circula-tion and trigger an immune response in joints.

Symptoms

The symptoms of Crohn’s disease and ulcerativecolitis overlap considerably, but it is usually possi-ble to distinguish them clinically. Crohn’s diseasecan affect any part of the bowel but typically affectsthe small bowel more severely and causes abdomi-nal pain, diarrhea, and loss of weight. Ulcerativecolitis typically affects the colon and rectum moreseverely and causes diarrhea with blood. Crohn’sdisease can cause fistulas (narrow channelsbetween that bowel and the skin) around the anus.Both diseases can be associated with fever, ERY-

THEMA NODOSUM, and uveitis (see EYE PROBLEMS).Uveitis, usually acute, recurrent, and affecting oneeye occurs in 5–10 percent of patients and is morecommon in patients with the HLA-B27 tissue type(see HLA) and arthritis affecting the spine.

IBD can be associated with arthritis affectingperipheral joints, the spine, and sacroiliac joints (seeANKYLOSING SPONDYLITIS and SPONDYLOARTHROPATHY)in 20–40 percent of patients. The peripheral arthritistends to affect a few joints (pauciarticular) and isasymmetrical. Large joints such as the knee andankle are often affected, but the small joints of a digitcan become swollen, causing the whole finger or toeto swell (a sausage digit). The arthritis can flit fromjoint to joint, is rarely destructive, and often settlesspontaneously over a few months. The sites wheretendons join bones are often inflamed (enthesopa-thy). Bowel symptoms of IBD often occur beforearthritis, but rarely joint symptoms can occur first.Flares in arthritis are related to flares in bowel dis-ease more so with ulcerative colitis than withCrohn’s disease, but the relationship is not strong.

If the spine is involved, inflammation typicallyaffects the large sacroiliac joints at the base of thespine and the small joints between vertebral bodiesand between ribs and vertebral bodies (spondyli-tis). This leads to pain and stiffness that is mostsevere in the mornings and tends to improve withexercise. The lower back and neck are affectedmore than other parts of the spine. The symptomsare similar to those of ankylosing spondylitis andare discussed in detail in that section.

Diagnosis

The diagnosis of inflammatory bowel disease isusually made by a gastroenterologist on the basis of

inflammatory bowel disease 131

the symptoms and endoscopy or X-ray studies. Thespecific findings are beyond the rheumatologicfocus of this book.

Arthritis associated with IBD is easy to diagnosebecause the patient is usually already known tohave IBD. Blood tests are not particularly helpful.Anemia caused by a combination of chronic dis-ease, blood loss, and poor absorption of iron, folate,and vitamin B12 is common. The erythrocyte sedi-mentation rate (ESR), a nonspecific marker ofinflammation, is often elevated (see Appendix II).Approximately 50 percent of patients with IBD andsacroiliac arthritis carry HLA-B27, but this test isnot useful for diagnosis. X rays of affected periph-eral joints are usually normal. X-ray changes in thespine and sacroiliac joints are similar to those ofankylosing spondylitis.


Treatment of the gastrointestinal symptoms ofCrohn’s disease and ulcerative colitis is not dis-cussed in detail here. Briefly, ulcerative colitis istreated with a combination of oral and rectal corti-costeroids and aminosalicylates. Aminosalicylatessuch as mesalamine are drugs related to SUL-

FASALAZINE but that lack the sulfa antibiotic compo-nent. If the disease remains difficult to control,AZATHIOPRINE or the closely related drug mercap-topurine is added. Emerging treatments underevaluation include TACROLIMUS, MYCOPHENOLATE

MOFETIL, and TUMOR NECROSIS FACTOR ANTAGONISTS

(TNF). A similar range of drugs is used to treatCrohn’s disease, but rectal enemas are not usedbecause the colon is seldom affected. INFLIXIMAB is

an established treatment for Crohn’s disease, and itis particularly helpful for healing fistulas.

The treatment of arthritis associated with IBD isvery similar to that of ankylosing spondylitis (seeANKYLOSING SPONDYLITIS for a detailed description),but there are few controlled clinical trials to guidedecisions about treatment. NSAIDs can worsen thegastrointestinal symptoms of IBD in some patientsand are used cautiously. Sulfasalzine is a usefultreatment for both inflammatory bowel and jointsymptoms. Azathioprine, methotrexate, and TNFantagonists are useful treatments for arthritis asso-ciated with IBD.

intestinal bypass arthritis Intestinal bypasssurgery may be done to assist weight loss inpatients who are morbidly obese or to bypass ablockage from a tumor that cannot itself beremoved. Up to 25 percent of these patients willdevelop an arthritis affecting the small joints of thehands, wrists, ankles, and sometimes the knees andneck. The arthritis may start two to nine monthsafter surgery and will last a variable time, fromweeks to years. There is often a rash, which canrange from small pustules to red blotches. The ill-ness is caused by overgrowth of bacteria in a loopof bowel that is a dead end. Intestinal bypass arthri-tis has become very rare since this type of opera-tion is seldom done these days. Treatment is withNSAIDs and occasionally corticosteroids. Antibi-otics can improve symptoms by decreasing the bac-terial overgrowth. If symptoms are severe,reversing the bypass will cure the arthritis.

132 intestinal bypass arthritis

J

joint aspiration See Appendix II.

joint fusion See ARTHRODESIS.

joint injection A technique for delivering drugdirectly into inflamed joints. In RHEUMATOID ARTHRI-

TIS, other inflammatory types of arthritis, andOSTEOARTHRITIS, a long-acting, depot corticosteroidcan relieve symptoms when injected into a swollenjoint. This is called an intra-articular injection—intra meaning “in” and articular meaning “joint.”The advantage of injecting a drug into a joint is thata high concentration can be delivered directly tothe site where it is most needed. Most drugs diffuseslowly out of the joint into the bloodstream, butthe dose injected into the joint is low. Therefore therisk of systemic side effects from drugs such as cor-ticosteroids are minimized.

Intra-articular injections of corticosteroids startto work within a day or two, and their benefit canlast for weeks and sometimes months. Occasionallythere is little benefit from the injections. If one ortwo injections into a joint are not effective, there isnot much point trying repeated injections. Steroidinjections can weaken tendons and, although thereis no definite proof, there is concern that repeatedinjections into a joint may damage it. Mostrheumatologists will try to limit the number oftimes a particular joint is injected. Tendinitis andbursitis can also be improved by a depot cortico-steroid injection into the bursa or around a tendon.In some people the results are dramatic and symp-toms resolve rapidly, but in others there is littleresponse. Corticosteroids can be injected into mostjoints, but the hip is usually not injected because itis a deep joint and difficult to reach.

Apart from corticosteroids, the other group ofdrugs often injected into joints are the hyaluronans

(sodium hyaluronate, trade name: Hyalgan, andhylan GF 20, trade name: Synvisc) that are ap-proved for the treatment of knee osteoarthritis.They are administered as a course of three to fiveinjections one week apart.

The usual procedure for a joint injection is thatthe physician explains the risks and benefits of theprocedure, sterilizes the skin with alcohol oriodine, and then injects the drug, keeping the nee-dles and the injection site sterile. Most rheumatol-ogists perform this procedure in their offices and donot drape the injection site with sterile surgicaldrapes. Some numb the skin with a local anaes-thetic before injecting the joint, others numb theinjection site by using a spray of ethyl chloride thatcauses local freezing, and others do not routinelyuse either numbing procedure because the discom-fort from a straightforward joint injection is usuallyminimal and may be less than the pain caused byinjecting local anaesthetic. After a joint has beeninjected patients are usually asked to rest the jointas much as possible for a day or two and arewarned that the joint symptoms may flare immedi-ately after the injection. Joint flares are much morelikely to occur after hyaluronan than corticosteroidinjections.

Intra-articular injections cause few side effects.Allergy or skin irritation from iodine or adhesivetape can occur. Corticosteroids can cause a smallarea of skin around the injection site to lose pig-ment. A few people feel flushed in the face for sixto 24 hours after an injection. Serious side effectsare rare; the most serious is joint infection. Thechance of this happening after a joint injection islow and estimated at about one in 1,000 or less. Ifa joint becomes infected the symptoms of INFECTIVE

ARTHRITIS develop days or weeks after injection.Most physicians warn patients about this possibility

133

and ask them to return immediately if the joint,becomes red, hot, and acutely painful. Intra-articu-lar injections can rarely cause bleeding into a jointbut this is extremely rare in a person whose bloodclots normally.

joint protection The principle of joint protection isto reduce the load on a joint or change its use insome way so as to provide a mechanical advantage.This may be important in caring for painful or unsta-ble joints. It is best illustrated by a few examples:

• Using a walking stick in one hand reduces theload on all the joints in the opposite leg.

• A high chair reduces the load through the kneeson rising (and the muscular force required to doso).

• Long-levered faucets give a mechanical advan-tage to the hand turning them.

• Using a wrist splint supports a grip that is weakbecause of a painful or unstable wrist.

• Long-handled reachers do away with the needto bend to pick clothes up off the floor.

• Buy potatoes that do not need to be peeled (andmake other lifestyle changes).

joint replacement Joint replacement is a salvageprocedure for a severely damaged joint. The primereason for replacing a joint is relief of pain with sec-ondary goals being improving or maintaining func-tion and maintaining personal independence. Jointreplacement must be planned within the context ofthe whole patient and his or her disease. A fit 65-year-old man disabled by advanced OSTEOARTHRITIS

in one hip poses no problem for this type of surgery.However, patients with RHEUMATOID ARTHRITIS mayrequire surgery at a much younger age, frequentlyhave more than one severely damaged joint at thetime of surgery, and may well have other significantconditions such as OSTEOPOROSIS or coronary arterydisease that make surgery more difficult or danger-ous. Factors that may need to be addressed in plan-ning surgery include:

• The demands that the patient is going to put onthe joint and his or her expectations followingsurgery. This includes age, as the expected lifes-

pan of a weight-bearing total joint replacementis only about 10 years in a moderately activemiddle-aged to elderly person. Although thetechnique and results of repeat joint replace-ment have improved markedly over the past 10years, the complication rate does increaseslightly with repeat surgery.

• The order in which joints are operated on. It isno good replacing a painful and disordered rightknee, for example, if the right foot is too painfulto stand on. Similarly, the results of replacingthe knuckle joints in rheumatoid arthritis will bepoor if that wrist is painful and disordered.Assuming all joints to be equally affected, theorder of surgery in the leg is usually foot, hip,knee, and lastly ankle. In the arm the orderwould usually be wrist first, then hand, elbow,and finally shoulder. Obviously, people seldomhave all joints equally affected, but consideringthe reliance of one joint on another for normalfunction is important.

• The state of the other limbs. During rehabilitationafter a right knee replacement, for example, theleft leg must be able to carry the patient’s weight.After lower limb surgery the patient often needsto start walking with the help of crutches or awalker, and his or her arms need to be able usethese and take some of the weight. If not, thismay need to be improved first (for example bylocal corticosteroid injections into painful jointsor use of splints). Lower-limb surgery is usuallydone before the upper limb.

• Sometimes two or more operations can be per-formed at the same time. This reduces the timethe patient has to spend rehabilitating and isalso cost-effective in requiring only one hospi-talization. Lower-limb and upper-limb surgerycan often be combined, and both hips or bothknees may be replaced simultaneously. A hipand knee on the same side, however, could notbe replaced together because the rehabilitationrequired is very different for knees and hips.

• The state of the cervical spine (neck). This is aparticular problem in people with rheumatoidarthritis who may develop instability betweenthe upper two cervical vertebrae that can lead todamage to the spinal cord if moved excessively

134 joint protection

during anesthesia. The cervical spine shouldalways be x-rayed with the head tilted both for-ward and backward to look for instability beforeany general anesthetic. If there is evidence ofearly damage to the spinal cord, the cervicalspine would have to be stabilized before anyother surgery was contemplated.

• Ongoing medication. NSAIDs and ASPIRIN areusually stopped five to seven days before majorsurgery to reduce bleeding. DMARDs are alsosometimes stopped because of the surgeon’sconcern about healing. However, this can leadto a flare of arthritis during the rehabilitationphase that can set back the patient considerablyand add to the cost of the procedure by prolong-ing hospitalization. Evidence now suggests thatpatients with rheumatoid arthritis who continuetaking METHOTREXATE throughout surgery andrehabilitation do better than those who stoppedit for a few weeks. This likely holds true forsome other DMARDS, but medication changes arebest discussed with the patient’s rheumatologistor internist.

• The choice of surgeon. This is one of the mostimportant decisions the patient must make.Undoubtedly, outcomes from joint replacementdo differ among different surgeons and amongdifferent hospitals. While it is possible in somehealth systems to find out the rate of infection orunplanned readmissions following surgery inparticular hospitals, getting this type of informa-tion on individual surgeons is seldom possible.The referring doctor should have a reasonableknowledge of a number of potential surgeons andbe able to discuss the patient’s choice. The sur-geon should clearly explain the proposed surgery,including personal experience with the particularoperation, what to expect afterward during bothrehabilitation and the long term, the range ofpossible adverse outcomes, and the surgeon’sassessment of the likelihood of these happening.Obviously, in some HMO and government-funded systems the choice may be limited.

• The most common serious complications of totaljoint replacement are infection, blood loss, andjoint instability. Deep-vein thrombosis and pos-sible pulmonary embolus (clots in the leg that

can travel to the lungs, blocking vessels there)should be rare, with modern management withlow-molecular-weight heparins (blood-thinningtreatment), compression stockings, and earlymobilization.

Total or partial joint replacement may be doneon a wide range of joints.

Shoulder joint replacement is best when done forsevere osteoarthritis. This is because the shoulder isessentially an unstable joint that requires normalmuscle and soft tissues to hold it in place. This isusually the case in osteoarthritis. On the otherhand, in rheumatoid arthritis the soft tissues haveoften been damaged by years of inflammation andresults of surgery are less predictable. Of primeimportance here is that the rotator cuff be intact(see ROTATOR CUFF SYNDROME for a description of therotator cuff). When the shoulder blade side of thejoint is too damaged to accept the prosthesis, pro-viding good pain relief is still possible by just replac-ing the head of the humerus (upper-arm bone).

In a normal elbow joint the bones making up thejoint are not constrained. That is, if there were notendons, ligaments, or capsule holding them to-gether, they would fall apart. Because there is usu-ally considerable damage to these soft tissues by thetime joint replacement is considered, the earlyelbow joint replacements were designed like a gatehinge (i.e., constrained). This means there is noneof the usual give in the joint and high forces aretransmitted to the cement between the bones andthe metal joint prosthesis. This led to early failureof the joint replacement. Where the soft tissues arehealthy (for example in posttraumatic osteoarthri-tis), using a nonconstrained prosthesis is possible.Advances in design have led to the use of semicon-strained prostheses where an axle prevents thejoint from falling apart (dislocating) but is not partof the weight-bearing surface and therefore doesnot create the same forces at the cement interface.Results of total elbow replacement are thereforemuch improved, and about 90 percent can beexpected to function for at least five years. Painrelief is good and function usually improved.Heavy lifting and significant physical work will leadto early wear and the need for repeat surgery orARTHRODESIS. Patients having this operation most

joint replacement 135

frequently suffer from osteoarthritis, rheumatoidarthritis, JUVENILE ARTHRITIS, or REACTIVE ARTHRITIS.

Hand and wrist surgery needs to be particularlycarefully planned with regard to the patient’srequirements, what is surgically possible, and whatother joints are involved. Ideally an occupationalhand therapist will draw up a list with the patientdetailing all the hand functions that have been lostor compromised. The patient can then roughlygrade these into necessary (e.g., feeding, dressing,personal hygiene), useful (e.g., typing, cooking),and desirable (e.g., hobbies) categories. Cosmeticappearance should never be a reason for surgery.Once the surgeon has assessed the hand, he or shecan then discuss with the patient what can be doneto improve the functions the patient has identified.Therapy following hand surgery is essential for agood outcome. In general, joint replacement in thehand and wrist can be done only when the subse-quent demands on the joint are going to be light.Otherwise arthrodesis is often a better surgicaloption.

The small joints of the hand can be replaced. Jointreplacement of the distal interphalangeal joints isseldom a good surgical choice since arthrodesisgives better results. In the proximal interphalangealjoints, soft tissue procedures and arthrodesis arealso generally preferred to joint replacement,although this can be done if the soft tissues arehealthy and the surrounding joints well preserved.In carefully selected patients joint replacement atthe metacarpophalangeal joints can be very benefi-cial. This is almost always combined with soft tissueprocedures to realign, tighten, or release the sur-rounding tendons and other soft tissues. This is nec-essary to straighten the joint and get it movingcloser to its original plane of motion. A variety ofprostheses are used. A full range of movement isnot possible, and the amount of movement postop-eratively will gradually reduce over a few years.Failure or loosening of the prosthesis is relativelymore frequent here than at other joints. Jointreplacement at the wrist is possible but indicatedonly for a severely damaged joint where movementis required since it is less reliable than fusion. Insomeone with two severely affected wrists it may beappropriate to fuse the nondominant wrist andreplace the dominant wrist.

Total hip replacement is now a reliable, com-monly performed procedure with excellent out-comes. It has one of the highest benefit-to-cost ratiosof all surgical procedures. Pain is almost alwaysimproved and function usually improves. Althoughrunning should be discouraged, limited recreationalactivities are possible. A prosthesis can last up to 20years, but in general, the more active the patient,the shorter the life span of the prosthesis.

Knee movement is complex, and designing pros-theses that adequately mimic the original joint hasbeen difficult. Design has improved rapidly, how-ever, and over 90 percent of total knee replace-ments can be expected to be functioning after 10years. Redoing the joint replacement increases therisk of complications. Knee joint replacement is par-ticularly likely to cause clotting in the leg veins, andthis can occur despite the most diligent precautions.Having strong quadriceps muscles (those in front ofthe thigh) and being able to straighten the leg areimportant for good joint function after surgery.Sometimes the surgeon will need to release the tis-sues behind the knee to get it straight enough. Acontinuous passive motion (CPM) machine is oftenused after knee replacement to improve the rangeof movement.

Ankle joint replacements have proven difficult,and a range of interventions is being explored. Theseare some way from becoming routine procedures.

juvenile arthritis (JA) Chronic inflammatory ar-thritis in children less than 16 years old is also calledjuvenile rheumatoid arthritis (JRA) in the UnitedStates, juvenile chronic arthritis (JCA) in Europe,and juvenile idiopathic arthritis (JIA) in bothEurope and the United States. First thought to beone condition, chronic arthritis in children is nowclassified into four groups, depending on the clini-cal features during the first six months of the illness.

• Pauciarticular JA

• Polyarticular JA

• Systemic onset JA (Still’s disease)

• Juvenile spondylitis (see SPONDYLOARTHROPATHY)

The frequency with which these diseases occurvaries considerably among different populations,

136 juvenile arthritis

with the occurrence generally being higher inNorthern Europe and populations that originatefrom there. For example, 86 per 100,000 Swedishchildren are affected compared with 31 per100,000 Puerto Rican children. There are also dif-ferences in the types of diseases found in differentpopulations. The pauciarticular type is much morecommon in populations of Caucasian Europeanorigin, and polyarticular disease is more commonin African and Indian populations.

Cause

The cause of JA is not known. Infectious andautoimmune causes have been proposed, butresearch to identify the mechanisms responsiblehas not been successful. Juvenile spondylitis, aswith spondylitis in adults, is associated with theHLA-B27 tissue type, indicating that there is anunderlying genetic predisposition.

Symptoms

The different types of JA have different symptoms.

• Pauciarticular JA About half the patients withJA have this subtype. It affects less than fivejoints in the first six months of the disease.These are most frequently the knees, ankles,wrists, and elbows. It occurs in girls five times asoften as in boys; 10–50 percent of patients haveinflammation of the eye, uveitis, that can lead toblindness (see EYE PROBLEMS). Between 10 and20 percent of this group have a positive antinu-clear antibody (ANA) test, and about 90 percentof the children that develop uveitis have a posi-tive antinuclear antibody test. The ANA testtherefore predicts a group at high risk foruveitis, but its absence does not exclude it.Uveitis, which seldom causes warning symp-toms until vision is affected, can occur inpatients with the other subtypes of JA but doesso less often. A subgroup of patients with pau-ciarticular JA overlaps with the juvenilespondylitis group, and some experts prefer toclassify them in that group. These patients oftenhave the HLA-B27 tissue type, pauciarticulararthritis with a lot of enthesopathy (inflamma-tion at sites where tendons join bone), and candevelop spondylitis. This subgroup is sometimes

called seronegative enthesopathy and arthritis(SEA) syndrome.

• Polyarticular JA Arthritis affecting five or morejoints in the first six months occurs in about 30percent of patients with JA. This group is dividedinto those with or without a positive rheumatoidfactor test. Those with a positive test have anarthritis very similar to adult RHEUMATOID ARTHRI-

TIS. Those with a negative test tend to have morefatigue, low-grade fever, and anemia but a betteroutcome. The rheumatoid factor-negative dis-ease involves very similar joints to the systemiconset type, knees, wrists, and ankles being mostcommon. Girls are affected four times as often asboys.

• Systemic Onset JA (Still’s Disease) About 10 per-cent of children with JA have mainly systemicsymptoms when their illness starts. It affectsequal numbers of boys and girls. Symptoms startsuddenly, and a high, spiking fever for severalhours every day is classical. Other symptoms caninclude sore throat, myalgia, arthralgia, loss ofweight, fatigue, abdominal pain, enlargement ofthe spleen and lymph nodes, pericarditis, andrash. The rash is typically a salmon pink, flatpatch that does not itch and is evanescent, fad-ing over a few hours. The rash tends to comeback with the spells of high fever, often late inthe afternoon. If a typical rash is present it is auseful clue to the diagnosis of Still’s disease. Thesymptoms of systemic onset JA can last forweeks and can recur, sometimes years later. Inmost patients polyarticular arthritis develops afew weeks or months after systemic symptoms.

Still’s disease usually occurs in children but canrarely occur in adults and is then called adult-onsetStill’s disease. The symptoms in adults and childrenare similar. Still’s disease starts for the first time insome adults, but in others a careful history revealsa previous similar, nearly forgotten, episode inchildhood.

• Juvenile Spondylitis Some experts prefer toregard the illnesses that are associated with theHLA-B27 tissue type and can cause spondylitisin children as a completely independent entity,

juvenile arthritis 137

but others regard them as a subgroup of JA.ANKYLOSING SPONDYLITIS, affecting young menmuch more often than women, can start inchildhood and causes symptoms similar to thoseoccurring in adults. Other causes of spondy-loarthropathy in adults such as REITER’S SYN-

DROME, PSORIASIS, and INFLAMMATORY BOWEL

DISEASE can also affect children.

Diagnosis

No specific diagnostic test is available. The diagno-sis is made on the basis of the clinical findings andexcluding other causes of arthritis. Viral infectionssuch as RUBELLA and PARVOVIRUS can cause arthritisin children, but the symptoms do not usually lastlonger than a few weeks. Leukemia can be mis-taken for JA in children. Acute bone pain can be asymptom of leukemia, and this can be mistaken forarthritis. In children with leukemia pain is usuallymuch greater than joint swelling, and examinationof blood or bone marrow usually provides the diag-nosis. Arthralgia, but not arthritis, is common inchildren with HYPERMOBILITY and can mistakenly bediagnosed as JA. Other types of inflammatoryrheumatic diseases such as SYSTEMIC LUPUS ERYTHE-

MATOSUS and VASCULITIS can occur in children andbe mistaken for JA.

Systemic-onset JA and adult-onset Still’s diseaseare particularly difficult to diagnose because highfever, elevated white blood cell count, and othersymptoms in a child usually indicate the presenceof an infection or a malignancy. The white bloodcell count in Still’s disease can be high enough tosuggest a possible diagnosis of leukemia. The cor-rect diagnosis, particularly in an adult, is usuallysuspected only after extensive investigations forinfection are negative.

In all types of JA, blood tests for rheumatoid fac-tor are usually negative. About 20 percent of chil-dren with polyarticular JA have a positive bloodtest for rheumatoid factor and a greater chance ofdeveloping severe chronic arthritis with deformi-ties and erosions. In pauciarticular JA manypatients have a positive ANA test but do not haveother features of systemic lupus erythematosus.Eye complications such as uveitis are more likely tooccur in young girls with pauciarticular JA and apositive ANA test.

In systemic-onset JA and adult-onset Still’s dis-ease, the white blood cell count and erythrocytesedimentation rate, markers of infection (ESR), orinflammation, are often elevated. Liver functiontests are also often abnormal. An extremely highblood level of ferritin, a protein that increases withinflammation, can be a clue to the diagnosis ofStill’s disease, but it is not a specific or sensitive test.In all types of JA, the ESR, although not useful fordiagnosis, can be a useful guide to response totreatment in some patients.

X rays are seldom helpful, because they areoften normal in the early stages of JA. X rays of thesacroiliac joints are very difficult to interpret evenin normal children and are therefore seldom help-ful in patients with JA with symptoms that suggestspondylitis.


As is the case for most types of inflammatoryarthritis in adults, JA is treated with nonsteroidalanti-inflammatory drugs (NSAIDs), corticosteroids,and disease-modifying antirheumatic drugs(DMARDs). In Still’s disease the systemic symp-toms often respond dramatically to treatment withan NSAID. Traditionally aspirin has been used, butmore modern NSAIDs, which do not have a risk ofcausing Reye’s syndrome, are effective. NSAIDsand corticosteroids can control symptoms but donot affect the progression of arthritis. In patientswith ongoing joint inflammation, treatment with aDMARD is added. The choice between DMARDs issimilar to that in adults (see RHEUMATOID ARTHRITIS)except that there is less experience with anti-TNFdrugs in children. In approximately three-quartersof patients with JA the illness becomes inactivewithout causing significant disability.

JA itself, and the corticosteroids that are oftenused to treat it, can slow the growth and develop-ment of children. Inflammation caused by arthritiscan affect the nearby growth plate that determineshow fast a bone grows and can lead to asymmetri-cal bone growth. The jaw is often affected, result-ing in an underdeveloped jaw (micrognathia). Hiparthritis in childhood can cause severe joint dam-age so that eventually hip replacement surgery isneeded later in life, even though the disease mayhave been inactive for many years. Patients with

138 juvenile arthritis

JA, particularly those with pauciarticular JA,should be examined regularly by an ophthalmolo-gist. If uveitis is diagnosed early and treated effec-tively, loss of vision can be prevented. In additionto medications and physical therapy, children withsevere arthritis need psychosocial, educational, and

vocational support to help them deal with chronicillness and its consequences.

juvenile rheumatoid arthritis See JUVENILE

ARTHRITIS.

juvenile rheumatoid arthritis 139

K

Kawasaki disease Also known as mucocutaneouslymph node syndrome, this is a form of VASCULITIS

occurring mostly in young children and havinglife-threatening complications. It is particularlycommon in Japan and is named after Dr. TomisakuKawasaki, who described the disease as recently as1967. It occurs worldwide but is more common indeveloped countries. In mixed-race societies suchas Hawaii, it is more common in children of Asianorigin. Boys are affected more than girls. Of thosechildren affected, 85 percent are under the age offive years.

Cause

Despite a lot of research, the precise cause is notknown. It appears to involve an abnormally strongimmune reaction to an infection. This immuneresponse causes the damage. The precipitatinginfection is most likely to affect the throat or lungsand is likely to be any of several infections ratherthan just one particular organism. The evidencesuggests that the affected child’s immune system isprimed to respond in this way whereas most peo-ple will not.

Although many blood vessels are affected inthe early stages, the main brunt of the immuneattack is borne by the medium-sized arteries,especially those taking blood to the heart, kid-neys, and gut. The neutrophil count in the bloodis very high, and these cells, as well as lympho-cytes, move into the walls of the affected bloodvessels where they cause inflammation. Thistends to affect scattered patches of the wall ratherthan the entire blood vessel. After the secondweek, the intensity of the inflammation starts tosubside and the area heals with scarring. Theremay be clotting in the blood vessels during thisstage. By the seventh week most of the inflam-

mation has settled, but the scarred areas of arterywall are weakened and bulge outward. Thesebulges are called aneurysms and frequently leadto narrowing of the artery itself and may lead toclotting and obstruction of blood flow.

Symptoms

The child becomes ill very suddenly with a highfever that usually lasts one to two weeks butsometimes longer. Reddening and thickening ofthe conjunctivas (thin outer layer of the eye)starts on the second or third day. Then the lipsbecome dry, red, and cracked and the inside ofthe mouth very red. The lymph glands in theneck swell and are tender to touch. There may bea reddish rash over the body while the fever ishigh. A very characteristic finding is the redden-ing of the palms and soles at about the same timeas the mouth. This is followed by peeling of theskin, starting at the fingertips, from about thetenth day.

During the first two weeks there is ofteninflammation affecting much of the heart. Thiscauses a rapid heart rate, sometimes leaking heartvalves, breathlessness, and changes in the heartsounds and EKG. If aneurysms and narrowing ofthe arteries in the heart develop, the child maydevelop angina or even a myocardial infarction(heart attack). These aneurysms can occasionallyaffect arteries to the gut, arms, and legs and causegangrene there. The brain may be affected, result-ing in drowsiness, loss of consciousness, orseizures. Paralysis of limbs and the nerve to theface have occurred.

There is often some protein leak into the urine,and pustules may develop on the elbows andknees. Arthritis affecting many joints develops in20–30 percent of children with Kawasaki disease.

141

Diagnosis

Kawasaki disease is diagnosed on the basis of clini-cal findings rather than special tests. The diagnosisrequires the presence of fever for five days plusfour out of five signs of mucocutaneous inflamma-tion. These include the reddened swollen conjunc-tivas with no discharge from the eye; the rash; thered, dry, cracked lips and reddened lining of themouth; the swollen lymph glands; and the charac-teristic changes in the hands.

In addition, the neutrophil count will be veryhigh in the blood and markers of inflammationsuch as ESR and C-reactive protein will be raised.Kawasaki disease may be difficult to differentiatefrom acute infections, and attempts to grow organ-isms from the child’s blood and throat swabsshould be made. These will be negative inKawasaki disease. The fluid surrounding the brainand spinal cord (CSF) will show increased numbersof cells, but again no organisms will grow from it.Echocardiography (ultrasound scanning of theheart) can show the aneurysms on the blood ves-sels and is done at regular intervals throughout theillness. If present, they should be followed up byechocardiography at one- or two-year intervals.Angiograms (injecting dye into the arteries of theheart and then taking X rays of the outlined arter-ies) is done when angina is severe, following aheart attack, or if surgery is thought necessary.


Treatment with INTRAVENOUS IMMUNOGLOBULIN (IVIG)

has dramatically improved the outcome of thesechildren. The immunoglobulin is obtained from theblood of many donors and is treated to destroy allknown infections before being used. It has complexeffects on the immune system but has been shownto be very useful in treating a number of diseasescaused by the immune system, especially variousforms of vasculitis. In Kawasaki disease it is givenas four daily infusions with the dose determined bythe weight of the patient. Low-dose aspirin is alsoused for its antithrombotic (anticlotting) effect. Insevere cases other antithrombotic agents such asdipyridamole and ticlopidine are often used.

The use of CORTICOSTEROIDS in Kawasaki diseaseis controversial. A study in 1979 showed thatpatients treated with corticosteroids developed

more aneurysms than those who did not. This ledto their avoidance in most patients. More recentstudies, however, have suggested some benefitfrom using corticosteroids. Researchers hope that alarger randomized study (see CLINICAL TRIAL) cur-rently underway will settle this uncertainty in thenear future.

Despite treatment with IVIG, 5 percent of chil-dren still develop aneurysms of the arteries to theheart and others develop a more general wideningof the arteries. These patients are at risk of devel-oping angina and heart attacks later in life andshould have long-term follow-up. Cardiac surgeryis necessary in a small number. A very small num-ber of patients may have a second attack ofKawasaki disease.

knee pain The knee is not only the largest joint inthe body, it is in fact two joints. The larger of thetwo is the joint between the thighbone (femur) andthe larger of the lower leg bones (tibia). Thekneecap or patella is a bone within the tendon ofthe quadriceps muscle (the large muscles in front ofthe thigh). The patella forms a joint with the femurthat shares the same capsule as the joint betweenthe femur and tibia. The latter joint has two half-moon-shaped pieces of cartilage called menisci thatboth guide the bones as they move and take about60 percent of the weight going through the knee.In addition, there are a large number of muscles,ligaments, and tendons acting to move or stabilizethe knee. Pain may arise from all these structureseither singly or in combination. Some causes ofknee pain are obvious while others may requireexpert examination and special investigations todiagnose. Some may arise outside the knee. A well-known source of pain referred to the knee is arthri-tis of the hip, for example.

Situated as it is in the middle of a weight-bearinglimb, the knee is especially susceptible to injuryfrom falling, twisting, direct trauma, long-termoverload, and various forms of arthritis. Generallyspeaking, the causes of knee pain differ in variousage groups and they will be discussed accordingly.This does not mean that these conditions occur onlyin children or adults, just that they are more com-mon in those age groups. Because so many struc-tures can give rise to pain, it may help to think

142 knee pain

about pain arising within the joint, around thejoint, and being referred from elsewhere separately.

Knee Pain in Children

Within the knee joint OSTEOCHONDRITIS DISSE-

CANS can occur in many joints but is most fre-quently in the knee. A fragment of cartilage andoften the underlying bone comes loose and thuscauses symptoms. Boys are affected more oftenthan girls.

PATELLOFEMORAL DISORDERS (between thekneecap and thighbone) are common causes ofpain in children and adolescents, particularly ado-lescent girls. The pain is felt in front of the knee,and none of the other specific conditions listed inthis section can be diagnosed. The pain is often feltduring or after sports and may wake the child atnight. These girls tend to be more knock-kneedthan average, but no dislocation or subluxation canbe demonstrated (compare with other patel-lofemoral disorders). They generally have weakquadriceps (large muscles in front of thigh). Somepatients have tight hamstrings (back of thigh mus-cles), and wearing high-heeled shoes may bring iton. Both of these latter conditions increase thepressure between the kneecap and the thighbonein the patellofemoral joint. The treatment is a com-bination of stretching the hamstring and strength-ening the quadriceps muscles. Surgery should beavoided.

MENISCAL TEARS are less common in childrenthan adults but may occur because of a discoid(abnormally shaped) meniscus. The reason for thisshape is not known. These are either treated eitherconservatively or by limited surgery, usually byARTHROSCOPY, leaving the outer rim of the meniscusintact. Cysts can also occur in the meniscus andmay be felt as a bulge along the joint line.

Bipartite patella refers to a condition where thetwo bone centers in the patella do not growtogether as normal and leave a thin layer of carti-lage between them. Because cartilage is weakerthan bone, this can fracture following repetitivestress. It heals well with splinting.

During development of the embryo the knee isdivided into three sections by shelves of tissue calledplicae. These normally disappear but can cause laterproblems if they persist. The one running down the

inner aspect of the joint (medial plica) most fre-quently causes problems by getting caught in themoving joint and becoming inflamed. This is knownas the plica syndrome. It is sometimes diagnosed onclinical examination but often only during arthros-copy done for unexplained knee pain. Treatment isby removal during arthroscopy.

INFECTIVE ARTHRITIS is a relatively more commoncause of knee pain in children and adolescents thanin adults. It usually complicates a blood-borneinfection but may follow a puncture wound. Infec-tion should always be considered in a child with amarkedly swollen, painful knee that comes on sud-denly since a delay in diagnosis can lead to long-term damage. Occasionally, infection can spreadfrom the bone to involve the joint.

Inflammatory joint disease is relatively less com-mon in children compared with adults. JUVENILE

ARTHRITIS of the pauciarticular type is the mostcommon to cause knee arthritis in children.

Around the knee The tendon of the quadricepsmuscle includes the kneecap or patella and thencontinues as the patellar tendon to attach to thelarger of the lower leg bones (the tibia) at a littlebump in the bone called the tibial tuberosity. At thestage when the tuberosity is still attached to themain bone only by cartilage, it can be excessivelystrained. The resulting inflammation causes pain,tenderness, and minor swelling. This is known asOsgood-Schlatter’s disease. It occurs particularly inactive children between the ages of 10 and 14 years.X rays may show some breaking up of the tuberos-ity. Treatment is with rest, avoidance of activitiessuch as jumping, and control of weight gain if thisis a problem. The condition usually disappears asthe cartilage separating the tubercle from the mainpart of the tibia changes to bone in the midteens.Occasionally a loose fragment of bone remains inthe tendon and needs to be surgically removed.

A condition very similar to Osgood-Schlatter’sdisease can occur where the patellar tendonattaches to the lower end of the patella. This isknown as Sinding-Larsen-Johansson syndrome. Itis managed in a similar way.

Tumors and OSTEOMYELITIS in the adjoining bonecan also cause pain felt in the knee.

Referred pain Pain may be referred to theknee as a result of hip disease. Conditions at the hip

knee pain 143

that are particular to children include Perthe’s dis-ease, transient synovitis of the hip, and slippedfemoral epiphysis (see HIP PAIN).

Knee Pain in Adults

Within the knee joint Meniscal tears becomemore common in young adults, often being sus-tained during sport. They often occur together witha ligament injury, especially a torn anterior cruciateligament.

OSTEOARTHRITIS can start in early adulthood ifthere has been significant trauma to the joint,removal of a meniscus, or certain metabolic diseases.Otherwise it is usually a disease of the older adult.

Chondromalacia patellae describes softening ofthe cartilage at the back of the kneecap where itforms a joint with the thighbone or femur. Thisgives rise to an aching pain in the front of the kneeespecially when it is kept bent for long periods, e.g.,in the movies, climbing stairs, or cycling. It mayresult from poor alignment of the patella with thefemur so that there is increased shear force on thecartilage during movement or from tight ham-strings. Treatment is primarily with strengtheningthe quadriceps and stretching the hamstrings.

Inflammatory types of arthritis such as RHEUMA-

TOID ARTHRITIS, ANKYLOSING SPONDYLITIS, psoriaticarthritis (see PSORIASIS AND PSORIATIC ARTHRITIS), andREACTIVE ARTHRITIS all commonly affect the knee.

The large joint between the femur and tibia isdivided into two halves, the medial or inner com-partment and the lateral or outer compartment.Between these compartments two ligaments, theanterior and posterior cruciates, wind around eachother and provide resistance (and therefore stability)to forward and backward sliding as well as rotationof the knee. The anterior cruciate ligament is one ofthe most common structures in the knee injured insport. When an athlete is taking weight on a footwith that knee bent and receives a force pushing theknee inward (either an external force or the individ-ual’s own body weight through loss of balance), theanterior cruciate may be torn along with other liga-ments such as the medial collateral ligament (seebelow). It can also be torn alone by a twisting forcewhen the knee is fully straightened. The patient mayhear a pop and feel the knee giving way, followed bypain and swelling. A complete tear of the anterior

cruciate usually causes the joint to fill up with blood,although it may sometimes leak out of the back ofthe joint if the capsule is also torn. The patient feelsthe knee is unstable to twisting movements.

An incompetent anterior cruciate ligament willoften lead to meniscal tears and early osteoarthri-tis. In athletes complete tears should be surgicallyrepaired as soon as possible. People with lesserdemands from their knees are usually treated byphysiotherapy first to see if they can gain adequatefunction through appropriate muscle strengthen-ing. A number of surgical techniques try to replacethe ligament. These involve using either a whole orpart of a tendon from another area, for examplecutting a strip of the patellar tendon and sewing itin the place of the anterior cruciate ligament.

Tears of the posterior cruciate are much lesscommon and cause less disability. They usuallyoccur when a powerful force drives the tibia back-ward on the femur with the knee bent. Surgicalrepair is not often required, and treatment is byputting the leg in a cast with a slight bend for sixweeks followed by intensive physiotherapy.

Synovial chondromatosis is a disease in whichcartilage starts to grow within the synovium or lin-ing layer of the joint. Many separate areas of carti-lage grow, with enlargement and swelling of thesynovium in the early stages. In addition to stimu-lating the synovium, the cartilage can interferewith the joint by becoming lodged between themoving surfaces. Later on the swelling of the syn-ovium reduces and the areas of cartilage becomepartly calcified so that they stand out clearly on X ray. Synovial chondromatosis can affect any jointbut the knee is by far the most common. It beginsbetween the ages of 15 and 50 and usually presentsas pain in the knee but can also cause lockingwhere the person is unable to straighten the kneebecause a piece of cartilage has become jammed inthe joint. Feeling the cartilage bodies is often possi-ble on examining the joint. Treatment is to removethose cartilage bodies likely to cause problems anda portion of the synovium. This is usually done byarthroscopy and may need to be repeated.

PIGMENTED VILLONODULAR SYNOVITIS affects theknee more frequently than any other joint.

Around the knee BURSITIS is common aroundthe knee and can be puzzling if the location of the

144 knee pain

bursas is not known. The bursa overlying thekneecap frequently becomes inflamed in peoplewho do a lot of kneeling on hard surfaces.Although known as housemaid’s knee, it is morecommonly seen in builders, carpet layers, and elec-tricians. People with inflammatory arthritis or goutare also more prone to this condition. The swellingwith some redness is very obvious. Often it settlesjust with avoidance of kneeling. Occasionally nee-dle aspiration is required and may be repeated. Thebursa should not be lanced since this may lead to aslowly oozing wound that can allow infection toenter the joint. Occasionally resistant cases requiresurgical removal of the bursa.

Just below the kneecap is another bursa, andinflammation of this is known as parson’s knee. Theanserine bursa lies over the inner aspect of the tibiajust below the joint line. Bursitis here frequentlyoccurs in association with a tendinitis of one of theoverlying tendons. Treatment is with rest andNSAIDs.

TENDINITIS may affect any of the many tendonsin the knee area, but some of the more commonproblems will be listed here. In general, patientswith an inflammatory arthritis are more likely todevelop these. Jumper’s knee is a tendinitis of thepatellar tendon as it attaches to the lower end ofthe patella. As the name suggests it often affectsthose involved in running and jumping activities.

Three inner thigh muscles all attach to the innerfront portion of the upper tibia just below the kneejoint. Their common attachment is known as thepes anserinus, which is another site of tendinitis.This is difficult to separate from inflammation ofthe medial collateral ligament (medial ligamentsyndrome) and anserine bursitis (see above).

The iliotibial band is made up of fibrous tissueand forms part of the support mechanism for theknee on its outer aspect. This may become inflamedfrom repeated rubbing against the lower end of the

thighbone, or a bursitis may arise between the two.Long-distance runners are most at risk, particularlyif they run on a camber. It is therefore usuallyknown as runner’s knee.

The knee is particularly susceptible to ligamentinjuries. In addition to the cruciate ligaments insidethe knee, a powerful ligament is on either side ofthe knee (medial and lateral collateral ligaments)that together with a thickening of the joint capsulefunction as supporting ligaments. The lateral collat-eral ligament is a thick, cordlike structure fairlyeasily felt over the outer aspect of the knee. It isdamaged by a force pushing the knee outward withthe foot or lower leg relatively fixed. The medialcollateral ligament on the other side is broad andnot easily felt in healthy people. It is frequentlyinjured at the same time as the anterior cruciateligament, sometimes with a medial meniscal injuryas well. Following injury the patient can sometimesbe left with a tender nodule at the upper end of theligament. X ray shows some calcification in thisarea. This is known as Pellegrini-Stieda disease. If itdoes not settle with rest and NSAIDs a local injec-tion of a low dose of a corticosteroid is helpful.

Popliteal cysts (also called BAKER’S CYSTS) areswellings at the back of the knee. Most of thesecommunicate with the knee joint, some beingbursa and others protrusions of the joint capsuleitself. They are common in people with rheumatoidarthritis and osteoarthritis. Popliteal cysts can burstand cause pain and swelling down the back of theleg. They are then often mistaken for a thrombosisin the leg veins (DVT). The cysts can be aspiratedand injected with corticosteroid but may recur.They can also be surgically removed or drained, butsmall cysts may not require any treatment.

Referred pain Pain referred to the knee fromanother part of the body is usually fromosteoarthritis of the hip joint.

knee pain 145

L

leukocytoclastic vasculitis See VASCULITIS.

livedo reticularis A reddish, purple lacy rashfound on the insides of the arms and legs that isassociated with ANTIPHOSPHOLIPID ANTIBODY SYN-

DROME and CHOLESTEROL EMBOLI SYNDROME.

loose bodies Sometimes called joint mice, theseare any objects that move freely within a joint.They may have been part of the joint such as piecesof bone, cartilage, or meniscus that have broken offor objects that have entered the joint such as frag-ments of bullets. Loose bodies often get coated withcartilage and bone in time and can then be seen onX ray. Many get drawn into the synovial joint lin-ing and can no longer float about the joint. If theyimpinge on the joint surfaces, they can cause painand limitation of movement. The treatment is sur-gical removal if they are troublesome.

lupus See sYSTEMIC LUPUS ERYTHEMATOSUS.

lupus anticoagulant See ANTIPHOSPHOLIPID ANTIBODY

SYNDROME.

Lyme disease This is a relatively new illness thatwas first recognized in the mid-1970s by Dr. AlanSteere and his colleagues as the cause of an unusualoutbreak of what first appeared to be juvenile arthri-tis in Lyme, Connecticut. A previously unrecognizedspiral-shaped organism belonging to the spirochetefamily was identified as the cause of Lyme disease byDr. W. Burgdorfer and colleagues in the 1980s andnamed after him. Lyme disease is an illness that canaffect the heart, skin, nerves, and joints and iscaused by a spirochete transmitted to humans by atick bite. It affects about 15,000 people in the United

States annually, making it one of the commonestdiseases transmitted to humans by animals. In theUnited States it occurs mostly in certain geographicareas, the northeastern states (Maine to Maryland),the Midwest (Wisconsin and Minnesota), and theWest (California and Oregon). In 1999, more than90 percent of cases of Lyme disease in the UnitedStates occurred in nine states—Connecticut, RhodeIsland, New York, Pennsylvania, Delaware, New Jer-sey, Maryland, Massachusetts, and Wisconsin. Lymedisease also occurs in Europe and has been reportedfrom most parts of the world.

Cause

Lyme disease is caused by a spirochete, Borrelia

burgdorferi. In the United States most infections arecaused by B. burgdorferi, but in Europe two differ-ent species, B. afzelli and B. garinii, are more com-mon. The spirochete is transmitted from its usualhost, most often a small animal such as the white-footed mouse or dusky-footed woodrat, to humansby the bite of a tick of the Ixodes ricinus group suchas I. pacificus and I. scapularis (also called I. dam-

mini). The white-footed mouse and other hostsharbor the spirochetes without becoming ill, andtherefore, an infected animal can serve as a reser-voir for infection for an entire summer. A younglarval form of the tick feeds on an infected mouseand then harbors the spirochetes until the nextyear when the tick develops into a more maturenymph form and attaches to another host such as ahuman and transmits the infection. The ticks aresmall, approximately the size of a pinhead, andhave to remain attached to their host for a longtime, 24 hours or more, to transmit infection effi-ciently. There are color pictures of the ticks thattransmit Lyme disease in the New England Journal of

Medicine 1992; 327:542. The infection rate is as

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high as 20 percent if a tick harboring the organismis attached for more than 72 hours and as low as 1 percent if it is attached for less than 72 hours.Infection is more common during the seasonswhen ticks are abundant, usually spring and sum-mer. White-tailed deer, which do not carry thespirochete, are often the preferred host for thespecies of tick that carries the infection. Thus deer,although not directly responsible for the infectionbut because they carry the ticks, are an importantdeterminant of how frequently infection occurs indifferent parts of the country.

Symptoms

One would expect that the first symptom would bea tick bite. But because the ticks are so small, lessthan half the patients with Lyme disease recall a tickbite. The symptoms of Lyme disease are highly vari-able, can mimic many other illnesses, and seem todiffer in the United States and Europe, perhapsbecause different species are the predominant causeof infection. Symptoms can be divided according tothe stage of infection and the affected organ system.

Skin In about 90 percent of patients in theUnited States, even in those who cannot rememberbeing bitten by a tick, a typical skin rash called ery-thema migrans develops about a week after the tickbite. Although it usually develops soon after thebite, it can occur several weeks later. The rash typ-ically develops at the site of the bite, is reddish, isannular (like the rings in the trunk of a tree), andslowly increases in size. The rash, as it slowlyexpands over several days or weeks, clears in themiddle. Similar but smaller secondary skin lesionscan occur at sites where there was no tick bite, andthese are thought to be caused by spirochetes thathave spread through the bloodstream from the siteof the initial bite. Erythema migrans fades evenwithout treatment, usually over about a month,but can persist for up to 14 months and can recur.The rash itself does not usually cause much itchingor pain but may be warm and may be associatedwith systemic symptoms such as arthralgia, myal-gia, fatigue, and headache. These systemic symp-toms are thought to result from the infectionspreading through the bloodstream to other partsof the body and are similar to those that occur witha viral infection such as flu.

In Europe, erythema migrans tends to lastlonger, spread more slowly, and be associated withfewer systemic symptoms. A chronic skin rashcalled acrodermatitis chronica atrophicans thatcauses patches of skin to become thin andunhealthy has been described in Europe but seemsto be rare in the United States. The organism hasbeen cultured from these skin lesions up to 10years after the initial infection.

Neurological A few weeks (two to eight onaverage) after erythema migrans has developed,approximately 15 percent of patients who have notreceived antibiotic treatment have symptoms indi-cating that the nervous system has been infected.These include headache, neck stiffness, difficultythinking, and inflammation of nerves resulting inneuropathy. The nerve that provides movement tothe face is often affected, resulting in weakness orparalysis to half the face (Bell’s palsy) or if bothnerves are affected, to both sides of the face. Theneurological symptoms usually resolve even with-out treatment. However, about 5 percent ofpatients who are not treated develop chronic neu-rological damage than can sometimes show upyears after the initial infection, even though thepatient may have had no symptoms in the inter-vening years. A wide range of chronic neurologicalcomplications has been described, includingdementia, peripheral nerve damage leading toshooting pain and numbness in affected areas,damage to the spinal cord causing weakness of thelegs (paraplegia), and damage to the nerves thatsupply the muscles of the eyes and face.

Cardiac Involvement of the heart occurs in 5 percent of patients, usually several weeks or afew months (two to eight weeks on average) afterthe initial infection and at the same time or soonafter neurological symptoms. Lyme disease canaffect the heart in several ways. Most often itaffects the conducting system that transmits mes-sages about heart rhythm, resulting in the mostcommon symptom—heart block. There are varyingdegrees of heart block of increasing severity. Infirst-degree heart block the only abnormality isthat the distance between the P wave of the ECG,reflecting electrical messages to the atria, and theQRS complex, reflecting messages to the ventricles,is a little prolonged. Patients have no symptoms

148 Lyme disease

and there are no adverse effects on the function ofthe heart. In second-degree heart block the delay intransmission of messages can lead to skipped beatsand symptoms of palpitations. Third-degree heartblock is the most severe and reflects a total lack ofcoordination between the atria and the ventricles.Patients may complain of fainting, dizziness, short-ness of breath, and weakness. Heart block can beintermittent and fluctuate in severity. Inflamma-tion of heart muscle (carditis) can occur and, ifsevere, can decrease the ability of the heart topump blood and cause symptoms of heart failuresuch as edema and shortness of breath. Inflamma-tion of the outer lining of the heart, the peri-cardium, is less common.

Musculoskeletal Arthritis occurs in more thanhalf of infected patients who do not receive antibi-otics. Of these patients, 90 percent develop arthri-tis within a year, usually after about six months,but it has occurred anywhere between four daysand two years after infection. The arthritis oftenaffects one joint (monoarthritis) but can migratefrom one joint to another. In most patients withLyme arthritis the knee is affected at some time intheir illness, but virtually any joint, including thetemporomandibular (jaw) joint, can be involved.Arthritis can cause an affected joint to swell a lot,but there is usually less pain than would beexpected for the amount of swelling. Arthritis isoften intermittent. After several attacks, though,some patients develop chronic arthritis even afterseveral courses of antibiotic therapy have eradi-cated the infection. A few patients have developedsymmetrical swelling of the small joints of thehands, much like rheumatoid arthritis. It is notclear if this unusual event occurs simply becausetwo common conditions, Lyme disease andrheumatoid arthritis, have developed in the sameperson or if this is a rare presentation of Lymearthritis. It is also not clear how the infectioncauses arthritis. B. burgdorferi has seldom been cul-tured from joint fluid, although it is often possibleto detect DNA of the organism using molecularbiology techniques. Some patients who have hadmultiple courses of antibiotics and have no evi-dence of infection with live spirochetes have recur-rent arthritis, suggesting that Lyme arthritis may bea type of REACTIVE ARTHRITIS.

Diagnosis

The unequivocal way to diagnose Lyme disease isto culture the organism from an affected tissue.However, this approach is seldom practical and ishelpful only early in the disease. The organism iseasily cultured from a small biopsy of the erythemamigrans rash. If the rash is typical, physicians in anendemic area usually make the diagnosis based onits appearance without a biopsy. Cultures from sitesother than the skin in patients who have early dis-ease and develop heart, CNS, or joint complicationsare seldom positive. The usefulness of molecularbiology techniques such as polymerase chain reac-tion (PCR) to detect B. burgdorferi DNA is limited asa diagnostic tool because even though the organ-isms may have been killed by antibiotic therapy,fragments may remain, causing a positive PCR test.Urine tests to diagnose Lyme disease are unreliable.

Blood tests are useful in people who have beeninfected for at least a month. In the first two weeksafter infection immunoglobulin M (IgM) antibodiesto B. burgdorferi can be detected in only about 30percent of patients. After four to six weeks mostpatients have positive antibody tests for IgG anti-bodies. If a patient who has been infected for morethan four to six weeks has a test that is positive foronly IgM and not IgG antibodies, this is likely to bea false-positive result. The type of blood test usuallydone to detect antibodies to B. burgdorferi is anELISA (enzyme-linked immunosorbent assay) thathas not been well standardized across laboratories.Because B. burgdorferi shares antigens with othercommon organisms, false-positive tests are com-mon and have given rise to a condition sometimescalled pseudo–Lyme disease that is discussed later. Formost laboratory tests the upper limit of normal is setat a level that excludes about 2 percent of thehealthy population with the highest measurements.The incidence of Lyme disease in states with thehighest rates of infection is approximately six newcases per 100,000 population per year (0.006 per-cent), much lower than the 2 percent cutoff for thelaboratory tests. This means that if one performedLyme antibody tests in the healthy population or inall patients with arthritis, false-positive resultswould be more than 100 times more common thana true-positive result. A more accurate test to detectantigens that are specific to B. burgdorferi is called a

Lyme disease 149

Western blot. This test is unlikely to detect antigensfrom other organisms and is usually performed ifthe ELISA is positive and Lyme disease is suspected.

There are several problems with blood tests forLyme disease that have led to confusion. The keyproblems are as follows:

• Early in the course of infection all blood testscan be negative.

• Some patients who receive antibiotics early inthe course of infection do not develop antibodies.

• A false-positive ELISA test for antibodies is verycommon.

• Tests are poorly standardized, and different lab-oratories can report different results on the samesample.

• In patients with Lyme disease the test for anti-bodies can remain positive years after the acuteinfection. Therefore, even if the infection iseliminated, the blood test can remain positive.

Because of these difficulties, Lyme disease canbe overdiagnosed, and any symptoms that developlater can be ascribed incorrectly to chronic Lyme dis-

ease. The firm diagnosis of Lyme disease is made onthe basis of both clinical findings and blood tests todetect antibodies to the organism. The Centers forDisease Control has proposed criteria to be used forsurveillance purposes. These are erythema migransor at least one clinical symptom of Lyme diseaseaffecting the heart, CNS, or joints and also labora-tory evidence of infection. A positive ELISA testshould be confirmed with a Western blot.


In most patients symptoms of Lyme disease resolvewithout treatment, but antibiotics speed theprocess and prevent long-term complications. Sev-eral antibiotics are effective against Lyme disease,and the stage of disease often determines which ismost appropriate. Most patients with Lyme diseaserecover completely.

• In patients with early disease and erythemamigrans and systemic symptoms, doxycyclinefor 14–21 days is preferred, except in childrenand pregnant women in whom amoxicillin is an

effective alternative. In patients unable to takethese drugs, cefuroxime is the third choice.Studies have shown that these drugs clear theinfection in more than 90 percent of people andrelapse is rare.

• If patients have CNS or cardiac involvement,intravenous ceftriaxone for two to four weeks iseffective. If someone is unable to take ceftriax-one, intravenous penicillin is an alternative.

• Lyme arthritis is treated for 28 days either withone of the oral antibiotic regimens such as doxy-cycline as used to treat early disease or intra-venous ceftriaxone for 14 days. Oral treatment ismore convenient, has fewer side effects, and ischeaper, but some patients have developed lateCNS symptoms despite having received oralantibiotics for Lyme arthritis. The usual approachis to try a course of oral antibiotics first and, if thisfails, to follow with a course of intravenous cef-triaxone. The arthritis can resolve and then recurdespite effective treatment that has eliminatedthe infection. About 10 percent of people withLyme arthritis, despite repeated courses of antibi-otics, go on to develop chronic inflammatoryarthritis. This is thought to be a reactive arthritisand not due to persistence of the organism,because a PCR test on the joint fluid or synovialtissue looking for B. burgdorferi DNA is usuallynegative. These patients have been treated withNSAIDs and occasionally SYNOVECTOMY.

• Chronic Lyme disease is a controversial entity.Some patients who have had Lyme disease havechronic symptoms of fatigue and pain similar toFIBROMYALGIA. Repeated courses of antibiotics donot improve symptoms and may be harmful.Several unconventional treatments for this con-dition, including prolonged courses of highdoses of antibiotics, have not been proven to beeffective. Also controversial is the entity ofpseudo–Lyme disease. This condition describespatients who have chronic pain, fatigue, anddisability and have had a positive blood test,usually an ELISA test, for Lyme disease but haveno classical physical findings. Some physiciansbelieve that these patients have fibromyalgiaand a false-positive blood test for Lyme diseaseand have been given an incorrect diagnosis.

150 Lyme disease

• Antibiotics are not the only treatment for Lymedisease. Prevention is important, and the risk ofacquiring Lyme disease can be decreased bywearing long trousers and socks that prevent theticks from attaching, by using insect repellents,and by checking for ticks after returning fromthe outdoors. Lyme disease can also be pre-vented in two other ways, preventive treatmentafter a tick bite and vaccination. The risk ofLyme disease after a bite by the species of tickthat transmits the disease is usually less than 1percent, probably because most ticks do not stayattached long enough to transmit infection veryefficiently. A single dose of doxycycline can pre-vent Lyme disease if it is given within 72 hours

of a bite, but preventive antibiotic treatment isseldom used because the infection rate is so lowand the species of the offending tick is seldomknown.

A vaccine to prevent Lyme disease was devel-oped and appeared to be safe and reasonably effec-tive but was removed from the market in 2002,probably because profits from the limited sales didnot cover the risks of litigation from patients whodeveloped arthritis or other symptoms after vacci-nation. Disadvantages of vaccination were the needfor three injections in the first year and boosterinjections later. Vaccination was recommendedonly for people with a high risk of infection.

Lyme disease 151

M

magnetic resonance imaging (MRI) See Appendix II.

magnets In about 1000 B.C., a shepherd, Magnes,found that his sandals were attracted to the groundand that this was due to the metal tacks in them.On digging, he unearthed magnetic oxide of iron,commonly known as lodestone. Later, in the 18thcentury, scientists discovered how to magnetizeordinary iron, and these magnets became popularboth for performing tricks and “healing.” Mesmer(of hypnosis fame) used them extensively inachieving miracle cures in the 1770s. In 1938, aScandinavian doctor reported experiencing painrelief when she applied magnets to painful areas.

Electric fields are always accompanied by amagnetic field, and a pulsed or variable magneticfield induces an electric field (Maxwell’s law).Most of the evidence for the biological effect ofmagnetism is in the use of electromagnetic fields.Researchers in this area have also developed themicrowave oven, cellular telephones, and mag-netic resonance imaging (MRI). There is good evi-dence that pulsed electromagnetic fields (PEMFs)stimulate bone growth and are effective for treat-ing nonhealing fractures. The 80 percent successrate is similar to open surgery but less invasive.Approximately 3 percent of long-bone fracturesresult in nonhealing, and the U.S. Food and DrugAdministration approved PEMF stimulators fortheir treatment in 1979.

Experimental evidence also indicates that PEMFaffects cartilage growth although not in the humanbody. Several short-term placebo-controlled studies(see CLINICAL TRIAL) show that PEMF has some effectin relieving pain in OSTEOARTHRITIS. Note that exper-imental work has shown very different effects oncells at different frequencies, and specific frequenciesmay be required to achieve specific results.

Evidence for the use of the static magnets sowidely advertised is less convincing. Several smallstudies show improvement in a number of chronicpainful conditions as well as arthritis in rats. Giventhe ease of studying the use of static magnets it issurprising that there are not more studies reported,and this may indicate the tendency to report onlypositive studies. Despite the considerable enthusi-asm over the past 10 years for the use of manyforms of magnetic therapy, the other side of thecoin is the debate over possible adverse effects.There has been concern particularly about whetherpeople living near power lines or cellular telephonestations are at increased risk of developing tumors.In 1995, the American Physical Society reviewedall the evidence regarding power lines and issued astatement that they could find no relationship withan increased risk of cancer.

meditation Meditation is defined as any activitythat calms the mind and keeps it focused in thepresent moment. This means that the individual isneither reacting to things that have happened inthe past nor making plans for the future. There aremany forms of meditation but they can be dividedinto two basic types.

1. Concentrative meditation involves focusing onthe breath, an image, or a sound (mantra) sothat the mind becomes still and aware. Zenmeditation is usually begun by counting breathsand progresses from simply being aware of thebreath to more advanced techniques. The well-known transcendental meditation involves theuse of a unique meaningless sound, the mantra.

2. Mindfulness meditation involves opening themind to thoughts, feelings, and images andallowing them to float through without reacting

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to them. This has been described as notingthoughts and feelings in a similar way to which apostal worker might note stamps, without eitherpositive or negative feelings about them.

Successful meditation induces a state of deeprelaxation. Studies have shown that this relaxationis associated with a lower heart rate, blood pres-sure, and breathing rate and with reduced muscletension and skin conduction. The levels of lactate(from burning energy) and catecholamines andcortisol (stress hormones) go down and the brainwaves change. Meditation is part of many mind-body programs and, in some form, is often includedin multidisciplinary pain programs. There is goodevidence that meditation can reduce pain levels ina number of conditions.

meniscal tears The menisci are two half-moon-shaped structures in the knee that guide the move-ment of the femoral condyles (lower end of thethigh-bone) against the tibia or lower leg bone (seeKNEE PAIN). They are made of a tough fibrocartilage,different from the cartilage lining the bones in thejoint. Menisci are joints other than the knee, such asthe temporomandibular joint, that can occasionallycause problems, but it is those at the knee that tear.As people age, the cartilage in the menisci developsdegenerative changes and stiffens and the meniscalproblems are therefore different at different ages.

Children very occasionally have an abnormaldisc-shaped meniscus that can catch in the jointand tear. Normal menisci are very unlikely to tearin children. If they are troublesome, the treatmentis to trim them back using ARTHROSCOPY, leaving arim around the joint margin.

Most meniscal tears occur in young adults, usu-ally during sporting activities. The typical injuryinvolves a twisting movement on a weight-bearingknee with the foot relatively fixed. Examplesinclude a basketball player landing unbalancedfrom a jump or a soccer player turning suddenly ona heavy field. In this sort of injury the meniscus istorn longitudinally so that the inner torn portionmay flap into the joint and cause locking, the hall-mark of meniscal tears. With a locked joint theindividual cannot take his or her weight on that legand cannot fully straighten it. There is often dam-

age or complete rupture of a ligament at the sametime. This is most often the anterior cruciate liga-ment. With a severe tear there is immediate, severepain followed by swelling of the knee within a fewhours. If the anterior cruciate ligament is also torn,blood will be inside the joint.

Lesser tears or those that do not result in carti-lage getting between the moving bones maybecome chronic. These may cause clicking withintermittent pain and tenderness along the jointline. The diagnosis is made on the history and useof provocation tests to demonstrate that a piece ofmeniscus interferes with normal joint movement(McMurray’s or Apley’s grinding test). An MRIscan will confirm the diagnosis and also show theextent of the tear and associated ligament damage,which will help in planning surgery. Arthroscopicsurgery is used if treatment is required. The outerthird of the meniscus (i.e., closest to the skin) is theonly part with a blood supply and therefore thepotential to heal. Tears in this portion may there-fore heal and are often sewn together. If the tear isthrough the inner two-thirds, however, the besttreatment is to remove the inner torn bit and cleanup the remaining edges (a partial meniscectomy).

In older individuals there is often no clear-cutinjury. These tears are likely largely degenerativeand are often horizontal through the meniscus.There is localized pain along the line of the joint,perhaps a bit of swelling, and often waking at nightbecause of knee pain. Plain X rays often showcoexisting changes of OSTEOARTHRITIS. MRI scan-ning confirms the diagnosis. Conservative treat-ment should be tried, but if not successful, a partialmeniscectomy can be done. Total meniscectomiesdefinitely predispose people to subsequentosteoarthritis. How great a risk factor partial menis-cectomies will prove to be is not yet clear.

Milwaukee shoulder This is a destructive arthri-tis affecting the shoulder and involving hydroxya-patite crystals. It affects mostly women over the ageof 70 years, frequently has blood in the joint, andis sometimes known as bloody old shoulders. Pain,swelling, and loss of range of movement come onover weeks or months. The pain tends to be con-tinuous, unlike OSTEOARTHRITIS where it is worsewith movement. The swelling is cool, unlike GOUT

154 meniscal tears

or INFECTIVE ARTHRITIS. The joint rapidly becomesunstable, and X rays show severe destruction of thejoint with loss of bone on both sides of the joint.Ultrasound or MRI will usually show destruction ofthe ROTATOR CUFF, which is considered important inthe development of this arthropathy.

Fluid taken from the joint is typically blood-stained and contains hydroxyapatite crystals. Theseare very small and can generally be seen only onelectron microscopy. Because of this they were dis-covered in these severely damaged joints only in1976 and are not routinely looked for. Their role inthe joint destruction is still not clear. There is a ten-dency for the Milwaukee shoulder to settle downin time, although this may take one or two years.Because of this and the limited success of any treat-ment, it is often managed conservatively.

Injection of CORTICOSTEROIDS into the joint is bestavoided since it has not been shown to be benefi-cial and may make the crystal deposition worse.Painkillers and NSAIDs are used where safe to doso but have only limited value. Using a long-actinglocal anesthetic to block the suprascapular nervethat runs over the top of the shoulder blade andsupplies the shoulder joint may give good painrelief. Surgery is difficult because of the degree ofdamage to the tissues around the joint.

mixed connective tissue disease The symptomsof rheumatic diseases often overlap, especially earlyin the course of the illness. When this happens andno specific diagnosis is obvious, the term OVERLAP

SYNDROME, or undifferentiated connective tissue dis-ease, is often used to describe the illness. In 1972,Dr. Sharp described a distinct subgroup of patientswith overlapping symptoms of SYSTEMIC LUPUS ERY-

THEMATOSUS (SLE), SCLERODERMA, and MYOSITIS whohad an antibody to extractable nuclear antigen(ENA) and named the condition mixed connectivetissue disease. The ENA antibody test has since beenrefined and is now named RNP (ribonuclear proteinantibody). Mixed connective tissue disease wasthought to represent a group of patients with a dis-tinct illness and prognosis. However, it is not clearthat this is the case. When patients with mixed con-nective tissue disease were followed for many years,their illness often evolved into classical SLE, sclero-derma, or myositis. Furthermore, the RNP antibody

test is not specific for mixed connective tissue dis-ease and occurs in patients with SLE and other clas-sical autoimmune diseases. Mixed connective tissuedisease is probably best thought of as a subset ofpatients with overlap syndrome who have antibod-ies to RNP. It is not clear that there is any clinicalusefulness in making this distinction.

Cause

As is the case for the autoimmune diseases thatcomprise mixed connective tissue disease, its causeis not known. The various theories proposed aredescribed under systemic lupus erythematosus,scleroderma, and dermatomyositis.

Symptoms

Patients have combinations of symptoms that over-lap various autoimmune diseases. These symptomsinclude Raynaud’s phenomenon, trouble swallow-ing, and tightness of the skin that are typical ofscleroderma; pleurisy, arthralgia, arthritis, mouthulcers, rash, and pericarditis that are typical of SLE;and muscle weakness typical of myositis. The pat-tern of symptoms can change over time, and inmany patients the illness evolves over time towardSLE, scleroderma, or myositis.

Diagnosis

The diagnosis is clinical. All patients have a positiveantinuclear antibody (ANA) test and by definitiona positive test for RNP antibodies.


The treatment of overlap syndrome involvesaspects of the treatment of SLE, scleroderma, andmyositis. The treatment for individual patients isselected according to the symptoms present.NSAIDs are often used to treat arthralgia andarthritis; corticosteroids to treat myositis, pleurisy,and pericarditis; immunosuppressive drugs to treatkidney disease; and antireflux drugs to treat diffi-culty swallowing. Patients are monitored becausetheir illness is likely to change over time and evolvetoward one of the classical autoimmune diseaseswith a prognosis similar to that disease.

morphea See SCLERODERMA.

MRI See MAGNETIC RESONANCE IMAGING in Appen-dix II.

MRI 155

multicentric reticulohistiocytosis A rare disor-der in which cells called histiocytes and multinu-cleate giant cells are filled with fat and infiltrateinto tissues, especially skin and joints. It is mostly adisease of middle age but can occur at any age. In60 percent of patients the arthritis starts before theskin is involved and diagnosis is then very difficult.The typical appearance in the skin is of nodules upto 2 cm in diameter, reddish in color, and number-ing from a few to several hundred. Hands, ears,face, chest, lips, and the inside of the mouth andthroat can all be involved. The arthritis resemblesthat of RHEUMATOID ARTHRITIS, except that the jointsat the ends of the fingers (distal interphalangeals)are often involved. It is often a highly destructivearthritis.

Other organs, including the lungs, heart, stom-ach, thyroid, and bone marrow may be affected.There may be a mild anemia, raised ESR, and mod-erately high cholesterol, but none of these help withthe diagnosis. X rays show destructive joint lesionsthat are difficult to differentiate from rheumatoidarthritis. Biopsy of the skin nodules or joint lining(synovium) shows the typical fat-filled cells. Manyconditions are associated with multicentric reticulo-histiocytosis. Nearly 50 percent of patients react positively to a skin test for tuberculosis (TB), and afew patients have had active TB. About a third haveother skin lesions, suggesting raised cholesterol(xanthelasma), and a number have had autoim-mune diseases. About a quarter have had cancers ofvarious kinds. These have included cancer of thebreast, stomach, lung, bowel, cervix, ovary, andblood and also melanoma.

Treatment is difficult. Successful treatment of anumber of cancers and TB has improved the jointand skin disease in a few patients. However, low-ering cholesterol levels, CORTICOSTEROIDS, andother medications used for rheumatoid arthritis aswell as blind treatment for TB (i.e., without a def-inite diagnosis) have not been particularly useful.The powerful immunosuppressants CYCLOPHOS-

PHAMIDE and CHLORAMBUCIL have improved orhalted the disease most consistently and are usedfor severe disease. Because of their potential sideeffects, however, mild disease is sometimes besttreated symptomatically with painkillers orNSAIDs.

myasthenia gravis An autoimmune disorder thatresults in muscle weakness and is caused by anti-bodies against receptors for a chemical messenger,acetylcholine, that transmits messages from nervesto muscles. Myasthenia affects about 10 people outof 100,000 and, although it can occur at any age,most often affects young or middle-aged adults andwomen more often than men.

Cause

Although about 80 percent of patients with myas-thenia gravis have antibodies against acetylcholinereceptors, the underlying cause of myasthenia is notknown. Individual patients form antibodies againstslightly different parts of the acetylcholine receptor,so it is not a case of a unique antibody causing thedisease. The approximately 20 percent of patientswho do not have antibodies against acetylcholinereceptors by standard tests may have them if a moresensitive assay is used or may have antibodiesagainst other muscle enzymes or receptors. There isan increased risk of myasthenia in patients withother autoimmune disorders such as thyroid disease,rheumatoid arthritis, and SLE. The reason for this isnot known. One possibility is that T lymphocytesthat have been activated by an underlying autoim-mune disease stimulate B lymphocytes to produceantibodies against acetylcholine receptors. The thy-mus gland, an organ that lies just underneath thesternum (breastbone), seems to play an importantrole in the cause of myasthenia. This observationwas first made when physicians noticed that patientswith a tumor of the thymus gland, called a thy-moma, developed myasthenia much more oftenthan other people did. The thymus plays an impor-tant role in programming lymphocytes to react, ornot react, against various antigens. Another clue tothe cause of myasthenia may be that PENICILLAMINE,a drug that was previously used to treat rheumatoidarthritis but has now been replaced by more moderndrugs, can cause myasthenia as a side effect. Theway in which penicillamine causes myasthenia isnot clear, but it can also cause other autoimmunediseases such as glomerulonephritis, suggesting thatit somehow activates autoimmune responses.

Symptoms

The key symptom of myasthenia is weakness thatcomes on, or gets worse, when a muscle is used

156 multicentric reticulohistiocytosis

repetitively. Myasthenia often starts in a few muscles,a type of disease called localized myasthenia, and atthis stage patients may not realize that symptoms arerelated to use. For example, myasthenia often startsin the muscles that move the eye or those that carryout the act of swallowing, and therefore a patientearly in the illness may notice only occasional doublevision, droopy eyelids, or difficulty swallowing. Inabout 80 percent of patients with myasthenia thefirst symptoms affect the eyes, but over time mostdevelop generalized disease with symptoms in manymuscles. In about 20 percent of patients the illnessremains localized to a few muscle groups.

Diagnosis

The clinical findings are helpful in diagnosingmyasthenia and in distinguishing it from rheuma-tological causes of weakness. In myasthenia theeye muscles are often affected, causing droopy eye-lids (ptosis) that fatigue easily. Ptosis can occur inother neurological diseases, but then it is almostalways fixed and does not fluctuate. If a physiciancan make ptosis appear by keeping a patient look-ing up for a time to fatigue the muscles that keepthe eyelids open, it is a valuable clue to the diag-nosis of myasthenia. Other clues are double visionand difficulty swallowing that fluctuates in sever-ity. DERMATOMYOSITIS AND POLYMYOSITIS are rheuma-tological conditions that cause muscle weaknessand have to be distinguished from myasthenia.Although these conditions often affect swallowing,the proximal limb muscles (thigh and shoulder) aremuch more severely affected in dermatomyositisand polymyositis and the eye muscles are usuallyspared. In myasthenia, muscle strength typicallyfatigues rapidly, but later in the illness weaknessmay be present all the time, making it more diffi-cult to distinguish from polymyositis.

Blood tests also help distinguish myasthenia frommyositis. In myositis the levels of muscle enzymes(creatine phosphokinase) are often elevated, but inmyasthenia they are usually normal. In myastheniaa blood test for acetylcholine receptor antibodies ispositive in more than 70 percent of patients. The testis more likely to be positive in patients with severegeneralized disease than those with localized myas-thenia. False-positive tests are rare but can occur inother autoimmune diseases such as SLE.

The classical test for myasthenia is called theTensilon test. Edrophonium (Tensilon) is a drugthat increases the levels of the transmitter acetyl-choline by inhibiting its breakdown. The increasedconcentrations of acetylcholine are able to over-come the blocking effects of the antibodies againstthe acetylcholine receptor, temporarily, and thesymptoms of myasthenia improve dramatically.Edrophonium is injected intravenously and symp-toms improve almost immediately, with theresponse lasting about 10 minutes. Mild side effectsoften occur, such as nausea, sweating, abdominalcramps, and lightheadedness from the test, butmore serious problems such as low blood pressure,vomiting, asthma, slow heart rate, and worseningof weakness are unusual.

Electromyography (EMG) is a test in which thinneedles are placed into muscles to measure theirresponse to electrical stimulation. The height of thesignal reflects the response and in myasthenia afterrepeated electrical stimulation the responsedecreases in amplitude.

A chest X ray or CT scan is often performed tolook for an enlarged thymus gland.

A combination of clinical findings, acetylcholinereceptor antibodies, a Tensilon test, and an EMG isused to make the diagnosis.


There are several different treatments for myasthe-nia that can be divided into three groups: (1) drugsthat increase the concentrations of the neurotrans-mitter acetylcholine; (2) drugs that modulate theimmune response; and (3) surgical removal of thethymus gland. Several drugs such as aminoglyco-side antibiotics, tricyclic antidepressants, andphenytoin can worsen the symptoms of myasthe-nia and should be avoided if possible.

Drugs that increase the concentrations of the

neurotransmitter acetylcholine Acetylcholine isreleased by the nerve and acts on its receptor tostimulate muscle response. Several drugs, such aspyridostigmine and neostigmine, inhibit the enzymeacetylcholinesterase that breaks down acetylcholine.These drugs, also called anticholinesterases, there-fore increase the concentrations of acetylcholine inthe nerve terminal. Increased concentrations ofacetylcholine can partially overcome the blocking

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effects of antibodies against acetylcholine receptors.Treatment with anticholinesterase drugs improvesthe symptoms of myasthenia, but it does not treatthe underlying problem. If very high doses of anti-cholinesterases are prescribed, they can cause highlevels of acetylcholine to accumulate in the nerveterminal and paradoxically cause weakness that isdifficult to distinguish from myasthenia.

Modulation of the immune response Manydrugs that alter the immune response have beenused to treat myasthenia, but CORTICOSTEROIDS arethe most widely used. Most patients treated withcorticosteroids improve, usually within a few weeks,and about 30 percent go into remission. High dosesof steroids can sometimes worsen myasthenia, somany physicians start with a medium or low doseand slowly increase it. If remission does not occur orif the disease relapses when the doses of cortico-steroids are decreased, another immunomodulatingdrug such as AZATHIOPRINE is usually added. In somepatients the combination of corticosteroids and aza-thioprine is not effective and alternative treatmentssuch as CYCLOSPORINE, INTRAVENOUS IMMUNOGLOBU-

LIN, or PLASMASPHERESIS are tried. The combinationof corticosteroids and azathioprine or another im-munomodulating drug controls myasthenia withlower doses of steroids than would otherwise be pos-sible, thus avoiding the side effects that often accom-pany high-dose steroids.

Surgical removal of the thymus gland Thymec-tomy is usually performed to remove the tumor inpatients who have a thymoma. If surgery is notpossible for technical reasons or because thepatient is in poor health, the tumor is treated withradiation therapy. Physicians noticed that thesymptoms of myasthenia improved after thymec-tomy in patients who had a tumor, and this led totrials of thymectomy in patients with myastheniathat was not associated with a thymoma. There areno definitive trials, and experts differ in theirassessment of the usefulness of thymectomy inmyasthenia. Nevertheless, because the currentconsensus is that it is useful, thymectomy is fre-quently performed in younger patients with gener-alized myasthenia. Symptoms can worsenimmediately after surgery, so it is important thatthe surgery be performed in a center with experi-ence in the management of myasthenia.

Treatment of myasthenia can usually controlsymptoms or put patients into remission, but pro-longed treatment is often needed. The symptoms ofmyasthenia can suddenly worsen, sometimes forno apparent reason and sometimes after an infec-tion or some other illness, and cause severe weak-ness affecting the muscles needed for breathing.This is called a myasthenic crisis and needs urgenttreatment. Sometimes this involves placing thepatient on a respirator in an intensive care until thecrisis has resolved.

myocarditis Inflammation of the heart muscle(myocardium) that can occur as part of manyinfectious and autoimmune illnesses.

Cause

The most common cause of myocarditis is a viralinfection. Why some viruses affect the heart, and doso only in a few people, is not clear. Lyme disease isanother infectious cause. Myocarditis is not com-mon in autoimmune illness but can occur in patientswith SYSTEMIC LUPUS ERYTHEMATOSUS, SCLERODERMA,

DERMATOMYOSITIS AND POLYMYOSITIS, and VASCULITIS.Another cause of myocarditis, RHEUMATIC FEVER, fallssomewhere between an infectious and an autoim-mune disease. Rheumatic fever is an autoimmunereaction to a streptococcal infection, usually a strepthroat, but by the time myocarditis occurs, theorganism may already be gone.

Symptoms

The symptoms of myocarditis vary and can includechest pain, tiredness, shortness of breath, rapidheart rate, low blood pressure, and symptoms ofheart failure such as edema. Inflammation of the heart muscle can also be associated withinflammation of other parts of the heart such as theheart valves (endocarditis) and the outer lining ofthe heart (pericarditis).

Diagnosis

The diagnosis is usually made clinically based onthe symptoms, ECG, and ultrasound examinationof the heart. Occasionally a biopsy of the heart isobtained by threading a catheter through one ofthe large veins in the groin or neck into the rightside of the heart and using a tiny forceps to obtaina small amount of tissue. This technique, endomy-

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ocardial biopsy, is safe and is used to monitorpatients who have had a heart transplant for signsof rejection but unfortunately provides only aminute sample of tissue that can be very difficult tointerpret.


There is no generally accepted specific treatmentfor myocarditis. The symptoms of heart failure aretreated with drugs to increase the elimination offluid (diuretics) or increase the efficiency of heartmuscle contraction (digoxin and angiotensin-converting enzyme inhibitors or vasodilators). Inpatients who have an autoimmune disease treat-ment with corticosteroids and other immunosup-pressants is often tried. Some types of myocarditislast only a short time and resolve completely, butothers can cause permanent heart muscle weak-ness and heart failure.

myopathy The term myopathy indicates any dis-ease of muscle that does not involve inflammation.Although not very common, there are many differ-ent causes of myopathy. Those involving arheumatic disease or treatment are discussed else-where in this book. The more common causes arebriefly discussed here. They all cause weakness astheir main symptom. EMGs and muscle biopsies(see DERMATOMYOSITIS AND POLYMYOSITIS) are oftenessential in making the correct diagnosis. Musclebiopsies in particular can be difficult to interpretand should be examined by a pathologist with aspecial interest in muscle disease at a center thatprocesses a large number of specimens.

Neuromuscular disorders Normal nerve func-tion is essential for healthy muscles, and anythingaffecting motor nerves will impact on muscle func-tion. Many such disorders will present with obvi-ously neurological symptoms.

• MYASTHENIA GRAVIS and Eaton-Lambert syndromeaffect the junction between nerve and muscle.

• Diabetic amyotrophy, Guillain-Barré syndrome,and others affect proximal nerves as they leavethe spine. Guillain-Barré syndrome is a fairly fre-quent cause of paralysis, affecting mostly youngadults but also older individuals on occasion. Typ-ically it starts with altered sensation in the feet

and then progressive weakness that affects thelegs first and steadily moves up the body. It canstop at any stage, but if it progresses to involvethe chest, the patient may need ventilation tostay alive. Swallowing, bladder function, andnerves of the head and face may be affected.About 70 percent of patients have had an infec-tious illness just prior to onset of paralysis, andthis is thought to trigger it. Diagnosis is madefrom the typical clinical picture, finding a highprotein level but normal cell count in the cere-brospinal fluid (the fluid that surrounds the brain and spinal cord) and excluding other possi-ble causes. Treatment involves care of a paralyzedpatient, prevention of thrombosis, ventilationwhen necessary, and plasma exchange or intra-venous immunoglobulin infusions in severe dis-ease. Typically 80 percent of patients make a goodrecovery, 15 percent are left with some disability,and 5 percent die. A poorer outcome is suggestedby older age of onset, preceding diarrheal illness,rapid onset of weakness, ventilation, and thepresence of antiganglioside antibodies.

Muscular dystrophies The muscular dystrophiesare a group of inherited conditions that cause pro-gressive muscle dysfunction. Each syndrome isunique in its genetic abnormality and presentation.Common muscular dystrophies include Duchenne’s,Becker’s, facioscapulohumeral, and limb girdletypes. Many of these present in childhood or earlyadulthood, and there is frequently a family historyto suggest the diagnosis. This group of diseases is notgenerally regarded as rheumatic and will not bedealt with in detail in this book.

Malignancy Malignancy can cause musclewasting and weakness because of poor nutrition,general debility, and the cytokines produced eitherby the tumor or against the tumor by the immunesystem. Certain tumors can also have specificeffects on nerves and muscles, and the Eaton-Lam-bert syndrome mentioned above is one. Carcinoidtumors may cause weakness of proximal muscles(shoulders and hips). Malignancy is also sometimesassociated with dermatomyositis and polymyositis.

Drugs A long list of drugs can cause a myopa-thy, and only the more common or important oneswill be listed here (see DRUG-INDUCED RHEUMATIC

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DISEASE). Drugs can cause a myopathy through dif-ferent mechanisms. PENICILLAMINE, hydralazine, andprocainamide can induce the immune system toattack muscle. Thiazide diuretics can lower potas-sium to the extent that it affects muscle function.Others like alcohol damage muscle directly. CHLORO-

QUINE, clofibrate, cimetidine, cocaine, COLCHICINE,gemfibrozil, CORTICOSTEROIDS, heroin, all the statins(cholesterol-lowering drugs), phenytoin, sulfon-amides, valproic acid, vincristine, and zidovudinemay all occasionally affect muscle function.

Metabolic

• Disorders of glycogen metabolism may be inher-ited and have their major effect on muscle. Thebest known of these is McArdle’s disease, butthere are many others.

• Disorders of fat metabolism are even less com-mon but can cause similar problems.

• A number of inherited abnormalities of mito-chondrial function may lead to myopathy (andother effects) occurring at different ages. Mito-chondria are small organelles within cells thatare crucial in energy processing.

• Myoadenylate deaminase deficiency causesproblems in providing a source of energy (ATP)for the cell. It is the most common of the meta-bolic myopathies. It may occur as a primary defi-ciency but has also been described as occurringsecondary to other muscle diseases.

• Many minerals capable of forming salts that arenormally present in constant amounts in thebody are essential for muscle function. High orlow levels of these may lead to weakness orspasm and cramping of muscles. These includecalcium, magnesium, phosphorus, potassium,and sodium.

• Kidney failure and liver failure may be associ-ated with muscle weakness.

Endocrine Although not common, muscle disease is well recognized in association with Cush-ing’s disease, hyper- or hypothyroidism, hyper-parathyroidism (a calcium disturbance resultingfrom an overactive parathyroid gland), Addison’sdisease (failure of the adrenal glands), andACROMEGALY.

myositis Inflammation of muscle has manycauses. While the various causes may produce arange of symptoms, the effect on muscle is alwaysweakness with or without pain and tenderness.The enzymes contained in muscle cells are releasedinto the blood in large amounts and can be mea-sured to assist in the diagnosis and to evaluate theresponse to treatment. The most useful of these isCREATINE KINASE or CPK (see Appendix II). Musclebiopsy and sometimes EMG are important in mak-ing the diagnosis (see DERMATOMYOSITIS AND

POLYMYOSITIS). The more important rheumatic dis-eases which present primarily as muscle diseasethat dermatomyositis, polymyositis, and INCLUSION

BODY MYOSITIS, which are discussed under thoseheadings. The connective tissue diseases, especiallySYSTEMIC LUPUS ERYTHEMATOSUS, SCLERODERMA, andthe OVERLAP SYNDROME may also be complicated byan inflammatory myositis, which is autoimmune innature. Note that the differentiation betweeninflammatory and noninflammatory (see MYOPA-

THY) is to a degree artificial. Conditions associatedwith drug ingestion and malignancies listed aboveas causes of myopathy may also be inflammatory.There are several other causes of myositis; some arediscussed below.

• Myositis ossificans results in sheets of calciumbeing laid down in or alongside muscle. This usu-ally follows trauma or surgery. The affected mus-cle, often in the thigh, is painful and swollen witha woody feel. Treatment is difficult. BISPHOSPHO-

NATES, diltiazem (a calcium channel blocker), andanticoagulants (blood-thinning medications) areoften tried. Exercise and stretching should beavoided during the acute phase. Myositis ossifi-cans sometimes resolves spontaneously.

• RHABDOMYOLYSIS.

• Viral infections are a common cause of muscleinflammation. This is usually mild and short-livedbut can cause significant problems on occasion.The influenza viruses, infectious mononucleosis,coxsackie, and rubella viruses are all well-described causes of myositis. Bacterial infections,parasites such as trichinella, and toxoplasma cancause myositis. In addition, some bacteria such asstaphylococcus and streptococcus may causeabscesses within muscle.

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N

neonatal lupus A rare condition in which somefeatures of systemic lupus erythematosus developin newborn babies.

Cause

It is thought that this autoimmune disease is trans-mitted from the mother to the child throughautoantibodies that cross the placenta and affect thebaby. This means that the disease lasts only as longas the mother’s antibodies remain in the infant.Women with SLE have a greater chance of having ababy with neonatal lupus, particularly if the motherhas a positive blood test for SSA or SSB antibodies(also called Ro and La antibodies). About half theaffected pregnancies occur in women who havenever had SLE or a similar illness, but many of themothers of babies with neonatal lupus do have SSAand SSB antibodies. The risk of having a baby withneonatal lupus is about 2 percent in women withSLE who have SSA or SSB antibodies and may behigher, about 5 percent, in those who have both. Ifa woman has already had one affected child, thenthe chance that the next child will be affected isabout 16 percent.

Symptoms

Sometimes babies of women with SLE develop thetypical skin rash of lupus. If this happens, it is usuallynot present at birth but develops a few weeks later.The rash is reddish, often affects the face and scalp,and is worse on parts of the body such as the face andscalp that are exposed to ultraviolet light. Neonatallupus does not mean that the baby has chronic lupus,and symptoms resolve as the baby clears the mater-nal antibodies. In neonatal lupus other features oflupus are uncommon, but thrombocytopenia canoccur because of autoantibodies to platelets.

A more serious and irreversible problem is heartblock, a condition in which the electrical messages

from the atria are not conducted to the ventricles.The first indication of this problem is when a preg-nant woman has routine checkup at about the 20thweek of pregnancy and the baby’s heart rate isfound to be very slow. Heart block can lead to heartfailure, and this can occur while the baby is still inthe uterus or after birth.

Diagnosis

All patients with lupus are usually closely moni-tored during pregnancy, but those who have SSA orSSB antibodies are monitored particularly carefully.This includes regular ultrasound examinations ofthe growing baby that provide measurements ofhow well the baby is growing and how the heart isfunctioning. The diagnosis of neonatal lupus affect-ing the heart is usually made by ultrasound. Neona-tal lupus causing a rash is usually diagnosed whenthe rash appears a few weeks after the baby is bornand has a typical appearance.


Antibodies that have crossed the placenta andaffected the baby cause the symptoms of neonatallupus. Symptoms such as skin rash resolve as thebaby clears the antibodies and do not need any spe-cific treatment. The developing heart of the babycan be seen on ultrasound. If inflammation of theheart (myocarditis) is suspected or if heart block isalready present, treatment with dexamethasone, acorticosteroid that crosses the placenta, can betried. Heart block, if it develops, is usually irre-versible and the baby will need a pacemaker soonafter birth. About a third of babies with congenitalheart block do not survive.

neuropathic arthritis (Charcot’s joint) A destruc-tive type of arthritis that occurs in patients withneuropathy.

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Cause

The health of a joint depends on the ability of thebody to make small adjustments to absorb shockand prevent injury. Patients with nerve damagethat affects their ability to feel pain or sense wherein space the joint is can sustain damage to a jointduring day-to-day activities. Repeated micro-trauma is thought to be the most important causeof neuropathic arthritis, but the abnormal nervefunction may also alter the blood supply to thejoint and increase the risk of arthritis.

Chronic syphilis causing nerve damage was acommon cause of neuropathic arthritis. Becausethere are effective antibiotics to treat syphilis, it isnow seldom a cause of Charcot’s joint. The mostcommon disease causing neuropathic arthritis isdiabetes. A rare condition called syringomyelia thataffects the spinal cord and the nerves to the armscan cause neuropathic arthritis of the shoulder.

Symptoms

The symptoms of neuropathy—numbness, tingling,decreased ability to feel pain and temperature, andpoor position sense—precede neuropathic arthritisbut may not have been noticed by the patient. Thearthritis typically occurs in a large weight-bearingjoint such as the ankle or knee in the limbs affectedby neuropathy. If the arms are affected by neuropa-thy, the shoulders can be damaged.

The symptoms are those of severe osteoarthritiswith bony swelling, effusion, pain, instability, andloss of function. Because of nerve damage, painmay be less severe than would be expected fromthe severity of the arthritis.

Diagnosis

The diagnosis is made from the symptoms and theX ray. The X ray shows destructive arthritis withbone debris. If the cause of neuropathy is notknown, blood tests for syphilis and diabetes areperformed.


No specific treatment is available for neuropathicarthritis. As far as possible the underlying neuropa-thy is treated, but nerve damage is often irre-versible. The affected joint should be protected andweight bearing reduced. Symptoms are treated as

for osteoarthritis, but intra-articular corticosteroidinjections are avoided. Joint replacement surgery isavoided if possible because the prosthetic joint willalso be damaged by microtrauma and there is ahigh failure rate.

nonsteroidal anti-inflammatory drugs (NSAIDs)A class of drugs that is anti-inflammatory and anal-gesic. Although NSAIDs effectively reduce pain andinflammation, they do not affect the overall out-come or progression of arthritis. Therefore, to treatrheumatoid arthritis, NSAIDs are often combinedwith disease-modifying drugs (DMARDs).

NSAIDs inhibit cyclooxygenase (COX) enzymesand thus decrease the production of prostaglandins.There are two COX enzymes, COX-1 and COX-2,that differ in their function. COX-1 is found inmany tissues at a low level of activity and hasimportant effects in promoting platelet aggregationand protecting against peptic ulcers. COX-2 is oftenpresent only in cells that have been stimulated, aprocess known as induction. COX-2 is induced inresponse to inflammation. Drugs that inhibit COX-2 decrease the formation of prostaglandins in cellswhere their production has been stimulated and aretherefore anti-inflammatory. Drugs that inhibitCOX-1 have two important effects. First, theydecrease the production of thromboxane, aprostaglandin-like substance that makes platelets inthe blood stickier. Thus aspirin, which inhibits COX-1, is used to prevent heart attacks. Second, becauseCOX-1 helps maintain the health of the stomachlining and protect against ulcers, drugs that blockCOX-1 increase the risk of peptic ulcers and bleed-ing from the GI tract. NSAIDs are classified accord-ing to whether they nonselectively inhibit bothCOX enzymes (nonselective NSAIDs) or whetherthey are more selective for COX-2 and spare COX-1 (COX-2–selective NSAIDs).

Nonselective NSAIDs

Most of the older NSAIDs inhibit both COX-1 andCOX-2 and thus have anti-inflammatory andantiplatelet effects and increase the risk of pepticulcers. Aspirin is a unique nonselective COX-inhibitor because in very low doses it binds to theCOX-1 enzyme of platelets and irreversibly inacti-vates it, making those platelets less sticky for their

162 nonsteroidal anti-inflammatory drugs

life span, usually about a week. The antiplateleteffects of other nonselective COX inhibitors aremuch shorter because they block only the enzymewhile the drug is present in the bloodstream. Thisis why aspirin is the drug used to prevent heartattacks and stroke and why physicians recommendthat patients taking regular NSAIDs who need car-diovascular protection should still take low-doseaspirin. Recent studies have made this area evenmore complex. In those studies, researchers foundthat taking a regular NSAID such as ibuprofenbefore aspirin seemed to block the long-termeffects of aspirin on platelets. This probably occursbecause the NSAID blocks the access site whereaspirin binds to the COX enzyme. However, ifpatients took aspirin first and then took ibuprofen,the long-term antiplatelet effects of aspirin werenot altered. Interestingly, a COX-2-selective drugdid not affect the antiplatelet effect of aspirin,whether it was taken before or after aspirin. It isnot clear how these findings will affect the wayaspirin is prescribed to patients who are also takingregular NSAIDs.

There are many nonselective COX inhibitorssuch as ASPIRIN, IBUPROFEN, DICLOFENAC, PIROXICAM,

NAPROXEN, and others. Selective COX-2 inhibitorsbelong to a new class of NSAIDs that was specifi-cally developed to be more selective for the COX-2enzyme and thus have anti-inflammatory effectsbut not affect platelets or cause peptic ulcers. Itincludes CELECOXIB, ROFECOXIB, VALDECOXIB, andseveral drugs that are close to being marketed.

Indications for NSAIDs

Almost any type of pain or inflammation has beentreated with NSAIDs. Generally, pain caused byacute inflammation such as gout responds well, butthat caused by nerve damage responds poorly.NSAIDs are used to treat pain and inflammationassociated with many kinds of arthritis and soft tis-sue problems, including RHEUMATOID ARTHRITIS,

OSTEOARTHRITIS, RHEUMATIC FEVER, STILL’S DISEASE,

JUVENILE RHEUMATOID ARTHRITIS, GOUT, ANKYLOSING

SPONDYLITIS, TENDINITIS, and BURSITIS. There is no good evidence that one NSAID is

more effective than another. A common miscon-ception is that the newer COX-2-selective drugs aremore effective than older, nonselective NSAIDs. On

average this is not the case, but people do responddifferently. Finding that different patients find par-ticular NSAIDs more effective is not unusual. How-ever, if a condition has not responded to treatmentwith two or three NSAIDs, it is unlikely to respondto others, and a different type of treatment may bemore appropriate.

Side Effects of NSAIDs

Millions of people take NSAIDs and serious prob-lems are relatively uncommon. Nevertheless,because NSAIDs are so widely prescribed, a signifi-cant number of people develop problems from tak-ing them.

Allergy Some people are allergic to NSAIDs.This reaction can be serious, causing urticaria (ablotchy red raised rash), swelling of the face andtongue (angioedema), and wheezing. This type ofallergy occurs more often in people who haveasthma or nasal polyps. If someone has had asevere allergic reaction to one NSAID, he or she islikely to have a similar reaction to other NSAIDs.

GI Indigestion and heartburn are commonand are often the reason people stop takingNSAIDs. Less common, but more serious, are pep-tic ulcers. These can be silent and occur withoutthe usual warning symptoms of indigestion orabdominal pain. NSAIDs should be taken withfood, but doing so does not necessarily preventpeptic ulcers. In many research studies endoscopyhas been performed on patients treated withNSAIDs, and small superficial ulcers are often visi-ble. These superficial ulcers do not usually causeproblems and frequently heal on their own. How-ever, some of them become deeper and can lead tocomplications such as bleeding or perforation ofthe stomach.

Bleeding from the GI tract can be slow or rapid.Slow loss of blood may cause no symptoms otherthan anemia occurring over several months. Alarge GI bleed will often cause vomiting of blood orpassing altered blood in the stool. One of the signsof bleeding from the stomach is pitch-black bowelmotions. Iron tablets that are used to treat anemiacaused by iron deficiency often color the stoolgreenish black, and this can cause confusion.Bowel motions with altered blood, in addition tobeing black, are also often runny and very smelly.

nonsteroidal anti-inflammatory drugs 163

Patients who pass altered blood should seek medical attention immediately since significantblood loss can be serious and should be investi-gated and treated.

• A complicated ulcer can occur in anyone takingNSAIDs but there are several factors thatincrease the risk of GI complications. Theseinclude being older than 65 years, taking ananticoagulant, having had a previous pepticulcer or bleeding from it, and taking an NSAIDcombined with a corticosteroid. The risk of acomplicated ulcer with nonselective NSAIDs canbe as high as three per 100 people per year.

• There are several ways to decrease the risk of GIside effects caused by NSAIDs. The most effec-tive is to avoid NSAIDs entirely, but this is notoften an option because limited alternativetreatments are available to treat musculoskeletalpain. If avoiding NSAIDs is not possible, thereare two choices. A COX-2-selective NSAID canbe used or a non-selective NSAID can be usedwith another drug to protect against pepticulcers. COX-2-selective NSAIDs such as cele-coxib, rofecoxib, and valdecoxib are less likely tocause GI complications than nonselectiveNSAIDs, but there are several controversiesregarding the safety and efficacy of COX-2-selective drugs.

One controversy regarding the COX-2-selectivedrugs is an observation made in a subgroup ofpatients from the CLASS study, a clinical trial thatexamined the GI safety of celecoxib. Investigatorsfound that patients taking celecoxib who continuedto take low-dose aspirin for cardiovascular protec-tion seemed to lose some of the GI benefits of tak-ing a COX-2-selective NSAID. In other words, therisk of peptic ulcer in patients taking celecoxib andlow-dose aspirin and those taking nonselectiveNSAIDs was similar. This information was obtainedby breaking the original study group into sub-groups, a statistical technique that is frowned uponbecause it has in the past led to conclusions thatwere not substantiated when larger studies specifi-cally designed to focus on that particular subgroupof patients were performed. Therefore, until furtherinformation becomes available, the potential nega-

tive effects of low-dose aspirin on the GI risk reduc-tion of COX-2-selective NSAIDs will be debated.

Several drugs appear to decrease the risk of GIcomplications associated with NSAIDs. MISOPROSTOL,a drug that is similar to a prostaglandin, protects thestomach against peptic ulcers. Its most common sideeffect, diarrhea, and the fact that it can cause abor-tion make it unpopular. Proton pump inhibitorssuch as omeprazole, lansoprazole, and rabeprazolethat effectively decrease the production of acid inthe stomach protect against ulcers caused byNSAIDs. However, large clinical trials to show thatthey reduce the risk of bleeding or perforation of thestomach have not been performed. Nevertheless,guidelines for physicians recommend that patientstreated with a nonselective NSAID who are at highrisk of GI complications should also receive miso-prostol or a proton pump inhibitor.

Cardiovascular All NSAIDs can cause somefluid retention. Usually this is mild and causes onlya little ankle puffiness, but it can be severe andworsen symptoms such as shortness of breath inpatients with heart failure. Blood pressure can alsoincrease, usually by only a small amount, but in afew people by a lot. Of some concern was theobservation in the VIGOR trial that patients pre-scribed rofecoxib 50 mg a day had a higher rate ofheart attack than those on naproxen. The VIGORtrial was a large study involving several thousandpatients that compared the GI safety of rofecoxib50 mg (twice the usual dose) and naproxen. Thestudy was not designed to look at differences incardiovascular safety, and this may have been achance finding. Another possibility is thatnaproxen, through its COX-1 antiplatelet effects,might protect against heart attacks. Rofecoxib,because it is selective for COX-2 would not beexpected to have these cardiovascular benefits.Another possibility is that rofecoxib increased therisk of heart attack. This controversy remains unre-solved. In many studies that used the standard doseof rofecoxib (25 mg) or another COX-2-selectivedrug, celecoxib, there was no increased rate ofheart attack. At present most experts believe thatcelecoxib and rofecoxib in standard doses do notincrease the risk of heart attack. Many researchersare studying the effects of COX-2-selective drugson the heart, and a clearer picture will emerge.

164 nonsteroidal anti-inflammatory drugs

Renal NSAIDs decrease the blood flowthrough the kidney and can decrease function,sometimes severely. Both selective and nonselectiveNSAIDs can affect kidney function. NSAIDs do notcause significant renal effects in most patients. How-ever, patients with diabetes, heart failure, kidneydisease, and those taking diuretics or ACE inhibitors(angiotensin-converting enzyme inhibitors—agroup of drugs that lowers blood pressure) have ahigher risk. In these people serum creatinine levelsare usually monitored to check kidney function.

Other Abnormal liver function tests, usuallymild, occur in 1–15 percent of people. Rashes, ring-ing in the ears, and a feeling of lightheadedness canoccur. Serious blood problems such as neutropeniaare rare. NSAIDs are avoided in the late stages ofpregnancy because they can cause premature clos-ing of the ductus arteriosus, a blood vessel that isimportant for maintaining the fetal circulation.

Drug Interactions

Nonselective NSAIDs, because they decrease plateletstickiness, can increase the risk of bleeding inpatients taking warfarin and other anticoagulants.Taking two different NSAIDs together (other thanlow-dose aspirin for cardiovascular protection) is notrecommended, because combining NSAIDs is notmore effective and increases the risk of side effects.

Methotrexate often appears as an interacting drugon pharmacy computers when patients fill a pre-scription for an NSAID. This is because many NSAIDscan increase the concentrations of methotrexate butusually by only a small amount. In rheumatologypractice, with the low doses of methotrexate used,

this interaction is seldom clinically important andmethotrexate is often prescribed together with anNSAID for RA.

NSAIDs can blunt the ability of drugs, particu-larly diuretics (water pills) and ACE inhibitors, tolower blood pressure.

Clinical Use

A simple analgesic such as acetaminophen is likelyto have fewer side effects than an NSAID and istherefore usually the drug of choice for patientswith pain that is mild and not associated with muchinflammation, for example osteoarthritis. If there isa significant inflammation, for example as inrheumatoid arthritis, an NSAID relieves pain andstiffness more effectively than acetaminophen.There are many unanswered questions about thechoice of NSAID. Some physicians believe thatCOX-2-selective drugs are safer because they havefewer GI side effects; others believe that a nonselec-tive NSAID with a drug to protect against pepticulcer in patients at high risk is likely to be equallysafe. The debate also includes the possibilities thatlow-dose aspirin, a drug required by many patientswith heart problems, may be less effective inpatients also taking a nonselective NSAID anddecrease the GI benefits of COX-2-selective NSAIDs.

Whichever NSAID is chosen, it is important toremember that NSAIDs treat symptoms and not theunderlying disease. If the problem is a self-limitedone that will heal over time, for example tendinitis,this may be all that is required. For an illness suchas rheumatoid arthritis, though, treatment with anNSAID alone will allow joint damage to progress.

nonsteroidal anti-inflammatory drugs 165

O

occupational therapy Occupational and physicaltherapists work with patients to maintain andrestore function, reduce pain and deformity, andprevent deterioration and injury. There is a lot ofoverlap between occupational and physical ther-apy. However, physical therapy tends to focus onproblems related to moving, walking, exercise, andmuscle-strengthening. Occupational therapy placesmore emphasis on modifying the home or work-place to suit the patient or teaching the patientskills that will be useful in the dealing with day-to-day activities. Occupational therapists also provideadvice about the many splints, orthoses, and aidsthat can significantly improve a patient’s quality oflife. Physical and occupational therapists both playimportant roles in the care of patients withrheumatic diseases.

olecranon bursitis The olecranon bursas arebetween the skin and the olecranon, which is thebony prominence at the back of the elbow. Thebursa is a sac lined with synovial tissue and con-tains a small amount of synovial fluid that allowsthe bony part of the elbow to move with minimalfriction against the many surfaces it comes upagainst. Perhaps because it is so exposed to traumait is one of the most common of the body’s manybursas to cause problems. This often occurs inyoung men in occupations such as carpet laying orcar mechanics or at any age because of recreationalactivities ranging from skateboarding and wrestlingto gardening. It may also occur as a result of aninflammatory arthritis.

A significant blow to the olecranon bursa cancause traumatic bursitis. If fluid is removed, it isusually bloodstained. Lesser, repeated trauma canalso cause bursitis, but the fluid is less likely to bebloodstained. If symptoms are minor, treatment is

with rest and elbow protection with or withoutNSAIDs. If more severe, the fluid can be aspiratedand a compressive bandage applied. If the patient isgoing to return to a work or recreational settingwhere similar trauma is likely to happen again, aprotective elbow guard should be recommended.

Because of the thin skin over the elbow and fre-quent trauma, it is relatively easy for infectingorganisms to reach the bursa through breaks in theskin. Infection should always be excluded by aspi-rating fluid from the bursa if there is doubt. Withestablished infection the skin is red and warm andvery tender. The blood count may show a raisedwhite cell count. Fluid from the bursa is thick andmurky because of all the cells in it, and growing theorganism from this fluid should be possible. Theseare commonly staphylococcal or streptococcalspecies from the patient’s own skin, but many ofother organisms may be introduced. Antibiotics andpainkillers are used, but the fluid must be removedfor successful treatment. This can be done as an out-patient as a simple daily aspiration in uncomplicatedinfections. If the patient has diabetes, HIV infection,or is otherwise immunosuppressed, then inpatienttreatment is preferred. In resistant cases surgicaldrainage or even removal of the bursa may be nec-essary. Antibiotics are continued for two weeks.

Olecranon bursitis also occurs quite commonlyin RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS (seePSORIASIS AND PSORIATIC ARTHRITIS), and GOUT. Theseare usually sterile inflammatory lesions, but thepatients are not immune to infection and thisshould be considered. Aspiration and injection of asmall dose of CORTICOSTEROID can speed resolution.

opportunistic infection An infection that occurswith immunosuppression and is caused by anorganism that would not normally infect healthy

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people. Immunosuppressed patients have a higherrisk of becoming infected, both with the usualorganisms that affect healthy people and withopportunistic organisms. The term nosocomialinfection means an infection acquired in the hospi-tal. Patients who are immunosuppressed have ahigh risk of nosocomial infection, and some ofthese are caused by opportunistic infections. Theconsequences of an infection are also often moreserious. For example, chicken pox is seldom a seri-ous condition in healthy people but can be fatal inimmunosuppressed patients.

Cause

The underlying cause of opportunistic infection issuppression of the immune system. The normalimmune response is a protective mechanism thatprevents infection. Patients with immunosuppres-sion, whether it be from AIDS, diabetes, cancer, ordrugs used to suppress the immune system, have agreater risk of unusual infections. These includeaspergillosis, tuberculosis, nocardiosis, and fungaland pneumocystis infections. Because theirimmune systems are suppressed, however, theseindividuals are also more likely to be infected withorganisms such as streptococci and staphylococcithat often infect healthy people.

Symptoms

The symptoms of infection can be changed byimmunosuppression. For example, corticosteroidswill often suppress much of the acute inflamma-tory response to an infection. Fever, swelling, andpain may be less severe in immunosuppressedpatients and may lead to the diagnosis of infectionbeing overlooked.

Diagnosis

The gold standard for the diagnosis of infection inimmunosuppressed patients, as it is in healthypatients, is culture of the infecting organism. Inspite of having a suppressed immune system, mostpatients can still mount enough of a response to aninfection to cause symptoms such as fever andmalaise. Physicians are particularly conscious ofthe risk of infection in immunosuppressed patientsand often draw blood for culture in patients withsymptoms such as fever that would otherwise bethought to be minor.

In patients with rheumatic diseases who are tak-ing immunosuppressive drugs, the diagnosis ofinfection is often complicated by the possibility thatthe rheumatic disease, and not infection, could becausing the symptoms. For example, if a patientwith vasculitis treated with the immunosuppres-sive drug cyclophosphamide develops a fever, thequestion arises whether this is due to an oppor-tunistic infection or active vasculitis. If the culturesof blood and other body fluids are negative, thedecision whether to treat someone for infectionwith antibiotics or for autoimmune disease withmore powerful immunosuppression is often basedon clinical judgment.


Distinguishing between infection and activeautoimmune disease, although sometimes difficult,is important, because the treatment can have neg-ative effects if the wrong diagnosis is made.Immunosuppressive drugs such as corticosteroidsand cyclophosphamide could worsen an infectionbecause they suppress the ability of the body tofight infection. To make matters more complicated,immunosuppressive drugs will often cause symp-toms such as fever to improve, leading to the erro-neous impression that the correct diagnosis hasbeen made. On the other hand, antibiotics will noteffectively treat a flare of an autoimmune disease,and can they sometimes cause fever.

If the specific cause of an opportunistic infectionis identified, usually through culture of an organ-ism, appropriate antibiotic or antifungal treatmentcan be started. Usually the infection responds totreatment and can be cured. However, if thepatient has an irreversible cause of immunosup-pression (such as HIV infection), opportunisticinfections can recur.

osteoarthritis (OA) This is the most commonform of arthritis and is very ancient, being presentin Neolithic skeletons. It is a major health problemfor dogs, horses, and other animals as well ashumans. The number of people suffering from OAincreases with age and at 65 years of age 80 percentof people will have X-ray evidence of OA. How-ever, X-ray changes do not necessarily mean thatperson will have problems from the OA, and only

168 osteoarthritis

10 percent of 65 year-olds will have symptoms. It isa major cause of pain and disability in the elderlyand has significant socioeconomic importance. OAis the most common reason for JOINT REPLACEMENT

surgery. People under the age of 65 years with OAwill have double the medical costs as those nothaving OA. As the population ages, it is estimatedthat 18 percent of the U.S. population (59 millionpeople) will have OA in 2020.

Cause

While the precise cause is not known, a lot isknown about the processes and risk factors. Riskfactors are any factor that is conclusively shown tobe associated with an increased risk of getting theparticular disease. It does not mean that the factorcauses the disease. There are many ways of classi-fying (or subdividing) OA. This section will take thesimple approach of dividing it into primary and sec-ondary. In secondary OA, there is a clear-cut cause.In primary OA, no such cause is apparent, althoughthere are well-known risk factors.

Whatever the cause, the processes are fairly sim-ilar in established disease. Indeed, OA has beendescribed as the common final pathway of jointfailure, resulting from various insults to the joint.The bones forming the vast majority of joints in thebody are covered by a lining of cartilage wherethey come into contact with each other. The carti-lage has no blood vessels, lymph ducts, or nervesand only very few cells, called chondrocytes. Peo-ple therefore do not feel their cartilage, and it getsits nutrients from the fluid secreted by the joint lin-ing cells (synovium). To the naked eye cartilagelooks like hard, glistening whitish plastic.

The cartilage is made up of arcing strands of typeII collagen that hold long, complex sugar and pro-tein molecules tightly in place. These moleculesattract water molecules very powerfully. Whenweight is applied to the cartilage some of the wateris squeezed out, and then as the weight eases off,the water is sucked back into the cartilage. Thisgives joints their sponginess and protects the bonesfrom the constant jarring to which they would oth-erwise be subjected. Normal joints contain a smallamount of fluid, which provides nutrients to thecartilage and reduces friction between the cartilageon each side of the joint. This fluid contains

hyaluronan, which has viscoelastic properties. Thismeans that it is viscous at relatively low speeds,allowing smooth sliding while walking and run-ning. At rapid speeds, however, it becomes elastic,providing give and bounce as, for example, whenlanding from a jump.

In early OA, the character of the synovial fluidchanges so that there is more friction and lesssponginess. The surface of the cartilage becomesworn and ragged, and strands of collagen are bro-ken, allowing the water-attracting sugar and pro-tein molecules to escape. As the disease progresses,cracks develop in the cartilage and it becomes thin-ner. Although traditionally regarded as a nonin-flammatory disease (see ARTHRITIS for classification),there is often low-grade inflammation, which con-tributes to the changes in cartilage and bone. Theloss of shock absorption by cartilage puts increasedstress on the underlying bone. This responds bydeveloping a thickened surface, growing bony pro-trusions around the edges of the joint (called osteo-phytes), and later forming cysts in the bone.

Risk factors for primary OA Obesity is animportant risk factor for OA. Studies have shownthat obesity contributes 21 percent of the risk forOA of the knee, compared with 9 percent for afamily history, 8 percent for a previous knee injury,and 1 percent for a previous meniscectomy. Therisk goes up with increasing weight. Over half theU.S. population is overweight. If the heaviest thirdreduced their weight to that of the middle third,there would be 20 percent fewer people with OA.Not only does weight loss reduce the risk of gettingOA, but it also reduces the speed of progressiononce the disease is established. The strongest asso-ciation with being overweight is with knee OA, butthere is also an association with not only otherweight-bearing joints but also with hand OA. Thisindicates that the effect of obesity is not purelythrough excessive loading of joints.

There are rare families who develop early OAwith great frequency. A number of mutations havebeen identified in the genes for type II collagen andother cartilage constituents. Although there isclearly a hereditary influence on other more com-mon forms of OA, especially hand and knee OA inwomen, the genetic basis for this has not been dis-covered and may be quite complex.

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Certain occupations are associated with OAdeveloping in particular joints. Examples includehip OA in farmers, finger OA in rock climbers, kneeOA in builders, and midfoot joint OA in balletdancers. Recreational exercise in people with nor-mal joints is not a risk factor for OA, but jointinjuries or biomechanical abnormalities do predis-pose athletes to OA, especially elite athletes.

It has been observed that women with OSTEO-

POROSIS have a lower risk of developing OA and viceversa. While this is interesting in looking at mecha-nisms, it is not useful in treatment and prevention.

Despite interest in the impact of hormonal fac-tors on OA, especially that of estrogen, there is noclear association.

Causes of secondary OA Metabolic causesinclude ACROMEGALY, HEMACHROMATOSIS, CPPD, andALKAPTONURIA.

Skeletal abnormalities leading to OA includecongenital dislocation of the hip, slipped femoralepiphysis, Perthes disease (all affecting the hip),developmental bony abnormalities, leg lengthabnormalities, and HYPERMOBILITY SYNDROMES.

Trauma is a frequent cause of secondary OA.This may be from an acute injury such as a fracturethrough the joint or dislocation, following jointsurgery, especially meniscectomy, at the knee (seeKNEE PAIN) or from repeated minor trauma.

Any inflammatory arthritis can lead to sec-ondary OA, the most common being RHEUMATOID

ARTHRITIS. INFECTIVE ARTHRITIS very rapidly damagescartilage and leads to OA.

Symptoms

Pain, crepitus (a grating in the joint), stiffness,instability, and loss of function are the symptoms ofOA. The pain usually starts gradually and isdescribed as a mild-to-moderate ache. It gets worsewith exercise and feels better with rest. Pain at restor at night can occur with advanced disease. Sincepeople cannot feel their cartilage, the pain obvi-ously comes from other structures. These includethe synovium or joint lining, the joint capsule, ten-dons and ligaments around the joint, muscles thatstabilize the joint, as well as bone and periosteum(the lining layer around bone). Because of all thesedifferent sources of pain, it is not surprising that thelevel of pain does not often agree with the severity

of the changes seen on X ray. It also explains whythe pain can change in character and intensity fromday to day.

The stiffness is mainly first thing in the morningand after resting for short periods during the day. Itseldom lasts more than 20 to 30 minutes, unlikeinflammatory arthritis. Loss of range of movementin a joint can cause many problems such as a poorgrip (fingers), difficulty combing hair and dressing(shoulders), inability to reverse in a car (neck), dif-ficulty getting in and out of a car (hips), difficultydescending stairs (knee), and limited ability to stride(ankle).

Hand OA often gives rise to bony swellings atthe distal interphalangeal joints, called Heberden’snodes, and at the proximal called Bouchard’snodes. These may be intermittently painful, but themain problem is a slow loss of range of movement.People with this nodal OA are at increased risk ofgetting knee OA. The base of the thumb joint is alsooften involved and leads to a weak grip. The wristis involved in some forms of secondary OA andoccupational OA. The spine, hips, and knees arefrequently involved, but apart from MILWAUKEE

SHOULDER syndrome, the elbows and shoulders arenot. Hip OA can sometimes be deceptive because itcan give rise to pain in the front of the knee.

Although OA is usually a slowly progressive dis-ease, certain factors can make it progress morerapidly. In nodal OA of the hands, there is some-times quite severe pain and swelling in one or twojoints that subsides over a month or two but is asso-ciated with more rapid cartilage damage. This occursin a form of OA called erosive OA because bone isslowly eaten away at the joints, leading to moredeformity than usual. This needs to be differentiatedfrom the crystal arthropathies, GOUT and CPPD. Goutin particular is much more likely to develop in jointsthat are already damaged, especially if they becomecold. Gout is usually recognized when it occurs inthe feet, ankles, or knees; it may not be suspected inthe fingers. In addition if it occurs in the hips, diag-nosis may be very difficult. CPPD frequently occursin association with long-standing OA.

Diagnosis

A typical history and examination is usually enoughto make the diagnosis in established disease. This is

170 osteoarthritis

then confirmed with the appropriate X rays. Thephysical examination and sometimes the X raysmay show minimal abnormalities in early disease.In this situation it is important to exclude othercauses of the symptoms. Blood tests are normal inprimary OA. The physical examination may promptinvestigation for one of the metabolic or inflamma-tory causes listed above. All patients under the ageof 55 years should have screening tests to look forthe excessive iron load found in hemochromatosis.The presence of chondrocalcinosis (calcium liningthe joint cartilage) on X ray suggests CPPD, andtesting for causes of this is appropriate. Mostpatients with CPPD, however, do not have anunderlying metabolic abnormality.

While the X-ray changes of OA are easily recog-nized, there are two confounding issues. First, paindoes not correlate well with the degree of X-raychange, especially in the hand. Second, becauseOA on X ray is so common, many people present-ing with another form of arthritis will have OAchanges that they may have had for years and thatare not necessarily causing their problems. MRIscans can show the joint in great detail, includingdepth of the cartilage, inflammation in ligamentsand other soft tissues, and so-called bone bruisingin areas of bone under particular stress. They arenot often indicated but are very good at sorting outexactly what is going on in difficult circumstances.

Treatment

The aims of treating OA are to relieve pain, improvefunction, and slow down progression. Actualimprovement of joint structure (for example,regrowing damaged cartilage) is an area of consid-erable interest and research but to date has not beenachieved with any certainty.

Osteoarthritis is very common. It is painful andcan have a major impact on an individual’s qualityof life but is not life threatening. It usually startstoward the end of a person’s working life when heor she has some discretionary spending money. Allthese factors make it the ideal condition forswindlers to make a lot of money from selling‘wonder cures.’ Needless to say, the authors are notthe first people to come to this realization and thereare many dubious treatments promoted for use inOA. The treatments listed below all have good evi-

dence supporting their use in OA (see CLINICAL

TRIAL for discussion of evidence). The text discussestheir place in treatment as well as other alternativetreatments that show promise.

Proven nonpharmacologic treatments:

• Education

• Aerobic and joint-specific exercise

• Joint protection and unloading

• Weight loss

• Footwear, orthotics, and appliances

• Heat and cold

• Self-help group telephone support

Proven pharmacologic treatments:

• Acetaminophen

• Topical counterirritants and capsaicin

• Nonselective nonsteroidal anti-inflammatorydrugs

• COX-2 nonsteroidal anti-inflammatory drugs

• Weak narcotic drugs

• Intra-articular corticosteroid

• Intra-articular hyaluronan

Surgery:

• Lavage

• Osteotomy

• Joint replacement

Proven nonpharmacologic treatments Under-standing a chronic disease helps someone gain con-trol over it. Information and advice can be obtainedfrom the patient’s doctor, specialist nurses, theArthritis Foundation, or relevant Internet sites (seeAppendix III). Written material, self-help groups,and exercise classes are all helpful in this regard.

Exercise has been shown to be beneficial. Thishas been best studied in knee OA, where specificexercises to strengthen the quadriceps musclesimprove function and reduce pain. Other stretchesand exercises can be used to improve functionwhen other joints are involved. They are bestundertaken under the guidance of a physician orphysical therapist specializing in this area. Aerobicexercise to improve fitness has a nonspecific effect

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on reducing pain levels. This also makes weightloss easier. Resistive exercise can also improvefunction and decrease pain (see EXERCISE).

A range of devices available make everydayactivities easier (see ASSISTIVE DEVICES). These canimprove function without actually altering thearthritis. The use of a walking stick reduces theload put through a weight-bearing joint and canimprove mobility considerably if one knee or hip isthe most limiting factor. Occupational therapistscan help assess the likely utility of such a devicebefore the patient buys it, can also provide trainingin joint protection, and can advise concerningsafety issues around the house.

Weight loss improves pain and mobility byunloading weight-bearing joints. It has also beenshown to slow progression of OA, and this may bethrough effects other than mechanical unloading.While weight loss may on the surface seem to bethe most easily modifiable factor for the patientwith OA, everyone who has tried to lose weightknows it is easier said than done. Those who join aprogram, whether that be a hospital-based multi-disciplinary program or a community-based pro-gram such as is run by Weight Watchers, are farmore successful than those who go it alone.

Cushioned insoles or specially constructedshock-absorbing shoes can reduce the impact ofwalking. Orthoses can be used to correct malalign-ment and to shift the line of weight bearing awayfrom the more severely affected side in knee OA.Knee braces can occasionally relieve pain in severedisease. Taping the kneecap may relieve pain whileappropriate exercises are being done.

The appropriate use of heat or cold packs can helprelieve pain. Cold packs are generally most effectivewhen there is a flare of pain in a joint (see ICE). Bro-ken-up ice cubes in a cloth, a bag of frozen peas, ora proprietary ice pack may be used. The cold pack isapplied for 20 minutes at a time, and the skin shouldbe protected from direct contact to prevent frostbite.HEAT, traditionally a hot-water bottle but more com-monly a wheat bag or gel that can be heated in amicrowave, is more helpful in relieving the painassociated with stiff, immobile joints.

Acupuncture may give pain relief in OA. It re-quires a course of treatments, and its effect lasts onlyfor up to four weeks after the course is finished.

Some experimental evidence suggests that elec-tromagnetism promotes cartilage growth, but thereis no evidence in humans. Several small studieshave suggested a weak benefit from pulsed electro-magnetic fields in OA patients, but larger studiesare needed before this can be recommended. Thereis no evidence that the stationary magnets that arewidely marketed do anything (see MAGNETS).

Proven pharmacologic treatments ACETA-

MINOPHEN is the first line of treatment. It is an effec-tive painkiller and very safe at usual doses. Themost common side effect is nausea. It can be takenoccasionally as required but is more effective whentaken regularly. It can also be used just beforeundertaking activities that the patient knows willcause pain. Which method is used will depend onthe severity of the pain. Patients need to be awarethat some other drugs contain acetaminophen incombinations, and this needs to be taken into con-sideration in order not to exceed the maximumdaily dose.

Many patients not responding adequately toacetaminophen will find improved relief fromNSAIDs. There are short-acting and long-actingforms of these, and they may also be used asrequired, although regular use is more effective.The most common side effect is irritation or bleed-ing from the upper gastrointestinal tract. This can bepartially prevented by the use of either MISOPROSTOL

or a proton pump inhibitor such as OMEPRAZOLE,

RABEPRAZOLE, PANTOPRAZOLE, or LANSOPRAZOLE.Unfortunately, one of the main risk factors for GIbleeding is increasing age (over 65 years particu-larly). Therefore, taking NSAIDs can be risky forolder people with OA.

The development of the COX-2 inhibitors CELE-

COXIB and ROFECOXIB in the last few years has par-tially overcome this problem. They carry a lowerrisk of GI bleeding than the traditional or nonselec-tive NSAIDs while still having a very good effect onthe pain and stiffness of OA. They have similar sideeffects to the NSAIDs as far as blood pressure andkidneys go.

Weak narcotic analgesics such as TRAMADOL oracetaminophen combined with CODEINE, HYDROCO-

DONE, or dextropropoxyphene are also a useful stepup from acetaminophen for more severe pain.They can all cause drowsiness in some people and

172 osteoarthritis

constipation if taken regularly. They are oftentaken at night with plain acetaminophen duringthe day for these reasons.

Injection of small amounts of CORTICOSTEROIDS

into the joints can relieve pain effectively. This ismost often used in the knees and at the base of thethumb. Injections are generally limited to two orthree per year in any one joint. There is slight leak-age out of the joint, and a number of patients(especially women) experience flushing after theinjection. This may last from six to 48 hours. Thereis a very slight risk of introducing infection withany injection, and they should not be done if thepatient has an active infection elsewhere.

Injections of hyaluronan substitutes were firstdeveloped to replace that substance in the alteredsynovial fluid in OA (see under Cause above). Twosuch substitutes, HYALGAN and SYNVISC, have beenapproved by the U.S. Food and Drug Administrationfor use in knee OA. Both are given as a course ofinjections, have a small risk of local reactions, and avery small risk of introducing infection. They providesome pain relief in roughly 70 percent of patients butin a smaller percentage as the OA becomes increas-ingly severe. The relief lasts for between six weeksand 12 months. Since they can be demonstrated tobe in the joint for only a few days (Synvisc longerthan Hyalgan), this effect must be for reasons otherthan the replacement of hyaluronan. These reasonsare not clear. There is no evidence that they slowdown progression of the disease, although research isin progress looking at this.

GLUCOSAMINE and CHONDROITIN SULFATE are bothconstituents of normal cartilage. They have becomevery popular among arthritis sufferers over the pastfew years and are often marketed in combination.A number of studies show pain relief that is mod-erate but better than placebo (See CLINICAL TRIAL forexplanation of placebo) when using them. Oneinternational trial suggests glucosamine may slowdown progression of OA. There are, however, sev-eral criticisms of this study and further informationis awaited.

Surgery Lavage (washing the joint out withsterile salty water) is effective in some patients, andthe effect can last for six months, but a recent con-trolled trial found no difference between placeboand lavage treatment. Because it is invasive, it is

usually tried only when most other appropriatetreatments have been tried. Lavage may be moreeffective if combined with a corticosteroid injection.

Osteotomy involves taking a wedge of bone outto alter the lie of the joint surfaces so that moreweight is taken through the least damaged areas.This is done most often at the knee in young patientswho want to delay a total joint replacement.

JOINT REPLACEMENT is an excellent treatment foradvanced OA of the hip or knee. The vast majorityof OA patients express great satisfaction with thisform of surgery. Other joints can also be replaced,but the results do not match those of hip and kneereplacements.

ARTHRODESIS still has a place in the managementof severe OA associated with incapacitating pain. Itgives excellent pain relief but with loss of all move-ment at that joint. It is most often used at the ankleand the base of the thumb in OA.

osteochondritis dissecans When a fragment ofjoint cartilage with its underlying bone becomesdetached and sometimes breaks off into the joint, itis known as osteochondritis dissecans. This affectsmainly children and adolescents and is more com-mon in boys. The child complains of an achingpain, especially during or after vigorous exercise.The joint may click or even lock if a loose bodyjams between the two bones. The joint is usuallyslightly swollen and may be tender. Although anyjoint may be affected, the knee is by far the mostcommon joint involved. The inner surface of themedial (inner) condyle of the femur (thighbone) isthe usual site.

The exact cause is not known, but trauma seemsto be involved with nearly half the patients report-ing an injury before the symptoms start. There isoften a family history and these individuals areoften short. X rays may provide the diagnosis, butif not, CT or MRI scans will with great accuracy.They will also show if the fragment is still in its cor-rect place if this is not clear on X ray.

If the fragment is in place, it may heal with restand avoiding vigorous activity, especially inyounger children. Maintaining good muscle tone inthe quadriceps (muscles in front of thigh) is veryimportant if this course is taken. If the pain contin-ues or the fragment seems to be coming off, it can

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be wired or screwed into place. This is usually doneby arthroscopic surgery (see ARTHROSCOPY AND

ARTHROSCOPIC SURGERY). Small loose fragments areremoved from the joint. If this leaves a bare patchon the joint surface, it can be cleaned and drilled. Itwill then heal over with hyaline cartilage.Although this is not as resilient as normal articular(joint) cartilage, symptoms will resolve. Youngerchildren in whom the osteochondritis heals with-out intervention have the best outcome.

osteomalacia (rickets) A disorder in which bonedoes not calcify normally, is weak, and deforms. Itis known as rickets in children.

Cause

Normal bone is formed when cells called osteoblastslay down a matrix called osteoid that then calcifieswhen calcium and phosphate are laid down to formhydroxyapatite. This process requires good-qualityosteoid and normal concentrations of calcium andphosphate in the body. One of the most importantregulators of calcium and phosphate levels is vita-min D. Any condition that leads to decreased cal-cium, phosphate, or vitamin D levels, or affects themineralization of bone can cause osteomalacia.

Vitamin D deficiency Vitamin D deficiency isthe most common cause of osteomalacia and canoccur in several ways. In many developing coun-tries dietary intake of vitamin D may be inadequate,but in developed countries this rarely happens,except in the elderly. More common is poor absorp-tion of vitamin D. This can happen in people whohave had part of their stomach and duodenumremoved to treat peptic ulcer and people withCELIAC DISEASE or any other disorder that affects theability of the bowel to absorb food and nutrients.Patients with liver disease can get osteomalaciabecause they are less able to transform vitamin D to25-hydroxy vitamin D, the precursor of the activeform 1,25-dihydroxy vitamin D. Similarly, patientswith kidney disease can get osteomalacia becausethe kidney is an important site where 25-hydroxyvitamin D is converted to 1,25-dihydroxy vitaminD. Sunlight aids the formation of active vitamin D.People who have borderline vitamin D levels candevelop osteomalacia if they spend all their timeindoors and are not exposed to sunlight.

Rare inherited types of osteomalacia are caused bylack of the enzymes needed to make the active formof vitamin D or by tissues not being able to respondto it. These usually cause osteomalacia in childhood.

Phosphate deficiency This is not a commoncause of osteomalacia because phosphate is con-served efficiently by the kidneys, but there are rareinherited disorders in which the kidneys leak phos-phate into the urine. Osteomalacia caused by phos-phate loss is usually diagnosed in childhood. Rarelysoft tissue tumors, most often in the abdomen, cancause phosphate loss in the urine and osteomalaciain adults.

Poor mineralization Occasionally even if sup-plies of calcium, phosphate, and vitamin D are ade-quate, osteomalacia can be caused by rareconditions that decrease the ability of bone to min-eralize (lay down the calcium and phosphate normally). Hypophosphatasia is a rare inheritedcondition associated with low or absent levels ofalkaline phosphatase, an enzyme that plays animportant part in mineralization of bone. This typeof osteomalacia usually presents in early child-hood. Another cause of poor bone mineralizationwas treatment with older bisphosphonates such asETIDRONATE. Bisphosphonates, a group of drugs thatinhibit bone resorption and formation, are used totreat osteoporosis and Paget’s disease. The newerpreparations do not cause osteomalacia.

Symptoms

Mild osteomalacia may not cause any symptoms,but severe disease can cause dull aching bone pain,particularly at the ends of long bones, that can bemistaken for arthritis. Osteomalacia in children canresult in soft bone that deforms as the child growsand leads to deformities such as bow legs. In adultsand children, affected bone is weak and fracturesmore easily. Weakness and pain of the muscles ofthe thighs and shoulders, a condition called proxi-mal myopathy, is often associated with osteomala-cia. In children, inability to walk caused by acombination of bone pain and muscle weaknessmay be the presenting symptom of osteomalacia.

Diagnosis

The diagnosis of early osteomalacia is usually madeincidentally. Sometimes an X ray performed for

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another reason shows poorly mineralized bone orfindings such as pseudofractures that are typical ofosteomalacia. Pseudofractures are narrow cracks inthe bone. If a bone scan is performed, they light upon the scan much as a fracture would. No one iscertain what causes pseudofractures, but they maybe may be stress fractures that heal more slowlythan usual. Routine blood tests may also give a clueto the diagnosis of osteomalacia. In contrast toosteoporosis in which all blood tests are normal,moderate or severe osteomalacia is almost alwaysassociated with abnormal blood tests. The alkalinephosphatase level is usually elevated in most typesof osteomalacia except the rare hereditary diseasehypophosphatasia. In patients with poor intake orabsorption of vitamin D the blood levels of the vit-amin, as well as calcium levels, are low. Osteoma-lacia caused by phosphate loss is associated withlow levels of phosphate in the blood and an abnor-mally high amount in the urine. Rarely a bonebiopsy is performed to diagnose osteomalacia. Oncea diagnosis of osteomalacia has been made, furthertests will be required to find out what the underly-ing cause is.


The treatment of osteomalacia depends on theunderlying cause but usually includes vitamin Dand calcium. Patients who are unable to make theactive form of vitamin D are treated with calcitriol,an active form of vitamin D. Patients who are losing phosphate may also need phosphate supple-ments. Osteomalacia responds rapidly to treat-ment. However, patients need to have their bloodlevels of calcium monitored because treatmentwith too much vitamin D can cause a high bloodcalcium concentration.

osteomyelitis Infection of bone, most often affect-ing the long bones. Chronic or partially treatedosteomyelitis can persist for months or years andcause destruction of normal bone architecture.

Cause

The most common cause of osteomyelitis is bacter-ial infection with organisms such as staphylococciand streptococci. Other bacteria seldom causeosteomyelitis, but gram-negative bacteria such as

salmonella can do so, particularly in patients withSLE, HIV, or another cause of immunosuppression.In some countries tuberculosis is a common causeof osteomyelitis.

Bone is usually sterile. Therefore to causeosteomyelitis, infecting organisms have to gainaccess. Usually bacteria spread to bone through thebloodstream from an infection at some other site.This is called hematogenous spread. Another waybacteria gain access to bone is by spreading from aninfection in nearby tissues such as skin or a joint.This is called contiguous spread. The third way bac-teria can get to bone is directly if there is penetrat-ing trauma or a fracture that exposes bone.

Anyone can get osteomyelitis, but patients withDIABETES MELLITUS, SICKLE-CELL DISEASE, and immu-nosuppression have a higher risk. Foot ulcers arecommon in patients with diabetes because they canaffect both the blood supply to tissues and thenerves that provide sensation to the foot. The com-bination of poor blood supply and decreased feelingin the foot often leads to ulcers caused by injuries orpressure. These ulcers can become infected, and thiscan spread to bone.

Symptoms

The first symptom is severe pain, usually in a leg.Osteomyelitis often affects the ends of bones closeto joints, and distinguishing osteomyelitis fromINFECTIVE ARTHRITIS can sometimes be difficult. Inboth conditions the patient will not want to movethe affected limb because of pain. The limb is oftenswollen, warm, and excruciatingly tender. Inyoung children and infants who cannot complainof pain, the only symptoms may be crying andrefusing to move a limb. Other symptoms of acuteinfection such as fever and malaise are common.

Apart from long bones, osteomyelitis oftenaffects the vertebrae. If this occurs the main symp-tom is severe localized back pain. Clues thatosteomyelitis rather than the more commonslipped disk is the cause of back pain are fever, con-tinuous pain, localized pain, pain at rest, and painat night.

Diagnosis

The diagnosis of osteomyelitis is usually suspectedclinically. Deciding if a superficial skin infection

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such as cellulitis has penetrated bone and causedosteomyelitis is sometimes difficult. X rays are nothelpful early in the illness because they are nor-mal. After the infection has been present for aweek or two, the X ray may show elevation andthickening of the outer lining of the bone—calleda periosteal reaction. Later in the illness X raysmay show areas of bony destruction and areas ofincreased density. Radionuclide bone scans areoften performed to try and differentiate soft-tissueand bone infection but tend to light up with both.Magnetic resonance imaging (see Appendix II) ismore helpful.

Blood cultures are performed routinely and maybe positive. Laboratory tests such as the whiteblood cell count and ESR are often elevated, butthis is not specific and occurs with any cause ofinfection or inflammation.


Antibiotics and surgery are important. The choice ofantibiotics is based on the organism isolated, andcombinations are often used. Before the results ofcultures are available and if no organism is isolated,the antibiotic selection usually covers staphylococcalinfection and, if clinically suspected, gram-negativeinfection. Antibiotics are usually administered intra-venously for several weeks to ensure high concen-trations of drug in the bloodstream. Once theinfection is controlled, patients often complete a fourto six week course of antibiotics at home. Theyreceive either intravenous drugs, given by a homehealth service, or oral antibiotics. Surgery is usuallyperformed early in the course of osteomyelitis, par-ticularly in adults. Surgery involves draining anycollections of pus in the soft tissues, removing deadtissue, clearing the bone of infection, and obtaininga bone biopsy for culture.

If the general health of the patient is good and theinfected bone was previously healthy, osteomyelitisusually responds to antibiotics and surgery, particu-larly if these are provided early in the course of theillness. If osteomyelitis is partially treated or if deadbone remains and acts as a reservoir for bacteria,infection can recur. If osteomyelitis is severe or nottreated early, it can cause death of part of the bone,leading to weakness and instability. Chronicosteomyelitis can be very difficult to treat because

eradicating the bacteria from areas of dead bonewhere antibiotics do not penetrate well is difficult.Some patients require antibiotic treatment for manymonths and repeated surgery before the infection iscured.

osteopath Dr. Andrew Taylor Still established thefirst school of osteopathy in Kirksville, Missouri, in1892. He emphasized the importance of treatingthe whole person as opposed to concentrating onthe disease. This was at a time when the scientificbasis of modern medicine was making hugeadvances, especially in the discovery of bacteria asa cause of distinct illnesses and in the classificationof disease. Still reacted against this disease-orientedapproach. Although mainstream medicine hassince swung back to taking a holistic approach, Dr.Still was ostracized at the time. Some of his beliefs,for example that spinal dysfunction caused infec-tions, were certainly difficult to accept and con-tributed to the reaction against him.

There are now a number of schools of osteopa-thy in the United States and graduates (DOs) prac-tice medicine with the same rights and privileges asgraduates from traditional schools of medicine.DOs are all trained in osteopathic manipulativetreatment and will use it if considered appropriatebut will also prescribe antibiotics or other pharma-ceuticals if these are considered appropriate. Theuse of mainstream therapies by DOs does not per-tain outside the United States.

The osteopath examines the patient for evidenceof somatic dysfunction. This is revealed by changesin tissue texture, asymmetry of bony landmarks,restriction of motion, or tenderness. Manipulativetherapy is aimed at restoring normal body mechan-ics, lymphatic drainage, and autonomic nervoussystem activity.

Some evidence supports the use of manipula-tion by an osteopath or other practitioner for acutelow BACK PAIN, neck pain, CARPAL TUNNEL SYNDROME,

FIBROMYALGIA, and possibly OSTEOARTHRITIS. How-ever, there are relatively few well-controlled stud-ies (see CLINICAL TRIAL) of osteopathy.

osteoporosis A condition in which bone mass and strength is decreased, resulting in fragility andincreasing the chance of a fracture. Many patients

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mistakenly use the terms osteoarthritis and osteo-porosis interchangeably. These are two unrelatedmedical problems. Although someone could haveboth osteoarthritis, a degenerative arthritis, andosteoporosis, it is important to recognize that theseare different problems.

Bone is a rigid, calcified connective tissue thatprotects and supports people’s bodies. There are twotypes of bone. Cortical bone is hard and dense, andit forms the outer layer. Trabecular or cancellousbone forms a scaffoldlike structure within the outercortical layer. Bone, in contrast to what one wouldthink, is not inert but is constantly being resorbedand replaced. Bone also acts as a reservoir for cal-cium stores. If the supply of calcium in the bodydecreases, bone can be resorbed to supply the min-eral. The cells that are important regulators of boneturnover are osteoblasts, which lay down new bone,and osteoclasts, which resorb bone. The remodelingof bone can be affected by hormones, drugs, andphysical activity. Hormones such as cortisol and theclosely related group of drugs CORTICOSTEROIDS

increase bone resorption. On the other hand, estro-gens and weight-bearing exercise decrease boneresorption. Women are more likely to developosteoporosis and fractures than men because theyhave a lower peak bone mass, lose bone morerapidly after menopause, and live longer.

Osteoporosis affects millions of people in theUnited States and is a major public health concern,causing 1.5 million fractures and 250,000 hip frac-tures annually. The chance of a 50-year-oldwoman having a hip fracture during her lifetime is14 percent for Caucasians and 6 percent for AfricanAmericans. It is estimated that it costs $10–15 bil-lion annually to treat these fractures. Osteoporosiscan be divided into two types, primary and sec-ondary. Primary, unlike secondary osteoporosis, isnot associated with any underlying illness and isnot caused by a drug.

Cause

Primary osteoporosis There does not seem tobe a single cause of primary osteoporosis, but sev-eral factors contribute. Bone mass differs even inhealthy people. Age has a major effect. Bone massincreases until people are in their 30s. The peakbone mass an individual reaches is an important

determinant of bone mass in later life. Good nutri-tion, calcium intake, and physical activity in child-hood will increase peak bone mass. Smoking inadolescence and early adult life will decrease it.After people achieve peak bone mass in their 30s,it slowly decreases as they age. In women there isa period of rapid bone loss around menopausewhen the effects of estrogen on bone are lost.

Apart from age, several other factors are associ-ated with low bone mass and osteoporosis. Smok-ing, low body weight, inactivity, inadequatecalcium intake, heavy alcohol use, early meno-pause, and a family history of osteoporosis all in-crease the risk.

Secondary osteoporosis The most commoncause of secondary osteoporosis is treatment withcorticosteroids. The risk is related to the dose andduration of steroid treatment. High doses of corti-costeroids, say 30 mg or more of prednisone a day,will cause osteoporosis in most people, but evenlow doses such as 7.5 mg a day or less increase therisk. Patients taking long-term corticosteroidsshould be monitored for osteoporosis. Often corti-costeroids are prescribed for a chronic illness suchas rheumatoid arthritis or SLE, illnesses that canthemselves predispose to osteoporosis.

Another common cause of osteoporosis is failureof the ovaries or testes to produce the sex hor-mones estrogen and testosterone. Menopause usu-ally occurs naturally, often around the age of 50,but a young woman whose ovaries are removedsurgically will go through menopause prematurelyand start to lose bone. In some young women theovaries stop functioning. For example, the ovariescan shut down in elite athletes and ballet dancerswho follow a rigorous exercise program. Thesepeople can develop osteoporosis even though theyare young and extremely physically active. Men-strual irregularity or complete disappearance ofcycles (amenorrhea) can be warning signs that ayoung female athlete is at risk for accelerated boneloss and osteoporosis. In athletes osteoporosis in-creases the risk of stress fractures. Most of the boneloss is reversible if ovarian function returns to nor-mal, but this often does not happen until the ath-lete decreases or stops competitive training. In mensex hormones are also important for maintainingbone health. Men whose testes are removed or stop

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producing the male hormone testosterone have amuch higher risk of developing osteoporosis.

An overactive thyroid (hyperthyroidism or thy-rotoxicosis) can cause osteoporosis. Replacementdoses of thyroid hormone prescribed for patientswith an underactive thyroid (hypothyroidism) canalso cause osteoporosis, particularly if the dose istoo high.

Other illnesses, for example hyperparathyroid-ism (overactive parathyroid glands), can cause sec-ondary osteoporosis, but these are unusual causes.Any severe illness that decreases mobility increasesthe risk of osteoporosis. Patients at highest risk arethose who are confined to bed and receiving highdoses of corticosteroids.

Fractures The reason osteoporosis is an impor-tant health problem is that it increases the risk offractures. Some of these fractures, for example ver-tebral fractures, can occur with normal everydayactivities, but hip, arm, and leg fractures are causedby falls. Therefore, for an individual the risk of frac-ture is affected not only by bone mass but also bythe chance of falling. Anyone can fall and fracturea bone. In fact, children often sustain fractures.However, as people age, the risk of fractureincreases because physical capacity declines andbone becomes osteoporotic and fragile. Balance,strength, vision, and coordination all decrease withaging and increase the risk of falling and thereforefracture.

Symptoms

Osteoporosis is usually silent, and most peoplehave no acute symptoms until they have fracture.The first noticeable sign of osteoporosis is loss ofheight. This shrinking is often ascribed to aging butis often a marker of significant osteoporosis.Patients with severe osteoporosis may lose some ofthe height of their vertebrae so that the spinebecomes curved forward, a posture that was some-times called a dowager’s hump because of thepropensity for osteoporosis to occur in elderlywomen. Apart from loss of height and curving ofthe spine, osteoporosis does not cause symptomsunless a fracture occurs. Because the bone is thinand weak, it is more likely to fracture after minorstress or trauma. A compression fracture in a verte-bra, sometimes called a crush fracture or wedge

fracture, often occurs with coughing or ordinaryday-to-day activities such as lifting a heavy object.The first symptom of a compression fracture isoften acute back pain. The pain is felt in the backover the vertebra affected and can be severe, limit-ing regular activities and even making sleeping orchanges in posture difficult. In contrast to chronicback pain that often affects the lower back foryears, an osteoporotic fracture causes suddensevere pain, often affecting the upper back. Thepain from an osteoporotic fracture can last forweeks and usually improves slowly. After someonehas had several compression fractures of the spine,though, there is often residual dull aching pain.More serious fractures involving the hip or radiususually occur only after a fall, and the symptoms—pain, swelling, and inability to use the limb—areusually obvious. Typically women with moderate-to-severe osteoporosis have Colles’ fractures (justabove the wrist) in their 50s, vertebral fractures intheir 60s, and hip fractures in their 70s. Colles’fractures should therefore be taken as a warning ofpotentially severe osteoporosis.

Diagnosis

Because osteoporosis causes so few symptoms, it isdifficult to diagnose unless people who are at riskare screened routinely and the diagnosis madebefore a fracture has occurred. No blood or urinetests are helpful for diagnosing osteoporosis,although a lot of research is directed at developingsuch tests. In fact, all the standard tests of bonehealth such as calcium, phosphate, and alkalinephosphatase are usually normal in patients withosteoporosis. Increased levels of biochemical mark-ers of bone resorption can be detected in the urineof patients with osteoporosis. These tests do not tellenough about an individual’s actual bone densityor risk of fracture to use them for diagnosis but canbe helpful to monitor response to treatment.

Osteoporosis is often not diagnosed until an X ray, often performed for an unrelated reason,shows thin bones and perhaps partial collapse of avertebra. Regular X rays are not a very good way todiagnose osteoporosis because approximately 40percent of the bone mass has to be lost beforebones appear thin on X ray. A diagnosis of osteo-porosis can be made much earlier by obtaining a

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measurement of bone mass. There are several tech-niques for measuring bone density, the best esti-mate of bone mass (see DEXA in Appendix II).

The diagnosis of osteoporosis is made by com-paring an individual’s bone density with that of theaverage healthy young adult, and this is expressedas a T score. The lower the T score, the thinner the bone and the greater the risk of a fracture. A T score of 2 2.5 is regarded as the point at whichthe risk of fracture rises steeply and has been deter-mined by the World Health Organization as indi-cating a diagnosis of osteoporosis. It is important toremember that fractures can occur in anyone ifbone is sufficiently stressed by a fall. Therefore theconcept of a threshold is a little artificial becausethe risk of breaking a bone is affected not only byhow thin the bone is but also by the chance offalling. The T score was developed to provide astandardized measure of bone density becausemany different techniques are used to measurebone density. It represents the relationship be-tween a person’s bone density and that of the aver-age young adult. A T score of 2 2 means that aperson’s bone density is two standard deviationsbelow average. People are not all exactly the same,and a standard deviation is a statistical measure-ment of the normal spread for any measurement,be it weight, height, or bone density. For any mea-surement, for example height, weight, or bonedensity, only 2.5 percent of people will fall belowtwo standard deviations from the average.

The risk of fracture almost doubles for adecrease in bone density of one standard deviation(i.e., a T score of 2 1). A T score of 2 2.5 wasselected, somewhat arbitrarily, as the bone densityscore at which the risk of fracture was increasedenough for all patients to be treated for osteoporo-sis. Most techniques for measuring bone densityreport the result as both a T score and a Z score.The Z score represents how far a person’s score isfrom the average of other people of the same ageand sex. The Z score is not as useful as the T scorefor deciding when a person needs treatment butmay indicate that a search for a cause of secondaryosteoporosis is required.

Once osteoporosis has been diagnosed, a carefulhistory and physical examination should be per-formed to make sure that there is no underlying

cause, in other words, to exclude causes of sec-ondary osteoporosis.


Prevention The most effective way to treatosteoporosis is to prevent it. Lifestyle changes thatprevent osteoporosis are also helpful for treating it.

• Avoiding Causes of Osteoporosis People who haveosteoporosis or want to prevent it should altertheir lifestyle to avoid smoking and drinking alot of alcohol since these decrease bone density.Avoiding drugs that cause osteoporosis is notalways possible. For example, if someone needshigh doses of corticosteroids to control an ill-ness, then avoiding these drugs may not be pos-sible. Most physicians agree that the lowest doseof corticosteroid that controls a condition shouldbe used, and in this way the negative effects ofthis class of drugs on bone is kept to a minimum.

• Increasing Peak Bone Mass If peak bone mass ishigh, then even if it decreases as the personages, it will remain higher than in a person whostarted with less bone and lost the same amount.Young adults can improve their peak bone massby ensuring an adequate intake of calcium andby exercising regularly.

• Exercise Severe inactivity such as bed restdecreases bone density. This is because thestresses placed on bone by exercise help remodeland strengthen it. Weight-bearing exercise suchas jogging, tennis, and weight lifting increasesbone density. Exercise such as swimming thatdoes not place much load on bones does notimprove bone mass. The importance of weightbearing on bone health is illustrated by the factthat astronauts lose a lot of their bone masswhile they are weightless in space even thoughthey perform exercises. Regular strenuous exer-cise can increase bone density. However, whenthe person stops training hard, bone densityquickly falls to its previous level. In other words,regular moderate exercise several times a weekwill maintain bone mass better than irregularbursts of intense exercise.

• Calcium and Vitamin D Two key requirementsfor healthy bones are calcium and vitamin D.Calcium is a major constituent of bone, and vit-

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amin D regulates calcium absorption from thegut. The modern diet tends to be low in calcium,which is found in high concentration in milkand milk products such as yogurt and cheese.Because people worry that cholesterol in theirdiet may increase the risk of heart disease, theyhave cut down on milk products, and conse-quently their calcium intake has decreased. Formost people a daily intake between 1,000 and1,500 mg of calcium is recommended. A cup ofmilk, one of the richest sources of calcium, pro-vides about 300 mg of calcium. For many peoplediet alone does not provide enough calcium anda supplement is needed. The amount of calciumin a person’s diet, combined with the amount intheir supplement, should add up to their recom-mended daily intake.

Many different calcium supplements are avail-able. The amount of calcium they provide varies.So that everyone understands exactly how muchcalcium a particular tablet provides, the label pro-vides information in milligrams (mg) of elementalcalcium per tablet. Calcium carbonate is a cheap,effective, and widely available preparation. Somepatients who do not have acid in their stomachs donot absorb calcium carbonate well and calcium cit-rate may be more effective for them. Calcium isabsorbed better if it is taken at the same time asfood.

A deficiency of vitamin D causes a bone disordercalled OSTEOMALACIA. This is different from osteo-porosis, which is not caused by vitamin D defi-ciency. However, an adequate intake of vitamin Dis needed to ensure adequate calcium absorptionand healthy bones. The recommended daily intakeof vitamin D is 400–800 international units (IU)andmost multivitamins designed for daily use containthis amount.

Medication If a person already has osteoporo-sis, the treatment involves not only all of the pre-ventive measures previously discussed but also adrug to improve bone density and decrease the riskof fractures. Most drugs currently used to treatosteoporosis slow the resorption of bone but usu-ally do not increase bone formation. Treatmentusually stabilizes bone density or increases itslightly. Three groups of drugs are commonly used

to treat osteoporosis: estrogen and the closelyrelated selective estrogen receptor modulators(SERMs) bisphosphonates, and calcitonin.

• Estrogen and SERMs After menopause womenhave a high risk of developing osteoporosisbecause the beneficial effects of natural estrogenon bone metabolism are lost. This can bereversed by estrogen replacement therapy. Likeall treatments for osteoporosis, the effects lastonly while the patient takes the treatment. Mencannot take estrogens to prevent or treat osteo-porosis because the female hormone causesbreast enlargement and other side effects. Sup-plementing the male hormone testosterone hasbeen tried as a treatment for osteoporosis buthas not been useful, except in men who have alow testosterone level.

Many women find that the other effects ofestrogen, for example decreasing the number ofhot flashes and improving mood, make it an attrac-tive treatment for osteoporosis. On the other hand,others gain weight, feel bloated, and dislike theuterine bleeding that comes with estrogen treat-ment. Recent studies have shown that women tak-ing some forms of estrogen replacement have aslightly increased risk of developing clots. This issimilar to the risk of taking oral contraceptives.There is also an increased risk of breast cancer. Forthese reasons estrogen replacement is no longerconsidered a first-choice treatment for osteoporo-sis. Drug companies have now developed a class ofdrugs, SERMs, that stimulate some of the estrogenreceptors in the body, particularly the receptors inbone, without stimulating estrogen receptors inother places, like the breasts or uterus. These drugsincrease bone density without causing uterinebleeding and do not increase the risk of breast can-cer. In fact, raloxifene (trade name: Evista)decreased the risk of breast cancer in preliminaryclinical trials, and there are now large studiesunderway to study this. SERMs do not alleviate theother symptoms of estrogen deficiency such as hotflashes.

Observational studies performed in large groupsof women seemed to show that estrogen replace-ment decreased the risk of myocardial infarction. Iftrue, this would be a very important reason to pre-

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scribe estrogens, because ischemic heart disease isthe most common cause of death in women, as it isin men. However, a large randomized, controlledtrial called the HERS study did not find any benefitof estrogens on the risk of heart attack. In fact, inthe early part of the study there were more cardio-vascular events in the estrogen than in the placebogroup. This was probably because estrogens (andSERMs) increase the risk of blood clotting. Someexperts believe that the wrong type of estrogen wasstudied and that the study did not continue longenough to show the beneficial cardiovascular effectsof estrogen. However, others believe that the origi-nal observational studies were wrong because theyselectively studied women who took more care oftheir health and took more estrogens. These samepeople believe that the results of the HERS study, adouble-blind, randomized controlled study thatfound no benefit, represent the true effect of estro-gens. However, until good scientific evidence sup-ports or negates the theory that estrogens protectagainst heart disease, most physicians are no longerprescribing estrogens to prevent heart disease.Because estrogens and SERMs increase the risk ofclotting, they are usually avoided in women whohave had a deep-vein thrombosis.

• Bisphosphonates This group of drugs bindsstrongly to bone and prevents it from beingresorbed. There are several bisphosphonates,including ETIDRONATE, ALENDRONATE, and RISE-

DRONATE. Many studies have shown that thenewer bisphosphonates such as alendronate andrisedronate increase bone density and reducethe risk of fractures by about 50 percent in peo-ple with low bone density.

Bisphosphonates are not absorbed from thestomach very efficiently. Therefore they should betaken on an empty stomach so that food and otherdrugs do not interfere with their absorption. Theycan also cause ulcers in the esophagus if they stickor reflux back up into the esophagus. To reduce therisk of this happening, the instructions for takingbisphosphonates usually advise patients not to liedown after taking them.

If patients cannot swallow or have an esopha-geal problem that makes it likely that tablets will

stick, there are bisphosphonates that can be givenintravenously. Generally these are used only inpatients too sick to take tablets by mouth. Theinstructions for taking a bisphosphonate are usu-ally as follows:

1. Take your tablet with a full glass of water firstthing when you get up in the morning.

2. Do not eat or drink anything, other than water,for at least 30 minutes after you have taken thetablet. Even coffee or fruit juice stops the drugfrom getting into your body. Waiting an hourbefore eating or drinking anything else willenhance the absorption of the drug.

3. After you have taken the tablet stay upright anddo not go back to bed. This is so that the tabletdoes not reflux back up your esophagus.

4. Take the tablet by itself, not with your othermedicines. Delay taking your other medicinesfor at least an hour.

These instructions are difficult for many patientsto follow regularly. Because these drugs bind soavidly to bone, most manufacturers have produceda tablet that can be taken once a week.

• Calcitonin This hormone produced by the bodyslows bone resorption. Drug companies havebeen able to manufacture calcitonin, and it is aneffective treatment for osteoporosis. Unfortu-nately, as occurs with most hormones, calcitoninis destroyed by acid in the stomach. Therefore,to get it into the body, it has to be given by aninjection under the skin or else as a nasal spray.The nasal spray is much more convenient to usethan injections but is probably less effective thanbisphosphonates in reducing the risk of osteo-porotic fractures. One advantage of calcitonin isthat if a patient has pain caused by an osteo-porotic fracture, it may reduce pain.

• Other Drugs Less evidence supports the use ofother treatments for osteoporosis. High doses ofvitamin D, parathyroid hormone, and fluorideare all being studied as alternative treatmentsfor osteoporosis. Early studies using fluorideshowed that although it increased bone densitydramatically, it did not decrease the risk of frac-tures. More recently studies have found that

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low doses of fluoride may decrease the risk offractures.

• Preventing Fractures Many people, includingscientists, forget that the point of treating osteo-porosis is not to increase bone density but todecrease the number of fractures. The two oftengo hand in hand, but not always. Early studieswith fluoride showed that it was able to increasebone density substantially, even more than bis-phosphonates, but unfortunately fracture riskwas not decreased. There were two importantlessons from these studies: First, not all drugsthat increase bone density automatically reducethe risk of fractures. Second and perhaps moreimportantly, fractures are more important thanbone density. So it is important not to forget thatthe aim of treating osteoporosis is to preventfractures and that many fractures are caused byfalls that could be prevented.

Simple things can reduce the risk of falling.Some of these are common sense: getting rid ofloose throw rugs and other objects that can tripsomeone, having nonslip surfaces, using a cane forsupport, not hurrying (for example to answer thetelephone), and keeping a night-light on to see theway to the bathroom. People with poor vision aremore likely to fall, so it makes sense for everyoneto have their vision checked from time to time.Alcohol and medicines that affect balance, such assleeping pills, increase the risk of a fall. So if some-one has osteoporosis and is at risk of falling, he orshe should try to avoid these drugs. Studies per-formed in nursing homes have shown that the riskof serious fractures, particularly hip fractures, wasreduced if patients at high risk wore hip protectors.These are appliances that provide padding aroundthe hip to protect the fragile bones. Unfortunately,most people who have a high risk of falling do notwant to wear bulky padding all the time to provideprotection on the few occasions when they do fall.Therefore, these protective devices are not popular.It may be useful to remember that skateboarders, agroup of people who often break bones, have rec-ognized the value of protective padding and toexplore the best way to use padding and shock-absorbing devices to protect the elderly against hipfractures.

osteosarcoma This is a highly malignant tumorthat starts within bone and spreads outward to theperiosteum (lining of the bone) and surrounding softtissues. It affects mainly children and adolescents butmay be increasing in frequency in adults. Mostosteosarcomas developing in people over the age of50 arise in bone affected by PAGET’S DISEASE. This isthe most feared complication of Paget’s disease.

The first symptom is usually pain that is constantand may be worse at night. There is often tendernessover the area. Later on there may be a swelling, andoccasionally a fracture may occur through the weak-ened bone. Blood tests often show a raised ESR andalkaline phosphatase (see Appendix II). The early X-ray changes may be difficult to interpret, with vagueareas of bone destruction (dark on the X ray) alter-nating with denser-than-usual bone. Lifting of theperiosteum and radiating streaks of new bone arethe most typical X-ray changes but may also be seenin other rapidly growing tumors. Both CT and MRIscans are very good at showing the extent of thetumor, and CT scans are usually done to look forspread into the lungs. A careful biopsy should bedone to confirm the diagnosis.

Osteosarcoma had a bad outcome up till the1970s, with only one in five patients surviving fiveyears from the time of diagnosis. Recent reportsshow 70 percent of patients surviving five years.This dramatic improvement is due to the develop-ment of adjuvant chemotherapy to supplementsurgical removal of the tumor and the aggressiveremoval of secondary tumors (usually from thelungs). Chemotherapy is usually begun beforesurgery. The ideal regimen is not yet clear, and sev-eral different ones are in use. If a limb is involved,it usually has to be amputated through or justabove the joint above the tumor. Although this isless radical than some of the surgery done beforechemotherapy, removing just the bone around thetumor in order to avoid amputation leads to ahigher recurrence rate. Radiotherapy is used onlyin special circumstances. The removal of nodules oftumor that have spread to the lungs or bone defi-nitely improves the outcome and may requirerepeated operations in the early years.

overlap syndromes The symptoms of rheumaticdiseases commonly overlap, particularly early in

182 osteosarcoma

the course of the illness. The term overlap syn-drome or undifferentiated connective tissue diseaseis often used loosely to mean that a patient has aconnective tissue disorder with clinical features ofseveral different autoimmune diseases withoutbeing typical of one. Some patients with overlapsyndrome may not fulfill the strict diagnostic crite-ria for any one connective tissue disorder, and oth-ers may fulfill the criteria for more than onediagnosis. Overlap syndrome is most often used todescribe an illness with some features of lupus,scleroderma, and dermatomyositis. MIXED CONNEC-

TIVE TISSUE DISEASE (MCTD) is another condition withfeatures that can overlap several autoimmune con-ditions. Patients with MCTD have a positive test forantibodies against ribonuclear protein (RNP), andpatients with overlap syndrome do not.

It is not usually difficult to separate SLE and RAbecause their symptoms are usually different.However, there are a few patients who have fea-tures that are common to both diseases. This arrayof symptoms has sometimes been called rupus, aterm derived from the amalgamation of the abbre-viations RA and lupus. Some rheumatologistswould call this illness an overlap syndrome orundifferentiated connective tissue disease.

Cause

As is the case for most autoimmune diseases, thecause of overlap syndrome is not known and is dis-cussed under the individual conditions.

Symptoms

In the early phases of many autoimmune diseasesthe clinical features can be similar. Rather than

make a diagnosis that may later turn out to beincorrect, many rheumatologists make a diagnosisof undifferentiated connective tissue disease oroverlap syndrome. As time passes the clinical fea-tures of the illness may evolve so that a clear diag-nosis of lupus, scleroderma, dermatomyositis, oranother autoimmune disease can be made. Patientswith overlap syndrome have combinations ofsymptoms that can occur in various autoimmunediseases. These include Raynaud’s phenomenon,difficulty swallowing, and tightness of the skin thatare typical of scleroderma; pleurisy, arthralgia,mouth ulcers, rash, and pericarditis that are typicalof SLE; and muscle weakness, typical of myositis.

Diagnosis

The diagnosis is clinical. Many patients have a pos-itive antinuclear antibody (ANA) test. If patientswith overlap symptoms have a positive test for RNPantibodies, the diagnosis is mixed connective tissuedisease.


The treatment of overlap syndrome involvesaspects of the treatment for SLE, scleroderma, andmyositis, with individuals treated according to thesymptoms they have. NSAIDs are often used totreat arthralgia and arthritis; CORTICOSTEROIDS totreat myositis, pleurisy, and pericarditis; immuno-suppressive drugs to treat kidney disease (which israre); and antireflux drugs to treat difficulty swal-lowing. Patients are monitored because their illnessis likely to change over time and evolve toward oneof the classical autoimmune diseases with a prog-nosis similar to that disease.

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P

Paget’s disease Although Sir James Paget firstdescribed this bone disease with “chronic inflam-mation and deformity” in the 19th century, there isevidence that it has existed since prehistoric times.It is common in the United States, Britain, Aus-tralia, and New Zealand but rare in Asia. Not onlydoes its occurrence vary in frequency betweencountries but also between areas within a country.Paget’s disease becomes increasingly common withincreasing age, being rare before the age of 40 yearsand then doubling in frequency every 10 yearsafter the age of 50. It affects 2–3 percent of thoseaged over 50 years in the United States with menbeing affected more than women.

Cause

Paget’s disease is characterized by areas of bonebeing resorbed by large cells called osteoclasts andthen replaced with new bone by cells called os-teoblasts. This process occurs in normal bone allthe time in a highly controlled manner so thatbones can adjust, for example to changes inweight, and repair. What distinguishes Paget’s dis-ease is that the osteoclasts are hyperactive, resorb-ing bone faster than normal and in a disorganizedfashion. The result is that affected bone is enlarged,is weakened, and has an unusually large bloodsupply. This increased blood flow causes thewarmth often felt over pagetic bones. The cause ofthis disordered bone behavior is not certain. How-ever, small viral inclusion bodies have been foundin the osteoclasts, suggesting a viral cause. Re-search has shown links with measles, respiratorysyncytial, or canine distemper viruses. It is thoughtthat viral infection of the osteoclasts early in liferesults in their abnormal behavior many yearslater. There is an aggregation in families, with 30percent of patients having at least one affected rel-

ative, indicating a possible genetic component tothe disease.

Symptoms

Many patients have no symptoms when they arediagnosed. This usually occurs when routine bloodtests show a raised ALKALINE PHOSPHATASE level (seeAppendix II) without any obvious cause. X rays arethen taken and show the Paget’s disease. Otherpatients may be diagnosed when the typical changesare seen on an X ray taken for an unrelated reason.Paget’s disease may present in a number of ways.

The skull, spine, sacrum, pelvis, and lower limbsare most frequently involved. Although seldomseen these days because of earlier treatment, theskull may become enlarged in a rather characteristicfashion with a large, bulging forehead. Deafness stillcommonly occurs and may be due to involvementof the skull with pressure on the auditory nerves orinvolvement of the small conducting bones (ossi-cles) in the middle ear. Rarely, the base of the skullmay be softened by pagetic involvement and moveupward under pressure. This can cause pressure onthe upper spinal cord and cerebellum and block theflow of cerebrospinal fluid, causing increased pres-sure within the skull. Paget’s disease affecting thespine may cause pain of its own accord or by com-pression of nerve roots as they leave the spine. Veryrarely, there may be pressure on the spinal corditself. Involvement of the pelvis often causes pain ordiscomfort, and some patients complain of a feelingof increased heat. In time this often affects the gait.If the bone around the hip joint is affected, the headof the femur (thighbone) may gradually pushthrough into the pelvis (protrusio acetabuli). Thelong bones of the legs are often affected. They canfrequently be felt to be warm and may bend becausethe bone is softer than usual. If bone close to a joint

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is affected, secondary OSTEOARTHRITIS often developsafter a few years. The long bones are at increasedrisk of fracture. This may occur after a fall or motorvehicle accident with a complete break in the boneor as pseudofractures. Pseudofractures do notextend right across the bone and occur particularlyon the outer surface of long bones that have bent.They are typically quite painful but do not otherwiseprevent the patient from mobilizing.

The most feared complication of Paget’s disease,OSTEOSARCOMA, is fortunately very rare. Less than 1percent of people with Paget’s disease develop thishighly malignant tumor of the bone that is very dif-ficult to treat. Patients may note an increase in painin one particular area with swelling, and the alka-line phosphatase level usually rises dramatically.Occasionally less malignant tumors, giant celltumors, may develop. If a patient with Paget’s hasan unrelated cancer that spreads, it not infre-quently spreads to pagetic bone because of theincreased blood flow there. Sometimes with wide-spread disease the blood flow can increase to suchan extent that it causes heart failure or makesangina difficult to control.

Diagnosis

The characteristic X-ray appearance of enlargedbones with alternating areas of increased resorptionand formation of bone together with a raised alka-line phosphatase level is usually sufficient to makethe diagnosis. Differentiating Paget’s disease fromsecondary bone tumors, especially prostate cancercan be difficult. Several very characteristic X rayfindings support a diagnosis of Paget’s disease. How-ever, if there is no history to help, it can sometimesbe impossible to differentiate on X ray. In these sit-uations a biopsy is usually required. Radionuclidebone scans are useful in showing the extent of boneinvolvement but do not differentiate Paget’s fromother bone diseases. CT and MRI scans are oftenused to show nerve or brain abnormalities. Audio-logical testing can differentiate between nerve deaf-ness and involvement of the conducting ossicles.Blood and urine tests can give more informationabout the rate of bone turnover but are seldomrequired. Alkaline phosphatase, type I procollagencarboxyterminal peptide, and osteocalcin all reflectbone formation. Urine hydroxyproline or pyri-

dinium cross-linked peptides reflect resorption ofbone. In general, the level of alkaline phosphatasereflects both the extent of bony involvement (themore bones involved, the higher the level) and theactivity of disease. It is useful for monitoring treat-ment in most patients, but is less helpful in thosewith skull involvement.

Treatment

Treating asymptomatic Paget’s disease is not alwaysnecessary. However, the available treatments haveimproved so much over the past 15 years thatmany patients are now treated at an earlier stage.Indications for treatment include:

• Pain from the Paget’s disease itself

• Preventing increasing deformity around a jointand therefore delay the development ofosteoarthritis

• Nerve entrapment, either present or impending;this should include any involvement of the baseof the skull or temporal bone (the auditorynerve passes through this)

• If surgery to an affected area is planned, thepatient should receive medical therapy first tolimit intra- and postoperative bleeding

• Heart failure or difficult-to-control angina; treat-ment reduces blood flow and thereby reducesthe workload of the heart

• Fractures that have either occurred or are likelyto occur given the extent of involvement of thebone

• High calcium levels, although this is rare unlesspatients are immobilized, as might occur forexample when they are hospitalized for anunrelated illness

Painkillers and NSAIDs should be used appropri-ately for pain, but they do nothing to alter the dis-ease process itself. This is achieved with eitherCALCITONIN or one of the BISPHOSPHONATES. Calci-tonin has been used for many years and is reputedto have pain-relieving effects as well as shuttingdown the activity of the osteoclasts. Both humanand salmon calcitonins are available. Salmon calci-tonin is more effective and is more commonly used.Calcitonin is administered by injections under the

186 Paget’s disease

skin either daily or every other day. Its use is limitedby side effects, principally flushing and diarrhea. Anasal calcitonin spray has recently become availablebut is not approved for use in Paget’s disease.

The first bisphosphonate to be used was ETID-

RONATE (trade name: Didronel). At the doses re-quired to treat Paget’s disease this interfered withnormal bone growth and was of limited use. Thenewer generation bisphosphonates have, however,revolutionized the treatment of Paget’s disease.These include PAMIDRONATE (trade name: Aredia)which has to be given as an intravenous infusion,ALENDRONATE (trade name: Fosamax), and RISEDRO-

NATE (trade name: Actonel). These are all highlyeffective in normalizing markers of bone turnoverand reducing pain. Pamidronate may cause short-lived flulike symptoms but is well tolerated. Thereare a number of different regimens for giving thesedrugs. Giving a course and then following a markerof Paget’s disease such as the alkaline phosphataseis usual to see when retreatment is required.

palindromic rheumatism A rare type of inflamma-tory arthritis that causes symptoms in one or a fewjoints for a few hours or days and then resolves com-pletely, only to recur days, weeks, or months later.

Cause

The cause is unknown. In approximately 50 per-cent of patients with palindromic rheumatism theillness evolves into classical rheumatoid arthritis(RA) and a few patients develop SLE. In manypatients though, the illness does not evolve intoanother rheumatic disease.

Symptoms

Acute attacks of severe arthritis causing pain,swelling, and redness in one or a few joints areusual. Knees, wrists, shoulders, and small joints ofthe hands are often affected. The symptoms can besevere initially, stopping patients from working orperforming day-to-day activities, and then oftensettle over a few days, even without any treatment.The attacks recur without warning and can be sep-arated by days, weeks, or months. The patient usu-ally has no symptoms between attacks. If the illnessevolves into RA, the attacks become more frequentand never resolve completely.

Diagnosis

The diagnosis is usually made from the history. Bythe time the patient sees the physician, the jointsymptoms have usually resolved completely. Goutis another cause of acute attacks of arthritis thatshould be considered. The acute attacks of goutclassically start in the big toe and take longer to set-tle, usually a week or two. Blood tests are not veryhelpful. During an attack of palindromic rheuma-tism the ESR can be elevated, but this is not specificand can occur in gout or other types of inflamma-tory arthritis. Those patients whose illness evolvesinto RA often have a positive test for rheumatoidfactor.


Palindromic rheumatism does not cause jointdestruction or deformity, but the symptoms can beincapacitating while they are present. Treatmentwith an NSAID, particularly if started when thepatient notices the first symptoms of an attack, canbe effective. If NSAIDs alone do not control theattacks, CORTICOSTEROIDS such as prednisone for afew days will help. If the attacks are frequent, reg-ular treatment with an NSAID or a low dose ofprednisone may decrease their frequency. If not,HYDROXYCHLOROQUINE, a DMARD used to treat RA,is often effective. If palindromic rheumatismevolves into RA, it is treated as RA.

panniculitis A rare condition that causes inflam-mation of fat just under the skin and causes painfulred lumps. Most panniculitis is caused by one offour conditions.

1. ERYTHEMA NODOSUM

2. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) or VASCULITIS.The panniculitis in SLE is sometimes called lupusprofundus and causes painful nodules that canulcerate.

3. Weber-Christian disease. This is a rare illnessthat causes recurrent attacks of panniculitis witharthralgia, abdominal pain, and fever, mostly inyoung women.

4. Pancreatic disease. Serious conditions such aspancreatitis or cancer of the pancreas can causepanniculitis. One of the functions of the pan-creas is to secrete enzymes that digest dietary

panniculitis 187

fat. Panniculitis may be caused by high levels ofpancreatic enzymes in the bloodstream thatdamage fatty tissue.

parvovirus Parvoviruses are small DNA viruseswith only limited genetic capabilities. They there-fore rely on host cells for certain functions. For thisreason, the only parvovirus that infects humans,the human parvovirus B19 (HPV-B19), has apredilection for rapidly dividing cells such as acti-vated lymphocytes. HPV-B19 is the cause of the ill-ness, erythema infectiosum, also known as fifth

disease or slapped cheek syndrome. This is a commoninfectious disease causing fever and rash mainly inchildren and often spreading rapidly throughoutsmall communities. Outbreaks often start in ele-mentary schools where up to 60 percent of suscep-tible children may be infected.

The acute illness starts as a flulike illness withfever, muscle aches, and headaches. The bone mar-row virtually stops producing red cells, and whitecell and platelet production is also affected. In mosthealthy people this is not serious since it lasts onlyabout two weeks. However, HPV-B19 can causelife-threatening aplastic crises in patients withhemolytic anemias such as the thallassemias. Thesepatients have red cells that break up after a shortertime than normal, and to maintain a reasonablelevel, they have to manufacture new red cellsmuch faster than usual. When red cell productionstops because of HPV-B19 infection (an aplastic cri-sis), these patients can become profoundly anemic.

Antibodies to HPV-B19 appear after about 10days, and these will clear the virus from the blood.They also allow diagnosis of the infection. IgM anti-bodies are detectable for about two months afterinfection and need to be present to identify a partic-ular illness as being due to HPV-B19. The IgG anti-bodies are detectable for the rest of that individual’slife and indicate only exposure to the virus sometime in the past. In different populations, between40 and 80 percent of people have evidence of beingexposed at some time. As the level of IgM antibodyrises, the rash, joint pain, and arthritis may appear.The patient is no longer infectious at this stage. Chil-dren often get an irregular red rash on the cheeksleading to the name, slapped-cheek syndrome. Jointpain is common in the acute infection, occurring in

8 percent of children and 80 percent of adults. Thereare four areas in which HPV-B19 is important inrheumatic diseases:

1. Acute B19-associated arthritis2. As a trigger of JUVENILE ARTHRITIS

3. As a possible trigger of RHEUMATOID ARTHRITIS

4. As a possible trigger of connective tissue diseases

Acute B19-associated arthritis The acute ill-ness is typically short-lived in children. Up to 80percent of adults get joint pain or arthritis. Arthri-tis is more common in women and on average lastssix to nine months. About two-thirds of those withjoint pain describe joint swelling, most often affect-ing the hands, feet, and knees.

B19 and juvenile arthritis Although usuallyshort-lived, acute arthritis has been reported aspersisting for over a year in a few children. The pat-tern of joint involvement has been variable, resem-bling rheumatoid arthritis in some andpauciarticular juvenile arthritis in others. There isin addition some evidence that HPV-B19 may trig-ger juvenile arthritis. A report from India showedthat many more patients with juvenile arthritis hadevidence of previous B19 infection than controls(see CLINICAL TRIAL for explanation of controls). AScandinavian study found that more than a third ofjuvenile arthritis patients undergoing joint replace-ment had B19 DNA in the joint lining of theaffected joints. These and other similar studies areinteresting but do not show proof of causation.

B19 and rheumatoid arthritis There are manydifficulties proving that an infection triggers rheu-matoid arthritis or other chronic arthritis. Re-searchers have tackled the problem in differentways and, although there are interesting findings,they are far from conclusive and not all the studiesare consistent. One approach is to follow up a groupof patients who develop B19-related arthritis andsee if any of them develop typical rheumatoidarthritis (i.e., a chronic, rheumatoid factor-positivearthritis that erodes joints). There are several suchstudies, but none of them have shown progressionto rheumatoid arthritis. Isolated reports discusspatients developing typical rheumatoid arthritisafter HPV-B19 infection, but these do not exclude achance occurrence. Another approach is to examinegroups of rheumatoid arthritis patients for evidence

188 parvovirus

of B19 infection. A number of studies using sophis-ticated techniques have shown that the virus per-sists, particularly in the bone marrow and jointlining of some patients with rheumatoid arthritis,despite blood tests being negative. The numbers ofpatients so affected are not great, however. A verydetailed study found B19 DNA in nearly 80 percentof joint lining specimens from rheumatoid arthritispatients. This was far more than in controls. Thestudy went on to show that the virus was alive andinfectious, and it could stimulate the type ofimmune response likely to cause rheumatoid arthri-tis. If these findings could be repeated, it would pro-vide strong evidence for HPV-B19 involvement intriggering rheumatoid arthritis. It is thought fromhistorical evidence that HPV-B19 is a New Worldvirus, reaching Europe only in the 16th century.This would fit with the emergence of rheumatoidarthritis.

B19 and connective tissue diseases There are anumber of reports of patients with HPV-B19 infectionthat is very difficult to differentiate from SYSTEMIC

LUPUS ERYTHEMATOSUS (SLE). These patients have hadfacial rashes, fever, joint pain and arthritis, musclepain, low white blood cell and platelet counts, andreduced COMPLEMENT levels, features all typical ofSLE. They also developed a number of autoantibod-ies. Most of these patients had positive ANA tests,some were positive for anti-DNA, Ro, and La anti-bodies (also found in SLE) and others for rheumatoidfactor or Scl-70 (found in SCLERODERMA). Many ofthese patients have had short-lived illnesses lastingweeks to months and settling with only symptomatictreatment, but a few have lasted for one to two years.This, however, indicates that HPV-B19 can cause anillness very like SLE or other connective tissue dis-eases, not that it can cause these diseases. In a studyof 99 SLE patients who had just been diagnosed,there was no evidence of recent HPV-B19 infection.

To summarize these findings, HPV-B19 infectioncan mimic both early rheumatoid arthritis and con-nective tissue diseases and has provided someinteresting insights for researchers. However,research has not yet shown that B19 can triggerthese diseases.

patellofemoral disorders The powerful muscles infront of the thigh (the quadriceps muscles) join to

form a strong tendon (patellar tendon) that passesover the front of the knee joint to attach a fewinches down the front of the tibia (the larger of thetwo lower leg bones). Within the tendon is a small,roughly heart-shaped bone, the patella, that forms ajoint with the femur (thighbone), running in agroove between the two curved condyles at its lowerend. This bone provides a mechanical advantage tothe quadriceps muscles in straightening the knee.This patellofemoral joint lies within the same jointcavity as the main knee joint (tibiofemoral) and isnot uncommonly a source of pain (see KNEE PAIN).

Infants can occasionally be born with a dislo-cated patella. The patella is usually small and theknee is in valgus (knock-kneed). The tissuesattaching to the outside of the patella are verytight, and the patella slips over the outer or lateralcondyle of the femur while the baby is still in theuterus. Surgery is required to release these tight tis-sues and realign the patella. Older children can gethabitual dislocation of the patella. The muscle andtendon attaching to the outside of the patella areagain too tight, and in order to bend the knee, thepatella has to slip over the lateral condyle. Unlessvery mild, this also has to be treated surgically withrelease of the tight tissues.

Recurrent dislocation or subluxation usuallyoccurs in adolescents, girls more frequently thanboys. This is different than habitual dislocation incause and is generally less severe. Typically, theseindividuals have a larger-than-usual angle betweenthe thigh and the patella tendon (called the Q angle)and will thus appear knock-kneed. This may bebecause of true genu valgum (knock-knee), thefemur may be twisted inward slightly (persistentfemoral anteversion), or the tibia may be turnedslightly out. Some patients also have a small highpatella (patella alta) or a small, lateral femoralcondyle, making it easier for the patella to slip overthe condyle. Some patients have a degree of HYPER-

MOBILITY. Complete dislocation is easily diagnosedeven if the patella has slipped back into place, butsubluxation can be more difficult. Here the patelladoes not actually leave the groove between the twocondyles but hits up against the inside of the lateralcondyle, causing pain. A careful examination and X rays usually lead to the correct diagnosis. Initialtreatment is by strengthening the quadriceps mus-

patellofemoral disorders 189

cle, particularly the one on the inner lower aspect ofthe thigh that controls the patella movement andprevents it from moving outward. If this muscle isstrengthened and the problem persists, surgery maybe necessary. The lateral tissues may be released asin habitual dislocation, or more radical procedurescan be done to correct the alignment of the patella.

Another cause of knee pain in adolescent girls isusually known simply as anterior knee pain. Thepain is often felt during or after sports and maywake the child at night. These girls tend to be moreknock-kneed than average, but no dislocation orsubluxation can be demonstrated. They generallyhave weak quadriceps. Some patients have tighthamstrings (the back of the thigh muscles) that maybe brought on by wearing high-heeled shoes. Bothof these latter conditions increase the pressurebetween the kneecap and the thighbone in thepatellofemoral joint. The treatment is a combina-tion of stretching the hamstring and strengtheningthe quadriceps muscles. Surgery should be avoided.

Bipartite patella refers to a condition where thetwo bone centers in the patella do not growtogether as normal and leave a thin layer of carti-lage between them. Because cartilage is weakerthan bone, this can fracture following repetitivestress. It heals well with splinting. Chondromalaciapatellae describes softening of the cartilage at theback of the patella. This gives rise to an aching painin the front of the knee, especially when it is keptbent for long periods (e.g., in the cinema) or climb-ing stairs or cycling. It may result from poor align-ment of the patella with the femur so that there isincreased shear force on the cartilage during move-ment or from tight hamstrings. Treatment is pri-marily with strengthening the quadriceps andstretching the hamstrings.

pericarditis The heart is enveloped in two mem-branes. The inner one, lying right against the heart,secretes a small amount of fluid so that the two lay-ers move easily against one another, thereby reduc-ing any friction to the constantly moving heart. Theouter layer is relatively tough and prevents exces-sive expansion of the heart, for example duringexercise. It also creates negative pressure that doesnot allow the heart to empty completely when itpumps out blood. These two layers of membrane

are together called the pericardium. Inflammationof the pericardium is called pericarditis.

Cause

Although pericarditis is not very common, thereare many conditions that can cause it. Only someof these are rheumatic diseases, but a brief list is asfollows:

Infections Viruses, bacteria, TUBERCULOSIS,fungi, and very rarely other infections such assyphilis can all cause pericarditis.

Ischemic heart disease A few patients developan autoimmune pericarditis after a heart attack orcardiac surgery (Dressler’s syndrome), while othersmay have pericarditis as part of the damage of aheart attack.

Uremia Patients with severe kidney failureoften develop pericarditis.

Tumors Many tumors will occasionally spreadto the pericardium. Most commonly a lung cancerspreads directly to involve the pericardium. Con-versely, radiotherapy of the chest for cancer isanother cause of pericarditis.

Trauma This may be either an injury that pen-etrates the chest and directly damages the peri-cardium or a blunt blow to the chest wall as in amotor vehicle accident.

Drug-induced lupus Procainamide and hydra-lazine were well-known causes but are seldom usednow. Isoniazid used to treat tuberculosis andminoxidil used to treat hypertension are still usedand may cause pericarditis.

Miscellaneous Other diseases such as hypothy-roidism, SARCOIDOSIS, FAMILIAL MEDITERRANEAN

FEVER, and severe anemia are occasional causes.Rheumatic diseases The best-known rheumatic

causes are SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), SCLE-

RODERMA, and RHEUMATOID ARTHRITIS. Pericarditismay also occur in Stills disease or systemic-onsetJUVENILE ARTHRITIS, MIXED CONNECTIVE TISSUE DISEASE,and the OVERLAP SYNDROME.

Symptoms

Chest pain is the most common symptom and isusually present when a rheumatic disease is thecause. The pain may be severe and is maximalbehind the breastbone but may also be felt in the leftchest and through to the back. Sometimes it canradiate into the arms as in a heart attack. Typically

190 pericarditis

sitting up or leaning forward relieves the pain some-what. Pain is not always present. Mild painless peri-carditis likely occurs more commonly thandiagnosed. Pericarditis is diagnosed in 20–30 percentof SLE patients at some time, although it is not amajor problem in all of these patients. If the spacebetween the two membranes fills with a lot of fluid(termed a pericardial effusion), the heart will beunable to fill normally (tamponade) and the patientmay be breathless and weak. When severe, this is alife-threatening disorder. Tamponade is not commonin the rheumatic disorders, occurring in less than 4percent of SLE patients with proven pericarditis.With long-standing inflammation the pericardiummay tighten around the heart again, restricting itsability to fill and pump blood (constrictive pericardi-tis). Occasionally in the CREST syndrome, this mayoccur as a result of calcification of the pericardium.

Diagnosis

There is often a crunching sound as the two mem-branes rub against each other in pericarditis. Thispericardial friction rub is the most important sign ofthe disease. If tamponade is present, there will besigns of increased pressure of blood in the veins ofthe neck. The ECG will often show characteristicchanges of widespread raised ST segments. A chest Xray may show an enlarged heart shadow. Anechocardiogram (ultrasound scan of the heart) isvery good at demonstrating fluid in the pericardialsac. It should be remembered that patients withrheumatic diseases may also get pericarditis due toinfections, drugs, or trauma. When the cause is indoubt, and especially if infection is likely, fluid maybe removed from the pericardial sac. This is aninvasive procedure and should be done under con-trolled conditions.

Treatment

Pericarditis of rheumatic origin usually responds toanti-inflammatory treatment with CORTICOSTEROIDS.This may be given in large intravenous pulses for arapid effect. All patients with recent onset of peri-carditis should be carefully observed for the devel-opment of tamponade. If this develops, removal ofpericardial fluid may be lifesaving. This is done byinserting a needle into the pericardium (usuallyfrom under the left-sided ribs close to the lower endof the breastbone). Either an ECG lead is attached to

the needle so that a signal can be seen when ittouches the heart or an ultrasound technician canassist in placing and monitoring the position of theneedle. When effusions keep recurring it may benecessary to cut windows in the pericardium toallow free drainage. If long-standing inflammationhas led to significant tightening or constriction ofthe heart, the only treatment is to peel the peri-cardium off surgically. In rheumatic diseases if thepericarditis is diagnosed and treated promptly, theoutcome is usually very good.

pharmacogenetics The terms pharmacogenetics andpharmacogenomics are often used interchangeablyand describe an area of intense medical research thatseeks to predict how an individual will respond to adrug based on his or her genetic makeup. This con-trasts with most other medical uses of genetics thatseek to find the genes that predispose people todevelop a particular illness or to intervene in a dis-ease by inserting modified genes (gene therapy).

There is a lot of variability between people intheir response to the same dose of a drug. A few areallergic, some have little or no response, some havea good response, and some have such a strongresponse that they develop side effects. This meansthat when a new drug is marketed, the standarddose chosen is the one that suits most people. Thisstandard dose will, however, be too low for somepeople and too high for others. Many factors affectresponse to a drug, some of these such as diet,smoking, alcohol intake, body weight, and kidneyand liver function are environmental, but geneticvariations also alter responses. The ultimate aim ofpharmacogenetics is to identify the genes that affectresponses to drugs and use this information to selectthe best drug, and the correct dose, for each indi-vidual. Pharmacogenetics can be divided into twobig areas: genes that affect the concentration ofdrugs and genes that affect the response to drugs.

Genes that affect the concentration of drugs

Most drugs, after they are absorbed, are metabolizedin the body. Usually this is a way of breaking downthe active drug and excreting it. Sometimes, though,an inactive drug, called pro-drug, is metabolized toan active drug. Drugs are metabolized by enzymes.Genetic variation can result in these enzymes, result-ing in increased or decreased activity compared with

pharmacogenetics 191

the usual enzyme amounts found in most people. Agroup of enzymes called cytochrome P450 (CYP),found in the liver and intestinal wall, metabolizemore than half of all drugs. The CYP enzymes arebroken down into families labeled 1, 2, 3, and so on.These are further subdivided into subfamilies labeledA, B, C, and so on and then into genes labeled 1, 2,and 3.

There are several genetic variants of CYP drug-metabolizing enzymes that affect how active theyare. For example, approximately 5–10 percent ofmost Caucasian populations have a variant ofCYP2D6 that is either inactive or poorly functional.This means that these people poorly metabolizedrugs that are substrates for this enzyme. Some-times this means that they will not respond to adrug. For example, codeine is activated to morphineby CYP2D6. Therefore, people with an enzyme thatfunctions poorly do not activate codeine well anddo not receive the analgesic benefits of codeinewhen they take it. More often, having a defectiveenzyme means that people accumulate high levelsof a drug. For example, the older antidepressantssuch as amitriptyline and nortriptyline are alsometabolized by CYP2D6, but in this case they areinactivated by it. Therefore, people with the inac-tive enzyme have higher blood levels of these anti-depressants and are more likely to have side effectsif they are given standard doses of the drugs.

Important genetic variations have been discov-ered in CYP3A, CYP1A2, CYP2C9, and CYP2C19.The clinical importance of a variation depends onthe drug affected. If the drug is effective and safeover a wide range of concentrations, genetic varia-tion is unlikely to be clinically important. On theother hand, if the concentrations of a drug that areeffective and those that cause side effects are close,a small increase or decrease in concentration canresult in side effects or lack of effect. For example,CYP2C9 is the enzyme responsible for metabolizingmost of the active component of warfarin, a drugused to prevent blood clotting. The concentrationof warfarin is critically important. If it is slightly toolow a blood clot can result, and if it is too high thepatient may bleed. Genetic variants of CYP2C9called *2 (star 2) and *3 are less effective and resultin a greater concentration and therefore greatereffect of warfarin in people who have these vari-

ants. At this stage it is not clear if genotyping peo-ple before they start warfarin will provide informa-tion that improves outcomes compared will theusual way warfarin is dosed and monitored.

Not all drugs are metabolized by CYP enzymes. Agenetic variation in an enzyme called thiopurinemethyltransferase (TPMT) slows the metabolism ofazathioprine and causes a substantial increase insensitivity to it. The homozygous form (both strandsof DNA are affected) of the gene associated withimpaired TPMT activity occurs in approximatelyone in 300 people. Although this is a relatively rarevariant, its consequences can be devastating. Ifsomeone with a defective TPMT enzyme takes stan-dard doses of AZATHIOPRINE (trade name: Imuran),bone marrow failure is likely to result because veryhigh levels of the drug accumulate. Genetic testingfor TPMT variants is now available.

The concentration of a drug in the body isaffected by many factors. Obvious ones are thedose of drug taken and the rate at which enzymeseliminate it, but less obvious are transport systemsthat move a drug across different barriers. Somecells have transporters that move drugs and othersubstances across their membranes. One of the bestknown is the multidrug resistance (MDR), alsocalled P-glycoprotein (PgP), transporter. The MDRtransport system was discovered when scientistsnoticed that some cancer cells became resistant toanticancer drugs because they had a protein, PgP,which enabled them to pump the drugs out of thecells. The MDR system is present not only in cancercells but also in healthy cells in the gut, kidney, andbrain. In the gut MDR pumps drug out of cells backinto the lumen and thus decreases absorption ofsome drugs such as CYCLOSPORINE that use thistransporter. In the brain MDR helps form what iscalled the blood-brain barrier, a barrier that pre-vents drugs from entering the brain. There aremany variations in the MDR gene that can alter theactivity of the transporter and thus affect concen-trations of drugs in different parts of the body.

New genetic variations in enzymes and trans-porters are still being discovered. To make mattersmore complex, there can also be variations in thepromoter area of genes. This area drives the activ-ity of the gene. Therefore, promoter variants canresult in the transporter or enzyme being more or

192 pharmacogenetics

less active even though the gene coding for it isnormal.

Genes that affect response to drugs Drugs actin different ways, but many bind to receptors thatthen activate a cascade of messengers. This meansthat two people who have the same concentrationof a drug can have different responses if they havedifferent receptors. Genetic variants in receptorsthat mediate the effects of drugs used to treatasthma appear to have clinical effects, but there ismuch less evidence that receptor variants alterresponses to antirheumatic drugs. For example,there is speculation that genetic variability in theTNF receptor may explain why some patientsrespond well to TNF-blocking drugs and others donot but the evidence is preliminary.

photopheresis (extracorporeal phototherapy) Apatient’s blood is removed, the white blood cells areseparated by centrifugation and exposed to ultravi-olet light, and then they are infused back into thepatient. To enhance the response to light, either thepatient takes a photosensitizing drug such asmethoxypsoralen before the white cells are sepa-rated or the photosensitizing drug is added directlyto the white blood cells before they are exposed tolight. Photopheresis has been used to treat severalautoimmune diseases including SYSTEMIC LUPUS ERY-

THEMATOSUS, RHEUMATOID ARTHRITIS, and SCLERO-

DERMA and some types of skin lymphoma. Photopheresis modulates the immune system,

but how it does so is not clear. Lymphocytes affectedby phototherapy are rapidly removed from the cir-culation. Because only about 10 percent of lympho-cytes are affected, depletion of lymphocytes is notthe main mechanism of action. More likely thealtered lymphocytes induce an immune responsewhen they are reinfused.

Photopheresis is usually performed on two daysevery four weeks for six to 12 months. There arefew side effects. However, drawing blood and rein-fusing it can sometimes be difficult if a patient hasfragile veins.

Anecdotal responses to photopheresis have beenreported in autoimmune disease, but there is notmuch scientific information to support the use ofthis treatment outside of clinical trials. One studyreported modest benefits on skin-thickening in

patients with scleroderma, but the design of thetrial was criticized and more studies are needed.

physical therapy Modern physical therapy hasbecome quite diverse and specialized. Giving a con-cise definition that will usefully inform the readeris difficult. In addition, many schools of thoughthave pursued particular philosophies and becomeidentifiable as separate from mainstream physicaltherapy. The American Physical Therapy Associa-tion includes four general activities in their 1995definition of care and services provided by or underthe supervision of a physical therapist:

1. Examining patients with impairments, func-tional limitations, or disability in order to deter-mine a diagnosis, prognosis, or outcome andtherapeutic intervention

2. Alleviating these impairments or functional lim-itations by designing, implementing, and modi-fying therapeutic interventions, which mightinclude the following:

(a) Therapeutic exercise(b) Manual therapy or manipulation(c) Prescribing or making ASSISTIVE DEVICES, pro-

tective devices, and other equipment(d) Using airway clearance techniques(e) The use of physical, mechanical, or elec-

trotherapeutic modalities(f) Patient education

3. Prevention of injury, impairment, or functionallimitation including the promotion of fitnessand health

4. Engaging in consultation, education, andresearch

For patients with rheumatic disorders, therapeu-tic exercise is perhaps the most important physicaltherapy intervention. The underlying philosophyhere is to identify the patient’s functional limitation.In other words, what in his or her daily life is diffi-cult or impossible to do? The reason for this inabil-ity (the impairment) can then be determined froma careful examination. With this knowledge the best way of alleviating the impairment (and therebyimproving function of daily activities) throughappropriate exercise can be determined and

physical therapy 193

implemented. EXERCISE in this sense might includeactivities and techniques to improve mobility, mus-cle strength and force, neuromuscular control, car-diovascular fitness, muscle endurance, balance,coordination, breathing patterns, posture awareness,and/or movement patterns. Hydrotherapy or exer-cise in water has particular advantages for peoplewith severe arthritis. Water provides buoyancy,unloading painful joints, and at the same time pro-vides all-around resistance. This allows a range ofstrengthening exercises to be done with very littlestress to the weight-bearing joints. In addition, manypeople find warm water soothing.

Manual therapy (manipulation) can be used toimprove the range of movement at joints or relievepain in dysfunctional joints but should be usedwith care in the inflammatory forms of arthritisbecause the connective tissues are often in poorcondition. Physical therapists frequently use heatand cold, massage, ultrasound, or electrotherapeu-tic modalities such as faradic stimulation or trans-cutaneous electrical nerve stimulation (TENS) torelieve pain or promote healing.

pigmented villonodular synovitis (PVS) A raredisease that causes the synovium to proliferate andinvade bone.

Cause

The cause of PVS is not known. It behaves like abenign tumor and causes the synovium to prolifer-ate in frondlike strands (villi) or form nodules thatcan invade and destroy adjacent bone. The prolif-erating synovium is rich in blood vessels, and smallamounts of bleeding cause hemosiderin, a type ofpigment, to accumulate.

Symptoms

PVS almost always affects one joint, most often theknee or hip. The affected joint gradually becomespainful, stiff, and swells from time to time. If syn-ovial fluid is present it may be heavily blood-stained. This is a clue to the diagnosis because onlya few conditions cause bloodstained synovial fluid.

Diagnosis

There are no specific clues to the diagnosis onphysical examination. The most important clue is

the presence of bloodstained synovial fluid in apatient with arthritis affecting one joint. An X raymay show early changes such as thinning of thecartilage or late changes such as bony erosions.MRI can show characteristically decreased signalintensity on both T1 and T2 images, a findingthought to be caused by the accumulation ofhemosiderin in the synovium. The definitive diag-nosis is made by ARTHROSCOPY with biopsy of thesynovium.


Treatment is surgical resection. Arthroscopic oropen synovectomy is often successful, but the dis-ease can recur and require repeated surgery orradiation therapy.

plantar fasciitis This is a very common cause ofpain in the heel or foot, especially in middle-agedor elderly individuals. It is more common in theoverweight and in those with flat feet.

Cause

Shortly after the heel strikes the ground in normalwalking, the foot goes into pronation to absorb theforce of impact. Pronation involves a loosening ofthe joints of the midfoot so there is more give and aslight turning out of the forefoot while the calcaneusor heel bone itself tilts over to the inside and dips itsnose down. This results in the force of landing andweight bearing being spread through a number ofbones, joints, ligaments, and muscles rather thanjust in a direct line through the heel to the ground.One of the important structures in this mechanism isthe plantar fascia. This is a tough, flat fibrous tissuethat spans the sole of the foot from the front loweredge of the calcaneus to the base of the toes sup-porting the long arch of the foot like an unusuallywide bowstring. It also sends further slips along thetoes that serve to tighten the plantar fascia when thetoes are curled up (as when taking off from thatfoot). As the foot goes into pronation the long archtends to collapse slightly, and the plantar fascia isstretched and stressed. This is a normal event. How-ever, if the stresses are suddenly increased by, forexample, rapid weight gain or large increase in dis-tance walked, then microtears can develop in theplantar fascia. This results in small areas of inflam-

194 pigmented villonodular synovitis

mation that can accumulate and cause pain. Thiscommonly affects the middle section of the plantarfascia or its attachment to the calcaneus.

A similar process can occur with normal or mini-mal stresses if the structures themselves are abnor-mal. This can occur in patients with inflammatoryarthritis such as RHEUMATOID ARTHRITIS who areprone to develop overpronation or in people who arenaturally flat-footed. Patients with SPONDYLO-

ARTHROPATHIES are also prone to develop inflamma-tion at the attachment of the plantar fascia to thecalcaneus with relatively little stress.

Symptoms

People usually complain of pain underneath thefoot just in front of the calcaneus. The pain oftencomes on after unaccustomed standing, walking, orathletic activity. The pain is often worst in themorning or after a rest and eases a bit with walking.

Diagnosis

The typical pain should suggest the diagnosis that isconfirmed on physical examination. Tendernesscan be produced by pressing on the front end of thecalcaneus toward the inner border of the sole ortoward the middle of the long arch of the foot. Painwill also be felt when the toes are pulled upwardsince this tightens the plantar fascia. X ray mayshow a heel spur, but this seldom affects treatment.

Treatment

Relieving the pressure over the attachment of theplantar fascia may improve pain on walking, espe-cially if there is a spur. This is achieved by using aheel pad either with a cutout below the tender areaor a softer gel material in this area. However, thisdoes not address the cause. Since pronation is animportant factor in most cases, an insole that sup-ports the long arch along the inner border of thefoot and acts to limit pronation is often used. Thiscan be combined with a pressure-relieving cutout.Weight loss and appropriate footwear are impor-tant for some people. Injection of a local anestheticand CORTICOSTEROID around the attachment of theplantar fascia is helpful in settling the inflammationdown quickly. Occasionally surgical release of thefascia is necessary, and sometimes removing a trou-blesome spur is helpful.

plasmapheresis (therapeutic plasma exchange)Removal and replacement of a patient’s plasma inorder to remove large molecules such as antibodiesand other proteins. The rationale for plasmaphere-sis is simple—if a disease is caused by antibodies,removing them should improve the disease.

Plasmapheresis is performed by drawing bloodout of a vein and passing it into a centrifuge thatseparates cells from plasma. The patient’s plasma isremoved and replaced with saline and albumin orplasma from the blood bank. The reconstitutedblood is infused back into the patient throughanother vein. Removing the entire plasma volumetakes about two hours, and doing this reduces theconcentration of large proteins in the circulation byabout 60 percent. Usually three to five exchangesare performed over seven to 10 days, removing 90percent of the patient’s own antibodies.

Side effects of plasmapheresis The side effectsof plasmapheresis are usually temporary andminor. Obtain venous access in patients with smallveins can sometimes be difficult. Unsuccessfulattempts to place a needle in a vein can cause localbruising. Removing blood during plasmapheresiscan lower the blood pressure to the extent that theperson becomes dizzy or faints. This can be treatedby infusing more fluid to replace the volume thathas been removed from the circulation. If toomuch fluid is replaced, it can cause shortness ofbreath due to heart failure. This is treated by slow-ing down the rate of fluid replacement or treatingwith a diuretic that increases urine production.

Blood will clot in the plastic tubes used toremove it unless it is mixed with an anticoagulant.The anticoagulant used, citrate, can bind calcium inthe patient’s blood and cause muscle cramps andnumbness or tingling around the mouth and in thehands and feet. Calcium supplements will improvethese symptoms but are seldom needed.

Allergy to the replacement plasma is rare but cancause a rash or a more severe allergic reaction.Patients taking ACE inhibitors (angiotensin-converting enzyme inhibitors), a class of drug usedto treat high blood pressure or heart failure, mayflush and have low blood pressure during the pro-cedure. The reason is that ACE inhibitors slow thebreakdown of a bradykinin, a chemical produced

plasmapheresis 195

when the blood is processed during plasmapheresis.Patients are asked to discontinue ACE inhibitors forat least 24 hours before plasmapheresis.

Viral infections such as hepatitis C can be trans-mitted in the replacement plasma, but this is rarebecause donors are screened. Plasmapheresis isexpensive.

Indications for plasmapheresis Plasmapheresisis used as an emergency treatment for patients whohave a serious illness caused by a circulating anti-body or protein. The procedure reduces theamount of antibodies, but only temporarily. There-fore treatment with immunosuppressive drugs todecrease production of new antibodies is oftenstarted at the same time.

The indications for plasmapheresis are contro-versial. Generally GOODPASTURE’S SYNDROME, MYAS-

THENIA GRAVIS, Guillain-Barré syndrome, and aclosely related disease, chronic inflammatorydemyelinating polyneuropathy, as well as throm-botic thrombocytopenic purpura (see THROMBOCY-

TOPENIA), CRYOGLOBULINEMIA, and hyperviscositysyndrome are accepted indications.

Controlled trials show that plasmapheresis had no benefit in rheumatoid arthritis, kidney dis-ease due to SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)and polymyositis. The SLE trial was criticized be-cause plasmapheresis alone was compared withstandard immunosuppressive drugs. Plasmaphere-sis, although it temporarily decreases proteins, cancause a rebound increase in antibody production ifit is used without immunosuppressive drugs.Plasmapheresis is used empirically in critically illpatients with SLE or VASCULITIS.

podiatrist A doctor of podiatric medicine (D.P.M.degree), specializing in the treatment of foot andankle disorders. Podiatrists train for four years at apodiatric school and then spend several years in aresidency program.

Podiatrists deal with problems such as bunions,corns, calluses, ingrown toenails, hammertoes, clawtoes, foot pain, flat feet, diabetic foot problems, andfoot and ankle injuries. Treatment usually involvesorthotics, devices designed to correct or improve footand ankle biomechanics. Examples of orthotics arewedges to correct uneven leg length or adjust theangle of the ankle or forefoot, shoe inserts to provide

greater shock absorption and decrease pressure onpainful areas, arch supports, braces, and fitted shoes.Podiatrists also perform foot and ankle surgery.

polyarteritis nodosa This was the first form ofVASCULITIS described, in 1866, in Germany. It isuncommon, affecting about five per million per-sons per year in England, nine per million in Min-nesota, but up to 77 per million in AlaskanEskimos. All ages and races are affected, but it ismore common in men than women and usuallyaffects those in middle age.

Cause

In most patients with polyarteritis nodosa definingthe precise cause is difficult. Circulating immunecomplexes are often found in the blood system.These are complexes of antibodies or immunoglob-ulins together with sometimes identifiable antigensthat can become large enough to lodge in vesselwalls. Here they may initiate an immune attack onthe vessel wall that is the primary manifestation ofthe disease. Small- and medium-sized arteries areaffected in polyarteritis nodosa. Biopsy specimensshow localized destruction of the vessel walls, par-ticularly by neutrophils. These areas are weakenedand may bulge as they heal, giving rise to smallnodules that could be felt along the course of arter-ies and the origin of the earlier name, periarteritisnodosa. Feeling these today is unusual because thedisease is diagnosed and treated much earlier.

There is a strong association with chronic HEPATI-

TIS B infection in some parts of the world. Evidenceof hepatitis B infection is found in 10–50 percent ofpolyarteritis patients and probably accounts for thehigher incidence in Alaskan Eskimos in whom thisinfection is very common. Hepatitis B may be theantigen that drives the development of immunecomplexes. Antibodies directed against the vesselwall have also been found. It is possible that anti-gens on an infectious agent are similar to those onthe endothelium of the vessel wall. The antibodiesagainst the one may therefore cross-react againstthe other and direct the immune attack against theendothelium. Other infections that have beenlinked to the development of polyarteritis includehepatitis A, cytomegalovirus, PARVOVIRUS, andHTLV1.

196 podiatrist

At the site of damage in the vessel wall, is oftenovergrowth of endothelial cells and fibrous tissue,presumably in an attempt to repair the damage.This sometimes leads to blocking off of the artery.In addition, many factors promote coagulation(clotting) during a vasculitic illness. Clots mayoccur not only in damaged arteries but also inveins, whose slower blood flow makes them sus-ceptible to this.

Symptoms

As with many forms of vasculitis, polyarteritisnodosa can start and progress in many differentways. The most frequently involved organ is in factthe kidney (70 percent), although this is seldomwhat leads to the diagnosis. More commonly thejoint, skin, or nerve manifestations lead to investi-gation and diagnosis. Most patients will experiencea degree of fever, weight loss, loss of energy, andgeneralized aches. More specific symptoms includethe following.

Skin Half of all patients develop skin lesions.The earliest lesions are often small purplish blackspots on the feet and legs that can easily be felt tobe lumpy (palpable purpura). This may progress toulceration or even gangrene, usually affecting oneor several toes. LIVEDO RETICULARIS is common.

Joints More than 50 percent of patients havejoint symptoms. This may be widespread joint painor arthritis of the lower-limb joints. Occasionallypolyarteritis presents with a POLYMYALGIA RHEUMAT-

ICA-like syndrome. There is seldom damage to thejoints.

Kidney There is commonly a protein leak intothe urine, indicating damage to the filtering part ofthe kidneys (glomeruli). Occasionally this can besevere and cause nephrotic syndrome. Red bloodcells in the urine also signal glomerular damage.High blood pressure may be due to glomerulardamage or narrowing of the artery taking blood tothe kidney and affects 25 percent of patients.

Nerves Most patients, 50–70 percent, developnerve damage. Classically, this involves one or sev-eral peripheral nerves in the arms or legs. It startswith pain and altered sensation in the distributionof the nerve followed by weakness, developinghours or days later. Less commonly there is loss ofsensation in both legs in the area short socks would

cover. Very occasionally blood vessels in the brainmay be affected, leading to seizures or a stroke.

Gut The gallbladder and appendix are mostlikely to be affected, but blood vessels supplying theintestines (mesenteric arteries) may also becomenarrowed or clot. If severe these are surgical emer-gencies. The liver is seldom affected except wherethere is chronic hepatitis B infection.

Other Virtually any organ may be affected, butapart from the above, this is rare. Myocardialinfarction and heart failure have been reported.Lung lesions presumably due to vasculitis may befound. Testicular and eye involvement are also wellrecognized but uncommon.

Associated diseases A variant of polyarteritisnodosa called microscopic polyarteritis or micro-scopic polyangiitis affects the kidneys in almost allpatients and the lungs in many. Unlike classicalpolyarteritis nodosa, it does not usually affectmedium-sized blood vessels in the gut or otherparts of the body. Microscopic polyangiitis can alsocause eye and ear symptoms and can sometimes bemistaken for WEGENER’S GRANULOMATOSIS.

A polyarteritis nodosa-like syndrome can occurin patients with other rheumatic diseases such asRHEUMATOID ARTHRITIS, SJÖGREN’S SYNDROME, CRYO-

GLOBULINEMIA, hairy cell leukemia, and other blooddisorders. Metastatic cancer that is usually highlymalignant and septicemia (infection in the blood-stream) can mimic polyarteritis nodosa, althoughthe mechanisms of disease are different.

Diagnosis

When a patient presents with weight loss, malaise,joint pain, and several nerve lesions, the diagnosisis usually suspected immediately and soon con-firmed. However, polyarteritis can present in somany diverse ways that the diagnosis is notuncommonly delayed. Blood tests will show amarked inflammatory response with raised ESRand C-reactive protein. There is mild anemia,sometimes a raised white cell count, and low albu-min, but none of these findings are specific to poly-arteritis nodosa. Rheumatoid factor may bepositive, complement levels reduced, and hepatitisB markers positive.

A biopsy of involved tissue showing the typicalpattern of destruction of the vessel wall of a small

polyarteritis nodosa 197

artery is the usual confirmatory test. Skin, muscle,testes (if involved), or a sensory nerve, the suralnerve, may be biopsied. If none of the involved tis-sue is accessible, an angiogram is performed. Thisinvolves the injection of dye into the arteries sup-plying the gut, liver, and kidneys and taking X raysthat show the arterial system very clearly. In poly-arteritis nodosa affected arteries have an irregulardiameter and typically appear beaded. The classicalsmall aneurysms (localized dilatations along thearteries) are seen less often these days because ofearlier diagnosis and treatment. It is important torule out the possibility of infection and consider thepresence of an underlying malignancy in allpatients.


The initial treatment should be vigorous to try toprevent irreversible organ damage from this poten-tially devastating disease. Over 85 percent ofpatients will die within five years without treat-ment. Initial treatment is with high doses of CORTI-

COSTEROIDS. This may be given as intravenouspulses of methylprednisolone every day or everyother day for three doses initially and changed todaily PREDNISONE thereafter. Although they areeffective in controlling the inflammation, cortico-steroids may increase the tendency for arteries tothrombose. For this reason many rheumatologistsalso use an antiplatelet agent at the same time.Low-dose ASPIRIN is usually used, although otheragents are becoming available.

When the disease is severe or does not respondrapidly to corticosteroids, cytotoxic drugs such asCYCLOPHOSPHAMIDE or CHLORAMBUCIL are usuallyused. These drugs may have some additional bene-fit in preventing the overgrowth of endotheliumand fibrous tissue that frequently leads to arteriesbeing persistently narrow once the acute disease issettled. They are also highly effective in settling theinflammatory response. If these are not effective orcontraindicated, INTRAVENOUS IMMUNOGLOBULIN

(IVIG) is a further option in the initial phase of theillness. The mechanism of its action remainsunclear, but it has been shown to be effective in anumber of forms of vasculitis.

Once the acute inflammatory phase is controlled,ongoing treatment is required, first to prevent

relapse and second to manage longer-term conse-quences of the disease and treatment. Because theside effects of corticosteroids and the alkylatingagents cyclophosphamide and chlorambucil aremostly related to long-term use, it is common to tryswitching to another agent for longer-term control.This is either METHOTREXATE or AZATHIOPRINE, whichare often combined with a small dose of prednisone.

Hypertension and other factors that might pro-mote atherosclerosis (the common age-relatedarterial narrowing) must be extremely well con-trolled in these patients who have suffered widespread damage to their arteries. Antiplatelettherapy should probably be continued for life.Anti-OSTEOPOROSIS treatment may be used to pro-tect against the effects of the corticosteroids, espe-cially in postmenopausal women. Infection is aconcern in patients receiving powerful immuno-suppression drugs as described above and shouldbe promptly treated. With modern treatmentapproximately 70–80 percent of patients can beexpected to be alive five years after diagnosis.

polymyalgia rheumatica (PMR) This syndromeaffects middle-aged and elderly people. It is charac-terized by pain and stiffness in the shoulders andhips. There are European paintings depicting theassociated condition, TEMPORAL ARTERITIS, togetherwith good written descriptions of polymyalgiarheumatica going back 600 years. However, it wasonly in the 1950s that the name polymyalgiarheumatica came into being. It is common in peo-ple of northern European origin, although it hasbeen described in many parts of the world. Innorthern Europe and the northern states of theUnited States, approximately 18 in 100,000 peopleover the age of 50 years develop the disease, mak-ing it a fairly common rheumatic disorder.Between 10 and 15 percent of patients with PMRdevelop a distinctive form of VASCULITIS, temporalarteritis.

Cause

Despite considerable research, the cause of PMRremains obscure. Since nearly all patients are agedover 50 years, there is clearly some relationship toage. However, the relevance of this is unclear.There is an increased frequency of the genetic allele

198 polymyalgia rheumatica

HLA-DR4 in patients when compared with controls(see HLA). This may indicate that patients have agenetically determined way of responding to anti-gens that predisposes them to getting the disease.There are certainly a number of families where twoor more members have developed PMR. However,there are also reports of husbands and wives devel-oping PMR that would support exposure to thesame antigen rather than hereditary factors as acause.

The walls of affected arteries in temporal arteri-tis (and sometimes in uncomplicated PMR) areaffected in patches. A chronic immune attackwhich classically leads to organized clumps ofimmune cells arranged in what is termed a granu-loma. Only arteries with elastic layers in their wallsare attacked, and the attack seems to be centeredon or close to this elastic layer. The smaller arterieslose the elastic layer, so mostly large or medium-sized arteries are affected. There have been a num-ber of postulated antigens that might initiate theimmune response, but none have stood up to fur-ther investigation.

Symptoms

Typically an older individual in good health devel-ops a low-grade fever and loses some weight. Tran-sient aches and pains may be present for weeks ormonths. The pain and stiffness settles in a shoulderand then moves to both the hip and the shoulderregion within a few weeks. Less commonly apatient wakes up one morning unable to get out ofbed because of the pain and stiffness. Lethargy anddepression are common. Severe stiffness on risingin the morning is characteristic, and it severalhours may pass before the patient is able to moveabout reasonably normally. This characteristic stiff-ness often returns when the individual sits down torest during the day. Pain and waking at night arecommon. Although movement makes the painworse, the pain usually described as being in themuscles rather than the joints. Muscle strength isnormal, although pain may make it difficult for thepatient to be sure of this.

Some patients do have an associated arthritis,usually affecting the knees, wrists, or sternoclavic-ular (between the collarbone and breastbone)joints. Between 10 and 20 percent of patients with

PMR develop temporal arteritis. On the otherhand, between 20 and 40 percent of patients withtemporal arteritis have symptoms of PMR. Tempo-ral arteritis is discussed separately.

Diagnosis

No diagnostic test is available for PMR. Biopsy of atemporal artery can confirm temporal arteritis ifthis is present and may occasionally be positive inuncomplicated PMR. However, in the absence of adiagnostic test it is important to exclude other con-ditions that can present in a similar way. This isparticularly important when the onset is atypical insome way. The ESR is almost always raised.Although polymyalgia with a normal ESR is fre-quently discussed, this is very rare. Typically theESR will be raised to between 50 and 100 mm perhour. Other markers of inflammation such as C-reactive protein will also be raised, and a rise inalpha globulins is common but nonspecific. Manystudies have shown a selective reduction in CD8+T cells in patients with PMR that returns to normalafter about one year of treatment. Researchershave hoped that this might provide a more specifictest for PMR, but confirmation is awaited. Theenzymes released by an inflamed or damaged liver(especially alkaline phosphatase) are frequentlymildly raised, and liver biopsies have shown mildinflammatory changes in PMR (see Appendix II fordescription of tests). The important characteristicsin making the diagnosis are some combination ofthe following: a Caucasian patient aged over 50years with persistent (more than a month) pain inthe shoulders and pelvic girdle, marked morningstiffness, no true muscle weakness, an ESR over 40mm per hour, and excellent relief with a small doseof PREDNISONE.

The fewer of these characteristics that are pre-sent, the less typical the illness is and the morelikely it is to be another illness presenting likePMR. RHEUMATOID ARTHRITIS starting for the firsttime in an older individual is well known to mimicPMR. Multiple myeloma and lung cancer are thetwo malignancies most likely to produce this typeof syndrome, but a number of other malignanciesthat have spread to bone can also do this.Osteoarthritis (OA) of the neck is very common.When combined with the lethargy, loss of appetite,

polymyalgia rheumatica 199

and raised ESR caused by an unrecognized low-grade infection, OA may lead to an erroneous diag-nosis of PMR. Leukemias and lymphomas mayoccasionally cause confusion as can MYOPATHIES,

MYOSITIS, and hypothyroidism.

Treatment

CORTICOSTEROIDS are almost always required. Withmild disease it is possible to try NSAIDs first. How-ever, these drugs have greatly increased toxicity inthe elderly. It is therefore often safer and more effec-tive to use corticosteroids, usually prednisone. Themajority of patients will experience marked-to-miraculous relief with 15 mg of prednisone daily.Occasionally patients will need higher doses, but thisshould prompt a careful consideration of whetherthe diagnosis is correct. The dose may be reduced to10 mg per day over two months and then very grad-ually reduced as symptoms and the ESR allow. Toorapid a reduction results in more relapses, and thesepatients end up taking more prednisone than theywould have with a more gradual reduction. Treat-ment is usually required for between two and fiveyears, when it may be stopped without any recur-rence of the PMR. A very small number of patientscontinue to take a small dose of prednisone formany years. If it is not possible to reduce the pred-nisone without a recurrence of symptoms or the cor-ticosteroid side effects are too great, anothermedication is usually added. This is usually AZATHIO-

PRINE, but METHOTREXATE has also been used.Once the initial inflammation is controlled, the

patient usually feels very much better. The most dif-ficult aspect of treatment is in limiting the corticos-teroid side effects. The risk of OSTEOPOROSIS shouldbe evaluated. Most patients will benefit from pre-ventive treatment, at least for the duration of theprednisone therapy. Corticosteroids and inflamma-tion may promote atherosclerosis. Since many PMRpatients are at an age where they are at risk of car-diovascular events, they should take an antiplateletagent such as low-dose ASPIRIN. This has not beensubmitted to controlled trial and is unlikely to bebecause of the cost of such a trial. Protection frombruising and limiting weight gain are also importantin long-term corticosteroid therapy.

Although there is some variation between dif-ferent studies, at least 50 percent of patients should

be able to stop treatment after two years and thevast majority by four to five years. Between 20 and50 percent of patients will suffer significant adverseeffects from the long-term prednisone therapy. Therisk of adverse effects is related to higher initialdoses, total dose taken, and longer duration oftreatment.

polymyositis See DERMATOMYOSITIS AND POLYMYO-

SITIS.

pregnancy Patients with rheumatic diseases facethree major questions during pregnancy.

1. What is the effect of drugs used to treat rheumaticdisease on pregnancy?

2. How can pregnancy affect rheumatic illness?3. How can rheumatic illness affect the pregnancy?

These questions are difficult to answer becauseeach individual’s situation is different and there isnot much information available from clinical trials.The treatment of rheumatic disease in pregnancy iscomplicated and best performed by a team ofphysicians bringing together obstetric and rheuma-tology expertise.

What Is the Effect of Drugs Used to TreatRheumatic Disease on Pregnancy?

A few drugs are generally considered safe whentaken in pregnancy because many women havetaken them and the rate of congenital abnormali-ties has not been increased. A few drugs are alsoknown to be unsafe in pregnancy because they areteratogenic—often causing abnormalities in theunborn baby. For most drugs, though very little isknown about risks in pregnancy because, as a gen-eral principle, drug exposure is avoided in pregnantwomen. Therefore limited information accumu-lates. The information provided by manufacturersis often not very helpful, and the package insert formost drugs contains the phrase “this drug is notrecommended for use in pregnancy and should notbe used unless the benefits are thought to out-weigh the risk.” Because the risks and benefits dif-fer in every patient, there are few rigid guidelines.For example, anticancer drugs are almost alwaysavoided in pregnancy because they are teratogenic.However, if a pregnant woman has cancer that

200 polymyositis

needs to be treated immediately to protect her life,physicians will usually recommend treatment,even though this might require termination of thepregnancy.

Known teratogenic drugs include METHOTREXATE,

CYCLOPHOSPHAMIDE, all the anticancer drugs, war-farin, and THALIDOMIDE. LEFLUNOMIDE is teratogenicin animals and has the disadvantage that it stays inthe body for many months after a person stops tak-ing it. There is very little information about theeffects of leflunomide on human pregnancy, but it isavoided. In fact, many rheumatologists try not to useit in women of childbearing age. If a woman who isable to bear children is treated with leflunomide andstops it for any reason, many rheumatologists willprescribe a course of cholestyramine to speed up theelimination of leflunomide. If a woman takingleflunomide wants to become pregnant, the drug isstopped, cholestyramine is prescribed, and bloodlevels of leflunomide are measured to make surethey are almost undetectable before the woman triesto become pregnant.

MISOPROSTOL is teratogenic and also stimulatesprostaglandin receptors on the uterus, causing it tocontract. Misoprostol is used in some countries toinduce abortion.

NSAIDs are not teratogenic in the classicalsense. However, if they are used in the lasttrimester of pregnancy, they can cause prematureclosure of the patent ductus arteriosus, a smallblood vessel that joins the circulatory systems ofthe lung and the body in the fetus and normallycloses only after birth. Premature closure of thepatent ductus arteriosus can cause PULMONARY

HYPERTENSION in the fetus. NSAIDs can also haveother harmful effects at the end of pregnancy andmay prolong labor and increase the risk of bleedingin the fetus.

CORTICOSTEROIDS are probably not teratogenic butcan cross the placenta and suppress the adrenalglands of the unborn baby so that after birth it can-not make enough cortisol. This is easily treated byprescribing corticosteroids for the newborn baby.Corticosteroids can also affect the growth of theunborn baby. Prednisone does not cross the placentavery well and is the preferred drug for treating themother. Dexamethasone, on the other hand, crossesthe placenta very well and is the preferred drug in

the rare situations where the corticosteroid is pre-scribed for the fetus. Corticosteroids are often usedto control SLE and other inflammatory rheumaticdiseases in pregnancy.

For some drugs such as HYDROXYCHLOROQUINE

and SULFASALAZINE, there are case reports of fetalabnormalities. However, many rheumatologistsbelieve they are relatively safe in pregnancy andcontinue treatment if the patient agrees that thebenefits outweigh the risks.

There are several important principles regardingmedicines in pregnancy:

• The time when most medicines are most likelyto harm the unborn baby is in the first weeks ormonths of pregnancy, often before most womenknow they are pregnant. This means that if apatient is taking medicines regularly and wantsto become pregnant, she should discuss thiswith her physician and plan the pregnancy.

• If a woman is taking a teratogenic drug, she andher partner should use reliable contraception toensure that she does not become pregnant.

• If a woman taking medicines becomes pregnantunexpectedly, she should notify both herrheumatologist and obstetrician immediately.

• Some of the drugs used to treat rheumatic dis-eases can have effects for weeks or months aftera woman stops taking them. They may need tobe stopped several months before trying tobecome pregnant.

• Generally to protect the baby, as few medicinesas possible are used in pregnancy. However, theyare often needed to control serious rheumaticdiseases. For example, uncontrolled SLE can bemore dangerous to the unborn baby than someof the medicines used to control it. Many womenwith different types of arthritis who have neededtreatment in pregnancy have had healthy babies.

• Smoking and drinking alcohol, sometimes notconsidered drugs, can have harmful effects onthe baby. Pregnant women should avoid them.

How Can Pregnancy Affect Rheumatic Illness?

Rheumatoid arthritis improves in about 75 percent ofpregnant women and sometimes goes into tempo-rary remission. This does not last, and the arthritis

pregnancy 201

often flares after pregnancy. There are a few womenwhose disease remains unchanged or even worsensduring pregnancy. Physicians do not understand whyrheumatoid arthritis (RA) may improve in preg-nancy. One theory is that the increase in levels ofhormones such as progesterone is responsible.Another is that pregnancy induces a state ofimmunological tolerance. In other words pregnancysuppresses the mother’s immune system so that itdoes not reject the unborn baby. As a result of thealtered immune response, the arthritis improves.

The choice of drugs to control RA is affected bypregnancy. Luckily, because RA usually improvesduring pregnancy, many women are able to stopDMARD therapy during pregnancy and manage onjust a low dose of prednisone.

Women with SLE were traditionally advised notto become pregnant because the risks to themother and the baby were considered to be toohigh. This advice has changed, and many patientswith SLE have had healthy babies. Pregnancy wasthought to worsen SLE. Several recent studies haveshown, though, that there is no increased fre-quency of lupus flares in pregnancy. Others havereported that a third of patients get worse, a thirdstay the same, and a third improve. Pregnancyaffects the choice of treatment for SLE, and terato-genic drugs such as cyclophosphamide are avoided.This means that ideally SLE should be under goodcontrol before pregnancy. A common complicationof pregnancy is preeclampsia, a condition charac-terized by edema, high blood pressure, and pro-teinuria. Untreated preeclampsia can progress toseizures. Preeclampsia is more common in womenwith SLE. When it occurs it can be confused with aflare of lupus nephritis that causes identical symp-toms. Eclamptic seizures can be confused with CNSlupus-causing seizures.

How Can Rheumatic Illness Affect the Pregnancy?

RA does not usually have any direct effects on preg-nancy. However it, and any chronic arthritis thataffects the hips and pelvis, can make it more difficultfor a woman to deliver vaginally. SLE can havedirect effects on pregnancy. Women with SLE havemore difficulty conceiving, more frequent abortionsand stillbirths, and a greater risk of premature deliv-

ery and babies with a low birth weight. Difficultieswith conception may be caused by the effects of SLEon ovulation. Women who have been treated withcyclophosphamide have a risk of ovarian failure,causing premature menopause. Spontaneous abor-tions (miscarriages) are more frequent, particularlyin women with the ANTIPHOSPHOLIPID ANTIBODY SYN-

DROME. If SLE decreases blood flow to the placenta,it affects the growth and development of the baby.This is monitored closely using ultrasound to mea-sure the blood flow across the placenta and to mon-itor growth. About 80 percent of pregnancies inpatients with well-controlled SLE are successful,resulting in the delivery of a live baby. The biggestrisk factor for a poor outcome is active lupus beforepregnancy. Other factors associated with fetal loss,are renal disease, previous fetal loss, and antiphos-pholipid antibody syndrome.

Women with lupus have a greater chance ofhaving a baby with NEONATAL LUPUS, particularly ifthe mother has a positive blood test for SSA or SSBantibodies (also called Ro and La antibodies). Therisk of having a baby with neonatal lupus is about2 percent in women with SLE who have SSA orSSB antibodies and may be higher, about 5 percent,in those who have both. Neonatal lupus can causea serious and irreversible problem called heartblock, a condition in which the electrical messagesfrom the atria are not conducted to the ventricles.The first indication of this problem is when a preg-nant woman has routine checkup at about the 20thweek of her pregnancy and the baby’s heart rate isfound to be very slow.

prepatellar bursitis Bursas are small, flat sacsthat develop where friction is likely to occur. Theyare lined by synovial cells that secrete a smallamount of fluid into the sac that then allows freemovement between the body parts on either side ofit. Bursas just beneath the skin such as theprepatellar bursa actually develop after birth. Thisbursa lies between the skin and the lower half ofthe patella or kneecap, an area where there wouldbe considerable friction during crawling or kneel-ing. When the prepatellar bursa becomes inflamed,it fills with fluid and can be seen to bulge in frontof the knee. There may be warmth and redness andkneeling becomes very painful.

202 prepatellar bursitis

Trauma either in the form of a significant blowas in falling onto concrete or recurrent traumafrom an occupation requiring considerable kneel-ing is the most common cause. Previously knownas housemaid’s knee it is now usually seen in car-pet layers and builders. Because it is so close to theskin surface, there is a risk of penetrating injuryintroducing infection. GOUT, CALCIUM PYROPHOS-

PHATE CRYSTAL DEPOSITION DISEASE, and RHEUMATOID

ARTHRITIS can also cause prepatellar bursitis. Treatment with NSAIDs may relieve pain. While

the bursitis settles protective devices should be wornby those with occupational exposure. Aspiration ofthe fluid may speed resolution and culturing thefluid may ensure that there is no infection. If it ispersistent, a small amount of CORTICOSTEROID may beinjected, especially if it is associated with an inflam-matory arthritis. Occasionally recurrent or resistantbursitis may require surgical removal of the bursa.

psoriasis and psoriatic arthritis Psoriasis is acommon scaly rash affecting about 2 percent of thepopulation in developed countries. There are areasof high incidence such as northern Russia and Norway (5–10 percent of the population) and lowincidence such as Latin America (less than 0.5 per-cent). The connection between psoriasis and ar-thritis was recognized as long ago as the 1850s. Formany years, however, this was thought to beRHEUMATOID ARTHRITIS occurring in patients withpsoriasis. Research in the 1950s clarified the distinction between rheumatoid arthritis and psori-atic arthropathy, which is now classified as one ofthe SPONDYLOARTHROPATHIES. Estimates vary, butaround 10 percent of patients with psoriasis willdevelop an associated arthritis. Men and womenare equally affected, although men predominate inthe spinal arthritis type and women in the rheuma-toid type (see Symptoms for discussion of differenttypes). Onset is most commonly between the agesof 20 and 40 years. THE HUMAN IMMUNODEFICIENCY

VIRUS (HIV) is changing the rates of occurrence ofboth psoriasis and associated arthritis, especially insub-Saharan Africa.

Cause

Most research has looked at the cause of the skindisease psoriasis rather than the occurrence (usually

later) of the arthritis. Unless arthritis is specificallymentioned, this discussion refers to psoriasis. Thereis a strong genetic component in its causation, andthere are also a number of well-known factors thatinitiate the rash or make it worse.

Roughly 30 percent of patients have a first-degree relative with psoriasis. In one large study achild’s risk of developing psoriasis was 4 percent ifneither parent had the disease. This increased to 28percent if one parent had psoriasis and to 65 per-cent if both parents were affected. If one identicaltwin develops psoriasis, then the other has a 70 per-cent chance of doing so as well. This risk drops to 20percent if the twins are not identical. There is there-fore a very strong hereditary component to psoria-sis. The nature of this, however, remains unknown.

Genetic studies have shown that in patients whodevelop psoriasis before the age of 20 years, thepsoriasis susceptibility gene is close to the Cw6allele on chromosome 6 (see GENETIC FACTORS for anexplanation of terms). Ongoing studies are tryingto unravel this area and find the precise geneinvolved. This area, however, is unlikely to beimportant in all patients. For example, West Af-ricans have a high rate of Cw6 but very low inci-dence of psoriasis. There are numerous weakassociations between psoriasis and other alleles,but much work is required before the associationswill be clear.

A genetic association with psoriatic arthritis asdistinct from psoriasis has been looked for withoutany clear results. There is a strong associationbetween HLA-B27 and the spondylitic form of pso-riatic arthropathy as there is in ANKYLOSING

SPONDYLITIS and SPONDYLOARTHROPATHY.Psoriasis is largely a cell-mediated disease (see

IMMUNE RESPONSE for an explanation). This meansthat a population of lymphocytes called T cells isdriving the immune attack directed at the skin,joints, and entheses (where tendons, ligaments, orjoint capsules attach to bone). The CD8 T cells aremuch more prominent in this than in other formsof arthritis like rheumatoid arthritis. Careful exam-ination of these CD8 T cells suggests that they areresponding to a small number of antigens. Theseantigens (thought to come from infectious agents)are similar in the skin and joints but frequently dif-fer in different patients.

psoriasis and psoriatic arthritis 203

Infection with bacteria called streptococci (a com-mon cause of a sore throat and fever) is well knownto initiate psoriasis or make it worsen. Evidenceindicates that other infections may also do this.

Trauma to the skin may result in psoriasis ap-pearing in the injured area in 25 percent ofpatients. This is known as the Koebner phenome-non. Interestingly, other patients sometimes have areverse Koebner phenomenon. Here trauma to a psori-atic plaque may lead to the skin clearing in theinjured area. The mechanisms underlying theKoebner phenomenon are unknown.

Drugs such as beta-blockers, HYDROXYCHLORO-

QUINE, and lithium may cause flares of the disease.Stopping CORTICOSTEROIDS is also well known to dothis. Psychological stress has been reported toworsen psoriasis or be associated with its onset.Sunlight usually makes psoriasis better but inabout 10 percent of patients may make it worse.

HIV infection is associated with severe psoriasisand psoriatic arthritis. The HIV epidemic in sub-Saharan Africa has lead to a dramatic increase inboth psoriasis and psoriatic arthropathies. Previouslyboth diseases had been rare. There are two maintheories why this has occurred. The first relates tothe increased susceptibility to infection that HIV-positive people have. This leads to a much greaterload of organisms in people living in Third Worldconditions. The second theory revolves around animmunological mechanism whereby dendritic cells(professional antigen-presenting cells) can bypassCD4+ T cells and stimulate CD8+ cells.

Symptoms

Psoriasis Typical skin plaques are reddishraised areas covered with thick silvery scales. Bothsides of the body are usually affected. Frequentlyaffected areas include elbows, knees, scalp, andbuttocks. Similar plaques may occur at sites oftrauma or surgical scars (Koebner phenomenon).The nails may be affected with small pits on theirsurface or heaping up of layers of skin underneaththe nail (subungual hyperkeratosis) and lifting ofthe nail off its bed (onycholysis). This can look verylike a chronic fungal infection.

Apart from the typical appearance describedabove, there are several well-known variations.

Guttate psoriasis is a form that usually comes onsuddenly in teenagers, often after an infection.There are many small plaques of 1–2 cm diameterscattered all over the body. Flexural psoriasis affectsthe back of the knees and front of the elbows(opposite to the usual form) and is particularlylikely to develop into generalized pustular psoria-sis. In palmoplantar psoriasis, the soles of the feetand palms of the hand are studded with small non-infective pustules.

There are three main complications of psoriasis.Generalized pustular psoriasis is characterized bysheets of small pustules that are not infective. Thisis often associated with a fever and generalized ill-ness and can be a life-threatening condition. Gen-eralized exfoliative dermatitis with erythroderma isanother life-threatening complication. More than80 percent of the skin becomes inflamed, the skinpeels off, and there may be widespread weeping ofserous fluid. The third complication is psoriaticarthritis.

Psoriatic arthritis In 75 percent of people withpsoriatic arthritis, the arthritis follows the rash by avariable period. In 15 percent they start at the sametime, and in the remaining 10 percent the arthritisprecedes the rash. In this last case the diagnosis maybe more difficult. Five different forms of arthritisassociated with psoriasis are distinguishable.

1. Oligoarthritis This is the most common form. A common pattern of involvement might be one knee and several proximal interphalan-geals (PIPs). The metacarpophalangeals, PIPs,and metatarsophalangeals as well as any of thelower-limb joints may be involved, althoughtypically only two to four joints are affected atany one time. Trauma to a joint can result in itbecoming inflamed. Dactylitis is often associatedwith this form. This is due to inflammation ofthe joints of a toe or finger as well as the tendonsheaths, giving rise to a diffusely swollen digit,the so-called sausage digit.

2. Rheumatoid Pattern Almost as common is sym-metrical arthritis affecting the small joints of thehands, wrists, elbows, knees, ankles, and feet.This is indistinguishable clinically from rheuma-toid arthritis. However, the rheumatoid factor is

204 psoriasis and psoriatic arthritis

negative and the patient has psoriasis. Researchhas shown subtle differences between the twodiseases in the inflammatory joint lesions whencarefully examined, but this is not usually ofpractical use in diagnosis and treatment. Recentstudies suggest that MRI scanning may showenough difference for psoriatic arthritis to be dif-ferentiated from rheumatoid, but this remains tobe confirmed.

3. DIP Arthritis A very characteristic appearanceis the swollen inflamed distal interphalangealjoint (DIP), the last joint in the fingers. This isoften associated with psoriatic nail lesions in thenail of the same finger. Sausage digits mayoccur. This form of psoriatic arthritis may occuralone or be associated with one of the otherforms.

4. Spondylitis This form is very similar to ankylos-ing spondylitis (AS). However, peripheral arthri-tis, especially of the knees, ankles, and hands, ismore common than in AS. Involvement of thesacroiliac joints (where the spine joins thepelvis) is more likely to be one-sided or predo-minantly one-sided than in AS. The neck isoften severely affected in psoriatic spondylitisand may become quite rigid, causing difficultywith driving, among other activities. Arthritis ofthe spine of the neck is commonly associatedwith scalp psoriasis.

5. Arthritis Mutilans Although rare, this is a verytypical manifestation of psoriatic arthritis. Thesmall joints of the hand become severely eroded.In one or more fingers destruction of the jointsbecomes so advanced that the finger shortens andthere are redundant folds of skin. In the absenceof a joint the finger is floppy and almost useless.

A characteristic of all forms of psoriatic arthritisis the inflammation at entheses. It is also seen inAS. Inflammation of tendons is also very common.About a third of patients with psoriatic arthritisdevelop EYE PROBLEMS. Two-thirds of these developconjunctivitis (inflammation of the most superficialcovering layer of the front of the eye), and nearlyone-third develop iritis. Iritis is inflammation of adeeper layer, also in the front of the eye, that canlead to significant problems if not treated promptly.

As mentioned above, people with DIP arthritisalmost always have nail involvement on the samefinger, and those with severe neck involvementoften have scalp psoriasis. Apart from these, thereis no particular association between the type ofpsoriasis and the type of arthritis. There is, how-ever, one further association that should be men-tioned. Pustular psoriasis of the palms and solesappears distinct from the more typical forms of pso-riasis and is not associated with the above forms ofarthritis. It is, however, associated with a hyperos-tosis affecting the chest wall and a noninfectiveform of osteomyelitis. This is described under theheading SAPHO SYNDROME.

Although the most common age of onset of pso-riasis is between five and 15 years, psoriatic arthri-tis usually starts much later. However, childrenmay get psoriatic arthritis. Unlike the figures givenabove for adults, in children 50 percent get thearthritis first, 40 percent get the rash first, and 10percent get both at the same time. The oligoarthri-tis and spondylitis forms are the main ones to affectchildren.

Diagnosis

The diagnosis is made on the clinical groundsdescribed. Most patients will have the rash of pso-riasis as an obvious clue. The rash, however, maybe very subtle. Minor scaling around the scalp mayhave been thought by the patient to be dandruff formany years. The rash of psoriasis is not always irri-tating, and patients can be relatively unaware ofsmall patches around the buttocks or belly buttonor, not seeing their relevance, not tell their physi-cian about these patches. Sometimes the arthritis ischaracteristic enough to be diagnosed as psoriaticeven in the absence of a rash, but this is not alwayspossible. Sausage digits, enthesitis, and markedtendon involvement are all in favor of psoriaticarthritis. Skin psoriasis is usually distinctiveenough to be diagnosed clinically. When there isdoubt a biopsy will confirm the diagnosis.

X rays may give valuable information in differ-entiating the arthritis from clinically similar butdistinct forms of arthritis. Characteristics when x-raying peripheral joints include the asymmetryand involvement of the DIPs (unlike rheumatoid


arthritis), a characteristic appearance of erosive dis-ease aptly termed pencil in cup appearance, thedevelopment of new bone along the outer marginsof bones (periostitis) and at entheses, and a ten-dency for joints to fuse. In the spine features thatdifferentiate psoriatic from ankylosing spondylitisinclude asymmetrical sacroiliac involvement, fewersyndesmophytes, less disease of the small facetjoints at the back of the spine, severe neck involve-ment with relative sparing of the lower spine, andfluffy new bone formation along the front of thevertebrae.


The treatment aims in psoriatic arthritis mayinclude the following:

1. Controlling the rash

2. Suppressing joint and tendon inflammation

3. Maintaining and improving musculoskeletalfunction

4. Preventing and minimizing disability

5. Providing psychosocial support in living with achronic rash and arthritis

Patients with milder disease may obtain most oftheir care from their primary health care provider.Those with severe disease, though, will need inputfrom a number of specialist providers at differenttimes. These may include rheumatologists, derma-tologists, orthopedic surgeons, physiotherapists,rehabilitation specialists, and counselors. Treat-ment in many areas needs to be highly individual-ized and is difficult to generalize. This particularlyincludes rehabilitation and counseling. Note that anumber of studies have shown that more patientswith psoriasis use alcohol excessively than the gen-eral population. The reason for this is unknown,but support in this area may be required. Anotherdifficulty in generalizing about treatment is thatpsoriatic arthritis is very variable. Some peoplehave intermittent, troublesome problems and oth-ers have unremitting, highly destructive disease. Ofall forms of chronic arthritis, psoriatic arthritis ismost likely to go into remission, often for periods oftwo to four years at a time. It is often possible tocome off all medication during these periods,

although a later relapse is not uncommon. Withthese provisos, a brief, general discussion of thetreatment of rash and musculoskeletal problemsfollows.

Skin psoriasis Topical treatments are tried firstbecause of their greater safety. They may includethe following.

• Various preparations of coal tar. This is safe andeffective for the common plaque psoriasis. It isused less often these days because it is messywhen applied to the skin, although some newerpreparations are easier to use. It can also stainskin or cause irritation. Coal tar shampoos andpreparations used in the bath are effective andcommonly used.

• Dithranol, often combined with salicylic acid, isanother older medication that still has a usefulrole in treatment. It is started at a low dose andgradually built up to avoid skin irritation.

• Salicylic acid preparations are useful in gettingrid of excessive scale.

• Corticosteroid creams and ointments are veryeffective and easy to use. There are many prepa-rations that are generally classed as mild, mod-erate, potent, or very potent. Once the psoriasisis controlled, it is important to step down thepotency and then reduce the frequency of use toprevent the rebound flare that occurs whenthese preparations are suddenly stopped. Theymay cause marked thinning of normal skin, andif applied to large areas, systemic corticosteroidside effects can develop due to absorption. Forthese reasons potent and very potent prepara-tions are best avoided in psoriasis.

• Calcipotriol (calcipotriene) is used as a cream orointment to the skin or as a lotion to the scalp.It is effective in mild-to-moderate psoriasis. It isimportant to limit the amount used since it is avitamin D derivative and large doses may causeraised blood calcium levels. It is odorless anddoes not stain but may cause some irritation tothe skin.

• Phototherapy is used in two forms: UVB light byitself is effective in mild-to-moderate psoriasis;UVA light can be used with a psoralen to potenti-


ate it. A psoralen, usually methoxsalen, may begiven two hours before exposure to UVA light orthe patient can bathe in psoralens before expo-sure. This form of treatment is given twice a weekfor four to six weeks only. It is delivered by spe-cialist centers and is closely controlled because ofthe increased risk of squamous cell skin cancers.

Systemic therapy is used for widespread or verytroublesome psoriasis. Because of the increased riskof adverse effects, some monitoring and specialistsupervision is required for these therapies. Forthese reasons as well as the fact that psoriasis isoften not very irritating, many patients, usuallyafter a number of years of trying various treat-ments, choose to live with their psoriasis, usingtreatment only when there is a flare. Systemictherapies include the following.

1. METHOTREXATE is very effective in all forms ofpsoriasis. It may be taken by mouth or as intra-muscular injections and is usually built up grad-ually from a low dose.

2. Acitretin (trade name: Soriatane) is a retinoidused in severe or extensive psoriasis. It is ametabolite of the older etretinate, which is aderivative of vitamin A. Acitretin is a teratogen(may induce abnormalities in the unborn fetus).Reliable methods to prevent pregnancy must bein place for at least one month before and forthree years after treatment with acitretin. Tetra-cyclines and vitamin A should be avoided, andliver function and lipid (cholesterol) levels needto be monitored. Dryness of mucous membranesand poor tolerance of contact lenses are quitecommon, and aches and pains may occur.Abnormal calcification of soft tissues may com-plicate treatment, and X rays should be taken tolook for this if the patient suffers unusual mus-culoskeletal symptoms.

3. CYCLOSPORINE is effective for severe and other-wise difficult-to-control psoriasis. It is a power-ful immunosuppressant, and adverse effects arenot uncommon with long-term use. Theseinclude tremors, increased hair growth espe-cially on the face, high blood pressure, and lesscommonly, kidney damage and infections.

Psoriatic arthritis First-line therapy comprisesNSAID therapy and local corticosteroid injection.NSAIDs are effective in many patients withspondylitis and/or mild peripheral arthritis. Earlyreports suggested that some NSAIDs might be bet-ter than others, but current evidence suggests thatthey are all potentially helpful. The individualagent should therefore be chosen more on the like-lihood of adverse effects in the individual patientthan on efficacy. While there is a theoretical con-cern that NSAIDs might lead to worsening of therash, this has not been borne out in practice. Whenone or two joints are resistant to treatment withNSAIDs or the patient has experienced adverseeffects, then injection of local corticosteroids intothe joint is highly effective. Depending on theactivity of the disease, this may give very long-lasting relief. It also does not seem to produce anyrebound flare, perhaps because of the small doseused and the fact that there is a gradual washout ofeffect as the body metabolizes the drug. Injectionsshould not be given through psoriatic plaques asgetting good antisepsis on a plaque is not possible.

Second-line therapy or DISEASE-MODIFYING ANTI-

RHEUMATIC DRUGS are indicated when the arthritis issevere and unresponsive to the measures above or deformity is developing as a result of the arthri-tis. Many drugs have been used to treat psoriaticarthritis. Evidence of varying strength shows thatSULFASALAZINE, AZATHIOPRINE, cyclosporine, metho-trexate, LEFLUNOMIDE, and TUMOR NECROSIS FACTOR

(TNF) ANTAGONISTS are effective. Other DMARDsare used because of evidence for their use in treat-ing other forms of inflammatory arthritis. Note thatthe lack of scientific evidence does not necessarilymean a drug does not work. It may just be that theappropriate study has not been done. The morecommonly used medications and some newer med-ications are listed below.

• Sulfasalazine is a relatively safe, well-toleratedmedication effective in some patients with pso-riatic arthritis. It is, however, less often effectivethan when used to treat rheumatoid arthritis. Inmoderate disease it is often tried first because ofits good safety profile. Rashes, headaches, nau-sea, and occasional liver toxicity are the mainadverse effects. Starting at a low dose and grad-


ually increasing to 2–3 g per day in divided dosesand taking the tablets with food lessens the nau-sea and headaches. Sulfasalazine may be used inHIV-associated disease since it does not suppressthe immune system.

• Methotrexate given in doses ranging from7.5–30 mg once a week is the drug used mostfrequently in moderate-to-severe psoriaticarthritis. It is effective for both skin and jointproblems. The main concern is the liver cirrhosisthat may occur with long-term usage. This was asignificant problem when methotrexate wasgiven in three divided doses over 24 hours forskin psoriasis but was less frequent when used inrheumatoid arthritis as a single dose. It remainsto be seen whether using it as a single dose inpsoriatic arthritis has a similar low rate of cirrho-sis. That is, the difference could be due to the dif-ferent dosage or the different diseases. Otherproblems include lung inflammation, acute liverinflammation, Sun sensitivity, and subtle mentaldisturbances such as impaired memory. Taking asmall supplement of folic acid slightly reducesthe number of adverse effects. Although thenature of psoriatic arthritis lends itself to theintermittent use of DMARDs (as opposed torheumatoid arthritis), methotrexate in particularis likely to be followed by a flare if stopped.

• Azathioprine has been used for many years andis effective for both skin and joints. It is rela-tively well tolerated, although a few people lackthe enzyme to metabolize it and cannot tolerateit at all. Liver toxicity, allergy, and a dose-relatedreduction in bone marrow activity are seen. Themain limiting factor in its use, however, is aslight increase in malignancy with long-termuse. This is mainly skin cancers and lymphomas.

• Cyclosporine is very effective in both skin andjoint disease. It works rapidly and would be usedmore but for the relatively frequent occurrence ofadverse effects (see above under Treatment). Forthis reason it has been used in combination withother drugs (usually methotrexate) to try to getby with a lower dose. While this is certainly effec-tive, it is not clear that combination treatmentwill provide a safer form of long-term treatment.

Stopping cyclosporine also has the tendency to befollowed by a flare. This may limit intermittenttreatment, although trials are under way to see ifthis approach will limit toxicity.

• Etretinate is effective for the arthritis as it was forthe rash until largely superceded by its metaboliteacitretin (see above). Relatively frequent adverseeffects limited the use of etretinate.

• PUVA therapy, when used for skin psoriasis, hasbeen found to improve arthritis in somepatients, especially those with spondylitis.

• HYDROXYCHLOROQUINE and PENICILLAMINE havebeen used but are not generally recommended.Hydroxychloroquine has made psoriasis worsein some patients, and penicillamine causes fre-quent side effects. Somatostatin, zinc, vitamin Dderivatives, colchicine, and many other treat-ments have been tried with either little successor limiting adverse effects.

• Recently TNF ANTAGONISTS have shown remark-able efficacy in psoriasis and associated arthritis.Both INFLIXIMAB and ETANERCEPT have been suc-cessfully used in patients with severe diseasealthough not in a controlled trial. Cost as well asconcern over long-term adverse effects is likelyto limit their use to those with severe resistantdisease. Leflunomide has also shown promise inearly clinical trials.

Psoriasis is a chronic skin condition that remitsand relapses over many years. Cure is not possible.Psoriasis can vary from a tiny patch that the patientforgets about to an itchy, profusely scaling rashcovering most of the patient’s body. Treatment isaimed at achieving a level of control that the indi-vidual finds acceptable. Many people benefit frombelonging to the Psoriasis Association or similarsupport group.

Psoriatic arthritis too is very variable in its sever-ity. Apart from the fortunately rare arthritis mutilansform, joint destruction tends to be less severe thanwith, for example, rheumatoid arthritis. There is amarked tendency for inflamed joints to fuse, espe-cially when spondylitis involves the neck. Remissionfor years at a time is not uncommon. HIV-associateddisease is more rapidly progressive, although some


lessening of the inflammation has been noted withthe onset of AIDS. Patients who are older at the timeof onset (over 60 years of age) appear to have amore severe and destructive arthritis than youngerpatients. The oligoarthritis form of arthritis mayprogress over years to a more rheumatoid patternwith many joints involved, but the frequency of thisvaries considerably among different studies.

pulmonary hypertension A pressure in the pul-monary arteries of 25 mmHg or higher. The pres-sure in the pulmonary arteries that carry bloodfrom the right ventricle to the lungs is much lowerthan the pressure on the left side of the heart thatsupplies blood to the rest of the body. When abnor-mally high pressures are in the blood vessels on theright side of the heart, this is called pulmonaryhypertension, a rare condition. When the pressureis elevated in the blood vessels in the rest of thebody (the left side of the heart), this is called sys-temic hypertension or more often just hyperten-sion or high blood pressure, a common clinicalcondition familiar to most people.

Pulmonary hypertension can be classified intoone of two types, primary or secondary. Primarypulmonary hypertension or PPH is when the mainabnormality is in the medium-sized arteries. Sec-ondary pulmonary hypertension is when otherconditions such as severe heart or lung diseasecause a secondary increase in the pulmonary arterypressure. Several connective tissue diseases, mostoften SCLERODERMA and SYSTEMIC LUPUS ERYTHE-

MATOSUS (SLE), are associated with a type of pul-monary hypertension very similar to PPH.

Dr. D. T. Dresdale first coined the term primarypulmonary hypertension and described the clinicalentity, an almost uniformly fatal illness more com-mon in young women, in 1951. Since then therehave been major advances. PPH is rare in the pop-ulation, affecting about one to two people per mil-lion. There are now more effective treatmentsavailable that have improved the prognosis.

Cause

The medium-sized arteries in the lungs of patientswith PPH have very thick walls and a narrowlumen, often with a small amount of clot in them.

The basic cause of PPH is obstruction of themedium-sized arteries, but the underlying mecha-nism of this is not known. Researchers noticed thatabout 6 percent of cases of PPH tracked in families,suggesting that in some patients there was a famil-ial or genetic cause. In others, though, the diseasewas sporadic. Dr. John Newman and his colleagueshave identified a gene that predisposes certain fam-ilies to developing PPH. By studying familiesaffected by PPH, these and other scientists linkedthe disease with mutations in a gene that codes forbone morphogenic receptor II (BMP II), a receptoractivated by a growth factor. Most patients withPPH do not have the familial type of disease. How-ever, the discovery of the genetic cause of thefamilial type may help scientists identify the othercauses of PPH. Since the discovery that there areabnormalities in the BMP II gene in 50 percent ofpatients with familial PPH, new data show that 25percent of patients with what was thought to besporadic PPH also have abnormalities. This suggestseither that they developed a new mutation of thegene or that the familial PPH is often incorrectlydiagnosed as sporadic PPH. Recent work also showsthat only about 20 percent of people in an affectedfamily who have the abnormal BMP II gene go onto develop PPH. In other words, one abnormalgene alone is not enough to cause the disease.There are likely to be other genes or environmen-tal triggers that determine who gets PPH.

A PPH-like illness can occur in patients withscleroderma, SLE, and HIV and after treatmentwith dexfenfluramine and fenfluramine, drugsused to suppress appetite and treat obesity. Someexperts classify these types of pulmonary hyperten-sion as variants of PPH, although there is an under-lying predisposing illness. Others, though, classifythem as causes of secondary pulmonary hyperten-sion. Secondary pulmonary hypertension canoccur as a result of any chronic lung or heart dis-ease. These are summarized in the following table.Scleroderma can cause pulmonary hypertension ofboth types. The PPH type of disease occurs moreoften with the CREST type of scleroderma and mayaffect up to 10 percent of patients. Secondary pul-monary hypertension with systemic sclerosisoccurs in patients with severe lung scarring.

pulmonary hypertension 209

Symptoms

The first symptom is unusual shortness of breathwhen exercising. This tends to come on graduallyover a few years. When the illness is more severechest pain, fainting, heart failure, and rhythmabnormalities occur.

Patients with limited scleroderma or CREST aremuch more likely to develop PPH-like pulmonaryhypertension than patients with what is usuallyconsidered the more severe type of scleroderma—generalized disease or systemic sclerosis. Pul-monary hypertension develops only in somepatients with CREST and usually does so aftermany years. The severity of CREST symptoms isnot related to the risk of developing pulmonaryhypertension. Some patients with CREST and pul-monary hypertension have such minor sclero-derma symptoms, only a few telangiectasia, someskin tightening across the fingers, and occasionalRaynaud’s phenomenon, that these symptoms areoverlooked and an incorrect diagnosis of sporadicPPH is made. In patients with CREST, a decrease inexercise tolerance can be the first clue that pul-monary hypertension has developed.

Diagnosis

Once the diagnosis is suspected, pressure in thepulmonary artery can measured by ultrasound. Insome patients the pressure is measured more accu-rately by placing a catheter in the right side of theheart by threading it up through a large vein in theleg. A chest X ray can show an enlarged heart, butin PPH and PPH-like conditions, the lung tissue isnormal. In patients with secondary pulmonaryhypertension caused by lung disease, the lungs areabnormal on chest X ray. A lung biopsy is usuallyavoided because there is a risk of bleeding. Noblood tests are helpful.

Treatment

Pulmonary hypertension has no cure, and thetreatment options are limited. More research infor-mation is available about treating PPH than PPH-like pulmonary hypertension Physicians often useinformation about PPH to decide how to treat pul-monary hypertension associated with SLE or scle-roderma.

Anticoagulation Although most types of pul-monary hypertension are not caused by bloodclots, most experts believe that damage to the lin-ing of blood vessels makes it more likely that smallclots will form in the blood vessels in the lungs andaggravate the obstruction. Therefore, most patientswith PPH receive warfarin, a drug that decreasesthe ability of blood to clot.

Vasodilators The blood vessels in PPH are verythick with narrow channels. At some stages of thedisease these blood vessels can still respond to drugsthat dilate them. Calcium channel blockers such asnifedipine and diltiazem are drugs developed totreat systemic hypertension. By dilating arteries inthe lungs, they can also decrease the pulmonaryartery pressure in some patients with PPH.

Recently, epoprostenol (trade name: Flolan), astable preparation of the prostaglandin prostacyclin,was found to improve symptoms and survival inPPH and symptoms in patients with PPH-like illness.Epoprostenol has a very short duration of actionand is therefore administered as a continuous intra-venous (IV) infusion. This means that patients haveto wear a pump that slowly injects the drug 24hours a day. The most common side effects ofepoprostenol are nausea, diarrhea, jaw pain, andcomplications such as infection at the IV site. Sev-eral research groups are studying ways of deliveringprostacyclin that do not require an IV pump. Oneexciting area of research is delivering the drug by

210 pulmonary hypertension

CAUSES OF PULMONARY HYPERTENSION

Primary Pulmonary Primary Pulmonary Secondary Pulmonary Hypertension Hypertension-like Disease Hypertension

Familial PPH CREST/scleroderma Heart valve abnormalitiesSporadic PPH SLE Heart failure

HIV Any chronic lung diseaseAppetite suppressants Sleep apnea Chronic liver disease Repeated pulmonary emboli

inhalation. Another stable preparation of prostacy-clin, trepostinil (trade name: Remodulin), can begiven by continuous subcutaneous injection.

The FDA recently approved bosentan (tradename: Tracleer) for the treatment of PPH. Bosentanis taken as a tablet and blocks receptors forendothelin, a very potent vasoconstrictor producedby the body. The most common side effect is abnor-mal liver function tests.

Nitric oxide, a gas produced in small amounts inthe body, is one of the strongest vasodilators dis-covered. Several research groups are using nitricoxide gas inhaled for several hours a day as anexperimental treatment for PPH. Nitric oxide worksthrough a messenger, cyclic GMP. A drug, sildenafil(trade name: Viagra), slows the breakdown ofcyclic GMP in the blood vessels of the penis and isa useful treatment for impotence in men. However,it also does so in the lungs and may be a usefultreatment for PPH, either alone or with inhalednitric oxide.

It is not clear if drugs such as epoprostenol,nitric oxide, and bosentan work entirely throughtheir vasodilating effects. Patients who do notvasodilate when they receive the drugs acutely stillseem to respond after a few months of treatment,suggesting that the drugs may have long-termeffects helping the thickened arteries to remodel.

Surgery A heart and lung transplant, or moreoften a single lung transplant, is used to treat PPHthat is not responding to medical treatment. A lim-ited number of organs are available. Many patientswith PPH associated with connective tissue diseasesare not placed onto the transplant list because oftheir associated illness. Transplantation usuallycures PPH but requires long-term immunosuppres-sion to prevent rejection.

Outcome

The prognosis of PPH is poor. Most studies showthat only about half of affected patients survivethree years. The new treatments improve symp-toms, but they have not been available for longenough to know how much they improve theoverall outcome. In clinical trials the effects of thedrugs have, on average, been small, for example a15 percent increase in the distance that patientscould walk in six minutes. Many experts believe

that the main role of the new treatments will be toact as a bridge to lung transplant surgery ratherthan to provide an effective medical alternative tosurgery.

pyoderma gangrenosum A rare skin rash thatcauses deep punched-out ulcers and can be associ-ated with rheumatic diseases.

Cause

The cause of pyoderma gangrenosum is notknown. In about half of affected people it occursalone. In the other half it is associated with achronic inflammatory illness such as INFLAMMATORY

BOWEL DISEASE, RHEUMATOID ARTHRITIS, SYSTEMIC

LUPUS ERYTHEMATOSUS, or less often, hepatitis C,HIV, sarcoidosis, and leukemia.

Symptoms

The first symptom is a skin ulcer. This can start as asmall nodule or blister that ulcerates and increasesin size rapidly. The lesions can occur anywhere butare more common on the lower legs, often at a siteof minor trauma. Characteristically, the ulcers havea purple- or violet-colored border and have apunched-out appearance with the edge of theulcerated skin overhanging the base of the ulcer.The ulcers of pyoderma gangrenosum can beextremely painful. Nonspecific systemic symptomssuch as fever, arthralgia, and myalgia are common.

Diagnosis

The appearance of the ulcer is often classical, but askin biopsy is usually performed to exclude othercauses of ulcers such as malignancy or infection.The biopsy appearance of pyoderma gangrenosum,although not specific, is helpful because it shows a large number of neutrophils infiltrating the tis-sue. No laboratory tests are helpful for making thediagnosis.


Pyoderma gangrenosum can be very difficult totreat. No specific treatment is always successful.Local wound dressing, elevating the leg, rest, andtopical antiseptics are usually tried, but mostpatients also require systemic therapy. Many drugsthat modulate the immune system have been tried.

pyoderma gangrenosum 211

CORTICOSTEROIDS are the primary drug treatment,but many patients are treated with additionalimmunomodulators such as METHOTREXATE, AZA-

THIOPRINE, DAPSONE, COLCHICINE, CYCLOSPORINE, and

INTRAVENOUS IMMUNOGLOBULIN. The ulcers respondslowly and often take a year or more to heal. Mostdermatologists try to avoid surgery if possiblebecause trauma appears to spread the lesions.

212 pyoderma gangrenosum

R

RA See RHEUMATOID ARTHRITIS.

radiculopathy See BACK PAIN.

Raynaud’s phenomenon A progressive colorchange of an extremity (usually a hand or fingers)from white to blue to red in response to cold oremotion. Exactly how many people suffer fromRaynaud’s phenomenon is unknown, but it isprobably about five percent of the population.

Cause

Blood flow to the skin is vitally important for con-serving or losing body heat. The greater the bloodflow through skin, the more heat is lost and viceversa. For this reason, blood flow through skin atnormal room temperature is 10 to 20 times greaterthan required to keep the skin healthy, and theblood vessels have the ability to alter blood flowenormously. Closing down the small arteries takingblood to the fingers, for example, is a normalresponse on walking out into the cold so that theindividual does not lose too much heat. If the coldis severe or prolonged enough, anybody’s hand cango white due to the marked reduction in bloodflowing just below the surface of the skin. Thechange to blue occurs when there is some bloodflow but not quite enough. Because the tissues arestarved of oxygen and the blood is moving slowly,more than usual oxygen is extracted from theblood, turning it blue. When the spasm of the arte-rial walls relaxes there are compensatory mecha-nisms that result in excessive blood flow throughthe area, giving a dusky red appearance. Peoplewith primary Raynaud’s phenomenon have thesame physiological response, but it is exaggeratedand occurs with much less cold provocation thannormal and also occurs with emotion. Those with

secondary Raynaud’s phenomenon also have thisexaggerated response but occurring on a back-ground of disease processes present in the bloodvessels that make the Raynaud’s more likely tooccur and more severe.

In diseases such as SCLERODERMA in which Ray-naud’s phenomenon is a hallmark, permanentchanges occur in the blood vessels. In particular,there is a buildup of collagen and fibrous tissue inthe walls of small arteries leading to permanentnarrowing that can be severe. When the smoothmuscle in the vessel wall contracts, such a nar-rowed artery can block off altogether. The smallblood cells called platelets are activated and releaselarge amounts of substances such as thromboxaneA2 and serotonin that can overwhelm the protec-tive mechanisms (such as prostacyclin secretion) ofthe endothelium (inner lining of blood vessel) andlead to contraction following little or no stimulus.

Many conditions can cause Raynaud’s phenom-enon or similar constriction of peripheral bloodvessels:

Primary Raynaud’s phenomenon This term isused when there is no recognized cause and noassociated disease. It is customary to wait two yearsbefore calling it primary because Raynaud’s may bethe first manifestation of a disease.

Secondary Raynaud’s This can be associatedwith several conditions.

Connective tissue disease Systemic sclerosis,DERMATOMYOSITIS AND POLYMYOSITIS, SYSTEMIC LUPUS

ERYTHEMATOSUS (SLE), RHEUMATOID ARTHRITIS, andthe OVERLAP SYNDROME are all associated with Ray-naud’s phenomenon. About 95 percent of patientswith systemic sclerosis have Raynaud’s, as do up to80 percent of overlap syndrome patients, 60 percentof SLE patients, and smaller percentages of patientswith polymyositis and rheumatoid arthritis.

213

Occupational People who operate vibratingmachinery sometimes develop Raynaud’s phenom-enon. This can also be produced by inappropriateuse of a crutch, causing pressure on the blood ves-sels in the armpit. There is no proven tendency forthis condition to develop into a connective tissuedisease. A few patients have developed connectivetissue diseases after use of vibrating machinery, butbecause they are so few this could be by chance.

Thoracic outlet An extra rib at the lower endof the neck or its fibrous remnant can cause thehand and arm to turn cold and white during cer-tain positions due to pressure on the large bloodvessels traveling toward the arm.

Drugs or toxins A number of medicationscause constriction of peripheral blood vessels aspart of their normal action, including most beta-blockers (used for high blood pressure and angina)and ergot preparations (used for migraine). Somepatients will be very sensitive to these effects, andothers may already have poor circulation to thefeet and hands. These patients will probably nottolerate these drugs. Some drugs can cause Ray-naud’s phenomenon as a toxic effect (e.g., bleo-mycin, an anticancer drug) as may other toxicsubstances, particularly polyvinyl chloride.

Hyperviscosity Conditions such as CRYOGLOBU-

LINEMIA, polycythemia, and paraproteinemia cancause sludging of the blood in smaller arteries andprecipitate constriction of the arteries.

Symptoms

Raynaud’s phenomenon is usually seen in the fin-gers but can also occur in the toes, ears, nose, andtongue. There is often pain and numbness with thewhite and blue color change and a sensation ofburning warmth with the redness. Only part of afinger may be affected, or several fingers, or it maybe more widespread. The whiteness may come onvery suddenly. Primary Raynaud’s may be precipi-tated by emotion as well as cold, but the other sec-ondary forms do not usually occur with emotion.Critical loss of blood supply such that tissues actu-ally die or are severely damaged does not occur inprimary Raynaud’s under normal conditions.

Small areas of tissue death at the tips of the fin-gers that form small scarred pits are, however, verytypical of systemic sclerosis. Gangrene can also

occur with complete absence of blood flow. This isusually associated with severe permanent narrow-ing of the blood vessels that do not then respond totreatment. Sometimes the tip of a toe or fingerdevelops dry gangrene, shrivels, and drops off. Thisis, fortunately, rare. In systemic sclerosis there isstrong evidence that a very similar process of inter-mittent severe narrowing of arteries taking bloodto internal organs such as the heart and kidneysoccurs. Certainly, the severe crises of high bloodpressure and kidney failure that used to cause thedeath of many systemic sclerosis patients beforeeffective treatments were discovered occurredmore frequently in winter.

Diagnosis

The diagnosis is made on the typical three-colorchange in response to cold or emotion. Thepatient’s description is usually enough, althoughprovocation tests can be done. The simplest is justto soak an affected hand in cold water and allow itto dry in the air. A careful history should be takento exclude the other causes listed above. An exam-ination will be directed at finding signs of connec-tive tissue diseases and assessing the state ofperipheral arteries. Smoking dramatically worsensthe arterial damage. This should be asked for in thehistory and measures taken to encourage thepatient to quit.


The treatment of Raynaud’s phenomenon dependson the severity. Many patients with primary Ray-naud’s will manage very well with simple measuresand not require any regular medication. Otherswith severe secondary Raynaud’s may need hospi-talization for intravenous therapy or surgery. Pro-longed ischemia (lack of blood supply) can beextremely painful, and appropriate pain relief maybe required.

Mild Giving up smoking and avoiding coldexposure are the keystones to self-management. Itis vital that the person’s whole body be warm andnot just the hands. Avoidance of cold may involvegiving up outdoor winter sports, having a range ofgloves for different situations, using the variousproprietary pocket hand warmers, and not gettingwet when it is cool or windy.

214 Raynaud’s phenomenon

Moderate All patients with secondary Ray-naud’s phenomenon should take low-dose ASPIRIN

as an antiplatelet agent. One group of the family ofcalcium channel blocking drugs (the dihydropy-ridines) is particularly effective in dilating periph-eral arteries. These include nifedipine, felodipine,and isradipine. They are usually used to lowerblood pressure. In that situation the warmth in thehands and feet that they produce is sometimesregarded as an adverse effect. Headache, flushing,and dizziness are possible adverse effects. The drugsmay be used continuously or just during the coldermonths.

Nitroglycerin is traditionally used as a tablet orspray under the tongue for angina. It is very effec-tive at dilating both arteries and veins. A gel formcan be applied to fingers or toes affected by severeRaynaud’s that does not ease with warming. Sinceit has a short action it is practical to use only toresolve an attack rather than regularly to preventattacks. The treatment involves rubbing 1–2 cm ofthe gel into the affected skin. A headache is theonly common adverse effect and occurs if too muchis used.

Severe This includes ulcers, critical reductionin blood flow with intractable pain or threatenedgangrene, or gangrene itself. Ulcers should be keptclean, and antibiotics do have some effect if there isinfection, although their penetration into theischemic area is poor. Some people apply topicalantibiotics directly onto the infected area in this sit-uation. Surgical removal of infected tissue may benecessary. The above treatments are used with fulldoses of the calcium channel blockers.

Prostacyclin is a substance that endothelial cellsproduce to counteract the effect of activatedplatelets. It is a very potent dilator of blood vesselsand an antiplatelet agent. Several forms can beadministered as a drug. Although work is beingdone on formulations that can be taken by mouth,these are not yet satisfactory. In severe disease ithas to be given intravenously. It unfortunately alsocauses headaches, vomiting, and diarrhea whenused in pharmacological doses. These adverseeffects limit how much can be given. The dose isgradually increased over three days to see whatlevel the patient can tolerate, and then this maxi-mum tolerated dose is continued for a variable

course. The effect of a course often lasts up to threemonths.

The nerve messages to arteries to constrict comealong sympathetic nerves that form a fine networkalong the outer wall of the artery. Removing thissympathetic nerve supply often results in gooddilatation of the artery. The sympathetic nerves canbe divided at the level of the neck, or the fine net-work can be stripped off each individual artery atthe level of the hand. Some surgeons feel that thisis more effective because some of the constrictingtissues around the artery are stripped off as well.Results are better if at least 2 cm of artery arestripped. Occasionally, surgical amputation isrequired.

Primary Raynaud’s phenomenon is a commontroublesome condition that can usually be man-aged with sensible lifestyle changes and intermit-tent medication. Some studies show that up to 60percent of patients with apparent primary Ray-naud’s will develop a connective tissue disease inthe first two years. This is usually systemic sclero-sis. Only a few will develop a connective tissue dis-ease later than two years after onset, and when thishappens, it is usually CREST syndrome. Fewerpatients who are less than 20 years of age whenthey develop Raynaud’s will have an underlyingdisease than those who develop it later. In its sever-est form, usually when part of systemic sclerosis,Raynaud’s phenomenon can cause intractablepain, cause loss of fingers and toes, and possiblycontribute to heart and kidney failure.

reactive arthritis Joint inflammation develops asa result of an infection in some other part of thebody, usually the throat, gut, or urinary and geni-tal organs. The arthritis is not infectious and gets itsname from the assumption that the immune sys-tem is reacting to an infection and, in doing so,causes the arthritis. An initiating infection cannotalways be found. The term reactive arthritis onlycame into being in the 1970s but is now widelyused and incorporates those patients with Reiter’ssyndrome (see Symptoms below). Hans Reiterdescribed the syndrome in an army officer in 1916,although reactive arthritis had probably been rec-ognized 200 years previously. The clear link to diar-rhea was established by Paronen after an outbreak

reactive arthritis 215

of shigella infections in Finland toward the end ofthe Second World War. Together with otherSPONDYLOARTHROPATHIES, reactive arthritis is fre-quently misdiagnosed if patients are not seen byrheumatologists. A recent study showed that 36percent of reactive arthritis patients diagnosed at aspecialist center had not had the correct diagnosismade before being seen there. Also many patientshave mild and transient disease. For these reasonsit is difficult to know how common reactive arthri-tis is. An estimate is that 10 in every 100,000 peo-ple will develop the disease each year. Outbreaks ofparticular infections can dramatically alter this.

Cause

There is no doubt that infections cause reactivearthritis. However, reactive arthritis is not infec-tious. While there remains much to be learnedabout how reactive arthritis develops, there is a gen-erally accepted broad outline of events. First aninfection develops. Particular organisms areinvolved (although the list is steadily increasing),and the infection usually involves a mucosal sur-face. Mucosal surfaces include the mouth, nasal pas-sages, throat, gut, and genital and urinary tracts. Asa result of this infection the immune systembecomes sensitized (or immunized) to parts of theorganism. This enables the immune system (bothcells and antibodies) to attack and destroy theinfecting organism (see IMMUNE RESPONSE). Duringthe infection either live organisms or fragments oforganisms are seeded into joints. In many cases itseems likely that cells of the immune system actu-ally carry fragments or bacterial products into thejoints. Some time later, after the infection hasresolved, sensitized immune cells (lymphocytes)recognize the presence of these bacterial products inthe joints and instigate an inflammatory response inan attempt to destroy them. This is reactive arthritis.

Although a number of different organisms maycause reactive arthritis, many of them have simi-larities. They are gram-negative (a staining prop-erty that has been used to identify organisms formany years), their cell membranes are rich in mol-ecules called lipopolysaccharides and peptidogly-cans and they can enter the human host’s cells andsurvive there. The most frequently implicatedorganisms are Chlamydia trachomatis, Clostridium dif-

ficile, Campylobacter, Salmonella, Shigella, and Yersinia.These organisms typically cause HLA-B27-associ-ated arthritis (see below). Other less frequentlydescribed organisms include Streptococci, Escherichia

coli, and treatment with bacillus Calmette-Guérin(BCG) (see DRUG-INDUCED RHEUMATIC DISEASE). Thislatter organism is instilled into the bladder ofpatients with bladder cancer to stimulate thepatient’s immune response to the cancer. A benignorganism that does not cause serious disease, it wasoriginally used to protect against tuberculosis. Ithas been shown to improve the outcome of bladdercancer, but a few patients do develop a reactivearthritis as a result. LYME DISEASE may be considereda reactive arthritis but is discussed separately.Viruses, including those causing HEPATITIS, PAR-

VOVIRUS, and RUBELLA, cause a reactive arthritis butare discussed separately since they are fairly dis-tinct from this group of diseases.

Patients with reactive arthritis are much morelikely to be HLA-B27 positive than the general pop-ulation (see ANKYLOSING SPONDYLITIS for a discussionof HLA-B27). This is, however, not as common asin ankylosing spondylitis. Clearly many peoplewithout this gene develop reactive arthritis that isindistinguishable from those with HLA-B27. Theremay be some broad differences in the type ofarthritis people develop, but this is not due to HLA-B27 alone (see Symptoms below).

Chlamydia trachomatis DNA and RNA haveconsistently been found in the joint fluid or liningin a significant proportion (up to 30 percent insome studies) of reactive arthritis patients. Thisindicates that the organism is alive in the joint.Finding other organisms implicated in causingreactive arthritis in the joint, has been very diffi-cult. There may be some differences betweenchlamydia and the other organisms.

Of the five classes of immunoglobulin or anti-bodies, IgA antibodies are most involved in fightinginfection at mucosal surfaces and are, in fact,secreted out onto these surfaces. A characteristicfinding in reactive arthritis patients is persistent IgAantibody formation. These antibodies are directedagainst many antigens on the causative organisms.Their persistence suggests that the organism or atleast large parts of it remain within the body, stim-ulating further antibody production.

216 reactive arthritis

During outbreaks of infections with a relevantorganism, not everyone develops a reactive arthri-tis. HLA-B27-positive people are at increased risk,but this accounts for only part of the risk. Forexample, in a recent outbreak of salmonella diar-rhea, 12 percent of affected people developed reac-tive arthritis. Just less than half of these wereHLA-B27 positive. Ongoing research is looking atwhether some people’s immune systems may bemore likely to allow these organisms to persist inthe body and therefore result in reactive arthritis.

Symptoms

Within the broad grouping of the term reactivearthritis, three fairly distinct clinical presentationscan be observed.

Oligoarticular reactive arthritis This causespain and swelling in a few joints, sometimes onlyone. The knee is the joint most frequently affected.If more than one joint is involved, it is usuallyasymmetrical, e.g., the ankle of one leg and knee ofthe other. Over 60 percent of this group is positivefor HLA-B27 and they may develop spondylitis.This form of arthritis typically follows infectionwith Campylobacter, Chlamydia, Clostridium difficile,

Salmonella, Shigella, and Yersinia organisms. Iflooked for (it is a research procedure only), bacter-ial products are often detectable in the joints.

Typically there has been some sort of illness daysor weeks before the arthritis, sometimes affectingseveral people in the family. This presumed infectionmay be quite mild. Abdominal pain in the daysbefore the arthritis starts is common. Many patientsfeel generally unwell with fatigue and mild fever.Knees, ankles, and hips are most commonlyaffected, then shoulders, elbows, or wrists. Fingersare only occasionally affected, although the presenceof dactylitis is typical. Dactylitis describes inflamma-tion of the small joints of a finger as well as the ten-dons running along it. This results in a generallyswollen finger with limited movement, sometimesdescribed as a sausage finger. Affected joints areswollen and warm but often with much less painand tenderness than their appearance suggests. Thearthritis can move from one joint to another overseveral days. Inflammation of the sacroiliac jointswhere the spine meets the pelvis can lead to low-back pain and stiffness. Occasionally the spine may

also be affected, but severe spinal disease is veryunusual. Inflammation of tendons (tendinitis) andtheir attachments to bone (enthesitis) are very com-mon and may cause marked disability.

Several skin conditions may occur with reactivearthritis. Keratoderma blenorrhagicum is a scalythickening of the skin on the soles of the feet orpalms of the hand similar to palmo-plantar PSORIA-

SIS. Indeed, this form of the disease is very similar tothe oligoarticular form of psoriatic arthritis. Circinatebalanitis (a rash on the penis) as well as inflamma-tion of the mucous membranes of the mouth,throat, and urinary tract may occur. When presentthis does not imply that the cause was a sexuallytransmitted disease. Similarly, although gut infec-tions commonly set off the arthritis, noninfectiousinflammation of the gut can clearly occur long afterthe infection has resolved.

Inflammation in the eye is a part of reactivearthritis, although not everyone gets it. Conjunc-tivitis is the most common manifestation, followedby uveitis (see EYE PROBLEMS). These quite com-monly recur. The heart is only occasionallyaffected, with breakdown of the electrical conduc-tion system being the most common occurrence.The kidneys may be affected very occasionally,usually in the presence of high IgA levels.

Reiter’s syndrome This is often described as aseparate entity. It is in fact a form of reactive arthri-tis just as described above. By convention, however,the term Reiter’s syndrome is used when there isarthritis, conjunctivitis, and urethritis occurringaltogether. Urethritis is inflammation of the tubecarrying urine out of the bladder. Skin manifesta-tions are more common with Reiter’s than without,but otherwise there are no major differences.

Reactive arthritis This may present as a poly-arthritis resembling RHEUMATOID ARTHRITIS. Thisform is not associated with HLA-B27, the patientsdo not develop spondylitis, and finding bacterialremnants in their joints has been difficult. Manyorganisms seem to able to induce this form ofarthritis, with streptococci being typical. Interest-ingly, BCG has been reported to cause both thisform and the oligoarticular form of arthritis.

Diagnosis

The symptoms suggestive of a preceding infectionor treatment for bladder cancer are important in


leading to a search for the causative organism.However, especially when only one joint isinvolved, ruling out INFECTIVE ARTHRITIS or GOUT byaspirating joint fluid for laboratory examination isimportant. Frequently nothing is in the physicalexamination alone that can differentiate these.When several joints are involved in the oligo-arthritic form, it needs to be differentiated from theother spondyloarthropathies. This may be very dif-ficult, especially if back pain is present. Sometimesa period of follow-up is necessary to differentiatereactive arthritis from ankylosing spondylitis oreven psoriatic arthritis if the latter rash is not obvi-ous. In the polyarthritis form it is likely that manypatients are in fact diagnosed with rheumatoidarthritis if the initiating infection is mild. Therheumatoid factor, however, is negative.

Nonspecific tests reflecting inflammation such asthe ESR, C-reactive protein, and white cell countmay be raised early on. The HLA-B27 test may bepositive but does not assist in the diagnosis. Earlyon in the disease X rays are unlikely to show anyabnormalities. Later on small bony outgrowths atthe previously inflamed attachments of ligamentsand tendons (entheses) are common. The use ofMRI has increasingly shown the importance ofinflammation at these entheses in reactive arthritis.Where there is doubt, such a finding on MRI maysupport the diagnosis of reactive arthritis. However,MRI scanning should not be necessary in mostpatients. Urine examination may show the pres-ence of white cells but no organisms. This indicatesa noninfective inflammation of the urinary tract.An attempt should be made to grow the organismpresumed to have initiated the arthritis, recogniz-ing that the infection may be over and that thismay no longer be possible. Cultures may be takenof stool, urine, and throat swabs. Because it is oftentoo late to grow the organism by the time thearthritis is present, the more useful tests are oftenthose that look at the body’s response to infections.By measuring the patient’s own antibodies, it issometimes possible to tell that there has recentlybeen an infection with a certain organism. Suchserological tests are available for Salmonella,

Yersinia, Neisseria gonorrhoeae, Campylobacter, Chlamy-

dia, and beta-hemolytic streptococci. A positive testfor one of these in a patient with reactive arthritis

strongly suggests but does not prove that theorganism initiated the arthritis.


The treatment of reactive arthritis will vary consid-erably, depending on the stage and severity of thedisease. At different stages the goal of treatmentmay be to prevent arthritis from occurring, to abortthe arthritis by treating the cause, or to controlinflammation in established disease.

When there is a reasonably high risk of arthritisoccurring after particular infections, it seems logicalto hope that early treatment may prevent arthritisfrom occurring. For example, scientists know thatabout 12 percent of northern European populationswill develop reactive arthritis if infected during anoutbreak of salmonella diarrhea. Normally only seri-ously ill patients would be treated with antibioticsfor this infection since it is a self-limiting disease andantibiotics may cause more harm than good. Couldphysicians, however, prevent most cases of reactivearthritis by very early antibiotic treatment? Twogood studies in this situation involving salmonellaoutbreaks have shown no benefit from early antibi-otic treatment. Against this there is some evidencethat treating urinary and genital infections causedby Chlamydia trachomatis reduces the likelihood ofreactive arthritis developing.

If the arthritis is caused by the immune systemreacting against the presence of an organism, treat-ing that organism with antibiotics might beexpected to improve the arthritis or settle it alto-gether. Many studies have now been done usingappropriate antibiotics for six to 12 months. Stud-ies on patients with reactive arthritis due to gutinfections have shown no positive result. As men-tioned above, Chlamydia trachomatis may be slightlydifferent in that evidence of living organisms in thejoint can frequently be found. Two studies suggestthat there may be some benefit of antibiotic treat-ment in chlamydia-induced arthritis. However, notenough patients had a good response to be sure,and a further study showed no benefit. Therefore,the answer at this stage is still unknown.

Treatment for established arthritis varies accord-ing to severity. One or two swollen joints will oftenrespond well to injections of CORTICOSTEROIDS intothe affected joints. As long as infection has been

218 reactive arthritis

ruled out, this is a very safe procedure. Cortico-steroid injections are also very useful in managingenthesitis and sometimes tendinitis. For morewidespread joint pain and arthritis, NSAIDs areeffective. Since many patients are relatively young,NSAIDs are fairly safe. For many patients this is allthat is required.

For more severe or sustained arthritis, DMARDsare used, most commonly SULFASALAZINE. This drugwas in fact designed over 60 years ago by a doctorwho believed that most arthritis was due to infec-tions. She therefore thought that a combination ofthe newly discovered sulfa antibiotics and a form ofaspirin (the sala- in sulfasalazine) would be aneffective treatment. An early trial was negative. Itwas hardly used for treating arthritis until the late1970s, although it was found to be very successfulin treating inflammatory bowel disease. However,it is now a well-established DMARD in many formsof arthritis and in controlled trials has been shownto be effective and safe in treating reactive arthritis.Sulfasalazine is usually used first, but if not suc-cessful METHOTREXATE or AZATHIOPRINE may be used.

Ice can give good relief to inflamed joints andtendons, and flexible splints can provide support,but the joints should not be immobilized. Conjunc-tivitis is treated with corticosteroid drops. Deeperinflammation in the eye (uveitis) is usually treatedwith corticosteroid drops and drops to dilate thepupils. However, uveitis can have serious conse-quences and patients may need specialized atten-tion from an ophthalmologist. The kidney disease isusually mild and seldom requires specific treat-ment. The skin conditions are treated in a similarway to psoriasis.

Most patients with reactive arthritis can expect agood outcome. The arthritis will often settle rela-tively soon, sometimes within a few weeks. Theremay, however, be recurrences that can be set off byinfections or other stresses. Studies of outcomevary considerably, but probably 70 percent ofpatients can expect to be free of arthritis five yearsafter diagnosis.

reflex sympathetic dystrophy (RSD, shoulder-handsyndrome, Sudeck’s atrophy, posttraumatic sympa-thetic dystrophy, algodystrophy, causalgia, complexregional pain syndrome) A rare condition that

causes continuous, severe, unremitting pain, usu-ally in one limb. It affects women more often thanmen and can occur at any age, including child-hood. Complex regional pain syndrome is now theofficial term, but the authors have used RSD sinceit is the most widely used term.

Cause

The cause of RSD is not known. It often occursafter an injury, for example after a fracture or gun-shot wound. After an injury there is a natural ten-dency to protect the injured limb, or it may havebeen immobilized in a cast, causing the hand orfoot to swell, turn blue and blotchy, and feel abnor-mal. These responses to immobilization can be pre-cursors of RSD. For example, frozen shoulder orstroke, which cause someone to keep his of herarm still, is often associated with swelling of thehand on the affected side. This occasionally pro-gresses to RSD. The severity of the injury does notseem to affect the chance of developing RSD, andsometimes RSD can follow a minor injury. RSDusually affects only one limb but can be bilateral.

Some experts have argued that RSD is a poorname for this condition because it is not a reflex andthe sympathetic nervous system may not play animportant part. The proposed alternative name,complex regional pain syndrome, describes the con-dition without inferring its cause but is not yetwidely used. RSD affects pain perception. Whetherthis is caused by abnormal nerve circuits in the brainor spinal cord or by abnormal regulation of sympa-thetic nerve fibers in the affected limb is not known.

Dogma suggests that abnormal sympatheticnerve activity plays an important part in the causeof RSD. The sympathetic nervous system is respon-sible for automatic biological functions such assweating and temperature control. There is someevidence in support of this theory because manyresponses that are regulated by the sympatheticnervous system are abnormal in RSD. For example,the affected limb often has abnormal sweating andtemperature regulation. In addition, blocking sym-pathetic nerves by injecting a drug can improvesymptoms. On the other hand, studies of sympa-thetic nerve activity yielded conflicting results andabnormal conduction in nerves that carry pain sen-sations, which may also be important.

reflex sympathetic dystrophy 219

Symptoms

There are three major groups of symptoms: pain,autonomic nerve dysfunction, and dystrophicchanges. Steinbrocker suggested that there werethree stages. Stage 1 is marked pain and swelling,stage 2 is dystrophic changes, and stage 3 is atro-phy. Many patients do not pass through all threestages.

Pain This is the major symptom of RSD. Ifthere was a preceding injury, the pain is out of pro-portion to the severity of the injury or the physicalfindings. Pain in RSD is often constant, burning,and difficult to localize, occurring both on the sur-face and in the deep tissues. The patient may feelpain in response to a stimulus such as light touchthat would not normally be painful (allodynia) ormay feel much more pain than would be expectedafter a slightly uncomfortable stimulus (hyperalge-sia). There is often exquisite tenderness so that apatient cannot bear to have the affected limbtouched.

Autonomic nerve dysfunction This leads tochanges in blood flow, temperature, and sweating.Compared with the opposite limb the affected onecan be pale, cold and clammy, or warm and dry.There is often swelling of the soft tissues withedema.

Dystrophic changes Later in the illness are dys-trophic changes so that the skin becomes thin andshiny, the nails thick and brittle, and the musclessmaller and weaker. Involuntary muscle spasms,muscle contractures, and atrophy can occur late inthe illness.

Diagnosis

The diagnosis is clinical, and there is no specificdiagnostic test for RSD. Blood tests are normal.Early in the illness a radionuclide bone scan of theaffected limb shows increased blood flow, and latein the illness, decreased flow. Late in the illness anX ray often shows osteoporosis in the bones of theaffected limb.


Patients with a fracture affecting the movement ofa limb, for example a wrist fracture, have a highrisk of developing RSD. Exercises to keep the fin-gers moving and prevent swelling in the hand may

prevent RSD. One study found that 500 mg of vit-amin C a day reduced the frequency of RSD after awrist fracture. Once RSD has occurred, the soonertreatment is started the better. The mainstay ofearly therapy is aggressive physical therapy torestore movement and pain control. Early in thedevelopment of RSD a course of CORTICOSTEROIDS

can help to decrease pain and swelling. NSAIDs areseldom very effective. A sympathectomy, removingthe sympathetic nerve supply to a limb, is oftentried. This can be achieved surgically by cutting thenerve or chemically by injecting a drug around thenerve. The results of a sympathectomy are variable.Many other drugs are used to treat RSD, includingdrugs that block the adrenergic receptors thatmediate sympathetic nerve responses, and calci-tonin, administered either as an injection or as anasal spray. BISPHOSPHONATES have also been tried.Treatment of RSD is difficult, and there have beenfew good clinical trials to evaluate how effectivedifferent treatments are. Many patients with estab-lished RSD have persistent symptoms.

Two recent trials describe modest improvementswith invasive treatments. In one study 36 patientswith RSD for at least six months received spinal cordstimulation and physical therapy and 18 receivedphysical therapy alone. To stimulate the spinal cord,surgery is performed to insert an electrode close tothe nerves as they exit the spine. A pulse generatorprovides a current that the patient can regulate. Thecurrent produces a feeling of pins and needles thatoverrides the pain. The investigators found thatstimulation decreased pain by about 25 percent, butfunction did not improve. The study was criticizedbecause patients were selected to receive spinal cordstimulation only if they responded to it, and theplacebo effects of surgery and using high-tech hard-ware was not controlled (see CLINICAL TRIAL).

The second study, performed in six women withRSD, examined the effect of baclofen, a musclerelaxant, injected into the epidural space aroundthe spinal cord on abnormal muscle spasms.Baclofen was administered continuously by a smallpump for up to three years, and most of thewomen improved with reduced spasms and pain.Injection of baclofen into the epidural space andspinal stimulation are expensive and invasive treat-ments but may be options for selected patients.

220 reflex sympathetic dystrophy

Reiter’s syndrome See REACTIVE ARTHRITIS.

relapsing polychondritis This is a rare disease inwhich there are intermittent bouts of inflammationaffecting cartilage. The first patient was reported in1923, but even by 1960 there were only 10 patientsreported. It can start at any age but usually does sobetween 40 and 50 years. Relapsing polychondritisoccurs in all races and affects men and womenequally. It is estimated that about three people inevery million develop the disease every year in theUnited States.

Cause

The cause is unknown. There is good evidence foran immune attack directed against type II collagen,the main constituent of cartilage in a number ofareas in the body. Immune cells are found at thesites of cartilage damage as are antibodies and COM-

PLEMENT components. Further antibodies directedagainst type II collagen are found in many, althoughnot all, patients. Levels of these antibodies parallelactivity of the disease in some patients. Approxi-mately a third of patients have another autoim-mune condition that usually starts before thepolychondritis. All the connective tissue diseases,many other inflammatory arthritides (see ARTHRI-

TIS), inflammatory bowel disease, diseases of bloodcells and the immune system, as well as PSORIASIS

and DIABETES have been associated with relapsingpolychondritis.

Symptoms

Cartilage containing type II collagen provides struc-tural strength to a number of widely separatedorgans. The distribution of these structures indi-cates the main areas of damage in polychondritis.About 10 percent of patients also get a VASCULITIS.The following describes roughly in order of fre-quency the typical manifestations of relapsingpolychondritis.

Ear The outer ear, or pinna, becomes inter-mittently inflamed in over 80 percent of patients.Because there is no cartilage in the lower flap of ear(where earrings are normally worn), this gives avery characteristic appearance. The rest of the earbecomes red and swollen, with the lower flapappearing normal. After repeated attacks the ear

softens and looks smaller and floppy. The canalleading to the eardrum can also be affected, closingoff and causing hearing loss. However, deafnessmore commonly follows small-vessel vasculitisaffecting the inner ear. This can cause dizziness,severe nausea that does not respond well to med-ication, and eventually profound deafness. Thisaffects about 30 percent of patients.

Nose The cartilage of the bridge of the nose isinvolved in 30 percent of patients at some stage ofthe disease. It becomes mildly swollen, red, andwarm, and this lasts from days to weeks. Afterrepeated attacks the cartilage collapses, causing adepression in the midpart of the bridge of the nose.This is known as a saddle nose deformity.

Respiratory tract The main windpipe or tra-chea that can be felt in the front of the neck takesair into the lungs, where it is distributed by smallerairways. Because of the pressure differences insideand outside of the chest wall, it is necessary to havesomething keeping the trachea open or it wouldcollapse. This is achieved by having C-shaped ringsof cartilage that can easily be felt regularly spacedall the way down the trachea. If these are affectedby the chondritis they may soften and start to col-lapse, leading to wheezing, coughing, choking, andshortness of breath on exertion. These patients areat increased risk of chest infections. Collapse of thetrachea can lead to death.

Joints Ankles, wrists, and elbows are most fre-quently involved, and over 70 percent of patientswill get arthritis during the course of the disease.Other joints may be affected. Attacks may lastweeks to months and do not parallel inflammationelsewhere in the body. Despite the severe pain,joint swelling is slight and there is relatively littledamage to the joints.

Heart and arteries Abnormalities of electricalconduction in the heart may occur. Inflammation ofthe attachment of the heart valves leads to theirbecoming leaky. When this affects the aortic valve(through which blood is pumped around the body),it can cause heart failure. Surgical replacement ofthe valve is often required and the surgery can bedifficult. The walls of the large arteries, especiallythe aorta, can become weakened and enlarge.

Eyes Many eye problems can occur, with 50percent of people having some problem. These can

relapsing polychondritis 221

include swelling behind (causing a bulging eye) oraround the eye. Inflammation of the white coatinglayer in front of the eye can occur, and occasionallythis is severe enough to cause destruction andbulging of the eye contents. Inflammation of otherparts of the eye (iridocyclitis, chorioretinitis, andkeratitis) may occur but are not common (see EYE

PROBLEMS). Vasculitis may affect the vessels at theback of the eye.

Kidneys A few patients develop inflammation ofthe filtering part of the kidneys (glomerulonephritis).

Skin A range of rashes have been described,but none are specific for relapsing polychondritis.Palpable purpura (purple-black spots that can befelt) and urticaria (hives) may be signs of vasculitis.ERYTHEMA NODOSUM, LIVEDO RETICULARIS, and throm-bophlebitis (inflammation of veins just under theskin) are all described.

Nervous system This is usually a result of vas-culitis causing loss of blood supply to an area ofbrain or nerves. Strokes, peripheral nerve lesions,or spinal cord lesions may occur.

Fever Nearly 50 percent of patients will have afever at some time. This frequently causes diagnosticconfusion, with a variety of infections being suspected.

Diagnosis

In its full-blown state relapsing polychondritis isnot difficult to diagnose. It is a rare disease, how-ever, and many doctors will not have previouslyencountered it. This may lead to the diagnosis notbeing considered. The various manifestations of thedisease may also not occur together. Many otherconditions can mimic isolated effects of polychon-dritis that may therefore not be diagnosed until apattern of disease becomes apparent. Commonlyused criteria for diagnosis require three of the fol-lowing seven features: (1) typical inflammation ofboth ears; (2) an arthritis as described above; (3)inflammation of the cartilage of the nose; (4) eyeinflammation; (5) inflammation of the cartilage ofthe trachea or voice box; (6) disturbance of innerear function, e.g., dizziness, nausea, and hearingloss; and (7) biopsy of cartilage showing typicalmild inflammation.

It is very important to evaluate the upper air-ways by breathing tests (spirometry) and usuallyCT scanning since disease here can be rapidly fatal.

Spiral CT scans are particularly useful in giving athree-dimensional picture of the inside of the tra-chea and main airways without the need for inva-sive procedures. Echocardiography (an ultrasoundexamination) is used to examine the heart, thevalves, and the first part of the aorta. CT or MRIscanning can accurately image the rest of the aortaand other large vessels. Usually the ESR, C-reactiveprotein, and white cell count will be raised, reflect-ing the inflammation. These are not, however, spe-cific for relapsing polychondritis. Anticollagen typeII antibodies cannot be measured in routine labo-ratories and are not always positive. Those patientswith other coexisting diseases may have abnormalinvestigations because of those diseases.


The aims of treatment are to minimize the pain anddisability caused by the less dangerous manifesta-tions and to try and prevent damage to those organsthat may result in death or severe disability. NSAIDsand low-dose CORTICOSTEROIDS are effective in treat-ing the arthritis and mild inflammation of the earsand nose. If the attacks are very severe or whenthere is involvement of the heart, major blood ves-sels, kidneys, or there is a vasculitis, then high-dosecorticosteroids are used. Ideally this can be taperedoff after the attack settles and discontinued. Relaps-ing polychondritis does not always respond to corti-costeroids, however, and does not always settlewithin a reasonable time period. In these situationsimmunosuppressive treatment is used. CYCLOPHOS-

PHAMIDE, AZATHIOPRINE, CYCLOSPORINE, and plasma-pheresis have all been reported to be successful, andDAPSONE and COLCHICINE have been used in milderdisease. It should be pointed out, however, thatrelapsing polychondritis is such a rare disease thatcontrolled trials of treatment will probably never bedone. The rationale for treatment will be borrowedfrom diseases that are more frequent and havesome similarities.

The trachea and major airways present specialproblems. If there is narrowing or collapse high upin the trachea, a tracheotomy tube can be insertedto prevent obstruction. For obstruction of airwayslower down it is possible to put stents in that holdthe airway open. However, there have been prob-lems with these devices. People with mildly col-

222 relapsing polychondritis

lapsible airways may benefit from using a pumpthat forces air into the lungs at night. This is knownas continuous positive airways pressure or CPAPand is quite frequently used in patients with SLEEP

APNEA. Leaking heart valves can be surgicallyreplaced, but the tissues may be weak and repeatsurgery may be required.

Profound deafness is not uncommon and is amajor cause of disability. Respiratory and heartcomplications contribute to the reduced lifeexpectancy of patients with relapsing polychondri-tis. About three-quarters of these relatively youngpatients will be alive five years after diagnosis.However, in those with vasculitis only 45 percentwill be alive at five years.

rhabdomyolysis Severe muscle damage causingtissue necrosis (death).

Cause

Rhabdomyolysis is not a specific disease, and it canbe caused by any condition that results in severemuscle damage. Such damage can occur fromdirect injury, for example if a person is crushed ina motor vehicle accident; after unusually severeexertion, for example in new recruits starting mili-tary training; or after repeated seizures. Muscledamage and rhabdomyolysis can be associated withmetabolic abnormalities such as a very low serumpotassium level. Muscle inflammation associatedwith viral infections is usually mild, but occasion-ally severe muscle damage can occur. Other causesof muscle inflammation, and occasionally rhab-domyolysis, are alcohol, cocaine, heat stroke, statincholesterol-lowering drugs, and polymyositis ordermatomyositis.

Symptoms

Severe muscle pain and swelling are common. Thiscontrasts with DERMATOMYOSITIS AND POLYMYOSITIS

where pain and swelling are seldom prominent.The patient may notice dark urine. This is causedby myoglobin, a pigment produced by musclebreakdown. Affected muscles are weak and painfulto move.

Diagnosis

In addition to the symptoms, a clue to the correctdiagnosis is a marked increase in the concentration

of creatine phosphokinase (CK or CPK), an enzymeelevated when muscle is inflamed or damaged.Myoglobin can be detected in the plasma and in theurine.


There is no specific treatment for rhabdomyolysis.The most serious complication is kidney failure.This occurs because high concentrations of myo-globin are toxic to the kidney. Kidney function canbe protected by ensuring that the patient hasplenty of fluids and that the urine remains dilute.If renal function deteriorates, some patients needdialysis for a few weeks until the kidneys recover.Rhabdomyolysis usually settles spontaneously.

rheumatic fever An immunological reaction to astreptococcal infection that causes fever and arthri-tis acutely but leads to chronic damage of the heartvalves. Rheumatic fever was common in the UnitedStates until the introduction of penicillin, when theincidence declined. However, it has not been eradi-cated, and episodic cases, or clusters of cases, stilloccur. Rheumatic fever is much more common indeveloping countries and seems to thrive underconditions of poverty and crowding. Childrenyounger than 15 years of age are at greatest risk.

Cause

Rheumatic fever is caused by an immunologicalreaction to an infection with a group A beta-hemolytic streptococcus. In some people this organ-ism is part of the bacterial population normallyliving in the nose and throat, but it can be invasiveand is the cause of strep throat. Streptococcal throatinfection itself is often self-limiting, even withouttreatment. However, one cannot predict whichinfections are likely to precipitate heart disease, andtherefore all are treated with antibiotics.

Scientists do not know why the streptococcussometimes lives happily as part of the usual bacter-ial population and at other times causes streptococ-cal throat infection that can lead to rheumatic fever.Only about 1 percent of streptococcal infectionslead to rheumatic fever. The genetic makeup ofboth the patient and the streptococcus seem to beimportant determinants of the type of infection andwho goes on to develop rheumatic fever. Rheumatic

rheumatic fever 223

fever is caused by antibodies against the streptococ-cus reacting against the patient’s own tissues.

Symptoms

Rheumatic fever occurs two to five weeks after astreptococcal throat infection. The throat infectionmay have been minor and by the time rheumaticfever occurs has usually resolved. Fever and arthri-tis are common symptoms. The fever can be veryhigh and responds to treatment with aspirin.Arthritis tends to affect large joints such as theknee, hip, ankle, wrist, and elbow. Arthritis tendsto be flitting, moving from one joint to another, oradditive, adding a new joint to the one that isalready affected. Arthritis in rheumatic fever causessevere pain that is out of proportion to the amountof swelling or obvious inflammation. The pain canbe so severe that the child is unable to walk.

Other less common findings are a rash callederythema marginatum, subcutaneous nodules, amovement disorder called Sydenham’s chorea, andcarditis. Erythema marginatum is usually a flat,pinkish rash with a clear margin, sometimes withclearing in the center. It can be very subtle andevanescent. Subcutaneous nodules are found inrheumatic fever but are rare. These nodules areusually smaller than a pea and are found over ten-dons. Sydenham’s chorea is a movement disorderthat causes abnormal movements of the hands andface. The patient often disguises these involuntarymovements by turning the movement into a semi-purposeful action. The result is that sometimeschildren with chorea are thought to be very fidgetyor unable to sit still. Sydenham’s chorea can recuryears later during pregnancy without any symp-toms of another attack of rheumatic fever. Carditisis inflammation of the heart. During acuterheumatic fever myocarditis, pericarditis, andendocarditis can occur. Myocarditis, inflammationof the heart muscle, often causes an increased heartrate and can cause heart failure. Pericarditis,inflammation of the outside lining of the heart, cancause chest pain and a pericardial effusion (fluidaround the heart). Endocarditis, inflammation ofthe heart valves, causes a murmur, a noise causedby blood flowing across an abnormal heart valve.

Repeated attacks of rheumatic fever can causechronic, permanent damage to heart valves. This

can cause heart rhythm problems, enlargement ofthe heart, and heart failure.

Diagnosis

The diagnosis of acute rheumatic fever is clinical.The Jones criteria are used for classification, butsome patients with rheumatic fever do not fulfillthe criteria. The Jones criteria require laboratoryevidence of a streptococcal infection and the pres-ence of two major criteria or one minor and onemajor criterion. The major criteria are carditis(myocarditis, pericarditis, or endocarditis), ery-thema marginatum, subcutaneous nodules, chorea,and arthritis. The minor criteria include fever, anelevated erythrocyte sedimentation rate (ESR),arthralgia, and a history of a previous attack ofrheumatic fever.

A throat swab may still be positive for strepto-coccus when rheumatic fever develops, or if it isnegative, an elevated antistreptolysin antibodylevel will suggest a recent streptococcal infection.The ESR is usually elevated, but other blood testsare not helpful. An electrocardiogram can show anincreased PR interval, a widening of the distancebetween the P and R waves. An echocardiogrammay show pericarditis or abnormalities of the heartvalves.


Preventing rheumatic fever is possible by treatingstreptococcal throat infections, particularly in chil-dren. If rheumatic fever develops, an NSAID, mostoften high doses of aspirin, relieves fever andarthritis. Penicillin is used to eliminate any remain-ing streptococci, and occasionally if there is carditis,a course of corticosteroids is prescribed. The acuteattack subsides within a few months, However, if apatient has had one attack of rheumatic fever pre-venting further attacks is important. The risk ofpermanent damage to the heart valves is muchhigher after repeated attacks of rheumatic fever. Along-term antibiotic, most often a monthly injec-tion of long-acting penicillin, is prescribed to pre-vent this. If there is permanent damage to heartvalves, surgery to repair or replace these may berequired. Heart valves that have been damaged byrheumatic fever have a greater risk of becominginfected (INFECTIVE ENDOCARDITIS).

224 rheumatic fever

rheumatoid arthritis (RA) A chronic inflamma-tory autoimmune disease that fluctuates in severityand affects the joints, causing swelling, pain, loss offunction, and eventually deformity. It can alsoaffect other organs. Purists maintain it shouldtherefore be called rheumatoid disease rather thenrheumatoid arthritis. RA has a major socioeco-nomic impact, not only by causing disability anddecreasing the earning capacity of affected peoplebut also by increasing use of medical resourcessuch as doctor visits, hospital admissions, and sur-gery. In the last 20 years improvements in thedrugs available to treat RA and recognition thatearly control of the disease is important haveimproved outcomes.

Cause

RA affects about 1 percent of the population in mostcountries. It is rare in some populations such as ruralWest Africans and more frequent in some, such asPima Indians. The cause of RA is not known. Severalideas have been proposed—most often that it iseither an infectious or genetic disease.

Infection An infectious cause has been sus-pected and hunted for decades but has never beenconvincingly or reproducibly proven. Patients withRA make antibodies to a wide range of antigenswhich has sometimes led researchers down mis-leading trails.

One of the first organisms suggested as a causeof RA was the Epstein-Barr virus (EBV), the organ-ism that causes infections mononucleosis (mono).In the 1970s, it was found that many patients withRA had antibodies against the virus, and specula-tion mounted that the virus played a role in thecause of RA. This was an attractive theory becauseit was known that EBV activated B lymphocytesand was associated with rare types of cancer, sug-gesting it could interact with the immune system.Most adults have been infected with EBV at sometime. Many experts think RA stimulates the B lym-phocytes to produce many antibodies, one ofwhich is the antibody against EBV, and that thevirus does not cause RA.

Several viral illnesses such as RUBELLA, PAR-

VOVIRUS, HEPATITIS, and HUMAN IMMUNODEFICIENCY

VIRUS (HIV) (see VIRAL ARTHRITIS) can cause arthritis,but efforts to isolate a specific virus from patients

with RA have not been successful. Similarly, infec-tion with Mycoplasma, Chlamydia, and Proteus havebeen considered as causes of RA, but the evidenceis not convincing.

Genetic causes Undoubtedly genetic factorsplay a part in determining who gets RA, because ittends to run in families. If someone has a parent orsibling with RA, that person’s risk of getting the dis-ease is doubled. However, genetic factors are notthe whole answer. If RA were entirely genetic, onewould expect that identical twins would have 100percent concordance. If one identical twin gets RA,though, there is about a 20 percent chance that theother twin, who has exactly the same DNA, willdevelop RA.

The genetic factors that increase the risk of RAare not clear (see HLA and GENETIC FACTORS).Rheumatoid arthritis has been known to be associ-ated with HLA tissue types since the 1970s, withthe risk of RA increased fourfold in individualswith the HLA-DR4 tissue type (new nomenclatureHLA-DRB1 0401, 0402, and so on, for the differentvariants of the 04 tissue type). The strength of theassociation varies in different populations and isweaker in African-American than in Caucasianpopulations. Several research groups are perform-ing genome-wide scans where the whole DNAsequence is examined in families with RA formarkers that track with RA to try to localize thesearch to smaller areas of the genome. So far, otherthan confirming the association with the HLAregion, the results have not been reproducible.

Other possible risk factors Women develop RAthree times as often as men and RA often seems toimprove in pregnancy, suggesting that hormonesmay influence the immune system in ways thatalter the risk of developing RA.

Cigarette smoking is associated with about a 50percent higher risk of developing RA, and RA ismore severe in smokers. The mechanism is notclear, but smoking stimulates many liver enzymesthat metabolize drugs and chemicals. Theseenzymes possibly convert an unidentified chemicalinto a by-product that affects the risk of RA.

RA is much less common in West Africa than it isin the United States, although critics argue that scien-tists are not certain about this because so few studieshave been done in Africa. Observational studies from

rheumatoid arthritis 225

Africa also suggest that as people move into urbanareas, where the risk of infections such as malaria isdecreased, the risk of RA increases. It has been pro-posed that chronic infection with an organism such asmalaria may stimulate the immune system and pro-tect against RA and that the Western-type lifestylewith excellent hygiene may increase risk. An argu-ment against this is that recent evidence suggests thatthe incidence of RA is decreasing in developed coun-tries such as the United States.

How RA Causes Disease

Although scientists do not know what causes RA,they do have an excellent understanding of howRA causes disease. Inflammation of the synoviumis central to the pathogenesis of RA. The synoviumthat is normally thin becomes thickened, hypertro-phied, and filled with fibroblasts and inflammatorycells such as lymphocytes and macrophages. Smallnew blood vessels form (angiogenesis). The prolif-erating synovium, called a pannus, replaces normalsynovium and is locally invasive, damaging theunderlying bone and cartilage.

Several cell types play an important role. T lym-phocytes were thought to be the key cell drivingRA, and drug companies produced antibodies thateffectively depleted T cells in patients with RA. Sur-prisingly, this had little effect on disease activity,suggesting that perhaps T cells were not critical tothe development of RA. Current opinion is that T cells do play a role in the pathogenesis of RA, butother cells such as macrophages, which produceCYTOKINES, are also important. B lymphocytes pro-duce antibodies, including rheumatoid factor,which is discussed later. Many mediators such as

the cytokines tumor necrosis factor (TNF) andinterleukin-1 and the chemokines amplify and sus-tain the inflammatory process. The strategy ofdeveloping drugs to block cytokines has led toeffective new drugs for RA.

Symptoms

The key symptoms and laboratory findings in RAare shown in the Table.

General symptoms RA is an illness that affectsmuch more than just the joints, and systemic symp-toms are common. Symptoms often start gradually,over months. Patients often experience difficultypinning down exactly when their illness started.The first symptoms are often vague and includefatigue, lack of energy, feeling depressed or washedout, and stiffness in the morning that lasts longerthan 30 minutes. The stiffness in most noninflam-matory causes of arthritis such as osteoarthritis lastsonly a short time and improves once the patient ismoving, whereas the stiffness in inflammatory dis-eases is much more severe and long lasting. It is notunusual for patients to say that their morning stiff-ness lasts until they take a hot bath or place theirhands under running hot water. Loss of weight canoccur with more severe RA and is part of the sys-temic illness. Lymph nodes can increase in size. Thisdoes not usually cause symptoms. However, if aphysician notices the enlarged nodes, it may triggera series of tests to make sure the patients does nothave cancer, infection, or lymphoma.

Joint (articular) symptoms Typically RAaffects many small joints in a symmetrical distribu-tion at the same time. The metacarpophalangealand proximal interphalangeal joints (knuckles) of

226 rheumatoid arthritis

COMMON SYMPTOMS AND LABORATORY FINDINGS IN RHEUMATOID ARTHRITIS

General Joint Extra-articular Laboratory

Morning stiffness Pain Rheumatoid nodules Anemia

Fatigue Symmetrical swelling Pleurisy High platelet count

Low-grade fever Stiffness Lung disease High ESR

Lack of energy Warmth Pericarditis Rheumatoid factor

Depression Loss of function Eye inflammation Normal white cell count

Loss of weight Deformity Felty’s syndrome Erosions on X ray

Lymph nodes Fusion Sjögren’s syndrome Inflammation on imaging

both hands and wrists are most often affected. Insome patients, though, the illness first causes symp-toms in the small joints of the feet. Affected jointsshow signs of inflammation such as warmth,swelling, pain, and reduced movement. In a fewpatients joint swelling and other symptoms can occurin short, sharp attacks that resolve completely untilthey recur. This is called PALINDROMIC RHEUMATISM.More frequently, however, RA causes persistentsymptoms in joints that may fluctuate in severity.

RA has a predilection for the small joints of thehands and feet, but most joints can be affected.Listing those that are seldom or never affected iseasier. RA seldom affects the distal interphalangealjoints (the last joint of the fingers) and does notaffect the lower back. It can affect hips, knees,shoulders, wrists, ankles, cervical spine (neck), andtemporomandibular joint (jaw). The joints of thesmall bones in the larynx (voice box) can becomeinflamed, causing hoarseness or narrowing of theairway. Symptoms vary in severity. Some patientsare so severely affected that they are unable tofunction, and others are able to continue their day-to-day activities with some limitations.

Early in the illness swelling predominates, andthis may lead to restricted movement of a joint andaffect the patient’s ability to make a fist or gripobjects. Later in the illness permanent deformitiescan occur. One of the most common is called ulnardeviation. If a patient stretches out his or her fingerswith the palms facing the ground, the fingersinstead of being straight point outward, away fromthe rest of the hand. Early in the disease the patientcan correct the deformity by using other muscles topull the fingers straight, but later the deformitybecomes fixed and permanent. Other commondeformities affect the fingers and wrist. A bouton-

niere (buttonhole) deformity affects the middleknuckle of the finger so that the joint is perma-nently flexed. It is called a boutonniere deformitybecause the joint sticks out between two slips of atendon so that the anatomy looks like a button pop-ping out of a buttonhole. A swan neck deformity iswhen the end joint of the finger is flexed and themiddle joint is hyperextended, so the finger ends upresembling a swan’s neck. If the wrist is chronicallyinflamed the whole hand can migrate downwardoff the wrist, resulting in a step-down or dinner fork

deformity. These deformities can be corrected surgi-cally, but such procedures do not necessarilyimprove function.

Late in the disease affected joints permanentlylose their ability to move through a normal rangeof motion or even fuse and lose their ability tomove at all. Fusion is a mixed blessing becausewhile joints that cannot move do not fulfill theirnormal function, they are also frequently lesspainful. In fact, a common surgical treatment forchronic pain in a joint that does not respond tomedical treatment and where movement is notvital is surgical fusion (ARTHRODESIS).

Joints move, stabilize, absorb shock, and helpwith balance. The major symptom of arthritis, apartfrom pain, is loss of function. This may affect dailyactivities such as walking, eating, dressing, andbathing but can also affect a person’s ability to holda particular job. A concert pianist and a bricklayermay seem to require very different tasks from theirjoints, but both jobs demand hands that can func-tion effortlessly. Frequently patients with RA haveto modify their lifestyle, hobbies, and employmentbecause of limitations imposed by their arthritis.

Extra-articular symptoms RA affects not onlythe joints but can also affect almost any organ. Forthis reason many experts prefer to call it rheuma-toid disease rather than rheumatoid arthritis.

Rheumatoid nodules Nodules ranging in sizefrom smaller than a quarter-inch to larger than aninch (RHEUMATOID NODULES) are a frequent manifes-tation of extra-articular disease and are a marker ofmore severe and aggressive RA.

Pleurisy The main symptom of pleurisy is chestpain that gets worse on taking a deep breath orcoughing. These symptoms can also occur inpatients who have a broken rib or inflammation orinfection of the lung. Many patients with RA havemild pleurisy without knowing about it. Moresevere disease causes symptoms of pleurisy andsometimes a collection of fluid in the space betweenthe lung and its lining (pleura). This is called apleural effusion, and because it can be caused bycancer, pneumonia, infection, and many other dis-eases, it often starts a train of tests to try and findthe cause. Unfortunately, there is no specific testthat differentiates between a pleural effusion causedby RA and other diseases. The pleural fluid in RA


often has a very low glucose concentration, but thisfinding is not specific.

Lung disease In addition to causing pleurisy,RA can affect the lungs in several other ways. Themost common is called interstitial fibrosis, whichcauses streaks of scarring throughout the lung tis-sue. Many patients with interstitial fibrosis do nothave any symptoms early on. However, if a chest Xray is taken, it can show scarring even at this stage.Why RA causes interstitial fibrosis is not clear, butmale sex, severity of RA, and smoking increase therisk. Severe interstitial fibrosis causes shortness ofbreath and cough, and it decreases exercise capac-ity. Tests of lung function usually show what iscalled a restrictive defect, in other words, the vol-ume of the lungs is decreased. Very occasionallylung disease can occur before arthritis symptomsoccur, resulting in confusion about the diagnosis.

RA can cause rounded nodules within the lung.This used to occur more commonly in people withpneumoconiosis, an occupational lung disease usu-ally acquired from working in coal mines, but nod-ules can occur in any patient. When only one or afew nodules are seen it can be very difficult to dif-ferentiate this from cancer, and a biopsy is oftenrequired.

Pericarditis Just as fluid can accumulatebetween the lung and its lining layer, it can alsoaccumulate between the heart and its lining layer,the pericardium. Again, many patients with RAhave mild pericarditis that does not cause majorsymptoms or problems, and they are not aware ofit. Mild asymptomatic pericarditis does not needany specific treatment. More severe disease thatcauses chest pain and a large pericardial effusionshould be treated. The symptoms of a pericardialeffusion are variable but can include chest pain ortightness, edema, and shortness of breath. Typicallythe chest pain from pericarditis is felt in the middleof the chest, varies with position, and can get worsewith breathing. Other heart problems are rare, butrheumatoid nodules have been found in the heart,where they may cause rhythm problems.

Eye inflammation Dry eyes, as a component ofSJÖGREN’S SYNDROME accompanying RA, are commonbut serious inflammation of the eye that threatensvision is uncommon. Scleritis, or inflammation ofthe fibrous layer of the eye, can cause pain, redness,

and more seriously, thinning and weakness of theeyeball. If this happens, the white part of the eyelooks blue or black because thinning of the liningallows the darker interior to show. Inflammation ofthe sclera usually causes a red, painful eye. The painis deeper, more severe, and more aching in charac-ter than the superficial scratchiness caused by con-junctivitis or episcleritis. Vision can be affected, andscleritis should be treated by an ophthalmologist.Treatment involves management of the underlyingRA and may require CORTICOSTEROIDS and immuno-suppressive drugs. In patients with severe RA,rheumatoid nodules can occur in the eye and causethe sclera to become thin, and if inflammation is notcontrolled, to weaken so that the inside of the eyeruptures through the wall and blindness results.(See also EYE PROBLEMS.)

Felty’s syndrome This rare complication of RAis discussed separately (see FELTY’S SYNDROME).

Sjögren’s syndrome See SJÖGREN’S SYNDROME.

Other symptoms RA rarely affects other organssuch as the liver, kidneys, or peripheral nerves, butRHEUMATOID VASCULITIS can occur and affect theseorgans. If symptoms of kidney disease such as pro-teinuria develop, they are more likely to have beencaused by drugs used to treat RA than the disease.

Diagnosis

The formal diagnostic criteria for RA were revised bythe American Rheumatism Association (now theAmerican College of Rheumatology) in 1987 andare shown in the table. These criteria were devel-oped mainly for research purposes to make sure thatresearchers in different countries were studying thesame disease and are not always helpful clinically.Since there is now more emphasis on diagnosingand treating RA as early as possible, before nodulesand erosions are present, some patients treated forRA may not fulfill the diagnostic criteria.

AMERICAN RHEUMATISM ASSOCIATION 1987 REVISED CRITERIA FOR THE CLASSIFICATION

OF RHEUMATOID ARTHRITIS

• Morning stiffness. This must affect the joints and last atleast an hour. Many patients with noninflammatoryrheumatic diseases such as osteoarthritis have morningstiffness, but this lasts for only a short time. Many patientswith uncontrolled RA say that they are stiff all day, butgenerally stiffness improves after a few hours.


• Arthritis affecting three or more areas at the same time.

• Arthritis affecting the wrists, metacarpophalangeal (MCP),or proximal interphalangeal (PIP) joints.

• Symmetrical arthritis.

• Rheumatoid nodules.

• A positive blood test for rheumatoid factor.

• X-ray changes such as erosions that are typical of RA.

According to these criteria, a patient who fulfillsfour criteria has RA. The first four criteria musthave been present for at least six weeks, and a per-son who has any four criteria at the same time canbe classified as having RA.

Laboratory findings in RA Laboratory testscan be helpful, but there is no specific diagnostictest for RA.

• A blood test called a rheumatoid factor (seeAppendix II) is often, but not always, positive.Patients, and some physicians, often make theerror of thinking that the test can definitivelymake or exclude the diagnosis of RA. About 80percent of patients with RA do have a positiverheumatoid factor at some time in their illness.This means that at least 20 percent of patientswith RA would be given the wrong diagnosis ifphysicians relied exclusively on the test. For mostlaboratory tests, the upper limit of normal is set sothat between 2.5 and 5 percent of normal peoplefall outside of the normal range. This means thatabout 5 percent of healthy people have a positiveRA factor, a number much higher than theapproximate number of people with RA, which isabout 1 percent of the population. To complicatematters, a positive rheumatoid factor occurs morefrequently in the elderly, in patients with otherautoimmune diseases such as SYSTEMIC LUPUS ERY-

THEMATOSUS (SLE), and in those with chronicinfections such as HEPATITIS C, TUBERCULOSIS, orINFECTIVE ENDOCARDITIS. In other words, the testfor rheumatoid factor is useful but must be inter-preted with the other clinical findings.

• Many blood tests become abnormal in RA becauseof inflammation. These tests are not helpful inmaking the diagnosis of RA because they are notspecific and can be abnormal with virtually anyinfection or illness that causes inflammation. An

elevated erythrocyte sedimentation rate (ESR) orC-reactive protein (CRP) are such tests. However,they can be useful in differentiating an inflamma-tory illness such as RA from noninflammatoryones such as osteoarthritis or fibromyalgia.

Anemia is common in RA, and it is usually atype of anemia called anemia of chronic disease.The white blood cell count is usually normal,sometimes useful in differentiating RA from SLE,where the white cell count is often low. Theplatelet count is often elevated (thrombocytosis)when RA is active.

Imaging findings An X ray of the hands or feetis often ordered. If RA is severe, this may show thetypical changes of narrowing of the joint space anderosions of bone around the joints. These X-raychanges are usually irreversible, so it does not makesense to wait for them to occur before making thediagnosis of RA. Later in the illness the X rays mayshow deformity and destruction of joints. Regular X rays are not very sensitive for detecting joint dam-age, and many researchers have studied imagingtechniques designed to detect joint inflammationand damage early. Radionuclide bone scans are verysensitive, and any joint or bone that has infection,damage, or inflammation lights up. Unfortunately,the test does not separate noninflammatory causesof arthritis such as osteoarthritis from RA. Thismeans that a bone scan in any person with arthritisusually lights up in the joints that are hurting—something that could largely have been determinedby simply asking the patient. More recently ultra-sound and magnetic resonance imaging (MRI) havebeen studied. Ultrasound has the advantages that itdoes not expose patients to radiation and is easy toperform. The disadvantages are that the quality ofthe images depends on the person doing the test andcan be difficult to interpret. Ultrasound can also beused to measure the blood flow to a joint. If a jointis inflamed the blood flow increases, and therefore,this technique has been explored as a way of deter-mining which drugs are effective for treating RA.Ultrasound is still mostly an experimental way ofstudying how a drug is affecting a joint. MRI is muchmore expensive but gives very clear images of jointinflammation and erosions. Other than in researchstudies, it is not used in clinical practice to diagnose


or monitor RA. MRI shows erosions before theybecome apparent on plain X rays, perhaps indicatingthe need for more aggressive treatment to slow thedisease process down.

Making the diagnosis The diagnosis of RA isusually made from the clinical findings. High-techtests such as MRI and ultrasound are not part of thediagnostic workup. Blood tests can be helpful, butmost rheumatologists will diagnose RA based onthe clinical findings, irrespective of the results. X rays are usually performed when a patients isfirst seen but are often not helpful for making adiagnosis because they can be normal in patientswith early disease. They are helpful because theyprovide baseline information so that the presenceof new erosions or joint deformities and responseto treatment can be tracked. The appearance oferosions early in the disease signals aggressivedestructive RA and may influence the patient’s andphysician’s approach to treatment.

RA can be confused with most other illnessesthat cause arthralgia or arthritis. However, SLE,OSTEOARTHRITIS, REACTIVE ARTHRITIS, VIRAL ARTHRITIS,

FIBROMYALGIA, VASCULITIS, and polyarticular GOUT

are most often mistaken for RA.

Treatment

The goals of treating RA include the following:

• To relieve pain

• To maintain and restore function

• To preserve muscle strength

• To prevent progression of disease

The treatment of an individual patient depends onthe severity of disease, the patient’s response to treat-ment, and the presence or absence of other condi-tions that may limit the drugs a patient can take. Toachieve the goals of treatment, a multidisciplinaryapproach is needed. This involves severalapproaches:

• Rehabilitation (see EXERCISE, OCCUPATIONAL THER-

APY, PHYSICAL THERAPY).

• Surgery (see JOINT REPLACEMENT).

• Drug therapy. Examples of the different anal-gesics, nonsteroidal anti-inflammatory drugs(NSAIDs), disease-modifying drugs (DMARDs),and corticosteroids used to treat RA are shownin the following table.


EXAMPLES OF DRUG CLASSES USED TO TREAT RA (TRADE NAMES IN PARENTHESES)

Analgesics NSAIDs DMARDs Corticosteroids

Acetaminophen Aspirin (Anacin and Methotrexate Prednisone (Deltasone,(Tylenol) many others) (Rheumatrex) Orasone)

• with Codeine Indomethacin Hydroxychloroquine Methylprednisolone(Tylenol #3) (Indocin) (Plaquenil) (Medrol)

• with hydrocodone Ibuprofen (Motrin, IM gold (Solganal)(Lortab, Lorcet, Vicodin) Advil)

• with oxycodone Naproxen (Naprosyn, Oral gold (Auranofin)(Percocet, Roxicet, Tylox) Aleve)

• with propoxyphene Diclofenac (Voltaren) Penicillamine(Darvocet N50, (Cuprimine)Darvocet N100)

Tramadol (Ultram) Etodolac (Lodine) Sulfasalazine (Azulfidine)

Flurbiprofen (Ansaid) Minocycline (Minocin)

Ketoprofen (Orudis) Azathioprine (Imuran)

Nabumetone (Relafen) Cyclosporine (Neoral)

Meloxicam (Mobic) Leflunomide (Arava)

Celecoxib (Celebrex) Etanercept (Enbrel)

Rofecoxib (Vioxx) Infliximab (Remicade)

Valdecoxib (Bextra) Anakinra (Kineret)

Analgesics ACETAMINOPHEN, because it appearsto be less likely to cause GI ulcers than NSAIDs, isoften the drug chosen first for many patients tocontrol pain. However, it does not have any anti-inflammatory effects and therefore is not helpfulfor controlling joint swelling or the pain that resultsfrom it in RA. In most patients with RA, NSAIDsare more effective than acetaminophen for reliev-ing symptoms caused by inflammation. However,late in the course of RA, damaged joints can causepain, even though there is little or no inflamma-tion. In this situation drugs to relieve pain can helpsomeone perform day-to-day activities, sleep com-fortably, and have a reasonable quality of life. Thefirst priority is to control inflammation, and usuallyif this is controlled, pain decreases.

If acetaminophen or an NSAID and adequatecontrol of RA with a DMARD do not control pain,the next step is to use a narcotic analgesic. Usuallyphysicians start with a weak narcotic such as TRA-

MADOL or CODEINE, often combined with aceta-minophen or aspirin. If this does not work, thepatient and physician need to consider the risksand benefits of stronger analgesics such as mor-phine and meperidine. These analgesics are moreaddictive than weaker narcotics, but they canenable patients with severe end-stage disease thathas not responded to other treatment to function.If a patient has severe pain from arthritis, surgeryto replace or fuse a joint is often more helpful thandrugs.

Nonsteroidal anti-inflammatory drugs NSAIDsare part of the symptomatic treatment of most typesof arthritis because they have analgesic and anti-inflammatory effects and are more effective thanpure analgesics such as acetaminophen in relievingthe symptoms of RA. In most patients with RA,NSAIDs alone are not sufficient. Although theyimprove pain, stiffness and swelling, and enhancequality of life, they do not treat the underlyingautoimmune problem nor do they alter the course ofRA. NSAIDs therefore are almost always used incombination with a DMARD. There is no good evi-dence that one NSAID is more effective thananother, but individual patients often find one drugmore helpful than another. The newer COX-2-selective NSAIDs cause fewer peptic ulcers and otherserious GI side effects but are no more effective inrelieving the symptoms of arthritis than the older

drugs. The response to NSAIDs varies amongpatients. Although pain and swelling improve byapproximately 30 percent on average, somepatients have a better response and some noresponse at all. Many patients with RA cannot takean NSAID, either because of allergy or other sideeffects such as decreased renal function. Their ill-ness can be treated effectively using DMARDs, cor-ticosteroids, and analgesics.

Disease-modifying antirheumatic drugs DMARDsare used specifically to modify the long-term courseof RA by decreasing inflammation. There is no stan-dard treatment for RA. Not all patients takeDMARDs, and many patients with similar diseasereceive different drugs.

• Which Patients with RA Should Take a DMARD?

The approach to DMARD therapy has changedcompletely over the last 20 years. Originally theapproach was to treat RA with NSAIDs alone foras long as possible and to reserve DMARDs forpatients with late and severe disease. This wasunderstandable, because the DMARDs availableat that time, GOLD and PENICILLAMINE, oftencaused serious side effects, and there was littleevidence to show that DMARDs changed theoutcome of RA. The modern approach to treat-ing RA is to use one or more DMARDs early inthe course of the illness and to try to control theinflammation. There are at least three com-pelling reasons for this change in approach.

1. There is good evidence showing that the ear-lier RA is treated the easier it is to control.

2. DMARDs, if started early in the illness,improve long-term outcomes in RA.

3. The side effects of DMARDs no longer out-weigh the problems caused by poorly con-trolled RA. Also, there are now many moreDMARDs available so that most patients canfind an effective drug that does not causeside effects.

The presence of rheumatoid nodules, a positiverheumatoid factor, many swollen joints and X-raychanges are markers for severe disease with anaggressive course and are indications that aDMARD should be used early in the illness. Thesedays, most rheumatologists, once they have made


a firm diagnosis of active RA, will recommendtreatment with a DMARD. RA is said to be activewhen joints are warm, swollen, and tender. Inother words, most patients with RA take DMARDs.There are a few exceptions. Rarely patients withRA go into remission on an NSAID alone and thereis little benefit to be gained from adding a DMARD.However, over time most of these patients will flareand need a DMARD. Some patients who have hadRA for 20 years or more have severely deformedjoints but little active inflammation. This is some-times called burned-out RA. In these patients therisks of DMARDs may outweigh the benefits.

• Which DMARD Should Be Used? The choice ofDMARD is based on several factors. The mostimportant are the characteristics of the individualDMARDs, the patient, and the severity of the RA.

DMARDs have different characteristics that affectchoice. Some are more effective than others, somecost more, and their side effects (discussed in Appen-dix II) differ. The antitumor necrosis factor (anti-TNF) drugs such as ETANERCEPT and INFLIXIMAB are atleast as effective as METHOTREXATE, the standard towhich other DMARDs are compared. Also anti-TNFdrugs act rapidly, within weeks, whereas most otherDMARDs act more slowly. However anti-TNF drugsare expensive, costing about $12,000 a year, andincrease the risk of infections. Anti-TNF drugs havealso been on the market for only a few years so theirlong-term side effects are not known.

In clinical trials, SULFASALAZINE, LEFLUNOMIDE,and methotrexate are all about equally effective.Sulfasalazine is widely used in Europe but not inthe United States. No one is sure why this differ-ence in practice occurred. In Europe, the feeling isthat although sulfasalazine causes more minor sideeffects than methotrexate, it is not an immunosup-pressant, it does not cause liver scarring ormethotrexate lung, and alcohol is not prohibited.On the other hand, U.S. physicians feel thatmethotrexate is better tolerated and more effectivethan sulfasalazine, and avoiding alcohol is not agreat hardship. Leflunomide, as is the case withmethotrexate, can also cause liver disease, but ithas the disadvantage that it stays in the body forweeks or months after a patient stops taking it. This

is particularly important for young women plan-ning to have a family, because leflunomide isharmful to the unborn baby. Leflunomide oftencauses loose stools, so if a patient already has diar-rhea, it is not a good choice.

MINOCYCLINE, AURANOFIN, and HYDROXYCHLORO-

QUINE are not as effective as methotrexate but sel-dom cause serious side effects. They are usuallyused to treat milder, early disease. Auranofin oftencauses diarrhea, and many patients cannot take it.

CYCLOSPORINE is expensive and the patient’s kid-ney function must be monitored closely. It is nomore effective than other DMARDs and is usuallyreserved for patients who cannot take otherDMARDs.

Gold injections and d-penicillamine are seldomused because they often cause side effects and havebeen replaced by more effective drugs. A fewpatients respond very well to gold injections, butmost develop side effects.

Rheumatologists vary in their approach toDMARD treatment. Some would use a cheap, rela-tively nontoxic drug such as hydroxychloroquinefirst; others would choose methotrexate or sul-fasalazine as their first-line agent. Except for anti-TNF drugs, it takes at least eight weeks to determineif a patient is responding to a DMARD. If there is apoor or partial response, the options are to increasethe dose of the first DMARD, to switch to anotherDMARD, or to use a combination of DMARDs.

• Which DMARD Combinations Are Used? Mostpatients with RA receive combination therapywith an NSAID, a DMARD, and sometimeslow-dose prednisone, but many also receivemore than one DMARD. Aggressive combina-tions of DMARDs are used to improve controlof RA. Many combinations used in clinicalpractice have not been fully evaluated in clini-cal trials. The risk of increased side effects hasto be weighed against the benefit of improveddisease control.

Hydroxychloroquine is used in combinationwith most other DMARDs. Other combinationsinclude the following:

Methotrexate + cyclosporine Methotrexate + sulfasalazine + hydroxychloroquine


Methotrexate + TNF antagonistsMethotrexate + leflunomideMethotrexate + anakinra

The combination of methotrexate and lefluno-mide has been associated with severe liver diseasein a few patients, and experts are debating thefuture of this combination.

Corticosteroids Corticosteroids are used inthree ways to treat RA.

1. High Doses for Flares Some rheumatologistsbelieve that a single high-dose pulse of an IVcorticosteroid such as methylprednisolone isuseful to control a disease flare. More oftenrapidly tapering oral dose packs or a long-actingintramuscular depot corticosteroid are used tocontrol flares. A typical steroid dose pack startswith 40–60 mg of prednisone a day and thensteps down to 0 mg over a week or two. Peoplewho take a steroid dose pack usually feel muchbetter, and this happens very quickly. Oftenunless something else is done, this is a tempo-rary solution and the symptoms come back atthe end of the steroid treatment. Depot intra-muscular corticosteroid injections have an effectthat lasts about three to four weeks.

2. Local Corticosteroid Injection A corticosteroidinjection into an inflamed joint will oftenimprove symptoms, sometimes for weeks ormonths (see JOINT INJECTION).

3. Low Dose Oral Corticosteroids The place ofsteroids in the treatment of RA has changed. Ini-tially when corticosteroids were first discovered,physicians thought that they were the cure forRA. However, the long-term side effects ofsteroids soon became obvious and there was aswing away from their use. In Europe, mostpatients with RA do not receive steroids, but inthe United States approximately 50 percent ofpatients with RA take low doses of steroids. Thereason for this difference in practice is not clear.In the United States, a low dose of a steroid suchas prednisone 2–10 mg is often started early inthe illness to try to control the disease rapidly.Steroids have the advantage that they workalmost immediately. The plan is usually to taperthe steroids slowly once a DMARD has started towork, but many patients remain on prednisone

2–5 mg a day in addition to a DMARD and anNSAID.

Several studies have shown that there are bene-fits and risks from low-dose steroids. The benefitsare a rapid improvement in symptoms and perhapsa slowing in the rate of joint damage. The majorrisks are an increased rate of osteoporosis andcataracts. Some studies have found an increased riskof infection and even increased mortality associatedwith corticosteroid treatment in RA. These studiesare controversial because patients were not ran-domly allocated to treatment with or withoutsteroids. In clinical practice patients with moresevere RA are treated with steroids, and some physi-cians believe that some of the apparent risks of low-dose steroids are in fact just markers of more severeRA. In spite of the controversy, rheumatologistsagree that if steroids are needed, the lowest effectivedose should be prescribed, and the patient must bemonitored for side effects such as osteoporosis.

Outcome

RA was often considered a relatively benign diseasethat often went into spontaneous remission inmany patients, seldom caused serious side effects,and therefore did not need aggressive treatment inmost patients. The pioneering research of rheuma-tologists such as Drs. Fred Wolfe and Theodore Pin-cus who followed cohorts of patients over a longtime and carefully measured what happened tothem has completely reversed those ideas. Physi-cians now know that severe RA is associated withfunctional disability and increased mortality. Morethan half of the patients with RA who are workingwhen the diagnosis is made will no longer be doingso in 20 years time, and approximately 25 percentwill need joint replacement surgery. Physicians nowalso know that RA is a chronic disease that rarelygoes into spontaneous remission, and there is nodrug that provides a permanent cure. This meansthat most patients need lifelong treatment. Recentevidence showing that good control of RA improveslong-term outcomes and improves survival.

Historically, the treatments for RA have not beenvery effective. In clinical trials a measurement calledthe American College of Rheumatology criteria for20 percent improvement, or ACR20, is used todetermine if a new drug is effective. The ACR20


requires a 20 percent improvement in the number oftender and swollen joints and a 20 percent improve-ment in three of five measurements (the patient’sglobal assessment of disease activity, the physician’sglobal assessment of disease activity, the patient’sassessment of pain, the degree of disability, and theESR or CRP). Most DMARDs achieve an ACR20response in about 50 percent of patients, and thesepatients are considered to have responded to treat-ment. Thus, RA is often not well controlled inpatients who are classified as responding to aDMARD in clinical trials. In clinical practice theresults of treatment are often better than in researchtrials. This is because patients with severe, long-standing disease are more likely to be enrolled inresearch studies. In clinical practice, though, patientswith early disease that responds well to treatmentfor RA are more frequent. Also in clinical practicecombinations of DMARDs are used, whereas in clin-ical trials that seldom happens.

Many experts believe that the modest goal for RAtherapies in clinical trials, a 20 percent improve-ment, is inappropriate and that research shouldfocus on findings treatments that frequently result ina 50 or 70 percent (ACR 50 and ACR 70) response.

rheumatoid nodule Between 25 and 40 percentof patients with RA develop rheumatoid nodules atsome time in the course of the disease. These nod-ules can occur anywhere. However, they are oftenfound just under the skin in areas of the bodywhere there is pressure or friction such as theelbows, hands, and feet. Rarely a patient can haverheumatoid nodules without any arthritis.

Cause

The nodules seem to be caused by a combination ofRA and some local factor such as friction, pressure,or injury that acts as a trigger.

Symptoms

RA nodules can be seen and felt, but they do notusually cause any symptoms. The nodules are usu-ally firm and movable but can be very hard andfixed to the underlying bone. They are not usuallytender. Because they get in the way, they some-times become painful if they are bumped or irri-tated by repeated friction. Most patients have

between one and four nodules varying in sizebetween that of a dime and a quarter. Some pa-tients, though, particularly those taking METHO-

TREXATE, develop many small nodules about thesize of a pea on their fingers.

RA nodules can rarely occur in other sites suchas the lung or heart. They do not usually causesymptoms in the lungs but in the heart can causerhythm abnormalities.

Diagnosis

The appearance and distribution of the nodules andthe fact that the person has RA make the diagnosiseasy and a biopsy is seldom needed. A rheumatoidnodule in the lung shows as a spot on a chest X rayand is difficult to distinguish from cancer or infec-tion without a biopsy. Virtually all patients withrheumatoid nodules have a positive blood test forrheumatoid factor. If this test is negative, the diag-nosis of rheumatoid nodule should be reconsidered.

Several other causes of skin nodules can be mis-taken for a rheumatoid nodule. GOUT, another ill-ness that causes arthritis and subcutaneousnodules, can be misdiagnosed as RA. The nodulesin gout are called tophi and can be mistaken for RAnodules. If a tophus and a rheumatoid nodule can-not be distinguished clinically, a rheumatologistmay insert a needle into the nodule and try to aspi-rate. An RA nodule is fibrous and there is no fluidor tissue in the needle. However, a tophus is madeof uric acid crystals and there may be a white,toothpaste-like substance in the needle. Under amicroscope this white substance is seen to consistof tightly packed uric acid crystals.


RA nodules are associated with more severe RA. Asthe disease responds to treatment the nodules, canbecome smaller or disappear. The response tomethotrexate is a little unusual because, althoughit is an effective drug for controlling RA, patientscan develop new nodules while taking it. Nodulesdo not need any specific treatment. If they ulcerateor become too much of a nuisance, a surgeon canremove them. Unfortunately, they sometimescome back in the same spot. Occasionally rheuma-tologists try to inject nodules with corticosteroids tomake them shrink, and this can be helpful.

234 rheumatoid nodule

rheumatoid vasculitis Rheumatoid arthritis (RA)can cause inflammation of blood vessels (VASCULITIS).This is rare and affects about 1 percent of patients.

Cause

Virtually all patients with RA and vasculitis have apositive rheumatoid factor. Vasculitis occurs inpatients who have had severe disease for a longtime, but why some patients get vasculitis and oth-ers do not is unclear.

Symptoms

The first symptoms of rheumatoid vasculitis areusually a rash or skin ulcers. The rash, caused byvasculitis of small blood vessels, is typical of LEUKO-

CYTOCLASTIC VASCULITIS, with raised purplish spots,usually on the legs, and small hemorrhages aroundthe base of the nails. If larger blood vessels areaffected, this causes leg ulcers. Vasculitis can affectthe blood vessels that supply the peripheral nerves.If this occurs, it can cause mononeuritis multiplex,a syndrome that causes symptoms in isolatednerves in different parts of the body. The nervesthat extend (bend back) the wrist and ankle areoften affected and cause symptoms known as footdrop and wrist drop.

Diagnosis

The diagnosis is often clinical. However, if there is a rash a biopsy is usually performed because it isan easy and noninvasive way of confirming thediagnosis.


The treatment for rheumatoid vasculitis is as forRA, but if vasculitis is progressing in spite of aggres-sive treatment, then high doses of CORTICOSTEROIDS,sometimes with CYCLOPHOSPHAMIDE are used.Rheumatoid vasculitis can usually be controlledwith treatment, but damaged nerves may notrecover.

rheumatologist A physician specializing in thediagnosis and treatment of rheumatic illness.Rheumatologists first train in internal medicineand then subspecialize in rheumatology. Pediatricrheumatologists are trained in pediatrics andrheumatology. Some rheumatologists also act asinternists for their patients and take care of all their

other medical problems, but many treat onlyrheumatic illness. Rheumatologists not only diag-nose and treat all types of arthritis but also condi-tions such as VASCULITIS, where arthritis is not themain problem. Several studies have shown thatpatients with RA treated by a rheumatologistreceive better care and have better outcomes thanthose who are not. Rheumatologists aspirate andinject joints but do not perform surgery. This isdone by orthopedic surgeons who often specializein one area such as hand surgery or hip and kneereplacement.

rotator cuff syndrome See also SHOULDER PAIN fora description of shoulder function and associatedconditions. The rotator cuff consists of a group offour muscles and their tendons that pass outwardfrom the scapula (shoulder blade) to attach to thehead of the humerus (upper arm bone). Theirattachments start from in front of the humeralhead and then pass over the top to just behind sothat they grip the head rather like four fingersreaching out to hold it in place. The central muscle,supraspinatus, helps raise the arm to the side andthe others help rotate the humerus. However, theirmost important physiological role is to control themovement of the ball-like humeral head as it rollsand slides on the shallow saucer-shaped glenoid(part of the shoulder blade) as the arm is moved bythe more powerful outer muscles. The supraspina-tus has to pass beneath the bony tip of the shoul-der (the acromion) and its fibrous extension toattach to the top of the humeral head. Thesupraspinatus is particularly prone to gettingsqueezed or trapped there. Rotator cuff problemsare reasonably common at all ages, but the causediffers at different ages. The term rotator cuff syn-drome includes tendinitis and tears that may bepartial or full thickness.

Cause

In younger patients the rotator cuff may be tornduring overhead sports such as swimming, tennis,volleyball, or throwing. Patients under the age of40 years usually have a partial tear. People takingpart in throwing sports who have even minorinstability are at high risk of getting rotator cufftears. Tendinitis or inflammation of the tendon

rotator cuff syndrome 235

occurs in a similar manner, and in many instancesboth are present. Complete tears are usually theresult of a violent fall with the arm stretched out.

Tendinitis comes on more slowly in the middle-aged patient and is associated with early degenera-tive or wear and tear changes in the tendon. Inaddition, loss of scapulohumeral rhythm becomesmore common and frequently causes impingementon the rotator cuff tendons. Dislocation of theshoulder in a middle-aged patient is usually associ-ated with a complete tendon rupture. In the olderpatient the pain tends to be less severe and of amore gradual onset. Many older patients first com-plain of the loss of range of movement rather thanthe pain. They are very frequently found to havetears without a specific history of injury.

Symptoms

Younger patients have a rapid onset of pain andcan usually relate it to a specific event or activity.There is aching in the shoulder and a sharp painwith lifting activities. The shoulder can usually bemoved through a full range despite the pain withtendinitis or partial tears. With a completesupraspinatus tear the arm cannot be lifted awayfrom the side.

Middle-aged patients have a more gradual onsetof pain and have some limitation of movement,especially reaching behind their backs. They areoften aware of the activities that make it worse.Working above shoulder height is painful and maybecome impossible. Night pain is common whenrolling onto the affected shoulder. As time goes onthere is often some associated weakness and loss ofscapulohumeral rhythm. Elderly patients presentwith similar symptoms but often without any obvi-ous injury or repetitive activity that might havecaused it.

Diagnosis

Rotator cuff tendinitis is suspected from the historyand confirmed by showing that the pain occurs asthe affected tendon is moved under the bony tip ofthe shoulder (acromion). The arm is raised abovethe head and then brought down slowly to theside. There is an arc of movement during whichthere is pain, and then the pain is relieved as thearm gets close to the body again and the swollen

inflamed part of the tendon passes beyond theacromion. With a complete tendon tear the armcannot be lifted away from the side by the patient.However if the examiner starts to lift the arm, thepatient can then continue to raise it using the del-toid muscle. Degenerative changes in the cuff maybe suspected when the head of the humerus is seento ride up underneath the acromion. This suggeststhat the rotator cuff is no longer competent to holdit down in place. The biceps tendon is injured inmany rotator cuff problems and may be tender totouch as it crosses the front of the shoulder.

Ultrasound examination is the best way to con-firm the diagnosis. It can show the swelling of thetendon that occurs in tendinitis as well as the ten-don crumpling up as it sticks when moved underthe acromion. It will also demonstrate tears accu-rately. X rays may show bony spurs below theacromioclavicular joint that can impinge on thesupraspinatus tendon, glenohumeral joint damage,or other bony changes. An MRI scan will show thechanges in the tendon just as well as ultrasound,but the arm cannot be moved during this to showthat the tendon is catching.


A certain amount of rest and alteration of activitiesis necessary to allow healing of tendinitis to takeplace. With mild tendinitis NSAIDs may improvethe pain and settle the inflammation. In moresevere tendinitis a CORTICOSTEROID injection intothe subacromial bursa is very effective in settlingthe inflammation. If there is an ongoing cause thismust be addressed or the condition will simplyrecur. This may be faulty swimming technique inthe young athlete or loss of normal scapular move-ment due to a functional scoliosis (curvature in thespine) in the older patient. Even when the initiat-ing event was traumatic, rehabilitation is oftenrequired to restore normal movement of the shoul-der complex as a whole. Younger patients withinstability need an intensive stabilization program.Sometimes severe instability will require surgicalintervention. Occasionally patients do not respondto these measures, particularly if they are unable toparticipate fully in a rehabilitation program. In thissituation the tip of the acromion can be surgicallyremoved and any inflammatory tissue cleaned

236 rotator cuff syndrome

away from the tendon. Bony spurs can also beremoved from the underside of the acromioclavic-ular joint. This surgery is usually done byARTHROSCOPY these days.

Partial tears of the rotator cuff tendons are ini-tially managed as for tendinitis, except that corti-costeroid injections are best avoided for the firstfour to six weeks to allow healing to take place.Complete tears in active young patients are usuallyrepaired surgically. In older patients rehabilitationis often tried first and surgery used only if the out-come is not good. If the biceps tendon and thesupraspinatus tendon are ruptured, then surgicalrepair should be undertaken since these patientsoften develop a severe destructive form of arthritisat the shoulder if repair is not undertaken.

rubella (German measles) A viral illness commonin childhood. In developed countries such as theUnited States rubella is now rare. Routine vaccina-tion of children against rubella has decreased theincidence of disease. Rubella, and the vaccine usedto prevent it, can cause arthritis and arthralgia.

Cause

The illness is caused by the rubella virus that istransmitted from person to person by contact or bydroplets when an infected person coughs, sneezes,or talks.

Symptoms

After someone has come into contact with aninfected person and becomes infected, the virusincubates for two to three weeks. The first symptomis usually a red, blotchy rash on the face, trunk, andarms. The lymph nodes behind the ear and at theback of the head are often enlarged, and manypatients have headache and a runny nose. Thesymptoms of rubella may be so mild that many

patients do not notice them. Some patients, partic-ularly adults, develop arthritis. The rash and arthri-tis often occur together at the time the patient ismaking antibodies against the virus, suggesting thatthe arthritis is due to antigen-antibody complexes.Rubella arthritis can affect large or small joints, andbecause it is often symmetric it can be mistaken forRA. However, rubella arthritis settles within a fewweeks without any specific treatment. There are afew reports of more persistent arthritis after rubellainfection. Arthralgia and myalgia are common afterrubella vaccination, but arthritis is not. If it doesoccur, the pattern of arthritis is the same as thatoccurring after natural rubella infection.

Diagnosis

Blood tests for antibodies against rubella are ele-vated in infected patients. If someone has recentlybeen infected the IgM antibody is elevated, but ifonly the IgG antibody is elevated it means that theperson was immunized against rubella or wasinfected in the past. The rubella virus has been iso-lated from inflamed joints in patients with arthritis,but this test is seldom performed.


There is no specific treatment for rubella or rubellaarthritis. NSAIDs will relieve arthritis symptoms,which usually last only a few weeks and resolvespontaneously. The most serious complications ofrubella are birth abnormalities in unborn babies. Ifa pregnant woman who is not immune to the dis-ease becomes infected with rubella, the chance thatshe will have a baby with abnormalities of theheart, brain, or other organs is high. This was theimpetus for recommending routine vaccination forall children. As a result of widespread vaccination,rubella is now very uncommon in the UnitedStates.

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S

SAPHO syndrome (sternoclavicular hyperostosis,acne arthritis) Synovitis, acne, pustules, hyperos-tosis, and osteitis comprise the SAPHO syndrome.This is a rare illness that affects young adults whohave arthritis associated with acne or skin condi-tions that cause pustules.

Cause

The cause of SAPHO syndrome is not known.Some rheumatologists believe that it is a type ofREACTIVE ARTHRITIS triggered by acne or acne-likeskin problems; others believe that it is an infectivearthritis caused by an unidentified organism. Mostattempts to culture an organism have failed. In afew cases, though, Propionibacterium acnes, theorganism that causes acne, has been isolated. Insome studies there was a small increase in the fre-quency of the HLA-B27 tissue type, suggesting agenetic component. SAPHO syndrome can occur inassociation with pustular PSORIASIS and INFLAMMA-

TORY BOWEL DISEASE.

Symptoms

Arthritis is usually asymmetrical and affects largejoints, a pattern characteristic of a reactive arthritis.Acne or some other skin condition that forms pus-tules is usually present, but the bone lesions canantedate the skin problems. If acne is the underly-ing skin condition, there are many large and deeppustules that cause painful lumps. Hyperostosis,thickening of a bone, often affects the collarbone(clavicle) and can resemble an infection (osteitis).Patients often develop pustules on their palms andsoles.

Diagnosis

The diagnosis is clinical. X rays may show hyperos-tosis or osteitis of the clavicle or another affectedbone. The X ray appearance of the bones often sug-

gests the diagnosis of OSTEOMYELITIS, and biopsiesmay have to be done to exclude this. Osteitis canaffect the clavicle, pelvis, ribs, jaw, and other bones.


Part of the treatment is to control the pustular skincondition, often with antibiotic ointments ortablets, but this seldom controls musculoskeletalsymptoms. NONSTERIODAL ANTI-INFLAMMATORY DRUGS

(NSAIDs), CORTICOSTEROIDS, SULFASALAZINE, COLCHI-

CINE, METHOTREXATE, and INFLIXIMAB have been usedto control the arthritis.

sarcoidosis An illness that causes inflammationin many organ systems, primarily the lungs.Arthralgia or arthritis occurs in approximately 25percent of patients. Sarcoidosis is more common inAfrican Americans than in Caucasians and usuallyaffects young adults, most often women.

Cause

The cause of sarcoidosis is not known. The similar-ity of the illness to tuberculosis and the observationthat sarcoidosis has been transmitted by organtransplantation suggest an infection, but manyresearchers have tried unsuccessfully to identify aninfectious cause. Characteristically sarcoidosiscauses granulomas in tissue. Granulomas, visibleunder a microscope, are clusters of inflammatorycells arranged in a pattern. Tuberculosis also causesgranulomas, but these have areas of dead tissue(caseation), whereas those in sarcoidosis are do notcaseate.

Symptoms

The symptoms of sarcoidosis depend on the organsinvolved. The lungs are affected in 90 percent ofpatients. The first symptom is often ERYTHEMA

NODOSUM and enlargement of lymph nodes at the

239

root of both lungs (bilateral hilar lymphadenopa-thy). The enlarged lymph nodes do not causesymptoms and may be discovered only incidentallyif a chest X ray is performed for some other reason.In most patients with enlarged lymph nodes the ill-ness resolves. Some do progress and developinflammation and scarring of the lung tissue thatcauses coughing and shortness of breath. Later inthe disease the lymph nodes in the lung are nolonger enlarged, but the scarring persists.

Sarcoidosis can involve almost any other organ.Rash; eye inflammation (see EYE PROBLEMS);enlarged parotid glands (the salivary glands in thecheeks); and heart, liver, nerve, and brain involve-ment can occur. Arthritis in early sarcoidosis occursat the same time as erythema nodosum and oftenaffects the ankles or knees. The constellation oferythema nodosum, bilateral hilar lymphadenopa-thy, and ankle arthritis is called Lofgren’s syn-drome. There is often swelling, warmth, andtenderness around the joint (periarthritis) as wellas directly over it. The arthritis associated withearly sarcoidosis usually resolves over severalmonths. A few patients develop chronic arthritis,which usually does not damage joints or cartilage.

Sarcoidosis can cause bone cysts, most often inthe small bones of the fingers in an area affected byskin rash. Muscle involvement is common, butmost patients do not have symptoms. A few candevelop painful nodular swellings in muscle orweakness with elevated levels of muscle enzymes,resembling polymyositis (see DERMATOMYOSITIS AND

POLYMYOSITIS).

Diagnosis

The diagnosis of sarcoidosis is usually suspected clin-ically and confirmed by biopsy of affected tissue thatshows granulomas without caseation. A biopsy isperformed not only to confirm the diagnosis of sar-coidosis but also to exclude infection and malig-nancy. Some physicians will accept a clinicaldiagnosis in patients with bilateral hilar lym-phadenopathy and erythema nodosum without abiopsy because the pattern is so classical. A blood testthat measures levels of angiotensin-convertingenzyme (ACE) is often elevated in patients withactive sarcoidosis, but it is not sensitive or specificenough to make or exclude the diagnosis.


Many patients with sarcoidosis do not need anyspecific treatment because the disease remits. Inpatients with eye, lung, joint, or other organinvolvement, CORTICOSTEROIDS are the first line oftreatment. Many other drugs are used to treatpatients who do not respond or who need highdoses of corticosteroids to control their disease.METHOTREXATE is one such drug, but patients withsarcoidosis may be more sensitive to side effectsand be more likely to develop hepatitis. Otherdrugs used to treat sarcoidosis are AZATHIOPRINE,

HYDROXYCHLOROQUINE, and CYCLOSPORINE. NSAIDsare prescribed to control pain, but there is no spe-cific treatment for arthritis associated with sar-coidosis. The treatment is usually determined bythe effects of the disease on other organs.

scleroderma (systemic sclerosis, progressive sys-temic sclerosis) A chronic illness characterized byincreased fibrous tissue in the skin and internalorgans, damage to small blood vessels, and the pres-ence of autoantibodies. Scleroderma is rare. Thereare approximately 10 new cases per million peopleper year. Women get it three times more often thanmen, and people aged 30–50 years are most oftenaffected. Scleroderma is divided into two major sub-groups, diffuse and limited scleroderma, dependingon how much skin is involved. The two groups havedifferent clinical symptoms and treatment.

Diffuse scleroderma (diffuse systemic sclerosis)

This involves rapid onset of skin changes that affectthe hands, face, and central parts of the body suchas the trunk, back, and abdomen within a year ofdeveloping RAYNAUD’S PHENOMENON. Organs such asthe lungs, GI tract, and kidneys are often affected.Very rarely scleroderma can affect the internalorgans and not the skin. This is called scleroderma

sine scleroderma. Limited scleroderma (limited cutaneous sys-

temic sclerosis, CREST syndrome) This involvesgradual skin tightening limited to the hands, fore-arms, face, and feet that develops after a patienthas had Raynaud’s phenomenon for many years.Apart from PULMONARY HYPERTENSION internalorgan involvement is much less common than indiffuse scleroderma.

240 scleroderma

In addition, there are rare variants of sclero-derma such as morphea or linear scleroderma thataffect only the skin and underlying tissue. Mor-phea consists of reddish patches of scleroderma-like skin scattered over the body. If it affects thewhole body it is called generalized morphea. Linearscleroderma is usually limited to one area andlooks like a scar or tight band of skin. It was calledcoup de sabre when it affected the face because itlooked as if the face had been scarred by a blowfrom a sword.

Cause

The cause of scleroderma is not known. Differentmechanisms such as increased production offibrous tissue, activation of the immune system,and damage to small blood vessels play a role. Whythey become activated, though, is not known.

There is some evidence suggesting an autoim-mune cause. Most patients with scleroderma havea positive blood test for autoantibodies such asantinuclear antibodies (ANA) (see Appendix II).Early in the disease there is some infiltration oflymphocytes in affected organs. Considering theamount of tissue damage, the amount of immuno-logical activation is unimpressive. Many trialsattempting to treat scleroderma with immunosup-pressive drugs have failed. This suggests thatalthough an early immunological trigger may beimportant, once the disease is established, otherfactors take over. The usual response to an injury isa rapid movement of inflammatory cells to theinjured site, resulting in the release of cytokinesand growth factors that activate fibroblasts thatform scar tissue and then become inactive. This isprobably the same process that is active in sclero-derma, but for reasons that are not understood, thefibroblasts remain active and continue to producefibrous tissue.

The key abnormality in scleroderma is thatfibroblasts, cells that produce fibrous tissue, areactivated so that normal tissue is replaced byfibrous tissue. Fibroblasts are part of normal con-nective tissue. They are usually inactive but canproduce exuberant amounts of fibrous tissue whenstimulated. Cytokines such as interleukin-1 andgrowth factors such as transforming growth factor-b(TGF-b) and platelet-derived growth factor (PDGF)

can activate fibroblasts. Why this occurs muchmore exuberantly in scleroderma than in otherinflammatory diseases is not clear. Interestingly,fibroblasts obtained from skin biopsies of patientswith scleroderma maintain their ability to produceexcessive amounts of fibrous tissue when culturedin the laboratory. These fibroblasts have no contactwith the patient’s immune system and thereforemust somehow have been reprogrammed to pro-duce excessive amounts of fibrous tissue indepen-dent of immune regulation. This observationsuggests that in scleroderma perhaps the immunesystem has long-lasting effects on fibroblasts. Theimplication is that in established scleroderma drugsthat decrease fibrosis may be more likely to helpthan drugs aimed at the immune system.

Symptoms—Diffuse Scleroderma

Skin Virtually all patients with sclerodermahave Raynaud’s phenomenon. It is important toremember that this symptom is common, even inhealthy people, and does not imply a diagnosis ofscleroderma. In diffuse scleroderma skin changesusually follow soon after the onset of Raynaud’s. Inearly disease the skin may be more puffy and ede-matous than fibrotic, but it soon progresses tobecome thick and inelastic. As people age the skinloses tone and becomes baggier so that lifting a pinchof skin from virtually anywhere on the body is easy.In patients with scleroderma the skin becomes tightand is difficult to lift by pinching gently. In patientswith severe disease the skin is totally immobile andis called hidebound. In clinical trials the severity ofskin involvement in patients with diffuse sclero-derma is scored by grading how difficult it is to pinchthe skin at several defined sites. This is called theRodnan score, after Dr. G. P. Rodnan.

Scleroderma can affect skin in virtually any partof the body but most often the hands, arms, face,and trunk. The skin and soft tissues of the handscan become so tight that the fingers can hardlymove. Small ulcers can develop at the tips of thefingers. Tight skin on the face can make someonelook younger because his or her wrinkles disap-pear. If the skin around the mouth is tight, it can bedifficult to open widely. Over several years the skinmay improve a little, but most of the changes arepermanent. This spontaneous improvement in skin

scleroderma 241

tightness is a feature of scleroderma that has madeit difficult for researchers to assess the true effect ofdrugs.

Joints, tendons, and muscles Arthralgia iscommon but arthritis is rare. Fibrosis can affecttendons and cause a symptom called a friction rub.This is a squeaky, rasping, scratchy noise thatoccurs when the tendon moves. Sometimes it isaudible without a stethoscope. The patient canoften feel the friction rub by placing a hand overthe tendon when it is moving. Fibrosis of tendons,skin, and the soft tissue underneath the skin canlimit or sometimes prevent movement at a joint(contractures). Patients often lose muscle bulk andbecome weak because of poor mobility and decon-ditioning rather than the disease itself. However,inflammation of muscle causing weakness of thethighs and shoulders can also occur. This proximalmyositis can be difficult to diagnose unless muscleenzymes are checked.

Gastrointestinal system Scleroderma can occurin any part of the gastrointestinal tract but mostoften affects the esophagus. Fibrous tissue in theesophagus impairs its ability to coordinate the mus-cle contraction and relaxation that is needed toswallow efficiently. Difficulty swallowing, reflux ofacid and food from the stomach into the mouth,and heartburn are common symptoms of gastro-esophageal reflux disease (GERD). This affectsmore than 80 percent of patients. Poor motility cancause reflux esophagitis (inflammation of the lowerpart of the esophagus), and this can lead to nar-rowing (stricture) that further impairs swallowing.

Scleroderma can affect the stomach and smallintestine, causing decreased motility that results indelayed emptying. This causes symptoms such asbloating, nausea, vomiting, loss of weight, abdom-inal pain, and constipation. The motility of thebowel can be slowed so much that it leads to symp-toms such as severe pain, abdominal swelling, andvomiting, a clinical situation that resemblesobstruction of the bowel and is called pseudobstruc-

tion. Paradoxically, partial obstruction of the bowelcan cause diarrhea. The decreased emptying ofloops of bowel allows bacteria to flourish, and thisresults in diarrhea. This is called the blind loop syn-

drome and can lead to malabsorption of essentialnutrients, particularly fat and the fat-soluble vita-

mins A, D, E, and K. Severe constipation can alsooccur and sometimes paradoxically cause diarrhea.The bowel becomes semiobstructed with hardstool, and the only stool that can squeeze past isliquid. This is called overflow diarrhea.

Scleroderma can sometime cause areas of weak-ness in the wall of the bowel, and small pocketsform. These fill with air and gas produced by bac-teria which show as many small air pockets on anX ray. This is called pneumatosis intestinalis.

Respiratory system The lungs are ofteninvolved in systemic scleroderma. Inflammation inthe lungs leads to formation of scar tissue, calledinterstitial lung disease. This can be mild and causeno symptoms or more severe, causing shortness ofbreath and cough. Shortness of breath, particularlywhen the person performs moderately strenuousactivities, is usually much more of a problem thancoughing. If a lot of fibrosis is in the lungs it maylead to infections that worsen the scarring. Severelung disease can lead to failure of the right side ofthe heart, which pumps blood to the lungs. It doesso by elevating the pressure in the pulmonaryarteries, a condition called secondary pulmonaryhypertension.

Renal disease One of the most serious compli-cations is scleroderma renal crisis. This usuallyoccurs early in the illness in patients with severediffuse scleroderma and consists of sudden onset ofhigh blood pressure and renal failure. The cause isnot known, and if a biopsy is performed, the kid-ney tissue itself is relatively normal. In contrastwith SLE, there is little inflammation and nodeposits of immunoglobulins clogging up the filtra-tion mechanism. In scleroderma renal crisis thesmall arteries of the kidneys are narrowed and donot carry enough blood through the kidneys.Patients with scleroderma renal crisis may not havesymptoms until kidney function is severely affectedand causes symptoms such as nausea, vomiting,fatigue, and anemia.

Heart Scleroderma often affects the heart,but this seldom causes symptoms. Occasionallyfibrosis of the heart can cause heart failure or anabnormal rhythm. Inflammation of heart muscle(myocarditis) and pericarditis can occur and seemto be more common in patients who also havemyositis.

242 scleroderma

Symptoms—Limited Scleroderma

Many patients with limited scleroderma have thefive classical symptoms that comprise the CRESTsyndrome: calcinosis, Raynaud’s phenomenon,esophageal dysmotility, sclerodactyly, and telang-iectasia. The term CREST syndrome is derived fromthe first letter of each of these symptoms, but it isalso often used to describe patients with limitedscleroderma who have only three or four of thesymptoms of CREST. Some physicians use theterms CREST syndrome and limited sclerodermainterchangeably.

Skin Virtually all patients with limited sclero-derma have Raynaud’s phenomenon, and this isoften present for many years before skin changesdevelop. Severe Raynaud’s leading to painful,poorly healing ulcers on the tips of the fingers,called digital ulcers, is more common in patientswith limited scleroderma than in those with diffusescleroderma. Digital ulcers are very painful andheal over several months. The skin changes of lim-ited scleroderma often affect only the hands andface but can be severe, leading to tight, shiny,poorly mobile fingers, or very subtle with just a lit-tle skin thickening. Tightness of the skin on the fin-gers is called sclerodactyly. Many patients also havetelangiectasia. These are small red spots, about thesize of a freckle, that consist of a network of bloodvessels. Calcinosis (deposits of calcium in the skinand soft tissues) is less common.

Respiratory system In addition to the mildnessof the skin and internal organ involvement, amajor feature that characterizes limited sclero-derma and differentiates it from diffuse disease ispulmonary hypertension. Patients with limitedscleroderma have a predisposition to develop pul-monary hypertension that is virtually identical toprimary pulmonary hypertension. Patients withdiffuse scleroderma can also develop pulmonaryhypertension, but this is usually milder and due tofibrosis of the lungs. In patients with limited scle-roderma and pulmonary hypertension, the lungsthemselves are fairly normal and the problem is inthe small blood vessels of the lungs. The walls ofthese small blood vessels become thick and fibrotic,and the channel through which blood can flow isnarrowed. Pulmonary hypertension develops inabout 5 percent of patients and causes symptoms of

fatigue, shortness of breath, fainting, and heartfailure.

Gastrointestinal system Limited sclerodermausually affects only the esophagus and causes thesame symptoms as diffuse scleroderma.

Diagnosis

The diagnosis of diffuse and limited scleroderma isclinical and depends on an astute clinician noticingthe typical skin changes. These can be very subtle,particularly in patients with limited disease. On theother hand, diffuse scleroderma is usually easy todiagnose because the skin changes are severe andoften progress rapidly. A skin biopsy is sometimesperformed but is seldom needed to diagnose sclero-derma. Other symptoms can be helpful in makingthe diagnosis. For example, virtually all patientswith scleroderma also have Raynaud’s phenome-non, and many have symptoms of GERD.

Blood tests are not particularly helpful; there isno specific blood test to diagnose scleroderma.Almost all patients with scleroderma have a posi-tive ANA test, a test usually thought of for SLE. Thepattern of the ANA test can give a clue to the diag-nosis. A nucleolar pattern is more common in dif-fuse scleroderma and a centromere pattern inlimited scleroderma. These patterns, however, arenot diagnostic for scleroderma. Blood tests can behelpful in following a patient with Raynaud’s phe-nomenon and no other features of autoimmunedisease. Someone who has a positive ANA test andRaynaud’s phenomenon would be followed moreclosely than someone with a negative ANA.

Tests for other autoantibodies are not specific orsensitive enough to make them helpful for mostpatients in clinical practice but are sometimes per-formed. An autoantibody, Scl-70, is found in about50 percent of patients with diffuse scleroderma,andanother, anticentromere antibody, in about 70 per-cent of patients with limited scleroderma. Anotherautoantibody, Jo-1, is found in approximately 20percent of patients and is associated with a higherrisk of developing lung disease.

Blood tests are helpful in diagnosing complica-tions of scleroderma. Anemia and a rise in theserum creatinine concentration are typical of scle-roderma renal crisis, and elevated creatine kinaselevels are typical of myositis.

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Other tests are often performed to diagnosecomplications of scleroderma. For example, if apatient has trouble swallowing, a barium swallowor an upper GI endoscopy will provide informationabout the function of the esophagus. X rays canhelp diagnose lung disease in patients with diffusescleroderma, but telling from X rays if the lung dis-ease is currently active or not is difficult. A high-resolution CT of the chest can be helpful in thissituation. Active inflammation shows up as a uni-form, smooth opaque area on the chest X ray,called a ground glass appearance. Old scarred areasshow up as streaky dense opacities. The CT scancan be very important in helping physicians decidehow to treat scleroderma lung disease. If there isactive inflammation, cyclophosphamide is the rec-ommended treatment. If there is irreversible oldscarring, the drug may cause more harm thangood. Many physicians are uncomfortable relyingentirely on the results of the CT scan to make thisdecision and order a bronchoscopy. This involvespassing a thin fiberoptic instrument through themouth or nose, between the vocal cords and downinto the lungs and using it to flush sterile salineinto a segment of lung and aspirate the fluid. Thisprocess is called bronchoalveolar lavage or BAL. Ifthe BAL fluid contains many inflammatory cellssuch as neutrophils, it is a good indicator that thereis active inflammation in the lung.

If pulmonary hypertension is suspected, thediagnosis can be made and the pressure in the pul-monary artery estimated by ultrasound. In somepatients the pressure is measured more accuratelyby placing a catheter in the right side of the heartby threading it up through a large vein in the leg.The chest X ray may show an enlarged heart, andin patients with CREST and pulmonary hyperten-sion the lungs are normal. In patients with diffusescleroderma and secondary pulmonary hyperten-sion the lungs are abnormal and the chest X rayshows a lot of scarring. A lung biopsy is usuallyavoided because there is a risk of bleeding.


There is no specific treatment for scleroderma. Thisis not because of lack of research effort. Virtuallyevery drug used to treat other rheumatologicalconditions has been tried. Clinical trials are difficult

to perform and interpret because scleroderma israre, varies in severity and outcome, and fewpatients are willing to take a placebo (see CLINICAL

TRIAL). Before researchers realized that the skinchanges of scleroderma often improved sponta-neously over time, many drugs tested in open-labelstudies acquired an undeserved reputation forbeing effective. Another important consideration isthat most clinical trials have focused on measuringskin changes. The effects of scleroderma on theskin are cosmetically important and, if severe, canaffect function, particularly of the hands, but donot shorten life. Thus many trials measured an out-come that was mainly of cosmetic significance. Inshort, many of the early studies on sclerodermawere not helpful.

Skin symptoms The treatment of Raynaud’sphenomenon is discussed under that heading. D-

PENICILLAMINE is a drug that was regarded, on thebasis of open-label studies, as an effective treatmentfor the skin changes of scleroderma. A placebo-controlled study compared two doses, 1,000 mg aday (an average therapeutic dose) and 125 mgevery other day (a dose much lower than the oneusually prescribed). The reason for comparing atherapeutic dose with one that was thought to beineffective was that it avoided randomizing somepatients to placebo. Therefore all patients receivedpenicillamine, but some received a dose that was sosmall it was virtually a placebo. The study found lit-tle difference between the two doses. Many rheu-matologists interpret these results as showing thatpenicillamine is not effective, but others interpretthem as supporting low-dose penicillamine as atreatment for scleroderma. The use of penicillaminedecreased after this study was published.

METHOTREXATE was effective in two uncontrolledstudies. However, a double-blind, placebo-controlledstudy of 71 patients with diffuse scleroderma pub-lished by Dr. J. E. Pope and her colleagues in 2001reported no statistically significant effect. There was a trend favoring methotrexate above placebo,but the benefits of methotrexate, if any, appear tobe small.

Relaxin is a chemical produced in pregnancythat decreases the production of collagen, allowingskin and soft tissues to stretch and accommodatethe growth and delivery of a baby. Preliminary

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studies with relaxin in scleroderma were promis-ing, but this was not borne out in later studies.

CORTICOSTEROIDS can improve the swelling andedema that are part of early scleroderma. Becausescleroderma renal crisis occurs more often inpatients taking corticosteroids, though they areusually avoided if possible.

Several other treatments have been tried withmixed results. These include PHOTOPHERESIS, COL-

CHICINE, gamma interferon, and CYCLOSPORINE. Notreatment has been convincingly effective. Cyclo-sporine often causes renal side effects such asdecreased renal function and high blood pressure,problems that are already common in patients withscleroderma, and is seldom used outside of clinicaltrials. A small preliminary study found that patientsresponded to MINOCYCLINE, and larger studies areunderway. Studies with TNF antagonists and BONE

MARROW TRANSPLANTATION are also underway. Respiratory symptoms Both major causes of

lung disease in scleroderma, interstitial fibrosis andpulmonary hypertension, can be treated. If intersti-tial lung disease causes lung fibrosis, this is irre-versible. If there is inflammation, aggressiveimmunosuppression can stabilize lung function andimprove the prognosis. CYCLOPHOSPHAMIDE has sta-bilized lung function in several small studies, and alarge study is being performed to determine if thebenefits outweigh the side effects of treatment.

Pulmonary hypertension is treated with vasodila-tors such as prostacyclin and calcium channel antag-onists or with an endothelin receptor antagonist.

Gastrointestinal symptoms GERD is managedwith general measures such as elevating the headof the bed, not eating or drinking for several hoursbefore bedtime, and eating small meals, but mostpatients also require medications. Proton pumpinhibitors such as OMEPRAZOLE, LANSOPRAZOLE, andRABEPRAZOLE decrease acid production in the stom-ach and improve reflux symptoms. Metoclo-pramide (trade name: Reglan) can improvesymptoms by decreasing spasm in the lower esoph-agus. CISAPRIDE (trade name: Propulsid) stimulatesesophageal motility, but a serious, sometimes fatalheart rhythm problem called torsade de pointes hasseverely restricted its use. If there is a stricture inthe esophagus, the patients may require eso-phageal dilation.

Agents that increase the motility of the bowelsuch as cisapride, erythromycin and ocreotideimprove symptoms of pseudoobstruction. Thecombination of erythromycin and cisapride mustbe avoided because the risk of torsade de pointes isincreased. If there is a blind-loop syndrome, rotat-ing courses of different antibiotics such as amoxi-cillin, tetracycline, and ciprofloxacin decreasebacterial overgrowth and improve symptoms. Insome patients with severe malabsorption, nutritionis provided intravenously. This is called total par-enteral nutrition or TPN.

Constipation can be very difficult to treat. It usu-ally requires a special diet, drugs to increase themotility of the bowel, and laxatives.

Renal symptoms Scleroderma renal crisis is aserious complication and can lead to permanentrenal failure requiring dialysis or lead to death.Blood pressure should be monitored carefully in allpatients with diffuse scleroderma, and hyperten-sion should be treated with an angiotensin-converting enzyme (ACE) inhibitor, a class of drugthat has improved the outcome substantially. Accel-erated hypertension that is not controlled can leadto renal failure. If this happens, dialysis is oftenneeded, but sometimes if blood pressure is con-trolled, renal function recovers slowly over severalmonths and some patients can come off dialysis.

The overall prognosis of scleroderma dependson the severity of organ involvement and trackswith the severity of skin involvement. Severe pul-monary hypertension, scleroderma renal crisis, andrenal or lung disease have a poor prognosis.

septic arthritis See INFECTIVE ARTHRITIS.

septic bursitis Bursas, or small sacs lined withsynovial cells close to joints and tendons, canbecome inflamed as part of most types of inflam-matory arthritis but can also become infected withbacteria. Usually bacteria gain access to the bursathrough superficial skin abrasions that can occur as part of usual day-to-day activities. The olecranon (over the elbow) and the prepatellar (infront of the kneecap) bursas become infected mostfrequently.

The symptoms of warmth, redness, exquisitetenderness, and decreased range of motion of the

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joint are similar to those that occur with otherinflammatory causes of olecranon bursitis such asgout or repetitive trauma. Usually septic bursitiscauses more severe symptoms, but infective andinflammatory bursitis can be difficult to distinguish.

Any activity that causes friction or repeatedminor trauma to a bursa can cause bursitis andincreases the chance of inflammation and infec-tion. For example, patients in nursing homes whocannot walk often develop olecranon bursitisbecause they rest their weight on their elbows.Occupations such as carpet laying or roofing canalso cause prepatellar bursitis. If bacteria gainaccess to the inflamed bursa, this can turn into aseptic bursitis.

Because of the difficulty in knowing whether thebursa is infected, a needle is often inserted into thebursa, fluid is aspirated and then sent to the labora-tory for culture. Infective bursitis is most oftencaused by Staphylococcus aureus infection. The infec-tion often responds to a course of oral antibioticsthat cover this organism. If the clinical response isdelayed, intravenous antibiotics, repeated aspira-tion of the bursa, or surgical drainage of the pusmay be needed. (See also BURSITIS.)

shingles See HERPES ZOSTER.

shoulder pain The shoulder joint is a very com-plex joint with numerous potential causes of pain.The design of the joint is such as to allow the great-est possible range of movement of the arm. Thereis a trade-off between stability and range of move-ment, and the shoulder joint is therefore inher-ently one of the least stable joints in the body.Strictly speaking, the shoulder joint should bereferred to as complex since there are in fact fourjoints that all move together to allow normalshoulder movement.

The glenohumeral joint This joint existsbetween the upper arm bone, the humerus, and ashallow saucer-shaped flattening of the shoulderblade or scapula. This is what is commonly calledthe shoulder joint. The different joints will be re-ferred to by their correct anatomical names toavoid confusion. Although sometimes called a ball-and-socket joint, the scapular saucer (glenoid) isfar too flat to be a socket and allows the head of the

humerus to slide across the surface to a certainextent during normal movement. The joint has acircular cartilage called the labrum that increasesthe saucer shape of the rather flat glenoid. Thejoint capsule that attaches to both bones, sur-rounding the joint and helping hold it together, hasto be quite loose to allow the huge range of move-ment possible at the shoulder. Without muscles tohold them together the humerus would thereforesimply fall away from the scapula.

The scapula To enable a greater range ofmovement than would exist at the glenohumeraljoint itself, the scapula also moves. It does this bysliding and rotating against the back of the chestwall under the guidance of muscles that attacheither to the spine or, on the other side, thehumerus or upper arm bone. This is not a true jointbut functions as one.

The acromioclavicular joint The scapula isjoined to the main skeleton by the clavicle. Thepowerful upper trapezius muscle (felt as a curvewhen running your hand down from neck toshoulder) comes from the spine in the neck andattaches along the upper surface of the clavicle andthe spine of the clavicle. The upper trapezius holdsthem up in the manner of one-half of a suspensionbridge. The joint between the scapula and clavicleis called the acromioclavicular joint and can be feltas a hard lump and groove on top of the shoulder.The acromioclavicular joint does not move verymuch and has short, powerful ligaments crossing itto give good stability.

The sternoclavicular joint The clavicle (oftencalled the collarbone) attaches to the skeleton ofthe chest at the sternoclavicular joint that lies justunderneath the chin if this is pushed down againstthe chest wall. The sternoclavicular joint has torotate quite a bit to allow normal shoulder move-ments to take place. It too has powerful ligamentsholding it in place.

While the shape of the bony glenohumeraljoint, the ring of cartilage (labrum) in it, and thesurrounding joint capsule and ligaments do providesupport and limit the range of movement of thehumerus, muscular support is more important atthis joint than at any other in the body. The mus-cle acting on the glenohumeral joint can be seen asbeing in two layers.

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1. An inner ring made up of relatively smallermuscles hold the head of the humerus in place,rotate it, and initiate or counterbalance move-ments produced primarily by larger muscles.These are known collectively as the rotator cuffmuscles.

2. The outer ring comprises a number of larger andlonger muscles known as prime movers. Con-traction of these muscles produces powerfulmovement of the arm. They often work in com-bination to produce the full range of movementand rely on the rotator cuff muscles to controlmovement of the head of the humerus.

Cause

Clearly there are many potential causes of shoulderpain. Many of these can be diagnosed by a skilledphysician on examination alone. However, shoul-der pain can sometimes be very difficult to diag-nose. MRI scans, ultrasound examinations, X rays,and ARTHROSCOPY may all be helpful. The maincauses of pain are discussed below.

Rotator cuff syndrome ROTATOR CUFF SYNDROME

is the most common disorder seen, especially inthose of middle age or the elderly. While most com-monly seen as an isolated condition, it not infre-quently complicates other forms of arthritis,especially RHEUMATOID ARTHRITIS. It is discussedelsewhere.

Calcific tendinitis Calcific tendinitis causesquite different symptoms than rotator cuff syn-drome. Although some patients may have hadintermittent catching at the shoulder for sometime, calcific tendinitis typically presents with sud-den severe shoulder pain restricting all movementat the shoulder. This condition usually affects peo-ple aged 40 to 60 years, and the supraspinatus ten-don is most frequently involved. An X ray willshow calcified tissue in the area of the rotator cufftendons. Note that people may have calcificationhere without any symptoms, in which case it is bestleft alone. Ultrasound or MRI scans may showdegeneration in the affected tendons. Blood testsare typically normal. Painkillers, NSAIDs, ice, andresting the arm in a sling may all help relieve painin the early stages. Corticosteroid injections mayhelp if there is an associated rotator cuff syndrome.Exercises to improve the rotator cuff function

should be started once the pain has settled. Surgi-cal removal of the calcium and repair of the rotatorcuff tendons is occasionally required.

Biceps tendinitis The biceps muscle has twotendons at the shoulder level. One of these (thelong head of the biceps) passes through the gleno-humeral joint over the head of the humerus. This,along with the rotator cuff muscles, is very impor-tant in controlling the movement of the head of thehumerus. For this reason bicipital tendinitis usuallyoccurs when there is an injury to other parts of theshoulder complex or instability of the glenohumeraljoint. There are therefore usually other abnormali-ties as well. Most commonly this is rotator cuffimpingement. Athletes performing overhead activi-ties are particularly likely to develop this combina-tion of injuries. Tendinitis of the long head of thebiceps can occur by itself, for example as an overuseinjury in weight lifters. Pain is felt in front of theshoulder, and the tender, swollen tendon can oftenbe felt as it crosses the front of the head of thehumerus in its groove. X rays may show abnormal-ities of the groove but are seldom done these days.Ultrasound is excellent for showing the swellingaround the tendon as well as the small tears in itthat often set off the inflammation. MRI orARTHROSCOPY are used to examine that part of thetendon lying inside the joint. Rest, NSAIDs, ice, andphysical modalities such as ultrasound may helpsettle tendinitis early on. A CORTICOSTEROID injectionalongside but not into the tendon is very helpful inresistant or chronic cases. Occasionally surgery isrequired, usually combined with other proceduressuch as repair of the rotator cuff. A gradual returnto activities with appropriate exercises will preventrecurrence. The most important aspect of treatingbicipital tendinitis is to diagnose any other disordersthat may have lead to it and address them. The mostcommon are rotator cuff problems and instability.

Biceps tendon rupture Complete rupture ofthe long head of the biceps occurs occasionally. Inthis case the muscle will bunch up a few inchesbelow the shoulder, especially when the elbow isbent up (that is, when the biceps is contracted).There may be bruising associated with such a rup-ture as well.

SLAP lesions This term is used to describetears in the labrum of the glenohumeral joint. This

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circular cartilage is particularly susceptible to tearsin active young people with minor instability of theglenohumeral joint. SLAP stands for superiorlabrum anterior posterior lesion, describing thecommon location of these injuries. They may occuras a result of repeated minor trauma or a singleepisode of trauma, as when the humerus is drivenup against the glenoid. MRI or arthroscopy isrequired to determine how severe the lesion issince treatment differs for the four grades of injury.Pain relief, changes in activity, and rehabilitationmay be enough but, especially in grades III and IV,surgical treatment may be required.

Glenohumeral arthritis Arthritis of the gleno-humeral joint occurs in a various conditions. Long-standing rheumatoid arthritis very frequentlycauses some secondary OSTEOARTHRITIS here. GOUT

occasionally occurs, and hydroxyapatite-relatedarthritis particularly affects the glenohumeral joint(see MILWAUKEE SHOULDER). INFECTIVE ARTHRITIS, NEU-

ROPATHIC ARTHRITIS, and AVASCULAR NECROSIS of thehumeral head are all rare but important causes ofshoulder pain.

Subacromial bursitis The head of thehumerus and glenohumeral joint lie underneaththe bony projection at the tip of the shoulder calledthe acromion. Separating them are the tendons of the rotator cuff and a bursa, the subacromialbursa. This is a thin envelope of tissue containingsynovial cells that secrete a lubricating substanceinto the interior that allows the rotator cuff tomove smoothly underneath the bony acromion.This bursa can become inflamed (subacromial bur-sitis) if there is impingement or increased pressuresuch as occurs in the rotator cuff syndrome. Lesscommonly bursitis may follow a fall onto theshoulder. A corticosteroid injection into the bursais very helpful in settling the inflammation butmust be combined with correction of the cause.This will most commonly be a rotator cuff syn-drome or a disordered scapulohumeral rhythm.The latter indicates that the precise coordinationbetween movement of the humerus and of thescapula has been lost.

Frozen shoulder The condition commonlyknown as frozen shoulder is a painful limitation ofshoulder movement in all directions. It is caused bycapsulitis or inflammation of the capsule of the

glenohumeral joint. The capsule shows an increasein fibrous tissue and shrinks, thus limiting move-ment of the joint. It affects about 2 percent of thepopulation but is more common in association withcertain other disorders. These include thyroid dis-ease, tuberculosis, lung cancer, after a heart attackor stroke, and especially, diabetes. Some diabetics,10–20 percent, will develop a frozen shoulder atsome stage. Having a frozen shoulder on one sideincreases the risk of having it on the other side toabout 10 percent. The frozen shoulder goesthrough three stages. The first stage is painful andlasts about three months. The second typically lastsfor six months (there is less pain in this stage butworsening limitation of movement). In the thirdphase there is gradual lessening of pain andincrease in movement. This process may take oneto three years.

Acromioclavicular joint dislocation Theacromioclavicular joint is commonly affected bytrauma in young people and osteoarthritis in olderpeople. Pain is usually felt in a relatively small areaover the joint, which is felt as a small bump andgroove on top of the shoulder. Pain is usually madeworse by bringing the arm across the chest underthe chin. The joint may be dislocated by a fall ontothe tip of the shoulder. Mountain biking, icehockey, soccer, and rugby are frequently involved.There are six grades of dislocation. The first threegrades reflect varying degrees of damage to thejoint ligaments but with the end of the clavicle stilleither touching or very nearly touching theacromion. These are usually treated conservativelywith pain relief and immobilization. Type III mayrequire surgical treatment occasionally. Whensevere pain persists the end of the clavicle can beremoved, and this often gives good pain relief withrelatively little loss of function. In types IV to VI theend of the clavicle is displaced well away from itsoriginal position, and surgical intervention isrequired to restore the connection to the acromion.

Acromioclavicular joint arthritis Osteoarthri-tis is quite common in the acromioclavicular joint.This may follow injury, may occur in isolation, ormay be part of a generalized osteoarthritis. Pain isfelt over the joint, which often develops markedbony swelling and tenderness. The pain is worstwhen raising the arm above shoulder height and

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when bringing it across the chest. X rays will con-firm the diagnosis. The shoulder complex shouldbe carefully assessed and dysfunction in the rotatorcuff scapulohumeral rhythm addressed as far aspossible. NSAIDs may help, and local heat andnonsteroidal creams may give temporary relief.Corticosteroid injections into the joint often givelonger lasting relief and are particularly helpfulbefore starting a shoulder rehabilitation program.Persistent pain that limits activity may require sur-gical removal of the end of the clavicle.

Osteolysis of the clavicle Occasionally aftereither an injury or following repeated minor stress,the bone of the end of the clavicle is resorbed. Thisis termed osteolysis. There is persistent pain andlimitation of movement. X rays will reveal the diag-nosis by showing loss of bone at the end of theclavicle. Rest or altering shoulder movements mayresult in considerable improvement and evenregrowth of the bone. However, surgical removalof the end of the clavicle is sometimes required.

Glenohumeral joint instability Instability atthe glenohumeral joint is increasingly recognizedas an underlying cause of pain at the shoulder. Itmay follow trauma or be due to inherent loosenessof the ligaments around the shoulder or wide-spread laxity as found in the HYPERMOBILITY syn-dromes. Dislocation of the joint is the most obviousmanifestation but lesser degrees of instability arenow more frequently recognized. Instability of theglenohumeral joint is traditionally separated intoanterior, posterior, and multidirectional. It can befurther classified according to how it occurred andwhether it is recurrent since this will impact on thetreatment.

Shoulder dislocation Anterior dislocation isoften caused by trauma, with the arm held awayfrom the body such as might occur when falling tothe side and putting one’s hand out to soften thefall. Initial treatment is to relocate the joint andimmobilize the arm. This dislocation is oftenaccompanied by damage to the labrum and liga-ments in front of and below the joint. Young ath-letes frequently require surgery to be able to returnto their sport, while older, less active individuals dowell with conservative treatment. Posterior disloca-tion is much less common and seldom requiressurgery.

Multidirectional instability is not often due totrauma. Although it may first be diagnosed after atraumatic dislocation, multidirectional instabilitywill more frequently cause other painful shoulderconditions. Especially common are rotator cuff syn-drome and bicipital tendinitis (see above). Shoul-der rehabilitation, usually a three- to four-monthintensive exercise program, is the treatment ofchoice, although surgical techniques which mayhelp if there is recurrent dislocation.

In a four-year study patients with nontraumaticshoulder dislocation had a good or excellent resultapproximately 90 percent of the time if their dislo-cation was posterior or multidirectional comparedwith only 45 percent with anterior dislocation. Intraumatic dislocation by contrast only 36 percent ofposterior dislocations and 13 percent of anterior dis-locations did well without surgery. Recurrent dislo-cation is much more common in young peoplewhen the dislocation is anterior and if it is traumatic.

Scapular pain Pain underneath the scapula orshoulder blade together with a snapping or grind-ing sound can be very difficult to diagnose accu-rately. Occasionally there may be an obviouslocalized cause such as a bony outgrowth from anunderlying rib. More often, however, it occurs withloss of scapulohumeral rhythm, and the paincomes from the soft tissues between the scapulaand ribs. This is often called a bursitis. Because thisarea is relatively hidden from direct examinationand imaging, being sure of the origin of the pain isdifficult. Correcting faulty shoulder complex move-ments is the best treatment. The area underneaththe scapula is sometimes injected, but there is a riskof puncturing the lung.

sicca syndrome See SJÖGREN’S SYNDROME.

sickle-cell disease (sickle-cell anemia) A genetic(inherited) disorder that results in an abnormalhemoglobin molecule and causes red blood cells tobecome fragile and sickle shaped. Sickle-cell dis-ease can cause several musculoskeletal problems.

Cause

Sickle-cell disease is an autosomal recessive geneticdisease. This means that someone has to inherittwo abnormal genes to have the disease. People

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with only one abnormal gene have sickle-cell traitand usually have no clinical abnormalities. A changein a single base of the DNA code leads to a change inone amino acid of the hemoglobin chain. Thishemoglobin S causes the red blood cells to be fragile,rupture easily, and sludge in small blood vessels.

Sickle-cell disease is more common in popula-tions of African or Mediterranean ancestry. Ap-proximately 8 percent of African Americans carrythe sickle-cell gene and one in 400 has sickle-cell disease.

Symptoms

The symptoms of sickle-cell disease start in child-hood. Because their red blood cells break more eas-ily, affected children are anemic and jaundiced.Jaundice refers to a yellow color of the skin andeyes caused by the accumulation of bilirubin, a pig-ment that is the end product of hemoglobin break-down. Children with sickle-cell anemia are smalland often have delayed puberty. Painful sickle-cellcrises occur. These crises are often precipitated byan infection or dehydration and last several days.There is acute pain that is probably the result of aninadequate oxygen supply to deep tissues becausesickled red blood cells sludge in small blood vessels.

Several musculoskeletal problems can occur inpatients with sickle-cell disease.

Arthritis Acute, reversible arthralgia andarthritis are common during sickle-cell crises. Moreserious is chronic irreversible arthritis caused bybone infarcts in and around large joints such as theknees and hips. These infarcts cause acute bonepain, and large ones can cause AVASCULAR NECROSIS,particularly of the hip or shoulder.

Osteomyelitis and infective arthritis Patientswith sickle-cell disease have a higher risk of devel-oping OSTEOMYELITIS and INFECTIVE ARTHRITIS. Differ-entiating the symptoms of osteomyelitis from asickle-cell crisis can be difficult. In many patientswith sickle-cell disease the spleen becomes less effi-cient at eliminating certain bacteria, for examplepneumococci and salmonellae, and infections withthese organisms are common.

Bony deformities In sickle-cell disease thebone marrow is hyperactive, trying to overcomeanemia. The hyperactive marrow can lead to defor-mities in the bones of the skull and spine. The skull

becomes thickened with a prominent forehead.The vertebrae may become deformed, leading tospinal deformities.

Other musculoskeletal complications Acutepainful swelling of a finger or toe (dactylitis) or thewhole hand or foot can occur in infants. GOUT ismore common in patients with sickle-cell diseasebecause the high turnover of red blood cells leadsto increased production of uric acid.

Diagnosis

The diagnosis of sickle-cell disease is usually easyand based on the family history, clinical findings,and blood tests. Under a microscope the bloodsmear shows sickle-shaped cells. The diagnosis isconfirmed by testing for hemoglobin S.


There is no curative treatment for sickle-cell dis-ease. Because the genetic mechanism is so wellunderstood and localized to one base in the DNAsequence, there are great hopes that gene therapywill lead to a cure.

Patients with sickle-cell disease should obtaintheir treatment from a center specializing in thecondition. Blood transfusions, antibiotics, anal-gesics, and hydroxyurea, a drug that increases thelevels of another type of hemoglobin, can all formpart of the treatment.

Avascular necrosis is treated as in patients with-out sickle-cell disease. Infective arthritis andosteomyelitis are treated with antibiotics but can bedifficult to control.

silicone implants In the 1990s, there was publicconcern that silicone was associated with anincreased risk of developing autoimmune diseasethat resulted in several lawsuits against companiesthat manufactured silicone for plastic surgery.

Without a doubt silicone can cause local inflam-mation. A fibrous scar forms around a breast im-plant. If the plastic container ruptures, releasingthe silicone gel into the breast, tissue inflammationresults. Consequently, most modern breast im-plants contain saline and not silicone. Whether sil-icone is associated with a risk of autoimmunedisease is much more controversial.

The first few, small series of cases seemed to sug-gest that silicone implants increased the chances of

250 silicone implants

developing scleroderma, SLE, fibromyalgia, andarthritis. These reports were difficult to interpretbecause the population group most likely to have abreast implant, women between the ages of 20 and45 years, were also the group with the highest riskof developing autoimmune disease. Several large,careful, well-designed studies have found noincreased risk of autoimmune disease.

Sjögren’s syndrome This is a common autoim-mune disease characterized by dry mouth and eyes,arthritis, other organ involvement, and an increasedrisk of malignancy. The dry eyes and mouth weredescribed over 100 years ago. However, it was onlyin 1933 that Sjögren, a Swedish ophthalmologist,described the connection with the arthritis andother manifestations. Although exact numbers aredifficult to obtain, Sjögren’s (pronounced sho-grins)syndrome is the second most common autoimmunerheumatic disease behind RHEUMATOID ARTHRITIS. Itaffects women nine times as often as men, and up to2 million Americans may have Sjögren’s syndrome.When occurring on its own it is called primary Sjö-gren’s syndrome. However, a significant number ofpatients developing Sjögren’s syndrome alreadyhave another autoimmune disease. It is then calledsecondary Sjögren’s syndrome.

Cause

The characteristic feature of Sjögren’s syndrome isreduced function of the glands that lubricatemucous membranes. This may occur in the eyes,mouth, throat, lungs, gut, or vagina. This is due inpart to damage to these glands by an immuneattack. Lymphocytes are attracted to the glands byCHEMOKINES. One of the most important chemo-kines here is called RANTES. The lymphocytes thenaccumulate in the gland and produce CYTOKINES

such as IL-1 and TNF, which have further effects onthe glandular cells as well as nerve function. Thisprocess leads to destruction of part of the gland butalso interferes with the function, i.e., the secretionof lubricating fluid. Antibodies also interfere withimportant signals in the gland, reducing secretionswithout actually causing destruction.

While the processes of gland destruction areunderstood in some detail, it remains unclear howand why this process is initiated remain unclear.

Viruses are an attractive link. That is, evidenceindicates that a viral infection could lead to persis-tence of the virus in the gland tissue. This wouldlead to an immune attack in the gland that, ingenetically predisposed people, could become self-perpetuating. There has been evidence involvingcytomegalovirus and Epstein-Barr virus, althoughnot conclusively. In addition patients with HIV orHEPATITIS C infection can develop a syndrome verylike primary Sjögren’s syndrome. At present it isnot clear whether hepatitis C initiates Sjögren’ssyndrome or merely causes similar but separatesymptoms. Research into the possible role of twoother retroviruses (HIV is a retrovirus), humanretrovirus 5 and HTLV-1, in Sjögren’s syndrome isongoing.

Relatives of patients with Sjögren’s syndromehave a higher-than-expected occurrence of bothSjögren’s syndrome and autoimmune antibodieson blood testing (without having any disease). Thissuggests a familial susceptibility to the disease. Twogenes, HLA-DR3 and HLA-B8, have been foundmore frequently than expected in Caucasian Sjö-gren’s patients, and other genes may be importantin particular racial groups.

Sjögren’s patients characteristically overproduceantibodies and may develop very high levels intheir blood. Some of these antibodies are autoanti-bodies, i.e., they react against parts of the individ-ual’s own body. The most characteristic of theseautoantibodies in Sjögren’s syndrome are anti-Roand anti-La antibodies, also called SSA and SSB(see Appendix II) antibodies (SS representing Sjö-gren’s syndrome). Rheumatoid factor and so-calledextractable nuclear antigens are common. Ro andLa are examples of extractable nuclear antigens.

The overproduction of other antibodies is alsocommon in Sjögren’s syndrome. Some of these aremonoclonal immunoglobulins (antibodies or partsof antibodies). This means that they are producedby one B cell and its progeny. B cells are the subsetof lymphocytes that produce antibodies. While thisfinding is characteristic of a blood cell malignancycalled multiple myeloma, it does not mean thatSjögren’s patients with this abnormality havemyeloma. However, these patients appear to be athigher risk of developing lymphoid tumors lateron. Some of the excess immunoglobulins may also

Sjögren’s syndrome 251

behave as CRYOGLOBULINS. There is clearly abnormalcontrol of B cells in Sjögren’s syndrome, and thoseB cells found in affected glands are activated. It hasbeen suggested that initially many different B cellsare activated, producing an assortment ofimmunoglobulins, and that this may become feweras time goes on, leading to monoclonal antibodiesand later possibly the development of lymphoidtumors. Secondary Sjögren’s syndrome may occurin association with rheumatoid arthritis, SYSTEMIC

LUPUS ERYTHEMATOSUS (SLE), SCLERODERMA, MIXED

CONNECTIVE TISSUE DISEASE, primary biliary cirrhosis,MYOSITIS, VASCULITIS, thyroid disease, or autoim-mune HEPATITIS.

Symptoms

Sjögren’s syndrome may occur by itself, called pri-mary Sjögren’s, or in association with anotherautoimmune disease, called secondary Sjögren’s.Unless otherwise mentioned, this discussion will beabout primary Sjögren’s syndrome. Secondary Sjö-gren’s is similar, but separating out the effects ofthe two diseases is sometimes difficult. Sjögren’ssyndrome has a very slow onset, and it can take upto 10 years before being recognized. A very widerange of problems may occur apart from the well-recognized reduction in secretions. However, apartfrom the reduced secretions, arthritis, and RAY-

NAUD’S PHENOMENON, these are not common. Gen-eral symptoms such as tiredness, muscle aches,joint pain without swelling, and low-grade feverare common and have often been present to somedegree for years before the diagnosis is made.

Eyes The main tear-producing glands areunder the upper outer eyelid. Since they are infil-trated with cells and antibodies they may enlarge,and the quantity and quality of the tears is reduced.Normally there is a thin tear film covering the frontof the eye and protecting it from drying out as wellas trapping dust particles. The tears are wiped overthe eye by regular blinking and drain into the nasalpassages through a small tube in the lower inner lid.The amount of tears produced can be measured bySchirmer’s test. This involves hooking a strip of blot-ting paper over the lower eyelid. Although this isuseful in diagnosis, the quality of the tears may bemore important than the amount. In Sjögren’s themucin in the tears is reduced, making the film break

up more easily as it covers the eye. Also the fat con-tent may drop, allowing tears to evaporate quicker.

Loss of tear protection causes drying and irrita-tion of the conjunctiva or outer layer of the eye.People often feel as though they have some grit inthe eye and may become sensitive to light. The eyemay appear red because of enlarged blood vessels.This is known as keratoconjunctivitis sicca and mayalso occur in other conditions. About 50 percent ofpatients feel they have dry eyes when the diagno-sis is first made.

Mouth The salivary glands may be similarlyinvolved. They quite often enlarge, and this may beintermittent. This enlargement is usually seen inboth cheeks near the angle of the jaw, but just oneside may enlarge at times. Reduced saliva leads todifficulty swallowing or talking for prolonged peri-ods, such as a teacher or receptionist might berequired to do. Taste may alter, and the mouthoften feels generally sore. People who have smokedtend to have more severe symptoms. The saliva isoften sticky and white. Studies show greater num-bers of bacteria growing in the mouths of patientswith Sjögren’s. Dental caries are a major problemfor almost all Sjögren’s patients, and very conscien-tious care of the teeth is required.

Other reduced secretions Dryness at the backof the mouth and throat may extend into the air-ways. Hoarseness is common, and these patientsare more susceptible to chest infections andobstructive airways disease. Loss of acid secretionin the stomach and reduced pancreatic secretionsmay occur. The latter may contribute to malab-sorption of food and vitamins. Vaginal dryness is acommon problem, and many patients complain ofa dry skin.

Joints Half of all Sjögren’s patients willdevelop arthritis, and many more will have jointpain without swelling. The arthritis may be the firstmanifestation of Sjögren’s or appear only yearsafter the diagnosis. Hands, shoulders, hips, knees,and feet are commonly affected.

Raynaud’s phenomenon This occurs in about40 percent of patients. Unlike in scleroderma,patients with Sjögren’s syndrome seldom developulcers from reduced circulation.

Lungs Lung problems are common in Sjö-gren’s syndrome but are only occasionally severe.

252 Sjögren’s syndrome

A chronic cough and frequent sinus infections aremost common. Occasionally this may lead tobronchiectasis (chronic lung infection) or obstruc-tive airways disease. Interstitial lung disease, inwhich there is an autoimmune attack on the airspaces where gas is exchanged leading to scarring,is less common. Occasionally lymphomas developin the lung (see below).

Heart Infants born to mothers with anti-Roantibodies are at risk of developing heart block (seealso NEONATAL LUPUS). This means that the electricalsignal does not pass from the upper heart to thelower pumping chambers, and the infant’s pulsewill not respond to signals to speed up in responseto the various stressors that require a faster heartrate. The intrinsic pulse rate without these signalsmay sometimes be too slow. Up to 15 percent ofadult Sjögren’s patients develop autonomic dys-function affecting the heart. Here the nerves thatspeed up or slow down the heart are affected sothat there is a poor blood pressure response toexertion or other stimuli. This may lead to weak-ness or fainting due to an inappropriately lowblood pressure.

Gut Difficulty with swallowing due to drynessof the gullet (esophagus) is common. There may bea mild inflammation with reduced function of thelining of the stomach. This leads to low levels ofacid being produced and can lead to vitamin B12

deficiency. Absorption of B12 requires it to bind toa small protein called intrinsic factor in the stom-ach. The production of intrinsic factor is reducedwith long-standing inflammation. Clinically, appar-ent pancreatitis is very uncommon, but investiga-tions have shown that mild pancreatic damageoccurs in up to 25 percent of patients. Nearly aquarter of Sjögren’s patients will have abnormalliver tests at some time. This may be due to cholan-gitis (inflammation of the bile ducts carrying bile tothe gut). In addition a high percentage of patientswith primary biliary cirrhosis (an autoimmune dis-ease producing a similar disease to cholangitis) willdevelop secondary Sjögren’s syndrome. Manyother autoimmune disorders have been reported inassociation with Sjögren’s syndrome. Some ofthese may lead to malabsorption, such as collage-nous colitis, ULCERATIVE COLITIS, or a vasculitis,causing reduced blood supply to the gut.

Kidneys About one in 10 Sjögren’s patientsdevelops detectable kidney disease. The typical dis-ease is called type I renal tubular acidosis. The kid-ney has difficulty getting rid of acid in the urine.This upsets the acid/base balance in the body andcauses a low potassium level. It can also cause kid-ney stones and very unusually kidney failure.There are no kidney-related symptoms unlessstones form. However, the biochemical abnormali-ties can cause marked weakness.

Vasculitis This affects up to one in 20 patients.It usually affects the skin but can occasionally affectother internal organs.

Nervous system Although uncommon, Sjö-gren’s patients may get a peripheral neuropathy(decreased function of the nerves to the feet andhands). There is disagreement whether patients getmore brain problems than the general population.

Thyroid Autoimmune thyroid disease occursquite commonly in association with Sjögren’s syndrome.

Lymphoproliferative disease Patients with Sjö-gren’s syndrome are 30–40 times more likely todevelop a lymphoma than the general population.Although this may sound very high, it should beremembered that lymphomas are rare diseases.These are quite often low-grade, including some thatwere previously called pseudolymphoma becausepathologists were not sure they really were tumors.

Diagnosis

Dry eyes, dry mouth, and intermittent swelling ofthe parotid glands strongly suggest Sjögren’s syn-drome. Strictly speaking this should be confirmedwith a biopsy of the minor salivary glands (frominside the lower lip) showing typically increased col-lections of lymphocytes. However, in practice a pos-itive anti-Ro (SSA) antibody with the typical clinicalfindings is often considered a firm diagnosis. Whilemany Sjögren’s patients will have a positive antinu-clear antibodies (ANA) test (see Appendix II) this isnot a good predictor of the diagnosis. It may indicatethe presence of another disease such as SLE or itmay be nonsignificant. There are many causes of drymouth. Medications, especially psychotherapeuticand antihypertensive ones, are common causes. De-hydration such as occurs in poorly controlled DIA-

BETES causes a dry mouth, as do certain viral

Sjögren’s syndrome 253

infections. Irradiation for tumors and hereditaryproblems with the salivary glands are rare causes.Viral infections, diabetes, and other conditions suchas SARCOIDOSIS, ACROMEGALY, cirrhosis, bacterial in-fections, and tumors can all cause swelling of thesalivary glands. The diagnosis of Sjögren’s syndrometherefore should not be made too readily withoutconsidering these alternatives. FIBROMYALGIA pa-tients commonly complain of dryness and havewidespread pain, causing some difficulty in diagno-sis. They will not, however, have a positive anti-Roantibody or evidence of inflammation.

Secondary Sjögren’s syndrome occurs in about 5percent of patients with rheumatoid arthritis,although symptoms like dry eyes are much morecommon. Sjögren’s syndrome is relatively easy todifferentiate from rheumatoid arthritis clinically.This is much more difficult when secondary Sjö-gren’s occurs in SLE, where salivary gland biopsymay be required to make this distinction.

A raised ESR and gamma globulin level reflect-ing the increased antibody production is very com-mon. The C-reactive protein, however, is usuallynormal. In addition to the ANA and anti-Ro anti-bodies mentioned above, rheumatoid factor, pari-etal cell, thyroid, microsomal, mitochondrial, andsmooth muscle antibodies are all found fairly fre-quently. A number of special tests are helpful inconfirming reduced tear production. Schirmer’stest involves putting a strip of filter paper over theeyelid and measuring the length of wetness afterfive minutes. Less than 5 mm indicates reducedtear secretion. If rose bengal stain is dropped intothe eye of a patient with keratoconjunctivitis sicca,it stains the damaged cornea or conjunctiva andconfirms this diagnosis. Another dye, fluorescein,can be used to measure tear break-up time. If thisis too quick, it indicates a mucin or lipid abnormal-ity. Measuring the rate of saliva flow (sialometry) isalso possible, although many factors affect this andinterpreting the result can be difficult. Scintigra-phy, in which a radioactive dye is injected intra-venously and the salivary gland uptake andappearance of dye in the mouth are measured, maybe more accurate but is seldom performed.


Sjögren’s syndrome is often a mild disease. Themost appropriate approach is to treat the individual

symptoms that cause trouble rather than a moregeneralized immunosuppressive approach as maybe used in diseases like SLE. Obviously with themore severe manifestations, systemic immunosup-pression will be required. This section will first dis-cuss treatment of the more common local problemsand then systemic treatment.

Dry eyes A wide variety of artificial eye dropsolutions are available, and these are very useful forpreventing symptoms. Since tears do drain awayquite quickly, they need to be applied regularly. Thismay vary from every hour or two to twice a day,depending on how dry the eyes are. Thicker, moreviscous preparations stay in the eye longer. These,however, cause blurring of vision, coat the eye-lashes, and are best used at night. Most teardropsolutions contain a preservative, and it is possible todevelop an allergy to this. In this case, preservative-free eyedrops can be used. Since they come in single-use containers, they are more expensive. Ifkeratoconjunctivitis sicca develops, corticosteroid-containing drops may be used but for only a week ortwo since there is a risk of cataracts or glaucomadeveloping. In severe keratoconjunctivitis there areseveral reports of the patient’s own serum (bloodwith all the cells and clotting factors removed) beingsuccessfully used as eyedrops. Soft contact lenses canprotect the cornea, although people with dry eyesoften do not tolerate them well and the lenses mayrequire regular wetting. Avoiding windy conditionsand low humidity (indoors, fans, or air-conditioningespecially) also helps prevent excessive drying.

Dry mouth For symptomatic relief, chewingsugar-free gum is probably best. This stimulatessaliva production. Lemon juice is also a potent nat-ural saliva stimulant but can erode tooth enamel.Proprietary saliva substitutes are available, butmost patients with mild symptoms prefer usingsugar-free gum and carrying a water bottle for reg-ular sips. It is important that these do not containacid or sugar because Sjögren’s patients are alreadyat high risk of caries. Oral pilocarpine increasessaliva in Sjögren’s patients. The main difficulty is ingetting the dose of pilocarpine right and avoidingthe sweating, tremors, and diarrhea that go withtoo high a dose. An oral alpha-interferon (seeCYTOKINES) preparation has been shown to increasesaliva production, but this is still experimental. Dry

254 Sjögren’s syndrome

foods are best avoided, and drinking water to assistswallowing is useful. Many patients have seriousdental caries before Sjögren’s is actually diagnosed,and progression can be very rapid. In addition toregular brushing and flossing, regular dental checksare recommended. A dentist with an interest in Sjö-gren’s syndrome is preferable but may not be avail-able in all localities. Application of a sodium fluoridevarnish to the teeth by a dentist has been shown toslow down caries. Fluoride gel can also be applied tothe teeth at night using plastic dental trays.

Other dryness Lubricating gels are used for vagi-nal dryness and moisturizing creams for the skin.

Systemic therapy NSAIDs, corticosteroids inlow doses, and HYDROXYCHLOROQUINE are helpful intreating the arthritis and fatigue. AZATHIOPRINE hasbeen used for treating a range of systemic manifes-tations with some success, although a recent con-trolled study of moderate-dose azathioprineshowed no benefit. Interstitial lung disease is usu-ally treated with pulses of intravenous CYCLOPHOS-

PHAMIDE, and CYCLOSPORINE has also been found tobe effective in a small number of patients. INTRA-

VENOUS IMMUNOGLOBULIN has been used with somesuccess in treating the peripheral neuropathy ofSjögren’s but is not standard therapy. Octreotidehas been successful in treating pseudoobstructionof the bowel. Midodrane may help the tirednessdue to low blood pressure and slow heart rate thatcan occur following damage to the autonomic ner-vous system (see above).

Other A herbal vitamin supplement calledLongovital (Amarillo Biosciences) was found toincrease salivary flow rate in a controlled trial.Acupuncture has produced improvement in symp-toms of dryness.

SLE See SYSTEMIC LUPUS ERYTHEMATOSUS.

sleep apnea (obstructive sleep apnea) A condi-tion in which a person, while asleep, has manyepisodes of stopped breathing. Patients with sleepapnea are fatigued and can be misdiagnosed ashaving FIBROMYALGIA.

Cause

Sleep apnea is due to an excess of soft tissuearound the airway. While the patient is asleep the

soft tissue at the back of the throat flops down andblocks the airway. The person does not breathe fora while, sometimes for 30 seconds or longer, andthen wakes up for a second and gives a snort, startsbreathing, and falls asleep without knowing whathappened. This can happen hundreds of time dur-ing the night so that the patient’s sleep is very dis-turbed. Obesity, a thick neck, male sex, anddrinking large amounts of alcohol at night allincrease the risk of sleep apnea.

Symptoms

The patient’s bed partner is often first to notice theloud snoring and periods of stopped breathingwhile asleep. The patient is not refreshed in themorning and falls asleep during the day while per-forming usual day-to-day activities. Musculoskele-tal symptoms of arthralgia and myalgia arecommon, and sleep apnea can be mistaken forfibromyalgia.

Diagnosis

The history from the patient’s bed partner is classi-cal, but to make the diagnosis a sleep study is per-formed. The patient spends a night in a sleeplaboratory where breathing and sleep patterns arerecorded.


Losing weight can improve the symptoms of sleepapnea in some patients, but most require continu-ous positive airway pressure (CPAP). This involveswearing a tightly fitting mask every night. CPAP isvery effective, but many patients find it inconve-nient and stop. Surgery to reduce the amount ofsoft tissue at the back of the throat can be helpfulin some patients. Patients with untreated sleepapnea are prone to work-related injuries andmotor vehicle accidents because they are tired andfall asleep for a few seconds while performing atask. Sleep apnea elevates blood pressure, cancause an abnormal heart rhythm, and is associatedwith an increased risk of stroke and heart failure.

soft tissue arthritis–related problems This is aterm used to describe a group of conditions affectingthe soft tissues of the musculoskeletal system such asmuscles, tendons, ligaments, their attachments to

soft tissue arthritis–related problems 255

bone, as well as some nerve conditions. It thereforeexcludes diseases primarily affecting bones andjoints and by convention excludes true inflamma-tory disease even when this affects muscle or ten-dons. It is really a classification of convenience sinceit does not imply any causal or mechanistic linkbetween the various conditions. These have largelybeen described elsewhere in this book as separateconditions. Broadly speaking, soft tissue problemscan be seen as generalized or local. Generalized con-ditions cause symptoms in many parts of the body,local in only one or a small area.

Generalized Soft Tissue Arthritis–Related Problems

FIBROMYALGIA

HYPERMOBILITY SYNDROME

Local Soft Tissue Arthritis–Related Problems

ACHILLES TENDON disordersBURSITIS

CARPAL TUNNEL SYNDROME

EPICONDYLITIS

FOOT PAIN, some formsGANGLION

Golfer’s elbow/medial epicondylitis; see EPI-

CONDYLITIS

HEEL PAIN, some formsHousewife’s knee; See PREPATELLAR BURSITIS

KNEE PAIN, some formsLateral epicondylitis/tennis elbow; see EPICONDYLITIS

OLECRANON BURSITIS

PLANTAR FASCIITIS

ROTATOR CUFF SYNDROME

Tarsal tunnel syndrome; see FOOT PAIN

TENDINITIS

The word tendinitis implies inflammation of thetendon and was first described as an entity in 1763,although no doubt it was felt long before then. Ten-dons join muscles to bone and transmit the pullingforce of the muscle. They are composed of spirals ofcollagen that are wrapped into bundles forming athick cord that is both strong and able to stretch.Because of the property of viscoelasticity, a suddenrapid muscle contraction will find the tendon rela-tively stiff while slower contractions allow greaterstretch. With repeated stretching the tendonbecomes more flexible. While this applies to all ages,maximum flexibility does slowly decrease with

increasing age. Longer tendons or those subject tosignificant friction are enveloped in a synovialsheath that has two layers that allow sliding to takeplace with little friction. Not all tendons have asheath. The tendon gets its blood supply from bothits muscle and the surrounding sheath if it has one.It attaches to the bone at an enthesis, and inflam-mation here (enthesitis) is described under ANKYLOS-

ING SPONDYLITIS and HEEL PAIN.

Inflammatory tendinitis can occur as part manyconditions, including RHEUMATOID ARTHRITIS, anky-losing spondylitis, connective tissue diseases, psori-atic arthritis (see PSORIASIS AND PSORIATIC ARTHRITIS),TUBERCULOSIS, GOUT, and giant cell tumors of thetendon. Most tendinitis, however, is due tomechanical strain and occurs following excessiverepetitive movement or repetitive movement with-out adequate training. Tendinitis may also followmore acute injury, especially if activities areresumed before adequate healing has taken place.Tendon malalignment leading to the tendon havingto transmit force at an angle to the line of its fiberscommonly causes tendinitis. Impaired blood supplyand fluoroquinolone antibiotics (see DRUG-INDUCED

RHEUMATIC DISEASE) are other causes. As a result ofinflammation and scarring around the tendon, itcan begin to stick or trigger. When this involves atendon that curls a finger up, for example, the fin-ger will be stuck in a curled position. Often, with alittle extra force, it will suddenly flick straight (trig-ger finger). This can also occur with stenosingtenosynovitis, in which the tendon sheath tightensaround the tendon. This is sometimes familial. Cal-cific tendinitis has a dramatic onset, with painmade worse by movement. It can be caused by cal-cium apatite crystals or CALCIUM PYROPHOSPHATE

DIHYDRATE DEPOSITION DISEASE. Attacks are mostcommon around the wrist, shoulder, and ankle.

Tendinitis is usually diagnosed by history andexamination. If there is doubt or a possibility thatthere is a tear, then ultrasound is the best methodto image tendons. It does, however, require anoperator with experience in musculoskeletal ultra-sound. MRI provides a good image of tendons andcan also show up associated bone or joint prob-lems. X rays will reveal calcific tendinitis and mayshow associated arthritic changes.

The type of immune response, damage, andrepair mechanisms will differ among the different

256 soft tissue arthritis–related problems

forms of tendinitis and between short-lived orlong-lasting (chronic) problems. Treatment has tobe directed to each individual’s situation. ICE andrelative rest, for example using a wrist splint, areuseful in settling the pain and swelling in mostforms and in allowing healing to start. NSAIDs areeffective but will seldom relieve pain to the extentthat normal use is restored. This is a good thingsince premature use is likely to lead to chronic ten-dinitis more often. If part of a generalized arthritis,better control of the disease as a whole may help. Inthese situations, however, injection of a smallamount of corticosteroid often resolves the inflam-mation. These injections must be given into thesheath surrounding the tendon and not the tendonitself. Despite the severity of inflammation in cal-cific tendinitis, there is a concern that corticosteroidinjections may slow resolution. Corticosteroid injec-tions are also the first-line treatment for tendonsthat are triggering. Surgery may be necessary ifthese fail. Surgery to remove the debris from withina tendon can also lead to healing of chronic ten-dinitis (see also TRIGGER FINGER, TROCHANTERIC BURSI-

TIS; and WRIST PAIN, some forms).

spinal stenosis A condition in which the spinalcanal or nerve root canal does not provide ade-quate space for the spinal cord or nerve root to passfreely. Early reports of typical symptoms as well asoperative findings date from the 1890s, well beforethe now more common disc protrusion wasdescribed. Spinal stenosis can affect the cervicalspine (neck) or lumbar spine (lower back). Thelumbar spine is affected much more often. Patientsare generally aged between 45 and 65 years, butyounger and older patients may be affected. Mendevelop spinal stenosis more frequently thanwomen, especially in the lumbar spine.

Cause

At least at the lower back level, the cross section ofthe spinal canal can be seen as a somewhatrounded triangle with equal sides, the base againstthe vertebral body and the apex pointing backwardtoward the spine. Spinal stenosis can occur at threesites at any given level. It can occur within the cen-tral spinal canal down which the spinal cord passes.It can occur in the lateral recesses that are theangles at each side of the base of the triangle. The

nerve root angles into the lateral recess beforeentering the nerve root canal and leaving the spine.Finally, spinal stenosis can occur within the nerveroot canal. Most of this discussion will refer to cen-tral canal stenosis, although the degenerativechanges may affect all three sites.

Degenerative spondylosis is the most commoncause both in the neck and back. This starts withwear and tear changes to the intervertebral disc. Toa certain degree these are normal aging events. Asthe disc loses height a greater load is put onto thetwo smaller facet joints behind the spinal canal, thedisc acting as a large joint in front of the canal. Asa response to this increased load, the facet jointcapsule thickens, and small bony outgrowths(osteophytes) grow out from the edges of thejoints. Similarly, a rim of extra bone growth devel-ops around the lip of the vertebral body, thus nar-rowing the canal space from all sides. In additionthe powerful ligament that runs down the lengthof the spinal canal, the ligamentum flavum, thick-ens. This can thicken from a normal 2–5 mm inwidth to 5–10 mm, causing significant narrowingof the canal and compressing the cord. Otherdegenerative changes may worsen the situation or,if severe, cause stenosis of their own accord. Theseinclude disc protrusion (see BACK PAIN), spondylol-ysis, and spondylolisthesis. Spondylolysis is a defectin the arch of bone from the vertebral body back-ward to the facet joints. Spondylolisthesis is therelative forward or backward movement of onevertebral body on another. In the presence ofdegenerative changes as described above spondy-lolisthesis can cause spinal stenosis with only 3–4mm of movement. It seems likely that disturbancein the blood supply to the nerve root from com-pression of the very small arterioles surroundingthe nerve plays a significant role in producing thesymptoms of spinal stenosis.

People may have developmentally small spinalcanals, and this is very common in people withachondroplastic dwarfism. Narrow canals have alsobeen described in other families with no otherbony problems. There is a range of canal widthwithin the population, and those toward the nar-row end of this range will be at greater risk ofspinal stenosis.

There are a large number of rare causes of spinalstenosis. It may follow disc space infection, bony

spinal stenosis 257

infection (osteomyelitis), tuberculosis of the spine,synovial cysts protruding into the canal and follow-ing trauma, or surgery. Excessive bone growth mayalso narrow the canal and cause compression. Thiscan occur in PAGET’S DISEASE, ANKYLOSING SPONDYLITIS

or DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS, andACROMEGALY. GOUT and pseudogout (see CALCIUM

PYROPHOSPHATE CRYSTAL DEPOSITION DISEASE) haverarely been associated with spinal stenosis as hasthe development of benign fatty growths within thecanal in people on long-term corticosteroids.

Symptoms

The most typical symptom is a rather diffuse painin the legs that comes on after walking a certaindistance or on standing for a period. This is calledneurogenic claudication. Patients have oftennoticed that the distance they are able to walk hasgradually been getting less for some time before thepain starts. The pain is usually relieved by move-ments that bend the lower back forward slightly.This maneuver widens the spinal canal slightly.Patients with spinal stenosis often describe a vaguenumbness or weakness in the legs. There may besciatic symptoms (pain in the area supplied by anerve root) that are largely one-sided, but the clau-dication symptoms are usually felt in both legs. Along history of low-back pain is common.

Pain that radiates down the leg with tinglingsensations and numbness and occurs in only cer-tain positions is very common. These symptomswill often have preceded those of neurogenic clau-dication. The positions likely to bring it on arestanding or bending backward. Occasionallypatients with spinal stenosis may develop caudaequina symptoms due to compression of the lowerfew nerve roots. This can lead to incontinence ofurine and feces, impotence, and loss of sensation inthat part of the rear end that would be in contactwith the saddle if one were riding a horse.

The findings on physical examination are oftenremarkably normal. Straight-leg raising is amaneuver that puts tension on the sciatic nerve tosee if it is being trapped by, for example, a pro-lapsed disc. It also flexes the lower spine forwardslightly and will therefore widen the spinal canal,relieving symptoms of spinal stenosis. If a patienttherefore describes symptoms suggestive of sciatica

but has very normal straight-leg raising, this shouldraise the possibility of spinal stenosis. In somepatients there may be abnormal findings such asweakness and absent reflexes after walking but notafter resting.

Cervical canal stenosis (in the neck) is less com-mon but has largely similar causes. Because itaffects the spinal cord much higher up, it will pro-duce different symptoms. By far the most commonpresentation is with spasticity (abnormal stiffnessof the limbs). Walking is experienced as difficult,and the patient is found to have abnormally briskreflexes in both legs and arms, depending onexactly where in the cervical spine the compressionoccurs. Disturbance in rectal or bladder sphincterfunction may occur. Weakness of an arm occurs inone-third of affected people and weakness of bothlegs or legs and arms in 10 percent. There may betwitching and wasting of the muscles of the hand.Some patients describe a vague alteration in sensa-tion, and loss of position sense may occur.Although cervical spondylosis is the commoncause, neck pain is found in only a quarter ofpatients.

Diagnosis

The diagnosis of spinal stenosis is often delayed.One reason is that the symptoms come on veryslowly and may be quite vague at the start.Another is that even if there is a good history ofnerve root symptoms, there may be no symptomsof nerve root impingement at rest. The lack of neckpain and the difficulty many patients have indescribing what they feel is wrong can make cervi-cal canal stenosis difficult to diagnose. Symptomsthat are particularly helpful in suggesting the diag-nosis include that the symptoms come on afterwalking a certain distance, that there is numbnessand weakness associated with the pain, and thatthe claudication affects both legs and is relieved byslight forward bending of the lower back. Once theclinical diagnosis is made it should be confirmedwith an MRI scan. This can demonstrate the typicaldegenerative bulging disc, bony enlargement of thefacet joints, synovial cysts, and ligament enlarge-ment. The canal may be unusually narrowed. PlainX ray and CT scans are good at showing up bonylesions such as Paget’s disease.

258 spinal stenosis


Nonoperative treatment NSAIDs are helpfulwith the pain and may help some of the leg symp-toms as well. Exercises aimed at reducing the lum-bar lordosis (curvature of the lower back) help towiden the canal and reduce symptoms. While a lor-dosis is normal in the lower back it has oftenbecome exaggerated, and even when not exagger-ated a slight reduction can help. The therapist willdetermine if there is excessive anterior pelvic tiltand advise how to correct this. Abdominal strength-ening exercises are a cornerstone but need to becombined with appropriate stretches. Injection ofcorticosteroids into the space surrounding the spinalcord has been used in lumbar canal stenosis but isnot a proven therapy. Cycling is a good exercise forthe lower legs since the lumbar spine naturallyflexes forward during exercise. These measuresshould be tried in all patients with mild symptoms,in those without critical nerve problems, and inthose in whom surgery is fraught with danger.

Operative treatment Severe spinal stenosisrequires surgery. The main indications are intoler-able pain, symptoms of the cauda equina syn-drome, or neurological dysfunction that is gettingworse. The aim of surgery is to enlarge the spacesthat the spinal cord and nerve roots pass throughwhile at the same time not removing so much bonethat the spine becomes unstable. There are severalsurgical approaches to achieve this. With the stan-dard single-level procedure, instability occurs inabout 2 percent of patients, and therefore fusion ofadjoining vertebrae is not routinely done. If there isassociated degenerative spondylolisthesis (slippageof one vertebra on the other), then the risk ofinstability is high and fusion is performed. It mayalso be done when there is scoliosis. ARTHRODESIS

may be done at a later stage for intractable pain orinstability following surgery.

Outcome In some studies 80–85 percent ofpatients operated on have a good result. A goodresult is relief of pain and a return to the level ofactivity that existed before onset of spinal stenosissymptoms. However, in another study only 41 per-cent of patients were 50 percent or more satisfiedwith the results of surgery one year later, althoughmost felt they had made the right decision to havesurgery. If there is wasting of muscles or abnormal

sphincter function, then some irreversible nervedamage has likely occurred and this will notrecover. It is unlikely that patients will be able toperform significant lifting or walking tasks, andprolonged standing is likely to be uncomfortable.This should be considered in planning a return towork.

splints Splints are devices that provide supportfor a limb or joint. There are many types, and theyare used for different reasons. Simple wrist or anklesupports, for example, may be bought over thecounter and provide very little actual support. Atthe other extreme rigid splints can be used toimmobilize a joint. Common reasons for usingsplints include:

• Comfort A firm, elasticized support can lend adegree of comfort to a painful wrist, for exam-ple. Some supports give a certain amount ofwarmth as well, which is also comforting.

• Proprioception A light elasticized ankle support,while providing virtually no physical support tothe ankle, assists in the return to activity after anankle sprain by improving proprioception. Itincreases the person’s awareness of the ankleand its position in space. This is impaired by theankle sprain and is one reason for sprainsbecoming recurrent.

• Support If movement is painful a splint thatlimits motion can protect a joint, e.g., a hingedknee splint that has metal strips up the sides sothat side-to-side movement is minimized. Thishelps some patients with osteoarthritis of theknee.

• Immobilization After trauma or surgery it maybe appropriate to immobilize a joint completely.This can often be achieved with a molded splintthat wraps around one side of a joint and is heldin place with bandages.

• Range of Motion Treatment Patients with painfuljoints naturally hold them in a position of com-fort, and in time, they may lose the ability tostraighten these joints because of tightening ofthe soft tissues. One technique to overcome thisis to use progressive splinting. If, for example, apatient cannot straighten one knee, this joint is

splints 259

stretched as straight as possible and a plaster castis molded to fit down the back of the leg in thisposition. At night the cast is strapped on and thepatient sleeps with the leg as straight as possible.As the soft tissues stretch, more casts are moldedto hold the leg a little straighter each time. Thisis most useful in children since their soft tissuesstretch more easily.

• Strengthening Following hand surgery particu-larly, splints are constructed that allow con-trolled movement of the fingers against elasticresistance to aid in the rehabilitation while sur-gical healing is still taking place.

spondyloarthropathy This term is used todescribe a group of conditions characterized bychronic or ongoing inflammation of the axial skele-ton. The axial skeleton consists of the spine and thelarge sacroiliac joints where the lower spine joinsonto the pelvis. There are other characteristics thatthese diseases share to a varying degree. In mostpatients it is possible, at least after a year or two, todiagnose the specific disease, and they are there-fore described separately in this book. The mainspondyloarthropathies are

• ANKYLOSING SPONDYLITIS

• ENTEROPATHIC ARTHRITIS, including CROHN’S DIS-

EASE, ULCERATIVE COLITIS, and WHIPPLE’S DISEASE

• Psoriatic spondylitis; see PSORIASIS AND PSORIATIC

ARTHRITIS

• REACTIVE ARTHRITIS

• Reiter’s syndrome; see REACTIVE ARTHRITIS

In addition to the typical spinal involvement,the other features that are shared to a variabledegree include

1. The presence of the HLA-B27 gene. This is dis-cussed in the ankylosing spondylitis sectionsince it is most closely associated with this dis-ease. However, all the above conditions occurfar more frequently in people carrying HLA-B27.

2. The tendency to develop an assymmetrical,lower-limb arthritis involving one to three jointstypically. In addition to the axial arthritis, many

patients will develop arthritis in an ankle andknee, for example, or a hip. This tends to bemore common in those with reactive arthritisand psoriatic spondylitis.

3. Associated inflammatory eye disease.4. An association with gut inflammation. Apart

from the enteropathic arthritis that is by defini-tion associated with a well-defined bowel dis-ease, nonspecific bowel inflammation has beenfound in many patients with ankylosingspondylitis. In a significant number of people,reactive arthritis develops after a bowel infection.

5. Enthesitis, which is typical. Inflammation of theenthesis or specialized area where tendons andligaments attach to bones is the pathologicalhallmark of these diseases. The reason for this isnot known.

Still’s disease See JUVENILE ARTHRITIS.

stress fracture A break that develops in bonebecause of fatigue failure rather than a suddenoverwhelming force. This may occur in normalbone as a result of excessive forces or in abnormalbone as a result of everyday stresses. These areclearly different conditions, although the end resultmay look very similar.

Cause

Stress fractures in normal bone occur predomi-nantly in athletes and soldiers. They result fromforces applied repetitively to an area of bone. As aresult of these forces remodeling of the boneoccurs. This involves bone cells called osteoclastseating away established bone followed by otherbone cells called osteoblasts laying down new bonebetter able to withstand the forces being applied.This process is quite common in athletes. Thosewho develop a stress fracture are on one end of aspectrum where the osteoclastic activity is not fol-lowed by adequate repair. Predisposing factorsinclude inadequate muscle strength or trainingbeyond muscle exhaustion. Muscles normally con-tribute to the shock-absorbing capacity of the lowerlimb. When this is lost there is increased impacttransmitted to bone. Stress fractures can also occurin the upper limbs, for example in baseball pitch-ers, simply due to the forces applied by muscle.

260 spondyloarthropathy

The most common cause of abnormal bones giv-ing rise to stress fractures is OSTEOPOROSIS. Patientswith RHEUMATOID ARTHRITIS and osteoporosis seem tobe at particular risk of stress fractures. This mayrelate to the deformities many rheumatoid patientsdevelop, leading to abnormal stresses being put onbones as well as the high use of CORTICOSTEROIDS.Other bone diseases such as OSTEOMALACIA, PAGET’S

DISEASE, and alcohol abuse are well-recognizedcauses. Some patients with HYPERMOBILITY SYNDROME

have bony fragility and develop stress fractures.

Symptoms

Pain is the predominant symptom. This is oftenexquisite when force is applied across the fracture,for example when standing or walking with a stressfracture in one of the leg bones. A few patients,however, have remarkably little pain and can con-tinue to walk with a fracture through their hipbone. Since the bones are not displaced they arestill able to take the person’s weight. Typical sites offracture in normal bones are the second metatarsaland tibia in athletes or soldiers. The metatarsal isthe bone running down from the midfoot to thetoe, and the fracture usually occurs nearer the toe.This is known as a march fracture. The area over-lying the fracture is often slightly swollen, andpressing over it is extremely painful. The tibia(larger of the lower-leg bones) is more frequentlyaffected in long-distance runners. The humerus orupper-arm bone may become involved in baseballpitchers.

In severe osteoporosis almost any bone may beinvolved, although some are more frequent. Thelower end of the tibia, the neck of the femur(thighbone), and the outer part of the sacrum(lowest part of the spine) are typical areas in thelower half of the body. Ribs are often affected, andvertebral collapse in the spine may be seen as astress fracture.

Diagnosis

When a typical site is affected in an athlete the diag-nosis is usually suspected immediately, often by theathlete. However, in a patient with active arthritisthe lack of obvious trauma and presence of painfuljoints may lead to a stress fracture being overlookedinitially. When it affects a long bone a very tender

lump can often be felt at the fracture site. An X raywill confirm the diagnosis but may not show thefracture early on. If the X ray is negative, a tech-netium bone scan will show the lesion. CT and MRIscanning are also effective in demonstrating stressfractures but are seldom required. It is important toexclude osteomalacia, a bone disease caused by lackof calcium or vitamin D, and a pathological fracturecaused by a tumor weakening the bone.


Relative rest and pain relief are required, and thefractures usually heal without specific treatment.For patients with a metatarsal fracture, for exam-ple, it is often adequate immobilization to wear astiff shoe, although occasionally a plaster cast willbe required. Attention to biomechanics and train-ing schedules may be needed for athletes, andavoidance of running on hard surfaces or cambersis essential. In patients with osteoporosis or otherbone disease, treatment of the underlying disease isobviously important.

CALCITONIN is effective in controlling the pain.This is given by injections under the skin and maycause flushing and diarrhea at the higher doses.The bisphosphonate group of drugs is also effective.These include PAMIDRONATE, ALENDRONATE, and RISE-

DRONATE. Most fractures heal within three to sixmonths but may occasionally take longer.

Sweet’s syndrome (acute febrile dermatosis) Arare condition described by Dr. R. D. Sweet in1964, consisting of fever, a high white blood cellcount, and a plaquelike skin rash. Sweet’s syn-drome is more common in women than men.Sweet’s syndrome can cause arthritis and can bemistaken for STILL’S DISEASE or VASCULITIS.

Cause

The cause of Sweet’s syndrome is not known. It isassociated with some cancers, particularlyleukemia, infections, drugs such as lithium, con-nective tissue diseases such as RA and SLE, andinflammatory bowel disease, suggesting that anabnormal immune response is responsible.Approximately 20 percent of patients with Sweet’ssyndrome have an underlying malignancy, usuallyaffecting the bone marrow.

Sweet’s syndrome 261

Symptoms

The characteristic symptoms of Sweet’s syndromeare fever and rash. Fever and other systemic symp-toms such as arthralgia, arthritis, myalgia, and con-junctivitis occur in most patients. Arthritis affectslarge joints such as knees, hips, wrists, and anklesbut can also affect the fingers.

The rash of Sweet’s syndrome usually consists ofred plaques that are often tender. The plaques can belarge, up to several inches in diameter, and can occuranywhere, including the face, arms, and trunk.Lesions on the legs can be mistaken for ERYTHEMA

NODOSUM, which can occur with Sweet’s syndrome.

Diagnosis

The diagnosis of Sweet’s syndrome is usually basedon the appearance of the rash and a skin biopsythat shows dense infiltrates of neutrophils aroundblood vessels but no vasculitis. Laboratory testsusually show an elevated white blood cell countand ESR, but these can accompany inflammationof any cause and is not specific. In most patientsextensive investigations have been performed tolook for an infection before the diagnosis of Sweet’ssyndrome is made. Blood cultures and other testsfor infection are negative.


Sweets’s syndrome does not respond to antibiotics.Because an infection is usually the first diagnosissuspected, most patients with Sweet’s syndromeusually receive several courses of antibiotics. ACORTICOSTEROID such as prednisone 1 mg/kg a dayis effective and rapidly reduces symptoms. The doseof corticosteroid is tapered over about six weeks.NSAIDs can improve joint symptoms and fever.Sweets syndrome usually resolves completely butcan relapse. Because Sweet’s syndrome in adultscan be the first sign of an underlying malignancy, athorough physical examination and basic screeningtests for malignancy should be performed.

synovectomy The synovium is normally a thinlayer of tissue surrounding most of the joints of thebody and lies inside the tough joint capsule. Inaddition, synovial tissue lines tendons where theyare subject to friction and is also found within bur-sas. Since cartilage has no blood supply of its own,

the synovium secretes nutrients into the joint spacefor the cartilage. It also contains nerves that feedback information about the state of the joint. Inmany forms of inflammatory arthritis (see ARTHRI-

TIS for definition) the synovium enlarges, becomingpacked with white cells that promote inflamma-tion. New blood vessels form and fluid leaks intothe joint, carrying enzymes and CYTOKINES thatcause damage to the cartilage as well as promotingmore blood vessel growth and causing pain andswelling. To a certain degree this also happens inOSTEOARTHRITIS, although much less aggressively.

Because the white cells and all the proinflam-matory molecules that they secrete enter by thesynovial blood vessels, it seems logical that if thesynovium is removed the arthritis will get better.Indeed this does happen, although it is not quite assimple as it once seemed. First the synovium willregrow, and second, removal of the synovium doesnot stop the cartilage from deteriorating. It may,however, dramatically relieve pain and swellingand improve function for months or years. Thereare two forms of synovectomy, surgical and radio-chemical.

Surgical This involves opening the affectedjoint and stripping out as much synovium as possi-ble. More and more this is being done byARTHROSCOPY. Although this is a less invasive pro-cedure, doing a complete synovectomy arthroscop-ically is difficult. Most synovectomies are done inpatients with RHEUMATOID ARTHRITIS. It is particu-larly indicated when one or two large joints are notresponding to adequate medical therapy. There issometimes a lot of synovitis around the tendonssince they cross the back of the wrist, and this canlead to damage and rupture of the tendons. A syn-ovectomy here is valuable in preventing rupture.Synovectomy can sometimes relieve pain for up to10 years, and about 70 percent of patients will havesome benefit.

Patients with JUVENILE ARTHRITIS of the pauciar-ticular type often have one or two troublesomejoints. If these can be successfully treated with syn-ovectomy, it may obviate the need to take poten-tially toxic medications. One study showed goodpain relief in 70 percent of pauciarticular patientstreated by synovectomy after seven years. In HEMO-

PHILIA, the large, swollen synovium may be a

262 synovectomy

source of recurrent bleeding, and synovectomy canreduce the frequency of bleeds. However, synovec-tomy seems to cause a significant loss of movementin these patients. Surgical synovectomy is also thetreatment of choice for a number of synovial dis-eases such as PIGMENTED VILLONODULAR SYNOVITIS,synovial chondromatosis (see KNEE PAIN), and raresynovial tumors.

Radiochemical This involves injecting aradioactive substance into the joint to damage thesynovium by irradiation. The substance needs to berelatively safe, easy to handle, and remain in thejoint. Although a number have been used over theyears, yttrium 90 is now used by most centers.Because it is a radioactive treatment, the centerneeds to be licensed to do it. A few centers com-monly undertake this treatment for a wide referralarea. Large joints such as knees, hips, and anklesare most commonly treated in this way. Smallerjoints in the hands were successfully treated in thepast, but radioactive injection was shown to be nobetter than corticosteroid injections in these jointsand is therefore no longer done.

synovial fluid See Appendix II.

systemic lupus erythematosus (SLE) A complexinflammatory disease potentially affecting manyorgans and systems in the body (e.g., neurologicaland cardiovascular). First described as a chronicskin condition in 1833, the systemic nature of SLEwas recognized in 1872. The first of the laboratorytests demonstrating autoimmunity, the LE cellpreparation, was discovered in 1948. Although nolonger used, this has been replaced by several othertests that make the recognition of SLE and relateddiseases easier. Studies have shown SLE to affectbetween 12 and 50 people per 100,000 populationin the United States and the developed world.Studies of a fairly rare disease that can range frommild to life threatening and predominantly affectvery different organ systems (and therefore presentto different types of specialists) are difficult. It is notclear, therefore, how much of the variation in thesestudies is real or due to the different approachestaken in doing the studies. SLE affects womenmore than men in a ratio of about 7 to 1. It affectsAfrican Americans more than Caucasians in the

United States but is rare in black Africans living inAfrica. Evidence also shows that SLE is more com-mon in Chinese and Filipino people. Adding to theuncertainty of how many people suffer from SLE isthe recent rise in self-diagnosis. A patient organiza-tion, the Lupus Foundation, ran a survey andfound that 2.4 million people in the United Statessaid that they had SLE. The U.S. governmentthought there were 239,000 people with SLE, andit seems likely that the true number is around halfa million.

Cause

SLE is an autoimmune disease of unknown origin.The term autoimmune implies that the body’simmune system behaves as though parts of thebody itself were foreign and therefore initiates aninflammatory attack to damage or destroy thoseparts as it would to any other foreign antigen. Whyit does this is unknown, but there are a number oftheories. Very simply put, the immune systemcould respond to a foreign antigen that is very sim-ilar to a self-antigen. Once the foreign antigen (e.g.,virus) is destroyed, the immune system mistakesthe similar self-antigen for the foreign one andcontinues a chronic inflammatory attack. The samegeneral theme could occur if the foreign antigencombined with a self-antigen or altered a self-antigen. In all these scenarios the immune systemcould start responding to other related self-antigens, a process known as antibody spreading.The initial recognition of a foreign or altered self-antigen can be by either circulating antibodies orlymphocytes known as T helper cells.

Although the initiating event remains theoreti-cal, much is known about who is at risk of devel-oping SLE and the abnormal immune processesthat lead to tissue damage. Only the main issueswill be touched here.

Genetics This clearly plays a role. There aremany reports of identical twins developing SLE.Between 5 and 10 percent of relatives of SLEpatients develop the disease. While the genetic con-tribution to SLE is clear, it is also complicated. Anumber of genes have been shown to be associatedwith an increased risk of developing SLE. However,they may have to act together with other geneseither known or as yet unknown, or different genes

systemic lupus erythematosus 263

may be important in different patients. People withthe ancestral haplotype (grouping of genes passeddown through millennia in one ancient family tree)HLA-A1, B8 (class I antigens) have long beenknown to be more likely than average to developautoimmune conditions including SLE. The class IIgenes HLA-DR2 and DR3 are also found more fre-quently than expected in SLE patients. People hav-ing a null allele (i.e., a nonfunctional gene) forCOMPLEMENT component C4 are at high risk ofdeveloping SLE. Genetic studies looking for an asso-ciation between genes for specific molecules thatplay a significant role in immune processes and thedevelopment of SLE have thrown up a large num-ber of such linkages. These include the genes forCYTOKINES TNF, IL-6, IL-10, IL-1Ra, and IL-10Ra;heat shock proteins; immunoglobulins or antibod-ies; complement receptors; and T cell receptorsamong others.

Sex hormones SLE occurs most frequently inyoung women, with a high female-to-male ratiobetween the ages of 15 and 65 years. However, thefemale-to-male ratio is 1 to 1 outside these years.This strongly suggests that estrogen plays a role inthe development of SLE, but how it does soremains unknown.

Autoantibodies SLE is termed an immunecomplex disease. This implies that there is exces-sive formation of antibodies (directed against self inthis case and therefore called autoantibodies) thatclump together with antigen and deposit out in thetissues, where they cause inflammation. Oncedeposited out in tissue these immune complexesmay bind to complement. Complement will releasefragments (C3a and C5a) that attract inflammatorycells. These mononuclear phagocytes and polymor-phonuclear leukocytes release substances thatattract other cells, cause the blood vessels tobecome leaky, and also cause direct damage to thesurrounding tissue. Platelets (the small blood cellsthat form clots) become activated and cause localthrombosis. Not all immune complexes are thesame, and they will differ in their ability to initiatethis cascade.

Many autoantibodies are tested for individuallyand have become important in various aspects ofdiagnosing and caring for patients with SLE. Some,such as the anti-DNA antibody, are named after the

substance against which they are directed. The tar-gets of others were not known when they were dis-covered, and they were named after the firstpatient they were described in, e.g., anti-Sm (forSmith), anti-Ro (SSA), and anti-La (SSB). Al-though the targets of these antibodies are nowknown, they retain the old names. The measure-ment of these autoantibodies may give differenttypes of information:

1. Assist in Making the Diagnosis (see Appendix II)Almost all patients with SLE will have a positiveANA test. A negative test therefore makes SLEunlikely. Anti-Sm, anti-double-stranded DNA(dsDNA), and anti-ribosomal P protein antibod-ies, when present, make the diagnosis of SLEvery likely, although they are not positive in allSLE patients. Antihistone antibodies (H2A,H2B) are found in a high proportion of DRUG-

INDUCED LUPUS but are not found whenhydralazine is the cause and seldom withminocycline. They are also found in other lupuspatients occasionally, and the whole pictureneeds to be considered. High levels of anti-RNPantibodies suggest that the diagnosis is actuallythe OVERLAP SYNDROME.

2. May Indicate Activity of the Disease In somepatients with a positive anti-dsDNA test, thelevel of the antibody rises before an increase indisease activity and may therefore indicate theneed for increased monitoring or treatment.This has been more useful in patients with kid-ney disease than others. Unfortunately this hasnot proved to be a simple relationship, and otherfactors need to be taken into account.

3. May Indicate an Increased Risk of Specific Complica-

tions Anti-dsDNA antibodies are associatedwith an increased risk of developing kidney dis-ease. Anti-Ro and anti-La antibodies are presentin a subset of patients with subacute cutaneouslupus erythematosus and, if found in pregnantwomen, indicate a risk of the baby being bornwith heart block and a transient rash (seeNEONATAL LUPUS). Antiribosomal P antibodies arevery specific for SLE and indicate an increasedrisk of developing liver disease or a psychosis.Antiphospholipid antibodies (see ANTIPHOSPHO-

LIPID ANTIBODY SYNDROME) are associated with an

264 systemic lupus erythematosus

increased risk of thrombosis, reduced plateletnumbers, and recurrent fetal loss.

4. May Cause Direct Damage It should be pointedout that most antibodies measured in SLE donot cause direct damage. They may have noapparent function and have simply been foundthrough careful research to give useful informa-tion, shown as above. Antibodies, however, maycause damage nonspecifically as immune com-plexes as described above, or they may directlyattack tissues. The anti-dnsDNA antibodies arecertainly important in causing kidney inflamma-tion. Although some are deposited there asimmune complexes, others appear to bind to theglomerular basement membrane in the filteringpart of the kidney. Some antibodies bind to lym-phocytes and play a role in the disorganizationof the immune system in SLE. Antibodies bind-ing to the lining cells of blood vessels (endothe-lial cells) have been found and may cause someof the vascular problems by direct attack,although there are many other mechanisms.

5. Are Useful for Research Defining the types ofantibody and their targets provide researcherswith clues as to the cause and mechanisms ofdisease. Naturally occurring antibodies also leadresearchers to make their own antibodies in thelaboratory. These have proven to be a very pow-erful tool for unraveling immune and biochem-ical processes over the past 20 years.

Cellular immunity Lymphocytes are whitecells that form a major part of the executive arm ofthe immune system (see IMMUNE RESPONSE). Theyare broadly divided into two groups, B cells and T cells. The B cells largely produce antibodies butcan also recognize potentially harmful antigens andpresent them to the T cells. Some T cells (cytotoxicT cells) can attack and destroy other cells. Thesecould be cancerous cells or normal cells infectedwith, for example, a virus. Other T cells, the T helper cells, recognize foreign antigens and stim-ulate both cytotoxic T cells and B cells to attack theforeign antigen. Other cells such as macrophagesare also involved in this cellular immune system. Alarge number of abnormalities have been describedin the cellular immune function of SLE patients,including reduced T cell numbers and function,

reduced natural killer cell function, increased spon-taneous activity of B cells, and increased respon-siveness to T cell-secreted growth factors as well asabnormal accessory cell function. Many of theseabnormalities may be a result of the chronicinflammatory process rather than the cause. Theimmune dysfunction in SLE is so widespread andcomplex that it is very difficult to tease out theimportance and cause of the various findings.

Viruses An attractive hypothesis to explainmany autoimmune diseases has for a long timebeen that someone is born with a genetic predis-position to respond abnormally to a particular im-mune stimulus. This person then meets theappropriate virus that switches on an immune re-sponse that becomes chronic and self-perpetuating.Studies looking for the implicated virus have a his-tory of turning up exciting finds followed by disap-pointment with further research. More SLEpatients than controls show evidence of previousinfection with the Epstein-Barr virus (EBV), thecause of infectious mononucleosis or glandularfever. Cytomegalovirus has been found causingserious organ damage in SLE patients, but there isno good evidence that it’s involved in the cause ofSLE. There are reports of SLE and SLE-like diseasesdeveloping after infection with human PARVOVIRUS

B19. If this is a cause of SLE, though, then it isresponsible for only a very few cases. Patients withHEPATITIS C infection often develop positive ANAtests and rarely develop an SLE-like disease. Therelationship with polyomaviruses and retrovirusesis also being investigated.

Complement Humans naturally form immunecomplexes as part of the response to many stimulisuch as infections. There are, therefore, protectivemechanisms to prevent immune complex-medi-ated disease. Complement is a series of proteinsthat work in a cascade to break large complexes upinto smaller (and therefore more soluble) ones andto bind the complexes to other cells so that theycan be removed from the blood. Deficiency of com-plement components C1, C2, and C4 are associatedwith a high risk of developing SLE, possibly due tothe impaired ability to clear the blood of circulatingimmune complexes.

Tissue damage There may be, therefore, adirect inflammatory attack on tissues mediated


through the mechanisms discussed above. Alterna-tively organ damage may occur because of loss ofblood supply. This can occur as a result of aninflammatory reaction to immune complexdeposits in the wall of the blood vessel or antien-dothelial antibody-mediated attack leading tothrombosis of that blood vessel. In additionpatients with the antiphospholipid syndrome areprone to developing noninflammatory thromboses.Antibodies acting in this way may cause choreaand widespread neurological dysfunction such asdepression and cognitive impairment (see Symp-toms below). In addition to these directly disease-related mechanisms of organ damage, SLE patientsare also susceptible to drug-related adverse effects(see Treatment below) and multifactorial diseasesuch as atherosclerosis (see Symptoms below).

Symptoms

SLE is a very diverse disease. It may come on grad-ually over years or present as a life-threatening ill-ness. Some patients have an annoying intermittentdisease, while others have an inexorably progres-sive life- and organ-threatening disease. Most SLEpatients will have nonspecific symptoms such asfatigue, nausea, loss of weight, and less frequently,fever. One or more of these symptoms is usuallypresent at the onset but does not differentiate SLEfrom many other conditions that could also causethis. The more specific lupus problems include:

Skin It is said that any rash can occur in SLE.However, a few are typical. The best known of theseis the butterfly rash over the nose and cheeks. The redraised lesions are itchy or painful and made worse orbrought on by exposure to sunlight. Similar rashesmay occur on other Sun-exposed skin. Half of lupuspatients are photosensitive. Not only does exposureto sunlight cause a rash, but it can also induce a flareof their disease in other organs. Subacute cutaneouslupus erythematosus (SCLE) is a distinct subset oflupus patients who develop raised papules or plaquesthat sometimes form circular lesions and typicallywax and wane in different Sun-exposed areas. Theymay have joint pain or arthritis but seldom any othermanifestations of SLE. Typically they have a positiveanti-Ro antibody. The skin lesions do not scar.

In contrast, discoid lupus lesions start as a papuleor plaque, become thicker, and spread, leaving a

central area of scarring. These typically occur on thecheeks but may affect other Sun-exposed areas andthe scalp, where they may cause permanent baldpatches (alopecia). Discoid lupus lesions can occuras the main feature of DLE or as part of a morewidespread SLE. Some of the other rashes that arecommon in SLE but occur in many other situationsinclude panniculitis, alopecia, urticaria, mouth andnose ulcers, LIVEDO RETICULARIS, and vasculiticlesions (see VASCULITIS). Panniculitis is felt as a deep,tender nodule and consists of inflammatory cellssurrounding an area of necrotic (dead) fat tissue.When alopecia is not associated with discoid lesionsthe hair usually grows back with successful treat-ment. Urticaria looks like hives and may be a man-ifestation of vasculitis.

Arthritis Arthralgia (joint pain) and arthritis(joint inflammation) affect more than 90 percent ofSLE patients and are present at the time of diagno-sis in over half. The arthritis affects the hands andwrists, knees, and hips most frequently but canaffect any joint. Unlike rheumatoid arthritis, it doesnot erode away the cartilage and bone at theaffected joints. However, a few patients do developdeformities of the fingers, called Jaccoud’s arthritis.The tendons may also become inflamed (tenosyn-ovitis) and occasionally rupture with very littleforce being applied. Some tendon ruptures areassociated with inflammation while others may berelated to corticosteroid therapy. INFECTIVE ARTHRI-

TIS is more common in SLE than the general popu-lation. SLE is a well-known cause of AVASCULAR

NECROSIS, and this should always be borne in mindif there is severe, unremitting hip pain.

Muscle disease SLE is one of the connectivetissue diseases that can cause polymyositis (see DER-

MATOMYOSITIS AND POLYMYOSITIS). However, a num-ber of patients with SLE also suffer muscle pain andweakness without the diagnostic changes ofpolymyositis. A MYOPATHY frequently complicateslong-term CORTICOSTEROID therapy at the doses thatpatients with severe lupus may require. This pre-sents as painless weakness of largely shoulder andhip girdle muscles of very slow onset and is there-fore quite often advanced before it is recognized.The muscle enzymes are normal. Muscle biopsyshows characteristic wasting of particular musclefibers (type II) without any inflammation. Very


occasionally long-term CHLOROQUINE or HYDROXY-

CHLOROQUINE therapy also produces a myopathy.Kidney disease This usually creeps up unno-

ticed by the patient until there is quite advanceddisease. For this reason it is important to do regularblood and urine checks to look for early signs of kid-ney disease, especially if the anti-dsDNA is positive.The urine is abnormal if there is more than 0.5 g ofprotein in all the urine passed in 24 hours or morethan five red cells and/or more than five white cellsper high-power field on microscopy. Kidney biopsycan give further information about the type andstage of the disease. Excessive leaking of proteinthrough the damaged filtration units of the kidney(glomeruli) may lead to the nephrotic syndrome(more than 3 g urinary protein per 24 hours). Thisleads to swelling of the legs and the collection offree fluid in the abdomen (ascites) and around thelungs (pleural effusions). Nephrotic patients areprone to infections and thromboses in both veinsand arteries. More severe or prolonged inflamma-tion that destroys the glomeruli reduces the numberof filtering units available and leads to kidney fail-ure. This can cause nausea, loss of appetite, tired-ness, itching, and in severe cases, diarrhea,drowsiness, coma, anemia, swelling, altered breath-ing, and fluid around the heart (pericarditis).

Neurological disease Migraine and otherheadaches that tend to be resistant to painkillersare the most common neurological symptom inSLE. Generalized seizures or those confined to asingle limb, for example, are characteristic but notcommon. Chorea is a jerky, sometimes complexmovement disorder that can affect most parts ofthe body. It can occur in other diseases and in lupusis often associated with the presence of antiphos-pholipid antibodies. SLE patients may suffer strokesfrom vasculitis of the blood vessels in the brain orvery similar problems from localized inflammationof the brain. Individual nerves, both those arisingfrom the brain and those in the limbs, may beaffected with diverse effects. The retinopathy (dis-ease of the back of the eye) seen in SLE patients isquite characteristic. A peripheral neuropathy caus-ing loss of feeling in the feet with or without weak-ness can occasionally occur. Also reported is aGuillain-Barré–like illness where progressiveweakness starts in the legs and moves up the body

a variable distance. If the muscles of respiration areaffected the patient has to be put on a ventilator.However, as long as complications can be avoided,there is often an excellent recovery. Transversemyelitis is a devastating manifestation of SLE inwhich the spinal cord is affected, causing paralysisof the lower limbs, loss of feeling below the affectedlevel, and loss of ability to control the bladder andbowel.

Long-term lupus patients may gradually developneurocognitive problems including poor memory,problems with numbers, and speech difficulties.While this may be a result of some of the specificconditions listed above, lupus patients with no pre-vious neurological problems may also be affected.A CT or MRI brain scan will often show thinningand shrinkage of the brain. Why this occurs isunclear, and no specific treatment is available.

Psychiatric disease Psychosis can be a manifes-tation of SLE. It may also complicate treatmentwith corticosteroids (usually moderate or highdoses). In the presence of both it is usual to reducethe corticosteroid dose and attribute the psychosisto SLE if it gets worse. Organic brain syndromedescribes a state of impaired concentration andmemory and possibly delirium in the absence ofany possible cause other than SLE. Depression iscommon in lupus and has been associated with theantiribosomal P antibody. This suggests that thedepression is actually caused by the lupus ratherthan a reaction to having a chronic debilitating dis-ease. Patients with lupus have been shown to havecognitive impairment (reduced mental ability)more often than the general population. However,there is nothing specific or characteristic aboutthese impairments.

Serositis The heart, lungs, and bowels eachhave a thin double layer of connective tissue sur-rounding them. This serves to separate them fromthe rest of the body and reduce friction betweenthese moving internal organs and their protectivebones and muscles. Normally there is a thin film offluid between the two layers. Inflammation cancause considerable pain but may also be painless.When it involves the lining of the lungs this istermed pleuritis, the heart pericarditis and thebowel peritonitis. Excessive fluid collects betweenthe layers and can be detected by chest X ray or


ultrasound examination and often by a carefulexamination. In SLE this collection is seldom largeenough to compress the heart or lungs and inter-fere with their function but may occasionally do so.When this occurs the fluid must be drained off withsome urgency.

Lung disease In addition to pleuritis lupusaffects the lungs in a number of ways. Pneumonitisis caused by immune complex deposition in smallblood vessels and the terminal air spaces of thelungs called alveoli. This is where gas exchangebetween air and blood takes place. Pneumonitis canbe sudden and severe when it is difficult to differ-entiate from infection. It may also come on slowlywith an irritating cough and shortness of breathduring activities. Pulmonary hemorrhage is a rarebut very serious occurrence, probably a result ofvasculitis affecting blood vessels of the lung. PUL-

MONARY HYPERTENSION may occur, although less frequently than in the CREST syndrome or SCLERO-

DERMA. In SLE it is particularly important to con-sider secondary pulmonary hypertension due toemboli or infarcts. In late-stage disease a rare butserious complication known as shrinking lung mayoccur. In this condition the chest X ray is normalbut the space occupied by the lungs becomes pro-gressively smaller with the diaphragm moving up.The patient complains of increasing shortness ofbreath, and lung function tests show reduced lungvolumes. Studies have shown abnormalities in boththe chest wall and the diaphragm, but the exactcause can be difficult to determine.

Heart disease Myocarditis or inflammation ofthe muscle of the heart may occur along withmyositis elsewhere (see Muscle disease) or in com-bination with pericarditis. The latter is usuallypainful and will lead to the diagnosis being sus-pected. If not accompanied by these other manifes-tations, myocarditis can be silent and present withestablished heart failure or heart rhythm abnormal-ities. Sophisticated testing suggests that it may bemore common than suspected. Coronary artery dis-ease will be discussed under atherosclerotic disease.

The heart valves may also be affected, leading toleaking valves, tight valves, or embolic events.Leaking valves impose a strain on the heart byrequiring it to pump increased quantities of bloodbecause a proportion leaks back. Tight valves that

do not open adequately thereby place an increasedstrain on the pumping chamber of the heart (aorticvalve) or inadequate filling of the left ventricle(mitral valve). Small collections of material maydevelop on the valves with pieces or emboli break-ing off intermittently and lodging in blood vesselsin the hands, feet, and brain particularly. Valveabnormalities are particularly associated with thepresence of antiphospholipid antibodies.

Gastrointestinal disease Almost any part ofthe gastrointestinal tract from the mouth to thelower bowel may be affected by SLE. Mouth ulcersoccur in roughly half of patients. Swallowing diffi-culties are usually due to the dryness of associatedSJÖGREN’S SYNDROME, but poor muscle contractionand reflux of stomach contents similar to that inthe CREST syndrome are also found. The mostcommon stomach complaints are those related toNSAID use, but there is an association with atro-phic gastritis and vitamin B12 deficiency.

SLE patients with abdominal pain may, of course,have any of the causes anybody else might have.However, it has been shown that if the SLE is activein a number of other areas it is much more likelythat the abdominal pain is directly related to lupusrather than due to something else such as gallstones.Most severely ill patients with an acute abdomenand active lupus have an ischemic bowel (loss ofblood supply) due to either vasculitis or a thrombo-sis. These patients need urgent surgery since they donot do well. SLE patients get bacterial overgrowth inthe small bowel more frequently than expected. Thiscauses bloating, diarrhea, constipation, and abdomi-nal pain and is treated with broad-spectrum antibi-otics. Chronic intestinal pseudo-obstruction iscaused by dysfunction of the smooth muscle in thebowel wall and has been reported in many SLEpatients. Protein-losing enteropathy (excessive pro-tein is lost in the stools) and various forms of malab-sorption are also rarely found. Many patients withCROHN’S DISEASE (a chronic inflammatory bowel dis-ease) have positive ANA tests, but it is not clear thatthere is a true association between the two diseases.Pancreatitis is usually associated with alcohol or gall-stones in the general population, and these may befactors in some lupus patients. However, some casesof pancreatitis in SLE patients appear to be due tothe disease itself and some related to medication.


Liver disease The most common cause of liverabnormalities on blood testing are medicationstaken for the SLE. These were most often aspirin,NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs),or AZATHIOPRINE. The liver is unusual in that in addi-tion to its normal arterial supply it has a large veinbringing blood into it for detoxification, the portalvein, and a large vein taking blood out toward theheart, the hepatic vein. Thrombosis of either ofthese veins can occur, especially in the presence ofthe antiphospholipid syndrome. If the portal veinthromboses, there is a build up of pressure in thegut and swelling due to fluid in the peritoneal cavity (ascites). If the hepatic vein thromboses(Budd-Chiari syndrome), ascites also occur, but inaddition there will be liver damage. Hepatitis orinflammation of the liver occurs and is associatedwith anti-dsDNA and antiribosomal P antibodies.The differentiation between viral hepatitis, espe-cially hepatitis C and SLE, can occasionally poseproblems. SLE can cause a false-positive screeningtest for hepatitis C, and many patients with chronichepatitis C develop positive ANA and joint pain. Inaddition, alpha interferon, used in the treatment ofhepatitis C, can occasionally induce SLE.

Blood system abnormalities Low white cellcount (leukopenia) as well as neutropenia andlymphopenia are common in SLE itself but occa-sionally can be a side effect of immunosuppressivemedication. Doing a bone marrow examination todifferentiate between these causes may be neces-sary. Lymphopenia is usually associated with activelupus elsewhere. A low platelet count is commonin SLE. Platelets are the smallest blood cells and ini-tiate clotting in response to damage to a blood ves-sel. A few patients present with bleeding and verylow platelets as the first manifestation of SLE. Theplatelet count can also vary with the activity of thedisease, improving with successful treatment.Patients with antiphospholipid syndrome fre-quently have a low platelet count without havingactive inflammation. Anemia is common, andthere are a number of possible causes. Chronicinflammation causes anemia as does kidney dam-age; blood may be lost into the gut; and SLEpatients may develop autoimmune hemolytic ane-mia. This hemolytic anemia is due to antibodiesdirected against the red cells.

The spleen is involved in the body’s normalprocesses for getting rid of immune complexes. It isprobably for this reason that the spleen is fre-quently enlarged in lupus, although it can also bedamaged and shrink. Many patients with lupushave enlarged lymph nodes at some time, and typ-ically these fluctuate in size. Very occasionallytumors may develop in the spleen or lymph nodes.

Complement levels are low in active SLE due toincreased consumption by immune complexes.Very rarely inherited low levels may be the cause oflupus.

Atherosclerotic disease Since improved treat-ment of SLE leads to increased life expectancy, ath-erosclerotic disease has become a more and moreimportant cause of illness and death in lupuspatients. A growing amount of evidence indicatesthat inflammation plays an important role in theinitiation and progression of the fatty plaques thatdevelop on the walls of blood vessels and finallylead to a manifestation of atherosclerosis. The fourmost common manifestations are myocardialinfarction, stroke, peripheral vascular disease (poorcirculation to the legs leading to dry gangrene insevere cases), and atherosclerotic kidney failure.Atherosclerosis is common in older individualseven if they do not have any risk factors. However,the presence of risk factors makes the disease pre-sent at a younger age and may make it moresevere. Risk factors are additive in that the more aperson has the greater the risk at, for example anygiven blood pressure or cholesterol level. The tradi-tional risk factors are smoking, high blood pressure,raised cholesterol, and diabetes. Obviously SLEpatients may also have these.

When the blood-vessel lining cells (endothelialcells) are activated they push signaling moleculescalled adhesion molecules, particularly ICAM-1 andE-selectin, through their walls to stick into the sur-face. White blood cells rolling by recognize these,activate, and stick onto the wall. Release of cytokinestakes place and a low-grade inflammatory process isset up. Activation of the endothelial cells is inducedby low-density lipoprotein (in patients with highcholesterol), advanced glycosylation end products(in diabetes), and also immune complexes, activatedlymphocytes, and antiphospholipid antibodies. Inthis way SLE may be a powerful risk factor for


atherosclerotic disease separate from more traditionalrisk factors. There may also be an effect through tra-ditional risk factors in that lupus may cause highblood pressure. Treatment with corticosteroids mayincrease blood pressure, cause diabetes, worsen cho-lesterol, and make platelets more sticky than usual.

Although the mechanisms are not completelyworked out, lupus patients are clearly at increasedrisk of atherosclerotic complications. Womenbetween the ages of 35 and 44 years have a verylow risk of myocardial infarction normally. How-ever, women at these ages with SLE have a 50times greater risk than those without. Even whenall the traditional risk factors were controlled for(see CLINICAL TRIAL), SLE patients had a nearly fivetimes greater risk of carotid atherosclerosis thancontrols. The carotid arteries take blood to thebrain.

Pregnancy and SLE Women with SLE havespecial problems with pregnancy. This is not just inthose with antiphospholipid antibody syndrome(see relevant section) but in many others as well.The remarks here relate mainly to SLE patientswithout the antiphospholipid syndrome. There issome disagreement about whether pregnancymakes lupus more active, but many people think itdoes. Certainly it does not improve in pregnancy asrheumatoid arthritis does. Patients with SLE whodo get pregnant tend to have slightly more miscar-riages, more premature deliveries, and babies witha lower birth weight than controls. Active kidneydisease is a strong predictor of a poor outcome forthe pregnancy. High blood pressure is a predictor ofpremature delivery and low-birth-weight babies(see PREGNANCY).

Patients with anti-Ro (SSA) antibodies may givebirth to children with NEONATAL LUPUS (approxi-mately one in four infants). This is caused by themother’s antibodies crossing the placenta and doesnot mean that the infant is going to have SLE.These infants have a characteristic rash, sometimesdisturbed liver tests and an abnormal blood count,and most seriously but less commonly, heart block.In heart block the electrical conducting system isdamaged so that impulses from the top half of theheart do not travel to the lower, pumping half,which therefore beats very slowly. The antibodiesclear in a few weeks, and the blood, liver, and skin

problems subside. However, the heart block may bepermanent, and the majority of infants require apacemaker. If mothers are shown to have the par-ticular anti-Ro antibody, the risk of their child hav-ing heart block is about 12 percent. Women withanti-Ro antibodies also seem to have a higher mis-carriage rate. This may be related to the heart blockdeveloping in utero.

Diagnosis

Because SLE can present in so many different waysand affect so many different organs, patients withSLE can apparently have quite different diseases.One patient may have trouble with skin rashes andarthritis, another mainly kidney disease, and athird psychiatric problems, yet they all have SLE.So that the diagnosis of SLE is fairly consistent fromplace to place, the American College for Rheuma-tology (ACR) developed and refined criteria forclassification of SLE. Currently the 1982 revisedcriteria are used. These are classification criteriaand are therefore not essential for the diagnosis.However, if a patient did not meet four out of the11 criteria, the evidence for SLE would have to bevery good. For example, a patient may have typicalkidney disease and positive ANA and anti-dsDNAtests and therefore have definite SLE despite fulfill-ing only three criteria. The 11 criteria include threetypical rashes, mouth ulcers, arthritis, serositis, kid-ney disease, nervous system or psychiatric disorder,blood abnormalities, positive ANA, and one of sev-eral other immunological tests. Each criterion hasclear definitions.

The diagnosis of SLE has become much easierwith improved immunological testing over the past15 years (see autoantibodies under Cause). Allpatients should be checked for lupus anticoagulantand antiphospholipid syndrome on diagnosis andfor any thromboses. Low white cell counts are com-mon as is anemia and thrombocytopenia or lowplatelet count. Thrombocytopenia is particularlycommon in patients with the antiphospholipid syn-drome. The ESR is usually raised in active diseaseand is a fairly reliable indicator of this, although itcan also be raised due to a high protein level, kid-ney impairment, and other unrelated factors. Theprotein level is sometimes raised because of theexcessive antibody formation. Low complement


components C3 and C4 usually reflect increased useto solubilize immune complexes but may occasion-ally be the result of an inherited deficiency.

If central nervous system involvement is sus-pected, an MRI scan may be helpful, although itcan be completely normal in lupus involving thenervous system. Newer magnetic resonance tech-niques such as quantitative magnetic resonance,magnetization transfer imaging, magnetic reso-nance spectroscopy, and diffusion-weighted imag-ing give further information in various ways but donot provide a diagnostic test. They are also notwidely available, and conventional MRI remainsthe technique of first choice. A lumbar puncture isusually done as well. This may show increased cellsor protein but may also be normal. A tracing ofbrain waves (EEG) is often abnormal but does notdetermine whether SLE is causing the abnormali-ties. Other organs are imaged as indicated by thepatient’s problems.


The treatment of SLE varies considerably frompatient to patient and from time to time, accordingto which problems are active at any particular time.Some therapies need to be ongoing, but others arerequired only to settle a given manifestation andcan then be discontinued. Since SLE can go intoremission there will also be periods when no treat-ment is required. However, except in very mild dis-ease, some form of ongoing monitoring is requiredsince activity can flare at any time. A number ofscoring systems have been developed to assess thedisease activity in this disease that can affect differ-ent organs at different times. The best known is thesystemic lupus erythematosus disease activity indexor SLEDAI. This notes the presence or absence of 24features of activity and weights them according toseriousness. The treatment of SLE is therefore verydependent on the particular manifestations andtheir severity. Much of this is highly specialized.This section will just give a brief overview of com-mon treatments used, some of the newer develop-ments, and then some comments on outcome.

General measures

• As mentioned above regular contact with a physi-cian experienced in treating SLE is important to

monitor both the disease and many of the thera-pies. Relying on symptoms is not sufficient sincekidney disease and blood or liver disorders, forexample, may cause no symptoms until welladvanced. These are more usually picked up onlaboratory testing.

• Sunlight is not only a frequent cause of rashesbut also causes systemic illness. Any excessivesunlight should therefore be avoided and high-factor sun protection worn when exposed.Wearing hats and long sleeves is advisable whenoutdoors in summer. Sunlight coming throughwindows can also cause problems. There is avariation in photosensitivity, and some SLEpatients are even sensitive to fluorescent light.

• Infections are common in patients with SLE andshould be looked for whenever someone devel-ops a fever. Antibiotic prophylaxis should beused for procedures on the teeth, bladder, orbowel in patients with heart valve abnormali-ties. An annual flu vaccine is advisable. If thespleen has been removed, vaccination againstpneumococci is essential. This is usually donebefore the spleen is removed unless it is anemergency.

• Some of the drugs used in SLE are potentiallytoxic to the fetus, and effective contraceptionshould be in place for women of childbearingage. Pregnancy in SLE should be carefullyplanned and treated as a high-risk pregnancyfrom the beginning (see PREGNANCY).

• Education leading to a better understanding ofthis rare and potentially severe disease is impor-tant in developing coping strategies. Informationis obtained from the patient’s physician, infor-mation booklets, and SLE patients supportgroups.

• No patient with SLE should smoke.

Established treatments Many treatmentstrategies in SLE have been developed on anempiric basis (i.e., without understanding exactlyhow they work) and refined through controlled tri-als where possible. Being a rare disease, however,makes it difficult for many treatments to be studiedin a controlled manner in enough patients. The fol-lowing drugs have an accepted role in treating SLE:


• NSAIDs are commonly used for muscle, joint, orsoft tissue pain and may be helpful for mildserositis. All the commonly used NSAIDs areeffective, although some people respond betterto one than to another. Patients with poor kid-ney function should take particular caution withusing NSAIDs since they will be more than usu-ally susceptible to the kidney-related side effectsof these drugs. Noninfectious meningitis is avery rare adverse effect of NSAIDs, and SLEpatients are said to be more prone to developthis than others, particularly with ibuprofen.

• Corticosteroids are the most frequently useddrug in sudden flares of disease and, in adequatedosage, are effective in most forms of SLE. Thereare skin and eye preparations (several availableas tablets), preparations for injection into jointsand soft tissues, and intravenous preparationsfor use in different situations. The particularform or preparation used is chosen to suit thepurpose and resolve symptoms with the mini-mum total corticosteroid dose. Once the inflam-mation is settled the dose is usually reducedsteadily to the minimum that will keep thingsunder control. If control is not possible at a lowdose, other agents will have to be added to avoidthe long-term adverse effects of corticosteroids.Although extremely safe in the short term, cor-ticosteroids have very significant long-termadverse effects. These are related to the totaldose and length of treatment (see CORTICO-

STEROIDS in Appendix II).

• Antimalarials are very useful in treating skinmanifestations as well as arthritis and help withthe mild nonspecific symptoms such as fatigueand mild fever.

• HYDROXYCHLOROQUINE is most commonly used,but others include CHLOROQUINE and quinacrine.Patients on long-term hydroxychloroquine dohave fewer flares. Rashes are not uncommonwith hydroxychloroquine, but the most concern-ing adverse effect is the possible toxicity to theeye with long-term use. These drugs bind to someof the pigment at the back of the eye (retina) andcan cause changes that lead to loss of vision. Withlow doses this is very unusual, but yearly eyechecks by an ophthalmologist are advised. Fortu-

nately the changes are visible before any loss ofvision occurs, and no deterioration occurs if thedrug is then stopped. There are concerns abouttoxicity to the fetus if the patient becomes preg-nant, although a growing number of lupuspatients have taken hydroxychloroquine duringpregnancy (to control active disease) and havehad normal healthy infants.

• AZATHIOPRINE is widely used in active SLE, espe-cially when it is only possible to control inflam-mation with only a relatively high dose ofcorticosteroids. When used in this situation, itlowers the number of flares, reduces the sever-ity of illness, allows a lower dose of PREDNISONE

to be used, and improves kidney function. Theseresults were seen in a four year randomized,controlled study. As would be expected, show-ing these results in shorter trials is difficult.There is some disagreement about its effective-ness in inflammation of the kidney (nephritis).Azathioprine would generally not be the drug offirst choice here, although it may be used lateron in therapy or in patients with mild disease.Adverse effects include liver reactions and lowblood counts, and regular monitoring blood testsare required for these to be picked up early. Itseems likely that some tumors of the lymphnodes (non-Hodgkin’s lymphomas) occur morefrequently in patients on long-term azathioprinetherapy, but this remains a very rare occurrence.

• CYCLOPHOSPHAMIDE is a potent immunosuppres-sive drug and has emerged as the drug of choicein severe kidney inflammation due to SLE. It isalso commonly used in other life- or organ-threatening situations such as vasculitis orinflammatory nervous system lupus. It is usuallybest given as intermittent pulses of intravenoustherapy. Common adverse effects include nauseaand vomiting and there is always a drop in whitecell count. Red cells and platelets may drop aswell but usually with longer term treatment.Patients on cyclophosphamide are at increasedrisk of infections. Fertility may be affected. Inmen who wish to raise a family subsequently, itis possible to store sperm obtained prior to treat-ment. Young women about to undergo treat-ment with cyclophosphamide have been treated


with the contraceptive pill to try to protect theirovaries. Now an agent called leuprolide caninduce a prepubertal state, and trials are underway to see if this will protect women’s ovariesduring treatment. Irritation of the bladder maybe severe if MESNA is not used to protect it. Thereis an increased risk of malignancy, usually after anumber of years, and predominantly cancer ofthe bladder. Because of these serious potentialadverse effects, cyclophosphamide is reserved forvery serious disease and increasingly, courses areshort with other agents being substituted oncethe disease is well controlled.

• METHOTREXATE has been less used in SLE than aza-thioprine. Some evidence does show that it iseffective, especially for arthritis, rash, and serositis.Its use is similar to that in rheumatoid arthritis.

• DAPSONE is used occasionally for skin lesions,especially one called lupus profundus.

• INTRAVENOUS IMMUNOGLOBULIN (IVIG) is used in anumber of autoimmune conditions, although itsmechanism of action remains unclear. In SLE itsmain use is in the treatment of thrombocytope-nia (low platelets).

• DANAZOL is a weak androgen (male hormone)that is useful in the treatment of thrombocytope-nia. It must not be used in pregnancy or whilebreast-feeding. The chief adverse effects are hor-monal, with disturbed menstrual cycle and some-times male hormone effects such as excess hairgrowth. Occasionally liver tumors can developwith androgenic agents including danazol.

• Attention to risk factors for atherosclerosis isvery important. Hypertension should be verywell controlled, lipid profiles known and treatedif necessary, prophylactic low-dose aspirin con-sidered, especially if corticosteroids are beingused, corticosteroid dose minimized, and homo-cysteine measured and controlled, especially inrenal impairment. The antiphospholipid syn-drome is a risk factor for thrombosis and needstreatment in its own right.

Newer and experimental approaches

• MYCOPHENOLATE MOFETIL is a newer immunosup-pressant that has shown promise in early studies

and is being investigated as a treatment forlupus nephritis. Mycophenolate mofetil is usedin clinical practice as an alternative to azathio-prine.

• DHEA or dehydroepiandrosterone has achievedsome popularity among patients with SLE. It is aweak androgen (male hormone). One random-ized controlled trial has shown minor improve-ment in activity scores and fewer flares. Thepatients on DHEA also felt better overall. In aone-year trial, more than half the patientsstopped taking DHEA, mostly because theyeither felt no better on it or they developed malehormone side effects, most commonly acne andincreased facial and body hair. DHEA may havea beneficial effect on bone density, which is fre-quently a problem in SLE patients. BecauseDHEA is available over the counter, people havebeen taking a variety of doses, sometimes dic-tated more by cost than evidence. There is littleinformation about the long-term side effects ofDHEA.

• Bromocriptine has undergone a well-conductedrandomized controlled study in SLE. It had beenfound that a number of SLE patients had raisedprolactin. This is a hormone released in thebrain that plays a major role in lactation but hasalso been found to have effects on the immunesystem. Although there were minor differencesin the groups of patients, this study showed noreal benefit of bromocriptine.

• CYCLOSPORINE was found to be effective in treat-ing patients with severe kidney inflammation(nephritis) in whom either azathioprine orcyclophosphamide had not worked. This was nota controlled trial, however, and the role forcyclosporine is not yet clear. Cyclosporine wascompared with prednisolone (a corticosteroid)and cyclophosphamide together in children withlupus nephritis. Although both groups didequally well from the kidney point of view, thoseon cyclosporine grew better. This was thought tobe due to avoiding the stunting effects of corti-costeroids in children. Concerns remain, how-ever, about using conventional courses ofcyclosporine in children.


• Stem cell or bone marrow transplantation (seeBONE MARROW TRANSPLANTATION) have been usedto treat a number of severe autoimmune dis-eases. In these procedures stem cells are firstobtained from the patient or a compatibledonor. The patient’s bone marrow (the organresponsible for making all blood cells) is de-stroyed using very high doses of cyclophos-phamide. In a variation of this a small group ofvery severe SLE patients have been treated with high doses of cyclophosphamide that allbut destroys the bone marrow. However, theremaining cells grow back after about twoweeks, and all patients in this group haveimproved, some quite dramatically. A numberappear to relapse about three years after theprocedure. This is a high-risk procedure andclearly appropriate only for people with severedisease resistant to other treatments.

• LEFLUNOMIDE, a relatively new drug that is wellestablished in rheumatoid arthritis, has beentried at high doses in SLE. Some patients haveresponded well but others hardly at all, and itsplace in the treatment of SLE is not clear.

• With the explosion of knowledge and rapidtechnological advances in immunology over thepast 10–15 years, the possibility of usingimmunological methods to alter immuneresponses has arisen. Antibodies are made inresponse to antigens, usually part of anunwanted foreign particle. It has been knownfor some time that antigens given by certainroutes in certain doses cause the immune sys-tem to accept them rather than produce animmune response against them (immune toler-ance). This immune response would involveantibody production by B cells orchestrated byCD4 T cells. Therefore, if the antigen that wasdriving autoantibody production in SLE couldbe given in the right dose by the right route, per-haps the autoimmune process could be turnedoff. Although this rather simplifies things, a lotof research has been done over the past fiveyears trying to develop a B cell toleragen (theantigen that could induce tolerance) or T cellvaccine that might achieve this. To date work

has been done only in animals that developlupus or with laboratory-grown cells. There aremany problems. One is that although the mole-cule against which autoantibodies are directedmay be known, e.g., DNA, the antigen is only asmall fragment of that molecule. Finding thespecific portion that is antigenic is difficult. Thisis compounded by there being more than oneantigen.

Outcome The average survival of patients withSLE has improved in recent decades. More than 90percent of patients survive five years from diagno-sis, and more than 80 percent survive 10 years.Within that there is some variation. Youngerpatients do better than older patients, and higherlevels of socioeconomic achievement also predict abetter outcome. Those without organ-threateningdisease or the antiphospholipid syndrome have vir-tually a normal life expectancy, whereas those withsignificant organ damage within the first year ofdiagnosis have a slightly reduced 10-year survivalof 75 percent. Deaths tend to occur early, in thefirst five years, or late, after 15 or more years fromdiagnosis. The improvement in survival has comemainly from a reduction in the early deaths.

The three main causes of death in SLE patientsare organ failure, infection, and cardiovascular dis-ease. Organ failure chiefly involves kidney failure,central nervous system involvement, or multiorganfailure from severe, active SLE. Patients are at riskof infection by virtue of having SLE as well as fromtheir immunosuppressive treatment. The mostcommon sites of fatal infections are the lung, blad-der, and joints. Most fatal infections are from bac-teria that commonly cause infections in the rest ofthe population as well. High corticosteroid dose,immunosuppressive treatment, and a low whitecell count are, however, risk factors for unusual oropportunistic infections. Cardiovascular diseaseleading to strokes, heart attacks, and impairedblood supply to the legs is made worse by the samethings that affect everyone else (smoking, highblood pressure, etc.), but the disease clearly plays amajor role as well.

systemic sclerosis See SCLERODERMA.

274 systemic sclerosis

T

tai chi chuan One of a group of therapies knownas “mind-body” therapies. In Tai chi chuan mythol-ogy the Taoist monk Chang Sanfeng created themovements that have become Tai chi chuan basedon a dream about a fight between a bird and asnake. This certainly gives a good image of themovements. It is the flowing from one pose toanother, blending the eternal and ephemeral.

There are claims that it massages the innerorgans, improving blood and lymph flow, increasesenergy flow, calms the mind and body, and opensjoints. Controlled trials in these areas are few. Acontrolled trial shows that Tai chi chuan does not make RHEUMATOID ARTHRITIS worse. There isinterest in the prevention of falls (especially inolder people), and controlled studies have shownimprovement in balance and strength in peopleundertaking Tai chi chuan for at least six monthscompared with control groups.

Takayasu’s arteritis (pulseless disease) A type ofVASCULITIS that affects large blood vessels. It affectswomen at least five times as often as men and usu-ally starts between the ages of 10 and 40 years.Takayasu’s arteritis occurs globally, but there arelarge geographic variations in frequency. It is com-mon in India and Japan, but in the United Statesthere are only approximately three new cases permillion people a year.

Cause

Takayasu’s arteritis affects large arteries such as theaorta and the blood vessels to the neck (carotidartery) and arms (subclavian arteries) and causesinflammation that leads to scarring and narrowing.The geographic differences in frequency ledresearchers to seek infectious or genetic causes, butso far no cause has been identified. In Japan a cer-

tain tissue type, HLA-Bw52 (see HLA) is associatedwith an increased risk of Takayasu’s arteritis, butthis is not the case everywhere. An autoimmuneprocess may be involved because affected arteriesare very inflamed and have a lot of white bloodcells infiltrating their walls. Takayasu’s arteritisoccasionally occurs in patients who have SYSTEMIC

LUPUS ERYTHEMATOSUS, ERYTHEMA NODOSUM, orINFLAMMATORY BOWEL DISEASE. The presence of anti-bodies to the inner lining layer of blood vessels, theendothelium, in some patients is an additional clueimplicating autoimmunity as a cause. However,even if an autoimmune reaction is the cause, thetriggers and mechanisms are not clear.

Symptoms

Nonspecific systemic symptoms such as loss ofweight, fatigue, athralgia, myalgia, and low-gradefever are common. High blood pressure is commonif the disease affects the arteries to the kidneys.Later in the disease symptoms caused by inade-quate blood supply to particular organs can occur.The pattern of these symptoms depends on theblood vessels and organs affected. For example, ifTakayasu’s arteritis affects blood vessels to the heartor brain, angina or stroke can occur. Inflammationat the base of the aorta often affects the aorticvalve, causing it to leak and lead to heart failure. Ifthe blood vessels to the arms or legs are affected,the patient may feel severe pain in the musclesduring exercise. This happens because the bloodsupply to the exercising muscle is inadequate. Thistype of limb pain that comes on with exercise anddisappears with rest is called claudication.

Diagnosis

The diagnosis is made based on the physical find-ings and imaging of the arteries, usually by ARTERI-

275

OGRAPHY (see Appendix II). The American Collegeof Rheumatology has published classification crite-ria that require three of the following six criteria.

• Onset of symptoms before the age of 40 years

• Claudication

• A decreased or absent pulse in one of the arter-ies in the arm

• A difference in blood pressure between the twoarms

• A bruit over a large artery; a bruit is a blowingnoise that can be heard with a stethoscope

• Narrowing of a large artery on arteriography that isnot explained by atherosclerosis or another disease

Classification criteria were developed mainly forresearch purposes and are not always helpful inmaking the diagnosis in an individual patient.

Physical examination is very helpful becauseatherosclerosis is extremely rare in young women,the group most likely to develop Takayasu’s arteri-tis. Therefore if there is no pulse in an artery in ayoung woman, the diagnosis should be suspected.Blood tests are not very helpful. The ESR (seeAppendix II) is a nonspecific marker of infection orinflammation that is often elevated, particularly ifthe disease is active. Arteriography is usually per-formed and shows smooth narrowing of largearteries. In patients with narrowing caused by ath-erosclerosis the narrowing is much more irregular.


CORTICOSTEROIDS, initially in high doses, are used tocontrol the disease. The dose of corticosteroid istapered slowly. If this is not possible, another drugsuch as METHOTREXATE is added. It is difficult forphysicians to know how active the disease is. Old,established scarring will not improve with aggres-sive therapy, but active inflammation will. The ESRcan be a clue to how active the disease is. Perform-ing arteriograms repeatedly is difficult because theprocedure is invasive, requiring that an artery bepunctured and dye injected into it. New MRI tech-niques are less invasive and have provided goodimages of arteries after dye is injected into a vein.These less invasive imaging techniques can easilybe repeated and may provide a way to evaluate the

activity and progression of the disease.Scarring and narrowing of arteries is permanent,

and some patients require surgery to bypass ablocked artery. Alternatively a stent (a steel framethat expands and keeps the artery open) can beplaced in the narrow segment of the artery. If thedisease affects the aortic valve, heart surgery toreplace the valve may be needed. Takayasu’s arteri-tis is a chronic disease. The overall prognosis is good,and approximately 90 percent of patients are alivefive years after diagnosis. Patients with progressivearterial disease or complications such as stroke orheart involvement have a worse prognosis.

tarsal tunnel syndrome This is the foot equiva-lent of CARPAL TUNNEL SYNDROME and is discussedunder FOOT PAIN.

temporal arteritis Also known as giant cell arteri-tis and cranial arteritis, this is an inflammatory dis-ease affecting large- and medium-sized arteries,particularly around the head (see VASCULITIS). It isfound throughout the world but appears to be morecommon in Caucasian people. It almost exclusivelyaffects people over the age of 50 years and womenthree times as often as men. In the United Statesbetween 15 and 20 people in every 100,000 overthe age of 50 get temporal arteritis each year.

Cause

The cause is unknown. Several families exist wheremore than one member has developed the disease.So-called clustering of the disease has also beenobserved in husband and wife, neighbors, friends,and small areas within a village. This suggests somefactor in the environment may trigger the disease,but no obvious candidates exist. A number of viruseshave been investigated as a possible cause withoutpositive results. One report found a strong associa-tion with contact with pet birds, but this has notbeen confirmed. Large- and medium-sized arterieshave an elastic layer in their walls, and it is here thatthe inflammatory attack seems to be concentrated.Lymphocytes, a few neutrophils, and the character-istic giant cells gather here to produce a granuloma-tous inflammation that affects blood vessels inpatches. The wall of the artery is damaged, and itmay clot off (thrombose). Arteries of the head and

276 tarsal tunnel syndrome

neck are particularly affected, but others may also beinvolved. These less frequently involved arteries areusually the aorta (the main blood vessel taking bloodfrom the heart to the rest of the body) and its imme-diate branches. Interestingly the blood vessels withinthe brain are seldom affected, although the mainsupply vessel, the internal carotid artery, is very fre-quently involved as is its branch to the eye.

Symptoms

General symptoms are common and may havebeen present for months before specific symptomsoccur that allow a definite diagnosis to be made.These include fever, weight loss, tiredness, and lossof appetite. Headaches in someone with thesesymptoms are the most suggestive specific symp-tom. Headaches often begin early and may be verysevere. They are most frequently felt over the tem-ple and are often associated with tenderness of thescalp to even light touch. The arteries running upacross the temple to supply the scalp (temporalarteries) may be swollen and tender and lack thenormal pulsation of an artery.

As with most forms of vasculitis, the most dev-astating effects are those that result from thrombo-sis of an artery and the consequent loss of bloodsupply to a part of the body. In temporal arteritisblindness due to thrombosis of an artery takingblood to the eye (usually the central retinal artery)is the most feared thrombotic complication. Someeye symptoms occur in over 30 percent of patients,but actual loss of vision occurs in less than 10 per-cent. This is not always complete. However, com-plete, sudden, painless loss of vision is the mostcommon form. If one eye is affected the other eyeis at high risk.

Pain in the jaw on chewing sometimes accom-panied by tingling of the tongue and loss of taste isvery characteristic but not very common. Occa-sionally splitting of the wall of the aorta or evencomplete rupture can occur. When the larger ar-teries are narrowed by vasculitis, it is sometimespossible to hear the sound of irregular blood flowthrough these vessels (termed bruits, pronouncedbrooees). Usually this is heard by the doctor listen-ing over the vessels with a stethoscope. Whenarteries of the head and neck are affected, thepatient can sometimes hear these bruits. Temporal

arteritis can also cause strokes, depression, confu-sion, deafness, and damage to the nerves to the feetand lower legs, although these are not common.Heart attacks have been described and liver func-tion test abnormalities are common, although sel-dom serious. There is an association betweentemporal arteritis and POLYMYALGIA RHEUMATICA, butmost patients with temporal arteritis do not havepolymyalgia. Between 5 and 10 percent of patientswith either temporal arteritis or polymyalgia have autoimmune thyroid disease. The thyroid dis-ease usually precedes the temporal arteritis bysome years.

Diagnosis

If there are typical symptoms such as newheadaches and jaw pain on chewing, the diagnosisis not difficult. However, these symptoms may beintermittent or not present in the early stages, anda patient may just present with mild fever andweight loss, for example. It is therefore importantto consider temporal arteritis in patients over theage of 50 years with these nonspecific symptoms.All the arteries running over the scalp should beexamined, not just the temporal arteries. The ESR isalmost always raised. The most definitive test is totake a biopsy of an artery that is thickened and ten-der and show that there is granulomatous inflam-mation invading the wall of the vessel. A fewpatients have had a positive temporal artery biopsybut a normal ESR, but this is very unusual. Thereis often a nonspecific rise in the alpha globulins (agroup of proteins in the blood) and in other mark-ers of inflammation such as the C-reactive protein.These are not any more helpful than the ESR,however. Abnormal liver tests are common but notusually of any significance.


CORTICOSTEROIDS (usually prednisone) are the main-stay of treatment. They are effective in controllingthe inflammation and preventing complicationssuch as blindness if used correctly. However, thetreatment usually needs to be continued forbetween two and three years, and there are signifi-cant side effects possible if prednisone is used forthis length of time. Indeed, after the first three tofour months, management of corticosteroid side

temporal arteritis 277

effects becomes more difficult than management ofthe vasculitis. The principles of managementinclude the following.

Adequate early treatment This is done toachieve control of the inflammation. For most peo-ple 40–60 mg of prednisone a day for the firstmonth is the preferred dose. Lower doses or rapidreduction lead to relapse, and higher doses exposethe patient to excessive amounts of prednisone thatare unnecessary in the vast majority of patients.Higher doses are traditionally used in thosepatients with visual symptoms.

Prevention of early thrombosis Inflamed arter-ies are at risk of thrombosing. Corticosteroids causealterations in the blood favoring thrombosis. Thereare numerous reports of patients with temporalarteritis going blind within 48 hours of startingprednisone therapy. While not proven it is possiblydue to this increased risk of thrombosis. A treat-ment to prevent this start low-dose ASPIRIN therapystarted at the same time or just before the pred-nisone. It is unlikely that controlled trials to testthis strategy can ever be done, but given currentknowledge it is safe and sensible.

Prevent osteoporosis Many patients will beolder women who are already at risk of postmeno-pausal osteoporosis. Corticosteroid therapy increasesthe rate of bone loss. Any at-risk individual startinglong-term corticosteroid therapy should receive pro-phylaxis for at least the duration of therapy. This isbest achieved with calcium and vitamin D supple-ments and a bisphosphonate such as ALENDRONATE,

RISEDRONATE, or cyclical ETIDRONATE, although otheragents are becoming available (see OSTEOPOROSIS).Hormone replacement therapy would not be a first-choice therapy here because of the slightly increasedrisk of thrombosis associated with its use.

Reduce the corticosteroid dose gradually Theideal rate of reduction is not known and will varybetween patients. As a general guideline, gradualreduction to 10 mg a day of prednisone over thefirst four to six months is reasonable. The dose isthen reduced more slowly, for example by 1 mgevery one or two months if the patient remains inremission. Reducing the dose too rapidly increasesthe risk of relapse, and patients who relapse end uprequiring greater amounts of prednisone. Patientsvary in how rapidly the corticosteroid dose can be

reduced. Monitoring both symptoms and the ESRis important when altering the dose.

Minimize the total dose of corticosteroids Thenumber and frequency of adverse effects from thecorticosteroids is proportional to the length oftreatment and the total dose of corticosteroids. Theabove strategies will minimize the total dose andthe common adverse effects.

A few patients will not be able to reduce theirprednisone dose within a reasonable time framewithout symptoms flaring. These patients may betreated with an immunosuppressive agent such asMETHOTREXATE, AZATHIOPRINE, or even CYCLOPHOS-

PHAMIDE with success. Temporal arteritis appears to be a self-limiting

disease. If patients are able to come off therapywithout any complications, they are likely to dovery well. The early problems are largely related tothe serious vascular disease and include blindnessand strokes. The later problems are related to thecorticosteroid therapy and include weight gain,vascular disease, osteoporosis, easy bruising, dia-betes, and poor control of blood pressure.

tendinitis See SOFT TISSUE ARTHRITIS–RELATED

PROBLEMS.

tennis elbow See EPICONDYLITIS.

thrombangiitis obliterans See BUERGER’S DISEASE.

thrombocytopenia A low platelet count. Plateletsplay an important role in blood clotting, and themajor problem caused by a low platelet count is anincreased risk of bleeding. Paradoxically, some con-ditions that cause a low platelet count such asheparin-induced thrombocytopenia (HIT) andthrombotic thrombocytopenic purpura (TTP)increase the risk of clotting.

Cause

A low platelet count is usually the result of one oftwo processes, decreased production or increased de-struction. Decreased production of platelets can oc-cur with any condition that affects the bone marrow,the site of platelet production. An example is cancerthat has spread to the bone marrow. Drugs, mostoften anticancer or immunosuppressive drugs, can

278 tendinitis

suppress the bone marrow and decrease its ability tomake platelets. For example, CYCLOPHOSPHAMIDE, adrug used to treat VASCULITIS and SYSTEMIC LUPUS ERY-

THEMATOSUS (SLE), can cause thrombocytopenia aswell as decrease the white blood cell count.

Increased destruction of platelets usually occursthrough immune mechanisms. This often occurs aspart of an autoimmune process, for example SLE,and the body forms antibodies against its ownplatelets. Another illness that causes the body to pro-duce antiplatelet antibodies is idiopathic thrombocy-topenic purpura (ITP), a rare condition of unknowncause that affects children more often than adultsand can trigger severe thrombocytopenia. Antibodiesagainst platelets can also develop in response todrugs. Many drugs such as sulfonamides, quinine,and quinidine can cause thrombocytopenia, but thebest example is heparin-causing HIT.

Platelets filter through the spleen, and any con-dition that enlarges it can lead to increased destruc-tion of platelets. This is one of the mechanismscontributing to thrombocytopenia in FELTY’S SYN-

DROME. Many infections, particularly viral infec-tions, are associated with thrombocytopenia.

Symptoms

Most patients do not have any symptoms until theplatelet count is very low, often less than 20,000per mm3. The first symptom is usually purpura, arash consisting of small, raised purple spots. Severethrombocytopenia can cause blood to ooze fromthe nose and gums or bleeding from the bowel. HITand TTP can be associated with the formation ofblood clots and can, for example, cause stroke orthrombosis in a vein or artery.

Diagnosis

There are two components, the diagnosis of throm-bocytopenia, and the diagnosis of the underlyingcause. Thrombocytopenia is diagnosed from ablood count (see CBC in Appendix II). It may be aspecific finding on a diagnostic CBC ordered in a patient who has purpura or a chance finding ona CBC performed for some other reason.

When a diagnosis of thrombocytopenia is made,a careful history and physical examination willoften reveal the cause. Mild thrombocytopenia iscommon in SLE. If a patient with rheumatoid

arthritis has an enlarged spleen and thrombocy-topenia, the diagnosis of Felty’s syndrome is likely.A careful history will reveal exposure to drugs thatcan cause thromobocytopenia. If a patient is clot-ting rather than bleeding and has thrombocytope-nia, it suggests a diagnosis of HIT, TTP, orANTIPHOSPHOLIPID ANTIBODY SYNDROME.

Heparin-induced thrombocytopenia occurs inapproximately 1 percent of people treated with thedrug, usually about a week after treatment has beenstarted. About 10 percent of these patients maydevelop arterial or venous clots. To prevent thesecomplications, the diagnosis of HIT must be madeearly and treatment with heparin discontinued.

TTP is an unusual and serious syndrome consistingof thrombocytopenia, anemia due to increased break-down of red blood cells (hemolysis), kidney failure,and CNS effects such as depressed level of conscious-ness. TTP was described by Dr. Eli Moschcowitz in1924. TTP can follow infection or exposure to certaindrugs such as ticlopidine and can occur in patientswith autoimmune disease such as SLE.


Thrombocytopenia does not need treatment unlessit is severe. If a drug is the cause, stopping theoffending drug will often cure the problem. Severeautoimmune thrombocytopenia is often treatedwith high doses of corticosteroids. If that does notcontrol the problem, other options are INTRAVENOUS

IMMUNOGLOBULIN (IVIG), aggressive immunosup-pression with cyclophosphamide, or removing thespleen (splenectomy). Platelet transfusions are sel-dom needed but may be required if a patient isactively bleeding. If a patient has an immunologi-cal cause for thrombocytopenia, the transfusedplatelets are rapidly destroyed and are not effective.

TTP is treated with PLASMAPHERESIS. Transfusionof platelets can be useful in an emergency, forexample if someone has serious bleeding caused bysevere thrombocytopenia, but is not useful forlong-term treatment of TTP. Thrombocytopeniausually responds to treatment but can recur.

tissue type See HLA.

TNF antagonists See TUMOR NECROSIS FACTOR

ANTAGONISTS.

TNF antagonists 279

torn cartilage See MENISCAL TEAR.

trigger finger The tendons that curl the fingersup into a fist are encased in a sheath as they runacross the palm of the hand. They can becomeswollen and catch in this sheath, which often alsoconstricts. This usually happens about a centimeterbefore the base of the finger and can result in thefinger sticking in a curled up position as thoughpulling a trigger, hence the name trigger finger.

Cause

When occurring on its own, trigger finger usuallyresults from repetitive grasping activities. The mus-cle involved is the flexor digitorum superficialis andlies in the forearm. Precipitating activities can occurin many situations, including driving for long peri-ods, sport, hand work in industrial settings, massage,prolonged card playing (trigger thumb), horsebackriding, and prolonged music practice. The three ele-ments that predispose some people to developingtrigger fingers are prolonged activity, poor tech-nique, and increased muscle tension (as, for exam-ple, if driving is stressful and the steering wheel istightly gripped for several hours at a time). Repeatedtrauma such as may occur with digging is anotherpossible cause. People with widespread inflamma-tory arthritis such as RHEUMATOID ARTHRITIS are espe-cially likely to develop trigger finger, often with verylittle or no obvious initiating factors. Prolonged play-ing of video games is a more recently describedcause and may coexist with calluses and joint pain asthe so-called arcade arthritis.

Symptoms

The first symptom is often waking up in the morn-ing and having pain and difficulty in straighteninga finger. It will often flick straight suddenly as thetendon thickening or nodule squeezes through thenarrowed part of the sheath. Sometimes it is neces-sary to use the other hand to pull the fingerstraight. Typically the triggering gets a little easieras the hand is used throughout the day.

Diagnosis

The typical history and a competent examination areenough to make the diagnosis in the vast majority ofpatients. Ultrasound scanning is excellent at showingthe tendon enlargement and triggering but is only

occasionally necessary. DUPUYTREN’S CONTRACTURE

and the cheiroarthropathy of DIABETES MELLITUS needto be excluded.


Management of trigger finger is divided into treatmentto relieve symptoms and ways to avoid recurrence.

Treatment

• A light splint can be applied for six weeks, andthis will result in two-thirds of patients beingcured at one year.

• NSAIDs may be used in conjunction with splinting.

• Injection of CORTICOSTEROID along the tendonsheath is quicker and more effective and there-fore the preferred treatment. Over 80 percent ofpatients are cured at one year following injec-tion of corticosteroid. In addition, most patientswho do not respond to splinting are cured byinjection. The injection should be done bysomeone trained in this procedure and must notbe given into the tendon.

• If these measures fail, surgical stripping of thesheath off the tendon is usually effective.

Prevention of recurrence

• The patient must be made aware of the activitiesthat might play a role in causation. Gettingexpert advice on technique, for example in play-ing a musical instrument, may be important.Some limitation on the time spent doing theseactivities is also important in the first month ortwo after successful treatment.

• Wrapping a small amount of clingfilm or wear-ing a short “finger sock” around the proximalinterphalangeal or middle joint of the affectedfinger improves awareness of movement andmay help in the first two weeks after injection.

• Learning muscle relaxation techniques is impor-tant where excessive muscle tension is thoughtto have played a role.

• Wearing a quilter’s glove may help thoseinvolved in repetitive movement.

Outcome Corticosteroid injection providespain relief in about five days and return to normalfunction in two weeks. With NSAIDs and splinting,

280 torn cartilage

return to normal function takes three to six weeks.When compared with surgery, patients havinginjection therapy had just as good results butreturned to work an average of four weeks earlierthan the surgical group.

trochanteric bursitis This bursa (see SOFT TISSUE

ARTHRITIS-RELATED PROBLEMS) lies just behind theouter bony point of the hip bone, the greatertrochanter. This may become inflamed, producingbursitis. Abnormality of the gait predisposes to thisbursitis. This may be related to, for example,OSTEOARTHRITIS at the hip, being overweight, ormuscle weakness around the pelvis. Another bursaoverlying the tip of the greater trochanter can alsobecome inflamed.

The pain from this bursitis is often worst whenlying on the affected side at night or when settingoff walking after a rest. There is a small area ofmarked tenderness about an inch behind and abovethe greater trochanter. Treatment involves injectionof the bursa with CORTICOSTEROID and correction ofany gait abnormality that might predispose to it.

It is likely that gluteal tendinitis is frequently mis-diagnosed as trochanteric bursitis. A similar group ofpeople are prone to develop this. Patients with bothconditions should be encouraged to stretch thegluteal muscles with knee to chest stretches. Thetwo conditions can be differentiated by ultrasoundor MRI scanning but in practice this is seldom done.

tuberculosis (TB) An infectious disease caused byMycobacterium tuberculosis that is spread from personto person by droplets that are coughed into the air.TB is a common disease worldwide, affecting mil-lions of people. It is more common in developingcountries. In the United States many cases occur inimmigrants. The majority of people exposed to TBdevelop a primary infection that causes some lunginflammation and enlarged lymph nodes but thenresolves. The infection then lies dormant, in mostpeople forever, and does not cause disease. How-ever, in some people the primary infection is notcontained and spreads to the lungs, causing pul-monary TB, or to the brain, kidneys, and otherorgans. TB that has been dormant can reactivatemany years after the primary infection. Any condi-tion that suppresses the immune system such as

HIV infection or treatment with CORTICOSTEROIDS orTUMOR NECROSIS FACTOR (TNF) ANTAGONISTS can causeTB to reactivate. TB affects the lungs primarily. Thereason for describing it in this book is that it occa-sionally affects bones or joints.

Cause

TB is caused by an organism, M. tuberculosis. Infec-tion spreads to other people from an infected per-son who has open TB. This means that the patienthas lesions in the lung that are breaking down andreleasing mycobacteria into the lung secretions.When a patient with open TB coughs, mycobacte-ria are launched into the air in microdroplets, andan uninfected person nearby can become infectedby inhaling them. Outbreaks of TB can often betraced back to a single infected patient. People whohave been exposed to TB in the past and developeda primary infection that was contained by theimmune system are not infectious. Only a few peo-ple who are exposed to TB develop disease. It isuncertain why this happens. Genetic and social fac-tors seem to play a role in determining whether theinitial infection is contained. In some countries avaccine called BCG (bacillus Calmette-Guérin) isused to prevent tuberculosis. BCG is a weakerstrain of mycobacteria that does not usually causedisease in humans but stimulates the immuneresponse to M. tuberculosis. More recently BCG has been used to treat bladder cancer by placing it into the bladder to stimulate the local immuneresponse. Arthralgia (0.5–5 percent) and arthritis(less than 1 percent) can develop in patientstreated for cancer using this vaccine (see DRUG-

INDUCED RHEUMATIC DISEASE and REACTIVE ARTHRITIS).

Symptoms

TB usually starts insidiously, causing fatigue, loss ofenergy, loss of weight, fever, and night sweats. Ifthe lungs are the main site of infection, cough,sometimes producing blood, is prominent. Otherorgans such as lymph nodes, kidneys, and men-inges (the lining of the brain) can be involved.

Musculoskeletal disease-caused TB is not com-mon in the United States, but in developing coun-tries it commonly causes spinal deformities. Themost common musculoskeletal complication of TBis spine involvement, sometimes also called Pott’sdisease. The infection settles in a disc between two

tuberculosis 281

vertebrae and slowly expands to destroy the boneof the adjacent vertebrae. The bone collapses andthe spine becomes deformed. If the infection affectsthe spinal cord, the legs may become paralyzed(paraplegia). The most common symptom of TBaffecting the spine is back pain. TB can affect virtu-ally any bone, but this is rare.

Tuberculosis affecting a joint causes chronicdestructive arthritis, usually of one large joint suchas the hip or knee. The affected joint is swollen andpainful, but swelling is often more prominent thanpain. Unlike INFECTIVE ARTHRITIS caused by bacterialinfection that is very acute, tuberculous arthritisstarts and progresses slowly over weeks andmonths. In addition to infecting and destroying ajoint, tuberculosis can rarely cause a reactivearthritis. This is called Poncet’s disease. Unliketuberculous arthritis, Poncet’s disease affects manyjoints, is not destructive, and settles spontaneously.

Diagnosis

A tuberculin skin test is used to diagnose previousexposure to TB. This is done by injecting a smallamount of tuberculin protein under the skin andmeasuring the wheal a few days later. People whohave not been exposed previously do not react,while those who have mount an immune responseand form a wheal. A tuberculin skin test is useful inseveral situations. If someone is exposed to a patientwith tuberculosis and is known to have had a neg-ative skin test which then becomes positive, it indi-cates transmission of TB. A tuberculin skin test isalso helpful in patients suspected of having TB.Most patients with active TB have a strongly posi-tive tuberculin skin test. Unfortunately, a tuberculinskin test usually remains positive forever and mostpatients with inactive TB also have a positive test.This means that a positive test could be the result ofexposure years ago, recent exposure, or activeinfection. Another limitation is that if a patient isseverely ill or taking immunosuppressive drugs thetest may be negative despite active infection.

Symptoms can provide a clue to diagnosis. TBshould be suspected in every patient with a chroniccough and fever or unexplained weight loss andfever. The X-ray findings can also be helpful. TBtypically causes scarring and small abscesses in theupper parts of the lungs. The presumptive diagno-

sis of TB is often made by finding the organisms inthe sputum or another body fluid. These organismsstain in a particular way on slides prepared formicroscopy and are termed acid-fast bacilli or AFBs.Some other mycobacteria are also acid-fast, and thedefinitive diagnosis is made when the organism iscultured, a process that can take several weeks.Molecular biology techniques that use polymerasechain reaction (PCR) to detect DNA specific for M.tuberculosis are much faster but are not widelyavailable. Occasionally the diagnosis can be madeonly from a biopsy of affected tissue that showschanges that are typical for TB and are very differ-ent from other infections or cancer.

Diagnosing tuberculosis affecting bone or joints ismore difficult. The clinical features provide someclues, as do the X-ray findings, which show destruc-tion of bone, but a biopsy is usually needed. Mostpatients with bone or joint TB do not have active pul-monary tuberculosis and are therefore not infectious.


The treatment of tuberculosis requires a combina-tion of three drugs for at least six months. One suchcombination is rifampin, isoniazid, and pyrazi-namide. Some tuberculosis organisms have becomeresistant to some of the common treatments.Patients with an infection caused by a resistantorganism often need treatment with four drugs forlonger than six months. Tuberculosis is cured if apatient takes the treatment correctly. Not complet-ing the course of treatment is a common cause offailure to cure TB and facilitates the development ofresistant organisms. One way to improve adherenceto treatment is directly observed therapy (DOT).This involves health care workers physically observ-ing a patient taking treatment twice a week. Ifsomeone develops a positive skin test but has nosymptoms of infection treatment with a single drug,isoniazid is often prescribed to help the immunesystem contain the primary infection.

tumor necrosis factor antagonists (TNF antago-nists) A class of drugs that blocks the inflamma-tory CYTOKINE tumor necrosis factor (TNF). Thesedrugs were initially developed to treat severe sepsis,which is associated with very high levels of TNF, butthey were not effective. Fortunately, later studies

282 tumor necrosis factor antagonists

showed that ETANERCEPT and INFLIXIMAB were effec-tive in patients with rheumatoid arthritis (RA) andhave revolutionized its treatment. TNF antagonistsare now also used to treat a wide range of otherautoimmune and rheumatic diseases, includingINFLAMMATORY BOWEL DISEASE, PSORIASIS, ANKYLOSING

SPONDYLITIS, JUVENILE RHEUMATOID ARTHRITIS, VASCULI-

TIS, STILL’S DISEASE, and BEHÇET’S DISEASE.

When they were first released, infliximab andetanercept seemed almost too good to be true. Clin-ical studies indicated they were very effective andhad virtually no serious adverse effects. Informationobtained after the drugs were marketed was alsoreassuring. For example, follow-up of patients whoreceived etanercept in clinical trials found noincrease in the rate of serious infection or cancer.However, wider use of TNF antagonists in the com-munity has generated reports—mostly case reportsor small series of patients—of serious infection,TUBERCULOSIS, atypical mycobacteria, aspergillosis,histoplasmosis, listeria, diabetes, cancer, VASCULITIS,

SLE-like autoimmune disease, multiple sclerosis-likedemyelinating disorders, liver disease, hematologicalabnormalities including aplastic anemia, severeallergy, and meningitis. The current recommenda-tions are that patients who have active or recurrentinfections should not receive TNF antagonists. Ifsomeone develops an infection while receiving aTNF antagonist, the drug should be discontinueduntil the infection settles. Many rheumatologistsscreen patients for tuberculosis by performing atuberculin skin test before starting treatment with aTNF antagonist. The effects of TNF antagonists inpatients with heart disease are interesting.

TNF levels are high in patients with heart fail-ure, and so studies using TNF antagonists as a treatment were performed. The initial studies wereextremely encouraging. Anti-TNF therapy im-proved the cardiac function in patients with heartfailure. However, subsequent studies have notborne out this optimism. Two large studies withetanercept in heart failure were stopped prema-turely because of lack of evidence of benefit. Ofgreater concern, in a study of infliximab in heartfailure there were seven deaths in the 101 patientsreceiving infliximab and none in 49 controls. Thisled to a warning letter to physicians to avoid inflix-imab in patients with heart failure.

Considering the many roles TNF plays in modu-lating the immune responses, some of the adverseeffects described after treatment with TNF antago-nists are not unexpected. However, a lot of re-search will be needed to define the frequency ofside effects compared with those of other drugsused to treat RA. All drugs have side effects. Com-parative information is needed so that patients andphysicians can make informed decisions abouttreatment choices for RA. Rare drug-induced sideeffects such as reactivation of tuberculosis that areuncommon in the background population areoften identified easily because they stand out.However, a drug-induced increase in the frequencyor severity of a condition that occurs often, such asheart failure, can go unrecognized. Overall TNF an-tagonists are remarkably safe, but studies to definetheir long-term safety profile will provide moredefinitive information.

The price of TNF antagonists has caused contro-versy. To treat an average rheumatoid patient with aTNF antagonist costs more than $10,000 a year. Atthis price not every patient with RA can be treated.Besides, in some patients RA can be controlled witholder drugs at a fraction of the price. So who shouldreceive TNF antagonists? One argument is that early,effective treatment of RA will be cheaper in the longrun because patients will be able to work and, in thelong term, will not need expensive treatments suchas joint replacement surgery. An alternative argu-ment is that the expensive treatment should bereserved for patients who have not responded to tra-ditional, cheaper DMARDs. Many HMOs take thesecond approach and require that a patient havefailed treatment with several DMARDs before treat-ment with a TNF antagonist will be authorized. Thecosts of anti-TNF drugs may decrease over timewhen there is more competition in the marketplace.Even so, society will have to decide how to rationhealth care resources, even in societies not accus-tomed to the concept of rationing.

An important consideration is that althoughTNF antagonists are probably more effective thanthe gold standard drug for RA, methotrexate, theyare not effective in every patient and do not cureRA. In the future tests will likely be developed topredict which patients are likely to respond to par-ticular treatments (see PHARMACOGENETICS).

tumor necrosis factor antagonists 283

U–V

ulcerative colitis See INFLAMMATORY BOWEL DISEASE.

undifferentiated connective tissue disease SeeOVERLAP SYNDROME.

uveitis See EYE PROBLEMS.

vaccination When a virus or bacteria invades thebody, the immune system recognizes small areas onthe microbe as foreign. These are called antigenicdeterminants. As a result of this recognition theimmune system is able to mount a response againstthe invading microbe and, hopefully, destroy it.Once the immune system has responded success-fully to an infection, it retains a memory of theimportant antigenic determinants. This enables theimmune system to mount another attack muchmore quickly and effectively should it come intocontact with the same microbe again.

This natural ability is utilized in vaccination. Byshowing a person’s immune system the importantantigenic determinants of important disease-causingviruses and bacteria, it is possible to pre-arm theimmune system and fully or at least partially protectthe individual from that disease. This is usually doneby killing the microbe and extracting parts that con-tain the important antigens. It can also be done bygiving people an infection with a closely related butmuch less dangerous microbe than the one that isbeing protected against. In this way, vaccination haspractically eradicated polio and diphtheria from thedeveloped world. Tetanus and hepatitis B are muchless common, and the fetal abnormalities caused byRUBELLA (German measles) are theoretically com-pletely preventable. Measles epidemics now occurevery seven years rather than every second year asthey did before vaccination. Several issues are rele-vant to the rheumatic diseases.

Immunosuppressed patients People on immuno-suppressive treatment, especially potent drugs suchas CYCLOPHOSPHAMIDE, AZATHIOPRINE, or high-doseCORTICOSTEROIDS, should not be given live vaccines.Although harmless to most people, these can causeserious illness in those without a competentimmune system. Live vaccines include those againstpolio, measles, mumps, rubella, chicken pox, tuber-culosis (BCG), typhoid, yellow fever, and the vac-cinia vaccine against smallpox. These are notabsolute contraindications. The use of live vaccinesdepends on the degree of immunosuppression andthe importance of having the vaccine. Immunosup-pressed patients may not respond very well to killedvaccines, but they will be safe.

Asplenia Patients who have no spleen arehighly susceptible to infections with certain bacteria.In rheumatic disease patients the likely reason fornot having a spleen is having it removed to treatresistant autoimmune THROMBOCYTOPENIA. Patientswith SICKLE-CELL DISEASE are often effectively with-out a spleen because it has shrunken up due to lossof blood supply. Protecting against some of the infec-tions these patients are at risk from is possible.Therefore, patients with sickle-cell disease and thoseabout to have their spleen removed should be vacci-nated against Pneumococcus, Haemophilus influenzatype b, and Meningococcus before, not after, surgery.

Protection of immunosuppressed children It isimportant to vaccinate the relatives and closefriends of children who are heavily immunosup-pressed to lessen the risk of those children gettingthe common infectious diseases that could be dev-astating for them.

Musculoskeletal adverse reactions Local reac-tions to vaccination are common, and there areother less common adverse effects. Only muscu-loskeletal reactions will be discussed here. Oral polio

285

vaccine quite commonly causes muscle aching.Rubella vaccine (usually given as part of themeasles, mumps, rubella (MMR) vaccine) is wellknown to cause a short-lived arthritis (see RUBELLA).Up to 15 percent of adult women get this arthritisafter rubella vaccination but much fewer men orchildren. A few patients appear to have developed alonger lasting arthritis, but it is not yet clear whetherthis is related to the vaccine. Thrombocytopeniaoccurs in one in every 30,000 people vaccinated forrubella. Very rarely, OSTEOMYELITIS may follow BCGvaccination for tuberculosis and musculoskeletalsymptoms following HEPATITIS B vaccination.

vasculitis Inflammation of blood vessels thatdamages arteries, veins, and the fine network ofcapillaries that joins them. The definition of vasculi-tis is deceptively simple but describes a vast range ofdiseases and symptoms. Vasculitis can mimic virtu-ally any illness, and therefore, making the correctdiagnosis can be difficult. Several illnesses canmimic vasculitis, for example cancer, infections,INFECTIVE ENDOCARDITIS, and CHOLESTEROL EMBOLI.

Cause

There are many different types and causes of vas-culitis, and they are described in detail under theirindividual headings. The cause of most types of vas-culitis is not known. Vasculitis typically affects sev-eral organs simultaneously. A rare type of vasculitis,CENTRAL NERVOUS SYSTEM VASCULITIS, affects only thecentral nervous system, most often the brain.

Kussmaul and Maier were probably the first todescribe vasculitis in 1866. Then over decadesphysicians described different types of vasculitis. In

1952, Zeek classified vasculitis into different sub-types, based mainly on the size of the blood vesselsaffected. Unfortunately, there is a lot of overlap, anda particular type of vasculitis can affect different-sized vessels. Consequently, many other classifica-tions evolved, but most rheumatologists still classifyvasculitis into three groups based on the size of thevessels most often affected (see the table below).

Vasculitis affecting predominantly the small ves-sels of the skin is often called leukocytoclastic vas-culitis, a name that describes its appearance undera microscope. The polymorphonuclear white bloodcells that invade the blood vessel wall are oftenpartially degenerated, and there is cellular debrispresent. The most prominent clinical feature is pal-pable purpura, a rash consisting of small, raised,purple spots. Leukocytoclastic vasculitis can occurwith other rheumatic diseases, for example RHEU-

MATOID ARTHRITIS and SYSTEMIC LUPUS ERYTHEMATO-

SUS (see RHEUMATOID VASCULITIS).Leukocytoclastic vasculitis is sometimes also

called hypersensitivity vasculitis. More correctly thisrefers to vasculitis that is caused by a specific anti-gen, for example a viral infection or drug. Manydrugs such as penicillins, sulfonamides, cephalospo-rins, thiazides, phenytoin, and captopril can causevasculitis (see DRUG-INDUCED RHEUMATIC DISEASE).Similarly many infections have been associated withvasculitis, including HEPATITIS B, HEPATITIS C, HIV,

Epstein-Barr virus, PARVOVIRUS, RUBELLA, herpesvirus, and many others.

Symptoms

Vasculitis damages blood vessels and can impair theblood supply to organs and cause them to malfunc-

286 vasculitis

THE PROPENSITY OF DIFFERENT TYPES OF VASCULITIS TO AFFECT BLOOD VESSELS OF PARTICULAR SIZE

Type of Vasculitis Size of Vessel

Large Medium Small

Temporal arteritis Often Sometimes Seldom

Takayasu’s arteritis Often Sometimes Seldom

Polyarteritis nodosa Seldom Often Sometimes

Wegener’s granulomatosis Rare Sometimes Often

Churg-Strauss syndrome Rare Sometimes Often

Leukocytoclastic vasculitis No Rare Often

tion. Severe vaculitis can cause irreversible damageto tissues. At the site of damage in the vessel wallthere is often overgrowth of endothelial cells andfibrous tissue, presumably a response to repair thedamage. This can block the artery, particularly ifthe blood flowing through the narrow channelclots. The symptoms of vasculitis depend on theorgans involved. Nonspecific complaints such asfever, loss of weight, arthralgia, and myalgia arecommon. Small-vessel vasculitis most often causesa rash consisting of small, raised, purple spots thatcan be felt as well as seen (palpable purpura).Other types of vasculitis cause symptoms that affecta range of organs. Temporal arteritis often causesheadaches and may cause blindness. Wegener’sgranulomatosis often affects the upper respiratorytract, sinuses, lungs, and kidneys. Polyarteritisnodosa is more likely to affect nerves and kidneys.However, there is overlap of symptoms betweendifferent types of vasculitis. (See the table below.)

Diagnosis

Diagnosing vasculitis can be difficult. The initialsymptoms often suggest infection or cancer as pos-sible diagnoses, but the constellation of symptomsand results of tests such as the ANTINEUTROPHIL

CYTOPLASMIC ANTIBODY or ANCA (see Appendix II)lead to the correct diagnosis. For many types ofvasculitis a biopsy of affected tissue is the mostaccurate way to make an unequivocal diagnosis.Because the treatment of vasculitis requires med-ications with potentially serious side effects, a cor-rect diagnosis is important.

Treatment

The treatment of different types of vasculitis variesand is described in detail under their individual

entries. As a general principle, though, more severevasculitis requires more aggressive treatment. If adrug or infection causes vasculitis that affects onlythe skin, specific treatment, other than stopping theoffending drug, is seldom needed. Treatment of moresevere vasculitis almost always involves immunosup-pression with CORTICOSTEROIDS, often combined withCYCLOPHOSPHAMIDE or another immunosuppressant.The outcome of vasculitis varies and depends on howsevere it is, how much organ damage has occurredbefore treatment, the response to treatment, and theseverity of the side effects of treatment. Patients withkidney involvement leading to renal failure and vas-culitis of the bowel leading to bleeding and gangrenehave a worse prognosis.

viral arthritis The most important viruses causingrheumatic disease have been discussed in separatesections in this book. These include HEPATITIS B,

HEPATITIS C, PARVOVIRUS, RUBELLA, and HIV. Otherviruses that may cause rheumatic symptoms will bebriefly listed here. Note that merely finding a virusin an inflamed joint does not prove that it hascaused the arthritis. Viral infections are common.With the increased blood flow to an inflamed joint,it is relatively easy for them to lodge there.

Also known as arboviruses, alphaviruses aremosquito-borne viruses that have been known formany years to cause arthritis. Alphaviruses belongto the same family as rubella, the Togaviridae.O’nyong-nyong has recently become a problem inUganda after disappearing for over 30 years. Itcauses a rash, fever, and arthritis.

Ross river virus in Australia and other SouthPacific islands is probably the best known of thealphaviruses. There is fever and rash, and the

viral arthritis 287

APPROXIMATE FREQUENCY OF SYMPTOMS AND LABORATORY TESTS IN DIFFERENT TYPES OF VASCULITIS

Symptom Wegener’s Churg-Strauss Polyarteritis Temporal ArteritisGranulomatosis Syndrome Nodosa

Upper airway disease 95% 60% No No

Gastrointestinal vasculitis 5% 60% 70% Rare

Nervous system affected 30% 15% 70% Rare

Eosinophilia Uncommon Common Uncommon No

Elevated ESR Common Common Common Common

Positive ANCA 85% C-ANCA 70% P-ANCA 15% P-ANCA No

arthritis affects mainly the hands, knees, and feet.Symptoms start about a week after being bitten byan infected mosquito. About 15 percent of infectedpeople will get arthritis. Adults are more severelyaffected than children. In Australia, 5,000 cases ayear occur, mostly during the summer months.Some people just get joint pain, but swelling ofjoints and tendons does occur and the arthritis maylast up to six years. Barmah virus can cause a verysimilar disease and is found only in Australia. Atleast seven other mosquito-borne viruses in Aus-tralia are known to cause arthritis.

Pogosta disease, Ockelbo disease, and Karelinfever are all caused by related alphaviruses innorthern Europe. Pogosta disease tends to causeepidemics every seven years and causes arthritis inover 90 percent of infected people.

Mumps is a rare cause of arthritis. Most patientsare young men. The arthritis may flit around orjust affect one joint. There is often associated fever.The arthritis may last up to six months but does notcause lasting joint damage.

Adenovirus, a common cause of upper respira-tory tract infections, has rarely caused an acute butshort-lived arthritis.

Varicella-zoster, Epstein-Barr, herpes simplex, andcytomegalovirus have all been associated with rarereports of arthritis.

Given the rarity with which the last six of theseviruses cause arthritis, the occurrence of arthritisat the same time as or shortly after infection withone of them should always give rise to a carefulconsideration of another separate cause of thearthritis.

288 viral arthritis

W–X

Wegener’s granulomatosis A rare type of VAS-

CULITIS that typically affects the sinuses, lungs, andkidneys. A limited form of the disease affectingonly the lungs or upper respiratory tract can occur,but most such patients eventually develop kidneyinvolvement. The features of the illness laternamed Wegener’s granulomatosis were describedby Dr. Heinz Klinger in 1931 and then by FriedrichWegener in 1936. It occurs most often in young tomiddle-aged adults and affects one to three peoplein 100,000. Some studies have suggested a sea-sonal variation in frequency, with the diseasemore likely to occur in spring, but others have notconfirmed this observation. Almost all patientswith untreated Wegener’s granulomatosis havedied in a year, but modern drugs have improvedthe prognosis considerably.

Cause

The cause of Wegener’s granulomatosis is notknown. Research has focused on infection, genet-ics, environmental exposures, and autoimmunityas potential causes. No genetic or infectious causehas been identified. Some experts still believe thatinfection plays a major role because many relapsesseem to occur after an infection, and eliminatingbacteria from the nose with chronic antibiotictreatment has reduced the frequency of relapses insome studies. Exposure to silica dust, fumes, andpesticides has been associated with Wegener’sgranulomatosis in some studies, but many patientshave no known exposure to any environmentaltoxin. In contrast to diseases like SLE where com-plexes of antibodies are deposited in affected tis-sues, in Wegener’s granulomatosis there are fewantibodies in tissues, and it is therefore sometimescalled a pauci-immune vasculitis. However, manypatients with Wegener’s granulomatosis have ANTI-

NEUTROPHIL CYTOPLASMIC ANTIBODIES or ANCA (seeAppendix II). There are two types of ANCA: C-ANCA directed against proteinase 3 (PR3); and P-ANCA, usually directed against myeloperoxidase(MPO) (see Appendix II). It is not clear if ANCAsplay a role in causing Wegener’s. ANCAs are di-rected against neutrophils and may activate themand contribute to the damage to blood vessels andtissues that is typical of Wegener’s granulomatosis.On the other hand, ANCAs may not play a directpart in causing disease but may be a response to tis-sue injury.

Symptoms

Wegener’s granulomatosis can affect virtually anyorgan and can mimic many illnesses. It usuallystarts gradually, with symptoms appearing overweeks or months. Some patients, though, havevery rapid onset and progression of disease. Com-mon initial symptoms affect the upper respiratorytract and lungs. Nonspecific complaints such asfever, loss of weight, arthralgia, and myalgia arecommon.

Upper respiratory tract The sinuses are oftenaffected, causing sinus pain, persistent sinusitis,and a bloody or purulent discharge from the nose.Inflammation can cause the nasal cartilage to col-lapse so that the nose changes shape. The middle ofthe nose sinks, causing a saddle deformity. The earsare often affected, and patients have symptoms ofpain, deafness, and discharge from the ear. Inflam-mation affecting the entrance to the airway cancause narrowing so that the flow of air into thelungs is restricted. Ulcers in the mouth and noseare common.

Lungs The lungs are affected in most patients,and symptoms such as coughing blood and short-ness of breath are common. Most patients usually

289

cough only small amounts of blood or blood-streaked sputum, but serious bleeding can occur.

Kidneys Wegener’s granulomatosis damages theglomeruli that filter urine and can decrease renalfunction, causing the blood levels of CREATININE torise (see Appendix II). If this is severe, it can causekidney failure. The symptoms of renal failure areweakness, fatigue, itching, anemia, shortness ofbreath, and swelling of the legs. Most patients withWegener’s granulomatosis have an abnormal URINAL-

YSIS (see Appendix II), but the small amounts of pro-tein and blood in the urine do not cause symptoms.

Skin Wegener’s granulomatosis, as do othertypes of vasculitis, typically causes a purpuric rash(small, purplish spots), but other rashes can occur.

Eyes Many patients develop eye inflamma-tion. Wegener’s granulomatosis can affect the eyes,causing scleritis (see EYE PROBLEMS) or inflamma-tion of the area behind the eye, pushing it forward(proptosis). Inflammatory tissue behind the eyecan destroy the eye, the bony cavity containing it,and the muscles that move the eye and is some-times referred to as a pseudotumor.

Diagnosis

Diagnosing Wegener’s granulomatosis can be difficultbecause early in the illness many of the symptomsare not specific. For example, differentiating thesinus symptoms caused by Wegener’s granulomatosisfrom those caused by other illnesses can be impossi-ble, but clues to the diagnosis are persistent or recur-rent attacks of sinusitis that cause destruction oftissues in the nose. Usually the diagnosis is suspectedbecause of the unusual constellation of symptoms.

Blood tests A positive C-ANCA is found in80–90 percent of patients with active Wegener’sgranulomatosis. The most common target for C-ANCAs is proteinase-3 (PR3), an enzyme found inneutrophils. A positive test can sometimes occur inpatients with lymphoma, cancer, infection, andother types of vasculitis. A positive C-ANCA (PR3)in a patient with classical features of Wegener’sgranulomatosis confirms the diagnosis, and someclinicians believe that a biopsy to make anunequivocal diagnosis is not required in this situa-tion. The level of C-ANCA has been studied as away to monitor disease activity and predictrelapses, but the results have been conflicting.

Other blood tests are not helpful in making thediagnosis but are useful for monitoring the effects ofthe disease and its treatment. The creatinine level isused to monitor kidney function and the white bloodcell count to prevent cyclophosphamide toxicity.

Upper respiratory tract The sinuses are oftenaffected on an X ray or CT scan. A biopsy of sinus tis-sue sometimes shows changes typical of Wegener’sbut more often changes of chronic inflammation.

Lungs The lungs are affected in most patients,and the X ray typically shows patches of inflamma-tion that may be nodular and have small cavities inthe center. A biopsy of lung tissue is the most accu-rate way of making the diagnosis. Biopsies per-formed with a bronchoscope passed through thenose under local anesthesia have a very low yield,and an open lung biopsy is needed. This involvessurgery through the chest wall. The biopsy showsvasculitis with neutrophils invading and destroyingthe walls of small and medium-sized blood vesselsand granulomas, which are palisades of cells sur-rounding a central area of dead tissue.

Kidneys A urinalysis is often abnormal show-ing blood and protein. The creatinine level may beelevated if kidney function is affected. Patients tak-ing cyclophosphamide need regular urine monitor-ing to detect bladder inflammation (cystitis). If thekidneys are involved, a biopsy can be performed. Itoften shows patchy inflammation of the glomerulithat are surrounded with crescents of inflamma-tory cells. This finding is not specific and can occurwhen other autoimmune diseases affect the kid-ney. However, a kidney biopsy can be helpful, par-ticularly if a lung biopsy is considered too risky.

Skin If there is a rash, a skin biopsy may showvasculitis.


General measures Regular contact with aphysician experienced in treating vasculitis isimportant to monitor both the disease and many ofthe therapies. Some of the complications of vas-culitis such as kidney failure cause no symptomsuntil well advanced, and regular monitoring of lab-oratory tests is important.

Infections are common in patients with vasculi-tis, particularly those taking immunosuppressivedrugs, and should be looked for whenever a patient

290 Wegener’s granulomatosis

develops a fever. An annual flu vaccine is advis-able, and vaccination against pneumococcus is rec-ommended.

Many of the drugs used to treat vasculitis can beharmful to the fetus. Therefore, women of child-bearing age should use effective contraception (seePREGNANCY).

Education that leads to a better understandingof this rare and often severe disease is important indeveloping coping strategies. Information can beobtained from physicians, information booklets,and patient support groups.

Patients with vasculitis should not smoke. Vas-culitis damages small blood vessels. Smokingcauses small vessels to constrict, increasing thechance that they will block up completely.

Most patients with significant ear, sinus, lung, kidney, or eye disease will benefit from seeing physicians specializing in these respectivesubspecialties.

Established treatments Before treatment wasavailable, patients with Wegener’s granulomatosissurvived an average of six months. Treatment withcorticosteroids increased this to 12 months. In the1970s, Dr. A. Fauci and his colleagues at theNational Institutes of Health (NIH) developed atreatment program that resulted in improved long-term survival to better than 80 percent.

CYCLOPHOSPHAMIDE, a potent immunosuppressivedrug, is the anchor of the NIH treatment program.The standard treatment for Wegener’s is dailycyclophosphamide combined with a corticosteroidsuch as prednisone, both given as tablets (seeAppendix I). Several studies have examined alter-native treatments that cause fewer side effects. Onesuch program uses monthly intravenous cyclophos-phamide, as is done for SLE. Intravenous cyclo-phosphamide does cause fewer side effects thantablets but does not seem as effective at keeping thedisease in remission. Cyclophosphamide, adminis-tered intravenously or by mouth, can have seriousside effects. Nausea, vomiting, and a drop in thewhite cell count are common. Red cell and plateletcounts may also decrease but usually with long-term treatment. Patients on cyclophosphamidehave a greater risk of infection. A range of commonand OPPORTUNISTIC INFECTIONS occurs in 40–70 per-cent of patients. Factors that increase the risk of

infection are high doses of corticosteroids and a lowwhite blood cell count. Pneumocystis carinii pneumo-nia (PCP) is a preventable, serious opportunisticinfection that can complicate treatment. The risk ishighest during the initial phase of treatment, andsome physicians prescribe antibiotics to prevent thisinfection.

Fertility may be affected. The risk of sustainedovarian failure and infertility after treatment withcyclophosphamide has ranged from 11–59 percent.The risk may be lower with IV pulse cyclophos-phamide regimens than oral regimens, but the dif-ference is not great. Cyclophosphamide alsoreduces the sperm count in men. Thus if the clini-cal situation allows, sperm or ova can be bankedbefore starting treatment with cyclophosphamidein order to preserve future fertility. Several strate-gies to preserve fertility have been tried. Youngwomen about to undergo treatment with cyclo-phosphamide have been treated with the contra-ceptive pill to try to protect their ovaries, but theresults of these studies were mixed. Early resultsfrom studies using a drug called leuprolide aremore promising. Cyclosphosphamide has signifi-cant long-term side effects. These are related to thetotal dose and length of treatment. CHLORMABUCIL issometimes used for patients who are unable to takecyclophosphamide.

CORTICOSTEROIDS are initially used in high doseswith cyclophosphamide to control inflammationand induce remission. Once the inflammation hassettled the dose is reduced steadily to the minimumcompatible with disease control. Corticosteroidshave significant long-term side effects. These arerelated to the total dose and length of treatment(see Appendix I).

METHOTREXATE has been used to treat Wegener’sand is effective, although probably not quite aseffective as cyclophosphamide, for inducing andmaintaining remission. In order to avoid the risksof long-term cyclophosphamide, many rheumatol-ogists will substitute weekly oral methotrexate forcyclophosphamide if a patient has been in remis-sion for a few months and is doing well.

AZATHIOPRINE is an alternative to methotrexatefor maintaining remission.

Trimethoprim/sulfamethoxazole is an antibiotic(trade name: Septra) that has been used to treat

Wegener’s granulomatosis 291

Wegener’s limited to the upper respiratory tract. Inpatients with disease affecting many organs it maydecrease long-term disease activity in the upperairways.

INTRAVENOUS IMMUNOGLOBULIN (IVIG) is occa-sionally added to the treatment of patients who areseverely affected and not responding to standarddrugs.

Newer and experimental approaches Prelimi-nary results from clinical trials with TUMOR NECRO-

SIS FACTOR (TNF) ANTAGONISTS, LEFLUNOMIDE, andMYCOPHENOLATE MOFETIL suggest that they may beeffective. More information is needed, though, todetermine how they should be used.

Outcome The usual treatment plan has twostages, to induce remission and then to maintain it. Most rheumatologists use high doses of cor-ticosteroids with cyclophosphamide to induceremission, but some use corticosteroids andmethotrexate in patients with milder disease. Thedose of corticosteroid is decreased, and thenmethotrexate or less often azathioprine is substi-tuted in place of cyclophosphamide to maintainremission. With modern treatment most patientswith Wegener’s go into remission after severalmonths of treatment. The goal then is to sustainremission for at least six months and then slowlytaper treatment. About half of patients withWegener’s relapse and need a second or multiplecourses of treatment. The prognosis is worst inpatients with severe lung or kidney disease.

Whipple’s disease When Whipple first describedthis disease in 1907, he described a rod-shapedorganism and wondered whether this might causethe disease. It took another 85 years to prove himcorrect. Whipple’s disease is rare and is foundmostly in middle-aged Caucasian men, often farm-ers or those with some involvement in farming.The disease affects many parts of the body, espe-cially joints, gut, and skin.

Cause

For many years it was known that there were rod-shaped objects in the lining of the small bowel ofpatients with Whipple’s disease that showed upwith a particular stain known as PAS. Evidencesteadily accumulated that this was an infection

causing the disease. However, it was impossible togrow the putative bacterium to prove that it wasactually an organism. With advancing technology,it eventually became possible, in 1992, to use poly-merase chain reaction (PCR) to prove that it was abacterium. The bacterium is called Tropheryma

whippelii. It has been shown to be present in manyorgans in affected people. Growing the organism inartificial media has since become possible, althoughthis is still very difficult and the PCR test is used fordiagnosis.

Symptoms

Over 80 percent of patients with Whipple’s diseaseget arthritis. This usually precedes the other symp-toms by five to eight years. Large joints areinvolved most commonly, especially the wrists,knees, and ankles. Hips, shoulders, and elbowsmay be affected, but smaller joints would beunusual. The typical arthritis causes attacks of jointpain and swelling occurring in different joints,sometimes lasting only six hours and sometimesdays. It may, however, become ongoing when it isoften confused with RHEUMATOID ARTHRITIS. It doesnot, however, cause erosive damage to the jointslike rheumatoid arthritis does. Less frequently itmay also affect the spine.

Often the appearance of diarrhea, abdominalpain, and weight loss results in the diagnosis beingmade. Chest pain due to pleurisy occurs. Involve-ment of the heart is less common, frequentlyaffecting the valves when it is involved. Lymphnodes may be enlarged. Darkish discoloration ofthe skin, rashes, thyroid involvement, and occa-sionally kidney involvement are other features.The brain may be affected with confusion, poormemory, loss of interest, and a form of dementia.

Diagnosis

The characteristic arthritis and absence of othercauses may lead to a small bowel biopsy being doneto show the typical PAS-positive material. How-ever, after other symptoms appear is the diagnosisoften considered and biopsies done. In most studiesthe diagnosis is made only about six years after thefirst symptoms. PAS-positive material can some-times be seen in joint fluid that is removed. How-ever, this stain will be done only if the diagnosis is

292 Whipple’s disease

suspected. It is now possible to identify the organ-ism using PCR. This has been successful in jointfluid, lymph nodes, and surgically removed jointlining as well as small bowel biopsies. It is hopedthat with the recent culture of Tropheryma whippelii,more widely available and user-friendly tests willbe developed to look for evidence of infection withthis unusual organism. X rays do not show any ero-sive destructive changes as they do in rheumatoidarthritis, which is the most commonly confuseddiagnosis. They may, however, show loss of jointspace (cartilage), especially at the wrists and hips.


Whipple’s disease was always fatal until antibioticswere shown to be effective. Somewhere between70 and 90 percent of patients can now be curedwith an adequate course of antibiotics. Antibioticsthat penetrate the brain should be used in casethere is some undetected infection there that reac-tivates once treatment is stopped. The brain has aspecial barrier (the blood-brain barrier) that meansnot all molecules that get into the bloodstream canget into the brain, and this includes some antibi-otics. A currently recommended treatment plan isas follows:

1. Start with a two-week course of streptomycin 1g per day and benzylpenicillin 1.2 million unitsper day.

2. Follow this with a one- to two-year course oftrimethoprim and sulfamethoxazole (cotrimox-azole, trade name: Septra) 960 mg twice daily.

With this treatment the diarrhea will usuallystop within a week and joint pain within a month.The patient will put on weight and feel generallybetter within the first few months, but neurologicalproblems such as confusion and poor memory maytake longer to improve. Although a very rare dis-ease, Whipple’s disease is very exciting since it is anexample of scientific advances leading to theunderstanding and cure of a previously fatal multi-system disease.

wrist pain Pain in the wrist can be caused by aproblem in any of the tissues in that area, mostoften bones, joints, tendons, and nerves. Pain

caused by problems in the fingers and hand cansometimes be difficult to differentiate becausesevere inflammation of the hand can causeswelling and pain that extends up to the wrist.

Bones Trauma causing bruising or a fracture isa common cause of wrist pain. A clue to the diagno-sis is that the pain and swelling follow a traumaticevent and there is intense tenderness directly overthe painful area. The patient usually remembers aninjury, particularly one that involved falling with thearm outstretched. Such an injury is the most com-mon cause of a fracture at the end of the radius andulna, the bones of the lower arm, called a Colles’fracture. Other common injuries are dislocation ofthe lunate and fracture of the scaphoid or hammate,small bones that form part of the wrist. An X ray pro-vides the diagnoses, and treatment is to return thebones to their original position and immobilize thewrist in a cast until healed. Treatment may requiresurgery. Occasionally the diagnosis of fracturedscaphoid is missed or the correct diagnosis is madebut the fracture does not heal, termed nonunion ofthe scaphoid. This can cause chronic wrist painmonths or years after the initial trauma that causedthe fracture and usually requires surgical repair.

Keinbock’s disease, also called avascular necrosisof the lunate, is a rare condition that causes chronicwrist pain and swelling, usually in young adults. AnX ray shows deformity and, later, increased sclerosis(denser and therefore whiter on the X ray) and col-lapse of the lunate, a small bone in the wrist.Surgery is usually needed to repair the damage, sta-bilize the wrist, and prevent later osteoarthritis.

Joints The joints of the wrist can be dividedinto three groups:

1. Joints between the lower end of the radius andulna and the small bones of the wrist

2. Joints between the small bones of the wrist (thecarpal joints)

3. Joints between the metacarpals, the raylikebones between the wrist and the fingers, andthe small joints of the wrist (the car-pometacarpal joints)

Virtually any type of inflammatory or nonin-flammatory arthritis can affect the wrist (seeARTHRITIS) but RHEUMATOID ARTHRITIS, JUVENILE

wrist pain 293

ARTHRITIS, and pseudogout (see CALCIUM PYROPHOS-

PHATE DIHYDRATE DEPOSITION DISEASE) are commoncauses of wrist arthritis. OSTEOARTHRITIS typicallyaffects the first carpometacarpal joint, the jointwhere the base of the thumb meets the wrist.

Tendons The tendons that flex the wrist andfingers run across the front of the wrist, and thosethat extend them run across the back of it. Inflam-mation of tendons (see TENDINITIS) can cause wristpain. One of the most common is DE QUERVAIN’S

TENOSYNOVITIS. This typically causes pain and some-

times swelling close to the lower end of the radius,the bone on the thumb side of the arm.

Nerves Pressure on a nerve as it passesthrough a narrow space can damage it. The usualsymptoms are pain, numbness, and tingling. En-trapment of nerves in the arm usually causessymptoms that affect the fingers and hand. InCARPAL TUNNEL SYNDROME, though, symptoms areoften poorly localized and can affect the wrist.

X rays See Appendix II.

294 X rays

APPENDIXES

I. Drugs Used to Treat Arthritis andRelated Conditions

II. Common Laboratory and Diagnostic Tests

III. Useful Arthritis-Related Web Sites

Please note that the side effects and precautionsdiscussed below are not complete. Common sideeffects and particular precautions are discussed topromote safe, intelligent use of medications. If youhave concerns that are not mentioned below andfor additional information, you should consult thepackage insert and your doctor or pharmacist.

acetaminophen (Trade names: Acephen, Aceta,Apacet, Panadol, Tylenol, and others) An analgesic(painkiller) used to treat pain of mild-to-moderateintensity. Acetaminophen is also an antipyretic andreduces fever, but it has little effect on inflamma-tion. Acetaminophen causes fewer serious gas-trointestinal side effects than NSAIDs and isrecommended as the drug of first choice forosteoarthritis. However, many patients find that anNSAID controls osteoarthritis pain more effectively.

Side effects In therapeutic doses acetaminophenseldom causes serious side effects. Nausea occurs butis not related to damage to the gut. Allergy and rashare rare. Liver damage has occurred, usually whendoses larger than that prescribed have been taken orif the drug is taken with concurrent alcohol con-sumption. In overdose fatal liver failure can occur.

acetaminophen with narcotics such as codeine/hydrocodone/oxycodone/propoxyphene

• acetaminophen with codeine (Trade names:Tylenol with codeine)

• acetaminophen with hydrocodone (Tradenames: Lortab, Lorcet, Vicodin)

• acetaminophen with oxycodone (Tradenames: Percocet, Roxicet, Tylox)

• acetaminophen with propoxyphene (Tradenames: Darvocet–50, Darvocet–100)

A combination of acetaminophen and a narcoticis prescribed for pain of moderate-to-severe inten-sity that has not responded to treatment withacetaminophen or an NSAID.

Side effects In therapeutic doses acetamin-ophen seldom causes side serious effects. Nauseaoccurs but is not related to damage to the gut.Allergy and rash are rare. Liver damage has oc-curred, usually when doses of acetaminophenlarger than the prescribed dose have been taken. Inoverdose fatal liver failure can occur. The narcoticcomponent of combination analgesics frequentlycauses minor side effects, including nausea, vomit-ing, constipation, dizziness, and lightheadedness.Allergic reactions resulting in rash or bron-chospasm are uncommon. Addiction is rare.

Aciphex See RABEPRAZOLE.

actonel See RISEDRONATE.

adalimumab A specially designed protein toblock the effects of tumor necrosis factor (TNF), aproinflammatory cytokine. Adalimumab is a fullyhuman monoclonal antibody that binds to TNF,blocking its effects, and acts a DMARD in RA.

alendronate (Trade name: Fosamax) A bisphos-phonate used to treat and prevent osteoporosis andto treat Paget’s disease.

Side effects Mild gastrointestinal symptomswith nausea, indigestion, and constipation are

APPENDIX IDRUGS USED TO TREAT ARTHRITIS

AND RELATED CONDITIONS

297

common. Difficulty swallowing, vomiting, erosiveesophagitis (ulcers in the esophagus), and allergicreactions are rare.

Bisphosphonates are inconvenient because theyneed to be taken on an empty stomach, first thing inthe morning, with a full glass of water. To prevent thetablet refluxing back up the esophagus, the patientshould remain upright for at least an hour after tak-ing the tablet. Bisphosphonates are very poorlyabsorbed, and therefore after taking the tablet thepatient cannot eat or drink anything other thanwater for at least 30 minutes. Most manufacturershave produced a tablet that can be taken once a weekthat is much more convenient than a daily dose.

allopurinol (Trade names: Lopurin, Zyloprim)Decreases production of uric acid by inhibitingxanthine oxidase, a key enzyme in the pathwayleading to uric acid. Allopurinol is used to preventfuture attacks of gout, particularly in patients withrecurrent attacks of gout, uric acid kidney stones,or deposits of uric acid in the soft tissues (tophi).

Side effects Common: Mild allergic rash.Uncommon: Can precipitate an acute attack of goutwhen treatment is started. To prevent this, manyphysicians also prescribe an NSAID or colchicinefor a few months. An allergic reaction called theallopurinol hypersensitivity syndrome causes severerash, often with blisters and peeling, and impairedkidney and liver function. This is very rare. Factorsthat increase the risk for the allopurinol hypersen-sitivity syndrome include impaired kidney functionand diuretic therapy. Bone marrow suppression israre but occurs frequently if allopurinol is pre-scribed with standard doses of azathioprine (tradename: Imuran) or mercaptopurine (trade name:Purinethol). Allopurinol inhibits the breakdown ofthese anticancer drugs; they should therefore beavoided or used in much smaller doses than usual.

Ambien See ZOLPIDEM.

amitriptyline (Trade names: Elavil, Endep,Enovil) A tricyclic antidepressant, a class of drugcommonly used to treat depression, chronic pain,or fibromyalgia.

Side effects Common: Sleepiness. Because ofthis effect, tricyclics with sedative side effects are

often used to improve sleep. The sedative effectscan persist, resulting in unwanted sleepiness dur-ing the day. This often becomes less pronouncedwith continued use. Anticholinergic side effectssuch as dry mouth and eyes, blurred vision, consti-pation, and slowness or difficulty passing urine canoccur, particularly when treatment is started, buttolerance to these side effects may also develop.Uncommon: Postural hypotension resulting indizziness when standing up suddenly, tremor, nau-sea, confusion, sexual dysfunction, GI symptoms,paradoxical stimulation rather than sedation, bonemarrow suppression, abnormal liver function tests,seizures, hair loss, and heart rhythm problems.

anakinra (Trade name: Kineret) An interleukin-1receptor antagonist, anakinra is a speciallydesigned protein that binds to the interleukin-1receptor and blocks the effects of the proinflamma-tory cytokine interleukin-1. Anakinra acts as aDMARD in RA and is being tested in otherrheumatic conditions.

Side effects Few serious adverse effects occur,but there is limited long-term information. Com-mon: Requires subcutaneous injection and minorskin injection, reactions resulting in redness anditching around the injection site are common. Theneutrophil count decreases modestly in 5–10 per-cent of patients and markedly in 0.3 percent ofpatients receiving anakinra. Uncommon: Infections(sometimes serious) are twice as frequent inpatients receiving anakinra than placebo. Seriousinfections (7 percent) and a serious decrease in theneutrophil count (3 percent) were more commonwhen anakinra was combined with etanercept.That combination is usually avoided.

Anaprox See NAPROXEN.

Ansaid See FLURBIPROFEN.

Aredia See PAMIDRONATE.

Arthrotec See DICLOFENAC.

artificial tears (Trade names: Artificial Tears, BionTears, Cellufresh, Hypotears, Isopto Alkaline, IsoptoPlain, Isopto Tears, Just Tears, Nature’s Tears,

298 The Encyclopedia of Arthritis

Ocucoat, Ocucoat PF, Refresh, Refresh Plus, TearsNaturelle, Tears Naturelle II, Tears Naturelle Free,Ultra Tears, and many others) Eye drops or oint-ments are used to protect eyes against dryness. Manycontain hydroxypropyl methylcellulose, or a similarchemical, that retains liquid. Artificial tears are usedto treat dry eyes that are often part of Sjögren’s syn-drome and many other autoimmune diseases.

Side effects Common: Mild blurring of vision.Uncommon: Irritation of the eye by preparationscontaining a preservative. This may be due to anallergic response to the preservative and can be over-come by switching to a nonpreservative-containingpreparation.

Ascriptin See CHOLINE SALICYLATE.

aspirin (Trade names: Anacin, Ascriptin, A.S.A,Bayer Aspirin, Bufferin, Easprin, Ecotrin, Zorprin,and many others) A nonsteroidal anti-inflamma-tory drug (NSAID) that inhibits cyclooxygenase(COX-1 and COX-2) enzymes, decreasing the for-mation of inflammatory mediators such asprostaglandins. Aspirin is prescribed for threemajor reasons.

1. Analgesic and anti-inflammatory effects: Aspirinis used to treat pain and inflammation caused bymany rheumatic and nonrheumatic conditions,including rheumatoid arthritis, osteoarthritis,rheumatic fever, Still’s disease (also known asjuvenile rheumatoid arthritis), and Kawasakidisease. NSAIDs do not affect the progression ofarthritis.

2. Antipyretic effects: Aspirin reduces fever.3. Antithrombotic effects: Aspirin, by irreversibly

inhibiting COX-1, reduces platelet aggregation,the initial step in the formation of blood clots.Aspirin is widely used to treat and preventmyocardial infarction and stroke. In patients withthe anticardiolipin antibody syndrome, aspirin isprescribed to reduce the risk of thrombosis.

Side effects Common: GI symptoms such asindigestion or heartburn and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factors

for complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and cotreatment with a corticos-teroid. NSAIDs can increase blood pressure, impairkidney function, and cause abnormal liver functiontests (usually mild), rashes, ringing in the ears, anda feeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticaria, and angioedema. Reye’ssyndrome is a rare condition that causes liver fail-ure and coma in children treated with aspirin for aviral illness.

auranofin (Trade name: Ridaura; also known asoral gold) A disease-modifying antirheumatic drug(DMARD) most often prescribed to treat rheuma-toid arthritis and occasionally used to treat psoriaticarthritis.

Side effects Common: Diarrhea, gas andcramping, itching, skin rash, mouth ulcers, and pro-tein in the urine. Uncommon: Serious allergic reac-tions such as a generalized skin rash with peeling,bone marrow suppression resulting in a low whitecell count or low platelet count, hepatitis, periph-eral neuropathy, fever, and lung inflammation.

azathioprine (Trade name: Imuran) An anticancerdrug that interferes with DNA synthesis, particularlyin cells regulating the immune system. Azathio-prine is metabolized to active products including 6-mercaptopurine, a related anticancer drug. Smallerdoses of azathioprine are used to treat rheumatic diseases other than cancer, and the mode of action ismore immunoregulatory as opposed to the celldestruction of cancer chemotherapy. Azathioprine isused as a disease-modifying antirheumatic drug(DMARD) to treat rheumatoid arthritis, usually inpatients unable to tolerate other DMARDs. It is alsocommonly used to treat systemic lupus erythemato-sus, dermatomyositis or polymyositis, vasculitis, andother connective tissue diseases.

Side effects Common: GI symptoms such asvomiting, diarrhea and nausea, and mild increasesin liver enzymes. Uncommon: Dose-related bonemarrow suppression can result in a decrease in thewhite blood cell and platelet count. A genetic vari-ation in an enzyme, thiopurine methyl transferase(TPMT), slows the metabolism of azathioprine and

Appendix I 299

increases sensitivity to the drug substantially. Thehomozygous form (both strands of DNA affected)of the gene associated with impaired TPMT activityoccurs in approximately 1 in 300 people. Genetictesting for the gene is becoming available. If stan-dard doses of azathioprine (trade name: Imuran) ormercaptopurine (trade name: Purinethol) are pre-scribed with allopurinol (trade name: Zyloprim),severe adverse effects, particularly bone marrowsuppression, are likely because allopurinol inhibitsthe breakdown of these drugs. Mouth ulcers, rash,herpes zoster (shingles) (caused by reactivation ofthe chicken pox virus), and an increased risk ofinfection occur. The range of infections is wide,including not only usual organisms but alsounusual ones. Pancreatitis, severe hepatitis, severelung inflammation, and serious allergic reactionsare rare. Azathioprine may cause a small increasein the risk of some malignancies such as lymphomaand leukemia.

Azulfidine See SULFASALAZINE.

Benemid See PROBENECID.

Bextra See VALDECOXIB.

Butazolidin See PHENYLBUTAZONE.

calcitonin (Trade names: Cibacalcin (human),Miacalcin (salmon)) A hormone that slows theresorption of bone. Calcitonin is used to treat andprevent osteoporosis and to treat Paget’s disease.Calcitonin nasal spray is used to treat and preventosteoporosis.

Side effects Common: Calcitonin injectionscan cause flushing, headache, nausea, diarrhea,redness at the injection site, and less often, an aller-gic rash or hypocalcemia (low blood calcium level).The flushing, nausea, and diarrhea can sometimesbe overcome by reducing the dose. Nasal calcitoninseldom causes side effects other than mild nasalirritation.

calcium

• calcium carbonate (Trade names: Alka-Mints,Calci-Chew, Caltrate, Os-Cal, Oyst-Cal 500,

Rolaids Calcium Rich, Titralac, Tums, Tums E-X,and many others)

• calcium citrate (Trade name: Citracal)

• calcium lactate Generic

• calcium phosphate dibasic Generic

Calcium supplements are used to prevent andtreat osteoporosis.

Side effects Common side effects are a chalkytaste and constipation. Calcium supplements rarelycause hypercalcemia (a high blood calcium level)or kidney stones.

capsaicin (Trade names: Zostrix, Capsin, Thera-gen, Trixaicin, Capsagel) An analgesic cream orointment. Developed from hot chilies, capsaicinmay deplete nerves that conduct pain signals of animportant neurotransmitter, substance P. Capsaicinis used to decrease joint pain, most often thatcaused by osteoarthritis. Capsaicin is also used totreat neuralgia (nerve pain) associated with dia-betes or occurring after herpes zoster (shingles).

Side effects Common: A burning sensationwhen initially applied (this decreases with chronicuse), skin irritation, and severe pain and a burningsensation if inadvertently applied to eyes, brokenskin, or genital organs.

carisoprodol (Trade names: Rela, Soma) A mus-cle relaxant used to treat painful muscle spasm andfibromyalgia.

Side effects Common: Drowsiness. Less com-mon: Flushing, nausea, vomiting, feeling light-headed, central nervous system stimulation,shakiness, and rash. Uncommon: Addiction, bonemarrow suppression, and allergy resulting in swel-ling of the face or tongue.

Celebrex See CELECOXIB.

celecoxib (Trade name: Celebrex) A nonsteroidalanti-inflammatory drug (NSAID) that inhibits thecyclooxygenase-2 (COX-2) enzyme, decreasing theformation of inflammatory mediators such asprostaglandins. Celecoxib is selective for COX-2and has little effect on COX-1 and therefore doesnot inhibit platelet aggregation. NSAIDs are used to


treat pain and inflammation due to many causesand for arthritis-related pain caused by rheumatoidarthritis, osteoarthritis, and bursitis. NSAIDs do notaffect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gastro-intestinal obstruction, or bleeding. Risk factors forcomplicated peptic ulcers caused by NSAIDs are ageolder than 65 years, previous peptic ulcer or bleed-ing ulcer, and cotreatment with a corticosteroid.The risk of peptic ulcers and their complications islower with selective COX-2–inhibiting NSAIDs,such as celecoxib, than nonselective NSAIDs.NSAIDs can increase blood pressure, impair kidneyfunction, and cause abnormal liver function tests(usually mild), rashes, ringing in the ears, and afeeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticaria, and angioedema. Patientsallergic to sulfonamides may have a higher risk of allergy.

Cellcept See MYCOPHENOLATE MOFETIL.

cevimeline (Trade name: Evoxac) A drug thatstimulates the cholinergic nerves to salivary glands,increasing the production of saliva, and used totreat the symptom of dry mouth that often occursin patients with Sjögren’s syndrome.

Side effects Common: Sweating, dizziness,headache, blurred vision, a runny or blocked nose,and GI problems such as nausea and diarrhea.

chlorambucil (Trade name: Leukeran) An anti-cancer drug that interferes with the formation ofDNA, particularly in white blood cells, and modu-lates the immune system. Smaller doses of chlor-ambucil are used to treat rheumatic problems thanare used to treat cancer. Side effects are less com-mon with these lower doses. Chlorambucil is sel-dom prescribed but is sometimes used to suppressthe immune system in patients who cannot takecyclophosphamide. Cyclophosphamide (and chlo-rambucil) are used to treat vasculitis, lupus affect-ing vital organs such as the brain and kidney,autoimmune eye disease, and Behçet’s disease.

Side effects Common: Bone marrow suppres-sion with a decrease in the white cell count and/orplatelet count. Less common: Rash, GI symptoms(nausea, vomiting, and diarrhea), and mouth ulcers.Herpes zoster (shingles), caused by reactivation ofthe chicken pox virus, and risk of infection areincreased. The range of infections is wide, includingthose caused by common organisms and also un-usual ones. Uncommon: Confusion, seizures, chang-es in menstrual cycle and infertility, lung fibrosis,severe hepatitis, fever, and increased risk of cancer.

chloroquine See HYDROXYCHLOROQUINE AND

CHLOROQUINE SULFATE.

choline magnesium salicylate (Trade name: Tril-isate) A nonsteroidal anti-inflammatory drug(NSAID) belonging to a subgroup called nonacety-lated salicylates that differs from other NSAIDs inthat it is a weak inhibitor of cyclooxygenase (COX)enzymes that decrease the formation of inflamma-tory mediators such as prostaglandins. NSAIDs areused to treat pain and inflammation due to manycauses and for arthritis-related pain caused byrheumatoid arthritis, osteoarthritis, and bursitis.NSAIDs do not affect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and cotreatment with a cortico-steroid. Nonacetylated salicylates are salicylates likeaspirin, but their different chemical structuremakes them behave more like COX-2-selectiveNSAIDs, so they do not inhibit platelet aggregationsignificantly and are less likely to cause serious GIcomplications. NSAIDs can increase blood pressure,impair kidney function, and cause abnormal liverfunction tests (usually mild), rashes, ringing in theears, and a feeling of lightheadedness. Uncommon:Serious allergy to NSAIDs can result in anaphylaxiswith bronchospasm, urticaria, and angioedema.

choline salicylate (Trade name: Arthropan) Anonsteroidal anti-inflammatory drug (NSAID)

Appendix I 301

belonging to a subgroup called nonacetylated sali-cylates that differs from other NSAIDs in that it is aweak inhibitor of cyclooxygenase (COX) enzymesthat decrease the formation of inflammatory medi-ators such as prostaglandins. NSAIDs are used totreat pain and inflammation due to many causesand for arthritis-related pain caused by rheumatoidarthritis, osteoarthritis, and bursitis. NSAIDs do notaffect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and cotreatment with a cortico-steroid. Nonacetylated salicylates are salicylates likeaspirin, but their different chemical structuremakes them behave more like COX-2–selectiveNSAIDs, so they do not inhibit platelet aggregationsignificantly and are less likely to cause serious GIcomplications. NSAIDs can increase blood pressure,impair kidney function, and cause abnormal liverfunction tests (usually mild), rashes, ringing in theears, and a feeling of lightheadedness. Uncommon:Serious allergy to NSAIDs can result in anaphylaxiswith bronchospasm, urticaria, and angioedema.

chondroitin sulfate See GLUCOSAMINE AND CHON-

DROITIN SULFATE.

cimetidine (Trade name: Tagamet) A histaminetype 2 receptor antagonist (H2-receptor antagonistor H2-blocker) that decreases acid production bythe stomach and is used to treat indigestion, refluxesophagitis, and peptic ulcers. H2-receptor antago-nists, except in high doses, do not provide adequateprotection against NSAID-induced peptic ulcers.

Side effects H2-receptor antagonists are gen-erally well tolerated and have few adverse effects.Common: Minor, transient symptoms such as diz-ziness, headache, and diarrhea. Uncommon: In-creased breast tissue with swelling in men(gynecomastia), rash, hepatitis, and myopathy.Cimetidine, because it inhibits liver enzymes thatmetabolize some drugs, increases the concentrationsof several drugs, including warfarin, theophylline,

phenytoin, quinidine, propranolol, and tricyclicantidepressants.

cisapride (Trade name: Propulsid) Stimulates GImotility by increasing the concentrations of achemical messenger, acetylcholine, in the bowelwall. Cisapride is occasionally used to improve GImotility in patients with scleroderma. It was usedto treat GERD (gastroesophageal reflux disease),but rare, serious side effects have resulted inrestricted use. It is no longer available on the gen-eral market in the United States.

Side effects Common: Rash, stomach cramps,diarrhea, and increased intestinal gas. Less com-mon: Nervousness, vomiting, and drowsiness. Rare: A serious, sometimes fatal, heart rhythmproblem called torsades de pointes. This usuallyoccurred when cisapride was taken in overdose orwith another drug that slowed its metabolism.Many drugs block the enzyme that breaks down cis-apride, leading to high concentrations and thepotential for fatal arrhythmias.

Clinoril See SULINDAC.

codeine (Codeine is usually prescribed as ageneric or as a combination analgesic. See ACETA-MINOPHEN WITH NARCOTICS) It is a narcotic analgesicthat decreases pain by acting through specific opiate receptors in the brain and is used to treatmoderate-to-severe pain not controlled by aceta-minophen or an NSAID. Codeine is occasionallyprescribed to suppress cough.

Side effects Common: Nausea, vomiting, consti-pation, poor appetite, dizziness, feeling lightheaded,and sleepiness. Uncommon: Feeling nervous or agi-tated, sleeping badly, an allergic reaction withurticarial rash (hives) or bronchospasm, confusion,feeling high, and addiction.

colchicine (Colchicine is usually prescribed as ageneric) It suppresses inflammation in acute gout,probably by altering white blood cell migration toareas of inflammation. Colchicine is used to sup-press and treat acute attacks of gout and also totreat familial Mediterranean fever.

Side effects Common: Dose-related nausea,vomiting, diarrhea, and stomach cramps. Less com-


mon: Decreased appetite and mild hair loss.Uncommon: Neuropathy, myopathy, rash, bonemarrow suppression, hepatitis, and decreasedsperm count.

collagen (Trade names: None) Also known aschicken collagen. Collagen is a potential treatmentfor rheumatoid arthritis but has been ineffective inmost clinical trials. The theory underlying the useof collagen is similar to the concept of allergy shotswith low doses of allergen desensitizing allergicresponses. Collagen taken by mouth was thoughtto make the immunologically active cells in thewall of the gut tolerant to collagen and thus toler-ant to the patient’s collagen, a major component ofjoints and connective tissue. There are ongoingstudies, but the evidence so far does not support arole for collagen treatment in rheumatoid arthritis.

corticosteroids Trade namesTablets: prednisone: Deltasone, Orasone

methylprednisolone: Medrol dexamethasone: Dexone

Injections: methylprednisolone: SoluMedrol hydrocortisone: Solu-Cortef dexamethasone: Decadron

Intra- methylprednisolone acetate: Depo-articular Medrolinjections: triamcinolone: Aristocort, Aristospan,

Kenalog

Corticosteroids are also called glucocorticoids orsometimes just steroids. They are related to corti-sone, a stress hormone produced by the adrenalgland, and differ from anabolic steroids used by someathletes to increase muscle strength. Corticosteroids,acting through glucocorticoid receptors found onmost cells, suppress the immune response. Variouspreparations are used to treat rheumatic diseases.

• Tablets: High doses of oral corticosteroids, oftenin combination with another immunosuppres-sant, are prescribed to control vasculitis, SLEaffecting organs such as kidneys or the brain,and dermatomyositis or polymyositis. After theillness is controlled the doses of corticosteroidsare tapered. Many patients with rheumatoidarthritis (RA) take low doses of corticosteroids,

usually in combination with a DMARD, to helpsuppress inflammation. Acute inflammation in ajoint (for example in RA) or in other organs (forexample pleurisy caused by SLE) can be treatedwith corticosteroid tablets, initially in high dosesand then tapering rapidly (sometimes referredto as a dose pack).

• Injections: Very high doses of pulse corticosteroidsare administered intravenously in situationswhere the need for treatment is urgent, such asvasculitis or SLE threatening life or an organ.

• Intra-articular injections: In rheumatoid arthri-tis, other types of inflammatory arthritis, andosteoarthritis, a long-acting depot corticosteroidis injected into a swollen joint to suppressinflammation. Long-acting depot corticosteroidsare also injected into bursas to treat bursitis ornear a tendon to treat tendinitis.

Side effects of intra-articular injections Thelocal injection of a long-acting steroid into a jointexposes the individual to a low systemic dose ofcorticosteroid that seldom causes adverse effectsother than occasionally aggravating pain andswelling for a day or two. An injection of a corti-costeroid directly into a tendon can weaken it andlead to rupture. There is concern, mainly theoreti-cal, that repeated intra-articular corticosteroidinjections could damage cartilage. Therefore, thenumber of injections into any one joint is kept to aminimum. Side effects such as bleeding or infectionin the injected joint are rare and result from theinjection itself, rather than the corticosteroid.

Side effects of oral and injected corticosteroids

The frequency and severity of side effects are doserelated; high doses invariably cause side effects, butlow doses do so less often. Side effects include os-teoporosis, hypertension, diabetes, cataracts, myo-pathy, increased appetite and weight gain, lowserum potassium concentration, cushingoid fea-tures (fat redistribution resulting in a moon-shapedface and obesity), increased skin fragility and bruis-ing, emotional lability, insomnia, depression, feelinglightheaded, and an increased white blood cellcount. Corticosteroids increase the risk of infec-tions. These can be regular infections, such as pneu-monia, but can also be less common infections, suchas tuberculosis. Avascular necrosis is uncommon.

Appendix I 303

cuprimine See PENICILLAMINE.

cyclobenzaprine (Trade name: Flexeril) A mus-cle relaxant used to treat painful muscle spasmand, less often, fibromyalgia.

Side effects Common: Drowsiness is common,and because of this, cyclobenzaprine is often takenat night to improve sleep. Anticholinergic sideeffects such as dry mouth and eyes, blurred vision,constipation, and slowness or difficulty passingurine are common, particularly when treatment isstarted. Tolerance to these side effects may develop.Nausea, confusion, and stomach upset can occur.Paradoxical stimulation, rather than sedation, isuncommon.

Rare: Hepatitis, allergy, and heart rhythm dis-turbances.

cyclophosphamide (Trade names: Cytoxan,Neosar) An anticancer drug that interferes withDNA synthesis, particularly in cells regulating theimmune system. Smaller doses of cyclophos-phamide are used to treat rheumatic diseases otherthan cancer with a mode of action that is moreimmunoregulatory as opposed to cell destruction asin cancer chemotherapy. Cyclophosphamide isused to treat systemic lupus erythematosus, vas-culitis, and other serious connective tissue diseases.Cyclophosphamide is prescribed as either a dailytablet or a monthly intravenous injection. Themonthly intravenous regimen is preferred for thetreatment of systemic lupus erythematosus and the daily oral dose for the treatment of vasculitis.

Side effects The side effects of cyclophos-phamide are related to the dose, duration, androute of treatment. The risk of infection is greaterwhen it is administered in doses that result in amarked decrease in the white blood cell count. Therisk of secondary malignancies increases with dura-tion of exposure. Common: Nausea, vomiting,bone marrow suppression resulting in low whiteblood cell count or thrombocytopenia, and ovarianfailure resulting in premature menopause andinfertility. Cyclophosphamide is metabolized toacrolein, a bladder irritant that frequently causescystitis (bladder inflammation), and occasionallyhemorrhagic cystitis (i.e., with blood in the urine).MESNA is a drug that is often prescribed with IV

injections of cyclophosphamide to protect the blad-der. Herpes zoster (shingles), caused by reactiva-tion of the chicken pox virus, and an increased riskof infection, particularly if the patient is also receiv-ing high doses of corticosteroids, can occur. Therange of infections is wide, including those causedby common organisms and unusual ones. Infertil-ity due to ovarian failure is common. Monthlyintravenous administration rarely causes bladderproblems and is associated with a slightly lowerfrequency of ovarian failure and infections thandaily oral administration. Uncommon: Lunginflammation, hepatitis, allergy, and delayed sideeffects such as increased frequency of bladder can-cer, skin cancer, and leukemia.

cyclosporine (cyclosporin, cyclosporin A) (Tradenames: Sandimmune, Neoral) Two preparationscontaining the identical drug—cyclosporine—areavailable. Neoral is a newer, microemulsion prepa-ration that is more completely and reproduciblyabsorbed than the older preparation, Sandimmune.Cyclosporine is an immunosuppressive drug whosemain use is to prevent rejection after organ trans-plantation. It also acts as a DMARD in RA and issometimes prescribed for other indications such aspsoriasis and psoriatic arthritis, dermatomyositis,Behçet’s disease, SLE, and autoimmune eye inflam-mation not responding to standard treatments.Cyclosporine decreases the production of thecytokine interleukin-2 (IL-2). This, and effects onother mediators, suppress the immune response.

Side effects Common: Nausea, vomiting,intestinal gas, cramps, diarrhea, increased hairgrowth, a small increase in blood pressure, tremor,headache, muscle cramps, decreased kidney func-tion, increased serum potassium and uric acid, anddecreased serum magnesium concentrations.Uncommon: Hypertrophy of the gums, gout,seizures, infection, and allergic reactions.

Cytotec See MISOPROSTOL.

Cytoxan See CYCLOPHOSPHAMIDE.

danazol (Trade name: Danocrine) A mild andro-gen (male hormone) that decreases the frequencyof attacks in hereditary angioedema and increases


the platelet count in autoimmune thrombocytope-nia. The mechanism of action in autoimmune dis-eases is unclear, but it increases the synthesis ofcomplement, a group of proteins that clear anti-gen/antibody complexes (see COMPLEMENT). It isalso used to treat endometriosis and fibrocysticbreast disease.

Side effects Common: Abnormal liver functiontests and androgenic effects such as acne, increasedfacial and body hair, irregular menstrual cycles,bleeding between monthly cycles, weight gain, andfluid retention. Uncommon: Hepatitis, pancreatitis,thrombocytopenia, low white blood cell count, andraised intracranial pressure.

Danocrine See DANAZOL.

dapsone (Trade name: Avlosulfon) A sulfonedrug similar in structure to sulfonamide (sulfa)antibiotics. The most common indication is leprosy,but it is also occasionally used to treat severe skinproblems caused by systemic or discoid lupus ery-thematosus, leukocytoclastic vasculitis, and pyo-derma gangrenosum.

Side effects Common: Rash and GI symptoms.Dapsone can cause dose-related hemolysis (break-down of red blood cells) and anemia, particularlybut not exclusively in individuals with a hereditarydeficiency of the enzyme glucose-6 phosphatedehydrogenase (G-6PD). A dose-related increase inthe concentrations of methemoglobin, a type ofhemoglobin that does not carry oxygen well,resulting in a dusky or bluish skin color, occurs.Uncommon: Low white blood cell count, severeallergic skin rash, and hepatitis.

Darvocet See ACETAMINOPHEN WITH PROPOXYPHENE.

Daypro See OXAPROZIN.

Demerol See MEPERIDINE.

Depen See PENICILLAMINE.

DepoMedrol See CORTICOSTEROIDS.

Desyrel See TRAZODONE.

dexamethasone See CORTICOSTEROIDS.

DHEA (dehydroepiandrosterone) (Available inhealth food stores in the form of natural prod-ucts/food supplements) DHEA is a precursor hor-mone secreted by the adrenal gland that isconverted to the androgenic (male) hormonesandrostenedione, testosterone, and androsteroneand the estrogenic (female) hormone estradiol. Inlimited clinical studies DHEA resulted in a smalldecrease in the corticosteroid requirements inpatients with mild SLE and an increase in bonedensity. It is also promoted as an antiaging hor-mone with little scientific support.

Side effects Common: Androgenic side effectssuch as acne, greasy hair, and increased body andfacial hair are more common in women; estrogenicside effects such as breast growth and tendernessare more common in men. Because DHEA is classi-fied as a food supplement and not a drug, it has notundergone rigorous safety or efficacy testing, andknowledge about the long-term responses ofmalignancies such breast and prostate cancer thatare hormone responsive are unknown.

diclofenac (Trade names: Cataflam [immediaterelease], Voltaren [enteric coated, extendedrelease], Arthrotec [diclofenac plus misoprostol]) Anonsteroidal anti-inflammatory drug (NSAID) thatinhibits cyclooxygenase (COX-1 and COX-2)enzymes, decreasing the formation of inflamma-tory mediators such as prostaglandins. Arthroteccombines diclofenac with misoprostol, a drug thatprotects against peptic ulcers. NSAIDs are used totreat pain and inflammation resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, Still’s disease (also knownas juvenile rheumatoid arthritis), gout, ankylosingspondylitis, and bursitis. NSAIDs do not affect theprogression of arthritis.

Side effects For the side effects of the miso-prostol component of Arthrotec, see MISOPROSTOL.Common: GI symptoms, usually indigestion orheartburn and fluid retention with ankle edema.Less common: Peptic ulcers with or without com-plications such as perforation, gastrointestinalobstruction, or bleeding. Risk factors for compli-cated peptic ulcers caused by NSAIDs are age older

Appendix I 305

than 65 years, previous peptic ulcer or bleedingulcer, and treatment with a corticosteroid. NSAIDscan increase blood pressure, impair kidney func-tion, and cause abnormal liver function tests (usu-ally mild), rashes, ringing in the ears, and a feelingof lightheadedness. Uncommon: Serious allergy toNSAIDs can result in anaphylaxis with bron-chospasm, urticaria, and angioedema.

Didronel See ETIDRONATE.

diflunisal (Trade name: Dolobid) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation, resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondyli-tis, and bursitis. NSAIDs do not affect the progres-sion of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and treatment with a corticosteroid.NSAIDs can increase blood pressure, impair kidneyfunction, and cause abnormal liver function tests(usually mild), rashes, ringing in the ears, and afeeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticaria, and angioedema.

Disalcid See SALSALATE.

Dolobid See DIFLUNISAL.

doxepin (Trade name: Sinequan) A tricyclic anti-depressant, a class of drug commonly used to treatdepression, chronic pain, and fibromyalgia.

Side effects Common: Sleepiness, and becauseof this sedative antidepressants are often used toimprove sleep. The sedative effects can persist,resulting in unwanted sleepiness during the day.

Anticholinergic side effects such as dry mouth andeyes, blurred vision, constipation, and slowness ordifficulty passing urine can occur, particularlywhen treatment is started, but tolerance to theseside effects may develop. Uncommon: Posturalhypotension resulting in dizziness when standingup suddenly, tremor, nausea, confusion, sexualdysfunction, GI symptoms, paradoxical stimulationrather than sedation, bone marrow suppression,abnormal liver function tests, seizures, hair loss,and heart rhythm problems.

doxycycline See MINOCYCLINE.

Duragesic See FENTANYL.

Easprin See ASPIRIN.

Ecotrin See ASPIRIN.

Elavil See AMITRIPTYLINE.

Enbrel See ETANERCEPT.

esomeprazole (Trade name: Nexium) A protonpump inhibitor (a class of drugs also known as PPIs)that decreases gastric acid production and is used totreat and prevent peptic ulcers and gastroesophagealreflux (GERD), common side effects of NSAIDs.

Side effects Proton pump inhibitors seldomcause side effects. Uncommon: Constipation, rash,dizziness, diarrhea, abdominal pain, and elevatedliver enzymes.

etanercept (Trade name: Enbrel) A speciallydesigned protein to block the effects of tumornecrosis factor (TNF), a proinflammatory cytokine.Etanercept consists of two receptors for TNF cou-pled together. TNF binds to the false receptors onetanercept and not the real receptors. In otherwords, etanercept acts as a decoy and mops up TNFbefore it binds to the real receptors where it wouldactivate inflammation. Etanercept acts as aDMARD in RA and is also used to treat juvenilerheumatoid arthritis (JRA) and psoriatic arthritis.Limited data support its use in vasculitis and anky-losing spondylitis.


Side effects Few adverse effects occur but thereis limited long-term information. Common: Itrequires subcutaneous injection, and minor skininjection reactions resulting in redness and itchingaround the injection site are common. Approxi-mately 5–10 percent of patients receiving etaner-cept will develop a positive antinuclear antibody(ANA) test, raising the concern that etanerceptmay increase the risk of autoimmune diseases suchas SLE. So far this has not been a problem, but thelong-term effects are not yet known. Uncommon:The risk of infections (sometimes serious) such aspneumonia is increased. Rare: Case reports or smallseries of patients developing diabetes, cancer, lym-phoma, VASCULITIS, SLE-like autoimmune disease,multiple sclerosis-like demyelinating disorders,liver disease, hematological abnormalities includ-ing aplastic anemia, severe allergy, meningitis andinfection with TUBERCULOSIS, atypical mycobacteria,aspergillosis, histoplasmosis, and listeria have beenreported in patients receiving TNF antagonists. TNFantagonists may increase mortality in patients withheart failure and should be avoided.

etidronate (Trade name: Didronel, also known asDisodium Etidronate, Sodium Etidronate). A bis-phosphonate used to treat and prevent osteoporo-sis and to treat Paget’s disease.

Side effects Common: Mild gastrointestinalsymptoms with nausea, indigestion, and cons-tipation. Uncommon: Allergic rash, fever, poormineralization of bone, and hypocalcemia. Bispho-sphonates are inconvenient because they need tobe taken on an empty stomach with a full glass ofwater. To prevent the tablet refluxing back up theesophagus, the patient must stay upright for at leastan hour. Bisphosphonates are very poorlyabsorbed, and therefore after taking the tablet thepatient cannot eat or drink anything other thanwater for at least 30 minutes. Etidronate is seldomused to treat osteoporosis because there is evidencethat alendronate and risedronate (other bisphos-phonates) prevent osteoporotic fractures moreeffectively.

etodolac (Trade name: Lodine) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,

decreasing the formation of inflammatory media-tors such as prostaglandins. Because etodolac tendsmore toward a COX-2-blocking effect, it may causeless GI side effects than nonselective NSAIDs.NSAIDs are used to treat pain and inflammation,resulting from a variety of causes. Common indica-tions are rheumatoid arthritis, osteoarthritis, gout,ankylosing spondylitis, and bursitis. NSAIDs do notaffect the progression of arthritis.


Evista See RALOXIFENE.

Evoxac See CEVIMELINE.

famotidine (Trade name: Pepcid) A histaminetype 2 receptor antagonist (H2-receptor antagonistor H2-blocker) that decreases acid production bythe stomach and is used to treat indigestion, refluxesophagitis, and peptic ulcers. H2-receptor antago-nists, except in high doses, do not provide adequateprotection against NSAID-induced peptic ulcers.

Side effects H2-receptor antagonists are gener-ally well tolerated. Common: Minor, transientsymptoms such as dizziness, headache, and diar-rhea. Uncommon: Rash and hepatitis.

Feldene See PIROXICAM.

fenoprofen (Trade name: Nalfon) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory mediatorssuch as prostaglandins. NSAIDs are used to treatpain and inflammation, resulting from a variety

Appendix I 307

of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondylitis,and bursitis. NSAIDs do not affect the progression of arthritis.


fentanyl (Trade names: Duragesic, Sublimaze)A strong narcotic analgesic used to treat severepain not controlled by acetaminophen, an NSAID,or by weaker narcotics, such as codeine orhydrocodone. Narcotics do not affect inflamma-tion but decrease pain by acting through specificopiate receptors in the brain. When used forintractable pain, fentanyl is applied to the skin ina patch that works over 72 hours. Heat, due toeither a fever or local application to the patch,should be avoided since it increases absorptionand may result in an overdose.

Side effects Common: Nausea, vomiting, con-stipation, decreased appetite, dizziness, lighthead-edness, sedation, and low blood pressure.Uncommon: Allergy resulting in an urticarial rashor bronchospasm, confusion, agitation, insomnia,euphoria, addiction, and suppression of respiration.

Flexeril See CYCLOBENZAPRINE.

fluoxetine (Trade name: Prozac) An antidepres-sant of the selective serotonin reuptake inhibitor(SSRI) type, a class of drug commonly used to treatdepression, chronic pain, and fibromyalgia.

Side effects Common: Anxiety, dizziness,insomnia, dry mouth, and GI side effects such asnausea and diarrhea. Uncommon: Tremor, confu-sion, rash, sexual dysfunction, sedation, andallergy.

flurbiprofen (Trade name: Ansaid) A non-steroidal anti-inflammatory drug (NSAID) thatinhibits cyclooxygenase (COX-1 and COX-2) en-zymes, decreasing the formation of inflammatorymediators such as prostaglandins. NSAIDs are usedto treat pain and inflammation, resulting from avariety of causes. Common indications are rheu-matoid arthritis, osteoarthritis, gout, ankylosingspondylitis, and bursitis. NSAIDs do not affect theprogression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and treatment with a corticosteroid.NSAIDs can increase blood pressure, impair kidneyfunction, and cause abnormal liver function tests(usually mild), rashes, ringing in the ears, and afeeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticarial rash and angioedema.

folic acid (folate) (Trade name: Folvite and manygeneric preparations) A vitamin used to protectagainst the side effects of methotrexate such asmouth ulcers, nausea, and changes in blood count.Folic acid is the precursor of folinic acid, whichblocks the effects of methotrexate.

Side effects Uncommon: Rash, flushing, andneuropathy in people who are deficient in vitaminB12. In high doses, folic acid can decrease the ther-apeutic efficacy of methotrexate.

folinic acid (Leucovorin, Tetrahydrofolate) (Tradenames: Wellcovorin) A vitamin used to protectagainst the side effects of methotrexate such asmouth ulcers, nausea, and changes in blood count.Folinic acid blocks the effects of methotrexate.

Side effects Uncommon: Rash, flushing, andneuropathy in people who are deficient in vitaminB12. In high doses, folinic acid can decrease thetherapeutic efficacy of methotrexate. Folinic acid isa vitamin.

Fosamax See ALENDRONATE.


gabapentin (Trade name: Neurontin) An anticon-vulsant (antiseizure drug) that is also used to treatchronic pain, particularly painful neuropathy.Gabapentin is structurally similar to the inhibitorycentral nervous system neurotransmitter gamma-aminobutyric acid (GABA), but this may notexplain its mechanism of action, which is uncertain.

Side effects Uncommon: Sleepiness, dizziness,double vision, loss of balance, fatigue, low whiteblood cell count, and GI symptoms.

gammaglobulin (intravenous immune globulin,IVIG) (Trade names: Gamimune, Gammagard,Iveegam, Polygam, Sandoglobulin) An immunoglo-bulin or protein produced by the body to fight in-fection. Gammaglobulin is most often used asreplacement therapy for patients who, usually be-cause of an inherited problem, do not make enoughgammaglobulin. Gammaglobulin is also used totreat idiopathic thrombocytopenic purpura (ITP)(see THROMBOCYTOPENIA), KAWASAKI DISEASE, andrare types of nerve damage such as chronic inflam-matory demyelinating polyneuropathy. Gamma-globulin has also sometimes been used to treat someautoimmune problems, such as SLE, dermato-myositis, vasculitis, and RA, that are not respondingto standard treatments, but the evidence supportingthese indications is limited.

Side effects Common: Flushing, increasedheart rate, chills, and shortness of breath duringthe infusion. Uncommon: Low blood pressure,serious allergic reactions, and aseptic meningitis.Gammaglobulin is made from pooled human bloodproducts, and despite extensive precautions, thereis a potential risk of transmitting a viral infection.

glucosamine and chondroitin sulfate (Availableas many dietary supplement preparations in healthfood stores) Glucosamine and chondroitin sulfateare substances found in the joints that, with otherraw materials, form the constituents of cartilage.Clinical trials, not always of rigorous design, suggestthat glucosamine is approximately as effective as anNSAID in the treatment of osteoarthritis. The mech-anism of action is unclear, and it may not be a sim-ple case of replacing the raw materials that make upcartilage but rather an anti-inflammatory mecha-nism. Large controlled clinical trials are underway.

Side effects Few, but studies are limited.

gold, oral See AURANOFIN.

gold injections (injectable gold) (Trade names:Solganal, an aurothioglucose gold preparation;Myochrysine [discontinued]; and Aurolate, a goldsodium thiomalate preparation) Gold is a disease-modifying antirheumatic drug (DMARD) used totreat rheumatoid arthritis and occasionally psori-atic arthritis. The mechanism of action is uncertain.

Side effects Common: Itching, skin rash,mouth ulcers, a metallic taste, and proteinuria.Uncommon: A severe skin rash with peeling, otherserious allergic reactions, bone marrow suppres-sion resulting in low white blood cell count orthrombocytopenia, hepatitis, peripheral neuropa-thy, fever, and lung inflammation. A nitritoid reac-

tion, characterized by feeling flushed andlightheaded immediately after a gold injection, isunpleasant but is not a true allergic reaction.

hyalgan See HYALURONAN INJECTIONS.

hyaluronan injections (viscosupplements, hyaluro-nic acid) (Two types of hyaluronan injections are available: Sodium hyaluronate, trade name:Hyalgan; and Hylan GF 20, trade name: Synvisc)Viscosupplement injections are used to treat os-teoarthritis of the knee. Their mechanism of actionis uncertain. Hyaluronic acid is a component ofnormal joint fluid that improves viscosity andshock absorption. Initially viscosupplements in-jected into an arthritic joint were thought toreplace the lubricant hyaluronic acid. However, theresidence time of hyaluronan in the joint is muchshorter than the duration of clinical benefit. There-fore, other mechanisms, probably anti-inflamma-tory, are likely.

Side effects Common: Knee inflammation re-sulting in pain and swelling and injection site irri-tation. Uncommon: Any intra-articular injectionhas a small risk of introducing an infection. Aller-gic reactions can occur.

hyaluronate See HYALURONAN INJECTIONS.

hydrocodone See ACETAMINOPHEN WITH NARCOTICS.

hydrocortisone See CORTICOSTEROIDS.

Appendix I 309

hydroxychloroquine and chloroquine phosphate(antimalarials) (Trade names: Plaquenil—hydroxychloroquine—and Aralen—chloroquine)Drugs used to treat malaria (antimalarials) thatwere found to act as disease-modifying antirheu-matic drugs (DMARDs) in rheumatoid arthritis andto improve skin and joint symptoms in SLE. Anti-malarials are also occasionally used to treat psori-atic arthritis but can cause a flare of the skindisease. Their mechanism of action is not known.

Side effects Common: Headache, blurredvision, and mild GI symptoms such as indigestionand nausea can occur. Uncommon: Two ocular sideeffects occur. The first is small flecks in the clearlayer over the lens of the eye, the cornea. The sec-ond, toxicity to the retina, is rare but can causeirreversible loss of vision. Other uncommon sideeffects are skin rashes, sometimes with hyperpig-mentation, myopathy, cardiomyopathy, dizzinessor deafness, and neuropathy.

Hylan GF 20 See HYALURONAN INJECTIONS.

ibuprofen (Trade names: Advil, Genpril, Ibuprin,Motrin, Nuprin) A nonsteroidal anti-inflammatorydrug (NSAID) that inhibits cyclooxygenase (COX-1and COX-2) enzymes, decreasing the formation ofinflammatory mediators such as prostaglandins.NSAIDs are used to treat pain and inflammationresulting from a variety of causes. Common indica-tions are rheumatoid arthritis, osteoarthritis, gout,ankylosing spondylitis, and bursitis. NSAIDs do notaffect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and treatment with a corticosteroid.NSAIDs can increase blood pressure, impair kidneyfunction, and cause abnormal liver function tests(usually mild), rashes, ringing in the ears, and afeeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticaria, and angioedema.

imipramine (Trade names: Tofranil) A tricyclicantidepressant, a class of drug commonly used totreat depression, chronic pain, and fibromyalgia.

Side effects Common: Sleepiness, and becauseof this sedative tricyclics are often used to improvesleep. The sedative effects can persist, resulting inunwanted sleepiness during the day. Anticholiner-gic side effects such as dry mouth and eyes, blurredvision, constipation, and slowness or difficultypassing urine can occur, particularly when treat-ment is started, but tolerance to these side effectsmay develop. Uncommon: Postural hypotensionresulting in dizziness when standing up suddenly,tremor, nausea, confusion, sexual dysfunction, GIsymptoms, paradoxical stimulation rather thansedation, bone marrow suppression, abnormal liverfunction tests, seizures, hair loss, and heart rhythmproblems.

Imuran See AZATHIOPRINE.

Indocin See INDOMETHACIN.

indomethacin (Trade name: Indocin) A non-steroidal anti-inflammatory drug (NSAID) thatinhibits cyclooxygenase (COX-1 and COX-2)enzymes, decreasing the formation of inflamma-tory mediators such as prostaglandins. NSAIDs areused to treat pain and inflammation, resulting froma variety of causes. Common indications arerheumatoid arthritis, osteoarthritis, gout, ankylos-ing spondylitis, and bursitis. NSAIDs do not affectthe progression of arthritis.



infliximab (Trade name: Remicade) A speciallydesigned protein to block the effects of tumornecrosis factor (TNF), a proinflammatory cytokine.Infliximab is a monoclonal antibody that binds toTNF, blocking its effects. Infliximab acts as aDMARD in RA and is also used to treat juvenilerheumatoid arthritis (JRA), psoriatic arthritis, andCrohn’s disease. Limited data support the use ofanti-TNF therapy in vasculitis and ankylosingspondylitis.

Side effects Common: Requires intravenousadministration and minor reactions during theinfusion include fever, chills, rash, and itching.These infusion reactions are seldom serious.Approximately 5–10 percent of patients receivinginfliximab will develop a positive antinuclear anti-body (ANA) test, raising the concern that it mayincrease the risk of autoimmune diseases such asSLE. So far, this has not been a problem, but thelong-term effects are not yet known. Uncommon:Infliximab is used with methotrexate to treat RA.The combination of infliximab and methotrexatecan cause a mild elevation of the liver enzyme testsmore often than methotrexate alone does. Uncom-mon: The risk of infections (sometimes serious)such as pneumonia is increased. Rare: Case reportsor small series of patients developing diabetes, can-cer, lymphoma, VASCULITIS, SLE-like autoimmunedisease, multiple sclerosis-like demyelinating disor-ders, liver disease, hematological abnormalitiesincluding aplastic anemia, severe allergy, meningi-tis, and infection with TUBERCULOSIS, atypicalmycobacteria, aspergillosis, histoplasmosis, and lis-teria have been reported in patients receiving TNFantagonists. TNF antagonists may increase mortal-ity in patients with heart failure and should beavoided.

intravenous immunoglobulin (IVIG) See GAM-

MAGLOBULIN.

Kenalog See CORTICOSTEROIDS.

ketoprofen (Trade names: Orudis, Oruvail) Anonsteroidal anti-inflammatory drug (NSAID) thatinhibits cyclooxygenase (COX-1 and COX-2)enzymes, decreasing the formation of inflamma-

tory mediators such as prostaglandins. NSAIDs areused to treat pain and inflammation, resulting froma variety of causes. Common indications arerheumatoid arthritis, osteoarthritis, gout, ankylos-ing spondylitis, and bursitis. NSAIDs do not affectthe progression of arthritis.


ketorolac (Trade name: Toradol) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation, resulting from a vari-ety of causes. Ketorolac is designed to treat acutepain, for example postoperative pain, for a fewdays and should not be used chronically.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDsare age older than 65 years, previous peptic ulceror bleeding ulcer, and treatment with a corticos-teroid. NSAIDs can increase blood pressure, impairkidney function, and cause abnormal liver func-tion tests (usually mild), rashes, ringing in theears, and a feeling of lightheadedness. Un-common: Serious allergy to NSAIDs can result inanaphylaxis with bronchospasm, urticaria, andangioedema.

Kineret See ANAKINRA.

Appendix I 311

lansoprazole (Trade name: Prevacid) A protonpump inhibitor (a class of drugs also known asPPIs) that decreases gastric acid production and isused to treat and prevent peptic ulcers and gastro-esophageal reflux (GERD), common side effects ofNSAIDs.


leflunomide (Trade name: Arava) A disease-modifying antirheumatic drug (DMARD) mostoften prescribed to treat rheumatoid arthritis andoccasionally psoriatic arthritis. Leflunomide altersthe immune response, particularly in lymphocytes,by blocking an enzyme, dihydrorotate dehydroge-nase, important for the formation of pyrimidines,components of DNA. Leflunomide can damage thedeveloping fetus in pregnant animals. Women ofchildbearing potential taking leflunomide requireadequate contraception, and the drug is avoided inpregnancy. Because it is cleared very slowly fromthe body over months or years, women of child-bearing potential who stop taking leflunomide aretreated with a course of cholestyramine (tradename: Questran), a resin that binds leflunomide inthe gut and helps to clear it from the body.

Side effects Common: Rash, mild increase inliver enzymes, loose or frequent bowel motions,diarrhea, and other GI problems such as cramps,nausea, and very occasionally vomiting. Uncom-mon: Hair thinning, loss of weight, infections, andlow white blood cell count.

Lodine See ETODOLAC.

Lortab See ACETAMINOPHEN WITH NARCOTICS.

magnesium choline salicylate See CHOLINE MAG-

NESIUM SALICYLATE.

meclofenamate sodium (Trade name: Meclomen)A nonsteroidal anti-inflammatory drug (NSAID)that inhibits cyclooxygenase (COX-1 and COX-2)enzymes, decreasing the formation of inflammatorymediators such as prostaglandins. NSAIDs are usedto treat pain and inflammation resulting from a

variety of causes. Common indications are rheu-matoid arthritis, osteoarthritis, gout, ankylosingspondylitis, and bursitis. NSAIDs do not affect theprogression of arthritis.


Meclomen See MECLOFENAMATE SODIUM.

meperidine (meperidine hydrochloride, pethidine)(Trade name: Demerol) A strong narcotic analgesicused to treat severe pain not controlled by aceta-minophen, an NSAID, or by weaker narcotics, suchas codeine or hydrocodone. Narcotics do not affectinflammation but decrease pain by acting throughspecific opiate receptors in the brain.

Side effects Common: Nausea, vomiting, constipation, decreased appetite, dizziness, light-headedness, sedation, and low blood pressure.Uncommon: Allergy resulting in an urticarial rashor bronchospasm, confusion, agitation, insomnia,euphoria, seizures, addiction, and suppression ofrespiration.

mesna (Trade name: Mesnex) A compound richin sulfhydryl (—SH) groups that bind acrolein andother metabolites of cyclophosphamide (tradename: Cytoxan) in the urinary tract and preventscyclophosphamide-induced bladder toxicity.

Side effects Common: A bad taste in themouth, headache, diarrhea, nausea, and musclepain. Uncommon: An allergic rash or urticaria.

methocarbamol (Trade names: Delaxin, Mar-baxin, Robaxin, Robomol) A muscle relaxant usedto treat painful muscle spasm and fibromyalgia.


Side effects Common: Drowsiness, dizziness.Uncommon: Flushing, nausea, rash, bone marrowsuppression, and allergic reactions.

methotrexate (MTX) (Trade names: Folex, Rheu-matrex) An anticancer drug that is used in lowdoses, usually administered once a week, as a dis-ease-modifying antirheumatic drug (DMARD) forrheumatoid arthritis (RA), psoriatic arthritis, andjuvenile rheumatoid arthritis and to treat systemiclupus erythematosus, dermatomyositis or polymyo-sitis, vasculitis, and other connective tissue diseases.Methotrexate is the gold-standard DMARD againstwhich new drugs to treat RA are compared. Inpatients requiring high doses of corticosteroids tocontrol an autoimmune problem, the addition ofmethotrexate may allow lower doses to be used, aso-called steroid-sparing effect. Methotrexate blocksan enzyme, dihydrofolate reductase, important insynthesizing the active form of the vitamin folicacid. This effect accounts for the anticancer effectsof methotrexate but is probably not the most impor-tant mechanism of action of methotrexate in arthri-tis, where increased release of a chemical mediator,adenosine, may play a role.

Side effects Common: Mouth ulcers, nausea,and mild increases in liver enzymes. Folic acid, avitamin, decreases the frequency of minor sideeffects. Uncommon: Vomiting, increased numberof rheumatoid nodules, fatigue, photosensitivity,hair thinning, hepatitis, liver cirrhosis, pneu-monitis (also known as methotrexate lung), bonemarrow suppression, and increased risk of infec-tion. Rare: Increased risk of some cancers such aslymphoma.

Miacalcin See CALCITONIN.

minocycline (Trade name: Minocin) A tetracy-cline antibiotic used as a disease-modifyingantirheumatic drug (DMARD) to treat rheumatoidarthritis. The mechanism of action in RA isunknown and may involve inhibition of enzymessuch as matrix metalloproteinases, effects unre-lated to its antibiotic actions.

Side effects Common: Diarrhea, nausea, andphotosensitivity. Tetracyclines are avoided in childrenbecause they cause discoloration of the permanent

teeth. Uncommon: Dizziness, rash, sometimes withdark discoloration of the skin (hyperpigmentation),and reversible DRUG-INDUCED LUPUS.

misoprostol (Trade name: Cytotec) A drugstructurally similar to a prostaglandin. NSAIDs,particularly the nonselective ones that inhibitboth COX-1 and COX-2, decrease the formationof prosta-glandins that stimulate inflammationand also those that protect against peptic ulcers.Misoprostol protects against NSAID-induced peptic ulceration by acting as a prostaglandinreplacement.

Side effects Common: Diarrhea and stomachcramps. If used during pregnancy, misoprostolcauses abnormalities of the unborn baby and cancause abortion. Uncommon: Nausea, vomiting,headache, and allergy.

morphine (Trade name: Kadian, MS Contin,Oramorph SR, Roxanol) A strong narcotic anal-gesic used to treat severe pain not controlled byacetaminophen, an NSAID, or by weaker narcotics,such as codeine or hydrocodone. Narcotics do notaffect inflammation but decrease pain by actingthrough specific opiate receptors in the brain.

Side effects Common: Nausea, vomiting, constipation, decreased appetite, dizziness, light-headedness, sedation, and low blood pressure.Uncommon: Allergy resulting in an urticarial rashor bronchospasm, confusion, agitation, insomnia,euphoria, addiction, and suppression of respiration.

Motrin See IBUPROFEN.

mycophenolate mofetil (mycophenolic acid)(Trade name: CellCept) An immunosuppressivedrug whose main use is to prevent rejection afterorgan transplantation. Mycophenolate suppressesthe immune system by interfering with DNA syn-thesis by blocking the formation of purines (build-ing blocks for DNA), particularly in cells such aslymphocytes. Some rheumatologists are usingmycophenolate to treat systemic lupus erythe-matosus and as maintenance treatment to keepvasculitis in remission. In patients requiring highdoses of corticosteroids to control an autoimmuneproblem, mycophenolate treatment may allow

Appendix I 313

lower doses of corticosteroids to be used, acting asa steroid-sparing agent.

Side effects Common: GI symptoms such asvomiting, diarrhea, stomach pain, and nausea.Uncommon: Bone marrow suppression, allergicreactions, mild increases in liver enzymes, herpeszoster, and increased risk of infection.

myochrysine See GOLD INJECTIONS.

nabumetone (Trade name: Relafen) A non-steroidal anti-inflammatory drug (NSAID) thatinhibits cyclooxygenase (COX-1 and COX-2) en-zymes, decreasing the formation of inflammatorymediators such as prostaglandins. NSAIDs are usedto treat pain and inflammation resulting from avariety of causes. Common indications are rheu-matoid arthritis, osteoarthritis, gout, ankylosingspondylitis, and bursitis. NSAIDs do not affect theprogression of arthritis.


Nalfon See FENOPROFEN.

Naprelan See NAPROXEN.

Naprosyn See NAPROXEN.

naproxen (Trade names: Aleve, Anaprox,Naprosyn; controlled-release [slow-release]naproxen: Naprelan) A nonsteroidal anti-inflam-matory drug (NSAID) that inhibits cyclooxygenase(COX-1 and COX-2) enzymes, decreasing the for-mation of inflammatory mediators such asprostaglandins. NSAIDs are used to treat pain and

inflammation resulting from a variety of causes.Common indications are rheumatoid arthritis,osteoarthritis, gout, ankylosing spondylitis, andbursitis. NSAIDs do not affect the progression ofarthritis.


Neoral See CYCLOSPORINE.

Neurontin See GABAPENTIN.

Nexium See ESOMEPRAZOLE.

nitroglycerin ointment (nittropaste) (Trade names:Nitro-Bid Ointment, Nitrol Ointment) A vasodilatorthat dilates arteries and veins and is most often usedto dilate the arteries in the heart in the treatment ofangina. Nitroglycerin ointment is also used in peoplewith RAYNAUD’S PHENOMENON and SCLERODERMA toimprove the blood supply to the tips of the fingers.

Side effects Common: Flushing, dizziness, andheadache.

nizatidine (Trade name: Axid) A histamine type2 receptor antagonist (H2-receptor antagonist orH2-blocker) that decreases acid production by thestomach and is used to treat indigestion, refluxesophagitis, and peptic ulcers. H2-receptor antago-nists, except in high doses, do not provide adequateprotection against NSAID-induced peptic ulcers.

Side effects H2-receptor antagonists are gener-ally well tolerated and have few adverse effects.Common: Minor, transient symptoms such as dizzi-ness, headache, and diarrhea. Uncommon: Rashand hepatitis.


Norflex See ORPHENADRINE CITRATE.

nortriptyline (Trade names: Aventyl Hydrochlo-ride, Pamelor) A tricyclic antidepressant, a class ofdrug commonly used to treat depression, chronicpain, and fibromyalgia.

Side effects Common: Dizziness, drowsiness,headache, anticholinergic side effects such as drymouth and eyes, blurred vision, constipation, andslowness or difficulty passing urine can occur, par-ticularly when treatment is started, but tolerance tothese side effects may develop. Uncommon: Pos-tural hypotension resulting in dizziness whenstanding up suddenly, tremor, nausea, confusion,sexual dysfunction, GI symptoms, paradoxicalstimulation rather than sedation, bone marrowsuppression, abnormal liver function tests, seizures,hair loss, and heart rhythm problems.

omeprazole (Trade name: Prilosec) A protonpump inhibitor (a class of drugs also known asPPIs) that decreases gastric acid production and isused to treat and prevent peptic ulcers and gastro-esophageal reflux (GERD)—common side effects ofNSAIDs.


orphenadrine citrate (Trade name: Norflex) Amuscle relaxant used to treat painful musclespasms and fibromyalgia.

Side effects Common: Drowsiness or dizzinessand anticholinergic symptoms such as dry eyes, drymouth, blurred vision, constipation, and particu-larly in men with prostate problems, difficulty pass-ing urine. Less common: Flushing, nausea, andrash.

Orudis See KETOPROFEN.

Oruvail See KETOPROFEN.

Os-cal See CALCIUM.

oxaprozin (Trade name: Daypro) A nonsteroidalanti-inflammatory drug (NSAID) that inhibits

cyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondyli-tis, and bursitis. NSAIDs do not affect the progres-sion of arthritis.


oxycodone (Trade names: Roxicodone, OxyCon-tin [a controlled-release or slow-release prepara-tion]; trade names of oxycodone in combinationpreparations with acetaminophen include Perco-cet, Roxicet, Tylox [see ACETAMINOPHEN WITH NAR-

COTICS] and those with aspirin include Percodan,Roxiprin.) A narcotic analgesic that decreases painby acting through specific opiate receptors in thebrain and that is used to treat moderate-to-severepain not controlled by acetaminophen or anNSAID.

Side effects Common: Nausea, vomiting, con-stipation, poor appetite, dizziness, feeling light-headed, and sleepiness. Uncommon: Feelingnervous or agitated, sleeping, an allergic reactionwith urticarial rash (hives) or bronchospasm, con-fusion, feeling “high,” and addiction.

oxycodone with acetaminophen (Trade names:Percocet, Roxicet, Tylox) See ACETAMINOPHEN WITH

NARCOTICS.

OxyContin See OXYCODONE.

Pamelor See NORTRIPTYLINE.

Appendix I 315

pamidronate (Trade name: Aredia) A bisphospho-nate used to treat Paget’s disease. It is also effectivein treating osteoporosis but is not commonly usedfor this purpose since it has to be given by intra-venous infusion.

Side effects Common: Pamidronate is adminis-tered as an intravenous infusion and can causeinflammation at the infusion site (thrombo-phlebitis). Uncommon: Fever, nausea, diarrhea,aching bones, rash, a low white blood cell, and lowplasma concentrations of calcium, phosphate, andmagnesium.

pantoprazole (Trade name: Protonix) A protonpump inhibitor (a class of drugs also known asPPIs) that decreases gastric acid production and isused to treat and prevent peptic ulcers and gastro-esophageal reflux (GERD), common side effects ofNSAIDs.


paroxetine (Trade name: Paxil) An antidepres-sant, a class of drug commonly used to treat de-pression, chronic pain, and fibromyalgia.

Side effects Common: Dizziness, insomnia ordrowsiness, dry mouth, and GI side effects such asnausea and diarrhea. Uncommon: Tremor, confu-sion, rash, sexual dysfunction, sedation, allergy,anticholinergic side effects such as blurred vision,constipation, and slowness or difficulty passingurine.

penicillamine (d-penicillamine) (Trade names:Cuprimine, Depen) A chelating agent that bindsmetals such as copper and lead and acts as a dis-ease-modifying antirheumatic drug (DMARD) inRA and is sometimes used to treat scleroderma. Inthe treatment of RA, penicillamine has largely beenreplaced by drugs with fewer side effects. The evi-dence supporting a role for penicillamine in sclero-derma is weak. The mechanism of action in RA isunknown.

Side effects Common: Rash, itching, urticaria,a metallic taste, and proteinuria. Uncommon: Al-lergic reactions, bone marrow suppression result-

ing in low white blood cell count or thombocy-topenia, glomerulonephritis, hepatitis, optic nerveinflammation, myopathy, fever, drug-inducedlupus, and myasthenia gravis.

Percocet See ACETAMINOPHEN WITH NARCOTICS.

phenylbutazone (Trade names: Butazolidin,Butazone) A nonsteroidal anti-inflammatory drug(NSAID) that inhibits cyclooxygenase (COX-1 andCOX-2) enzymes, decreasing the formation of in-flammatory mediators such as prostaglandins.Phenylbutazone has a reputation for being moreeffective than other NSAIDs for treating the symp-toms of ankylosing spondylitis. Because of itspropensity for causing bone marrow suppression, itis not generally available. Phenylbutazone is usedonly to treat pain in patients with ankylosingspondylitis that has not responded to other NSAIDs.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs areage older than 65 years, previous peptic ulcer orbleeding ulcer, and treatment with a corticosteroid.NSAIDs can increase blood pressure, impair kidneyfunction, and cause abnormal liver function tests(usually mild), rashes, ringing in the ears, and afeeling of lightheadedness. Uncommon: Seriousallergy to NSAIDs can result in anaphylaxis withbronchospasm, urticaria, and angioedema.Phenylbutazone can rarely cause bone marrowsuppression or failure.

pilocarpine (Trade name: Salagen) A drug thatstimulates the cholinergic nerves to salivary glands,increasing the production of saliva. It is used totreat the symptom of dry mouth that often occursin patients with Sjögren’s syndrome.

Side effects Common: Sweating, dizziness,headache, blurred vision, a runny or blocked nose,passing urine more often, feeling flushed, and GIproblems such as nausea or diarrhea.

piroxicam (Trade name: Feldene) A nonsteroidalanti-inflammatory drug (NSAID) that inhibits


cyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondyli-tis, and bursitis. NSAIDs do not affect the progres-sion of arthritis.


Plaquenil See HYDROXYCHLOROQUINE AND PHOSPHATE.

prednisolone See CORTICOSTEROIDS.

prednisone See CORTICOSTEROIDS.

probenecid (Trade names: Benemid, Probalan) Auricosuric that lowers serum uric acid levels byincreasing uric acid excretion in the urine and isused to prevents attacks of gout.

Side effects Common: Headache and GI symp-toms such as nausea and, less often, vomiting.Uncommon: Rash, itching, allergic reactions, pre-cipitation of an acute attack of gout, and bone mar-row suppression.

Propulsid See CISAPRIDE.

prosorba column (Protein A ImmunoadsorptionColumn) (Trade name: Prosorba Column) Bloodis drawn from the patient, passed through theprosorba column, and reinjected into the patient, aprocess known as apheresis. The prosorba columnis used to treat RA not responding to other treat-ments and to treat idiopathic thrombocytopenic

purpura (ITP) (see THROMBOCYTOPENIA). The col-umn contains a protein (protein A) from a com-mon type of bacterium (staphylococcus) and acts asa filter, removing proteins that promote RA or ITPfrom the blood passing through it.

Side effects Common: Apheresis (removingblood, filtering it, and returning it to the patient),whether using the prosorba column or not, oftencauses minor side effects of short duration such asjoint pain, fatigue, nausea, rash, low blood pres-sure, flushing, dizziness, tingling, fever, and chills.Uncommon: Many patients with autoimmune dis-eases have small fragile veins, and obtainingvenous access for apheresis can be a problem. CRYO-

GLOBULINEMIA has been described.

Protonix See PANTOPRAZOLE.

proton pump inhibitors See ESOMEPRAZOLE, LAN-

SOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE, andRABEPRAZOLE.

Prozac See FLUOXETINE.

rabeprazole (Trade name: Aciphex) A protonpump inhibitor (a class of drugs also known asPPIs) that decreases gastric acid production and isused to treat and prevent peptic ulcers and gastro-esophageal reflux (GERD), common side effects ofNSAIDs.


raloxifene (Trade name: Evista) A selective estro-gen receptor modulator (SERM) that acts on estro-gen receptors in bone without stimulating those inthe breast or uterus. Raloxifene is used to treat andprevent osteoporosis in postmenopausal women, andclinical trials are underway examining its role in theprevention of breast cancer in high-risk individuals.

Side effects Common: Hot flashes and legcramps. Uncommon: Blood clots in veins (deepvein thrombosis).

ranitidine (Trade name: Zantac) A histaminetype 2 receptor antagonist (H2-receptor antagonist

Appendix I 317

or H2-blocker) that decreases acid production bythe stomach and is used to treat indigestion, refluxesophagitis, and peptic ulcers. H2-receptor antago-nists, except in high doses, do not provide adequateprotection against NSAID-induced peptic ulcers.

Side effects H2-receptor antagonists are gener-ally well tolerated and have few adverse effects.Common: Minor, transient symptoms such as dizzi-ness, headache, and diarrhea. Uncommon: rashand hepatitis.

Relafen See NABUMETONE.

Remicade See INFLIXIMAB.

Rheumatrex See METHOTREXATE.

Ridaura See AURANOFIN.

risedronate (Trade name: Actonel) A bisphos-phonate used to treat and prevent osteoporosis andto treat Paget’s disease.

Side effects Mild gastrointestinal symptomswith nausea, indigestion, and constipation arecommon. Difficulty swallowing; vomiting and al-lergic reactions are rare.

Bisphosphonates are inconvenient because theyneed to be taken on an empty stomach with a fullglass of water. To prevent the tablet refluxing backup the esophagus, the patient must remain uprightfor an hour afterward. Bisphosphonates are verypoorly absorbed, and therefore after taking thetablet the patient cannot eat or drink anythingother than water for at least 30 minutes. Mostmanufacturers have produced a tablet that can betaken once a week to reduce the inconvenience.

Rituxan See RITUXIMAB.

rituximab (Trade name: Rituxan) A monoclonalantibody that targets B lymphocytes. The drug isused to treat certain types of lymphoma and isunder investigation as a treatment for rheumatoidarthritis, cryoglobulinemia, and systemic lupus ery-thematosus.

Robaxin See METHOCARBAMOL.

rofecoxib (Trade name: Vioxx) A nonsteroidalanti-inflammatory drug (NSAID) that inhibits thecyclooxygenase-2 (COX-2) enzyme, decreasing theformation of inflammatory mediators such asprostaglandins. Rofecoxib is selective for COX-2and has little effect on COX-1, and therefore it doesnot inhibit platelet aggregation. NSAIDs are used totreat pain and inflammation due to many causesand for arthritis-related pain caused by rheumatoidarthritis, osteoarthritis, and bursitis. NSAIDs do notaffect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gastroin-testinal obstruction, or bleeding. Risk factors forcomplicated peptic ulcers caused by NSAIDs are ageolder than 65 years, previous peptic ulcer or bleed-ing ulcer, and treatment with a corticosteroid. Therisk of peptic ulcers and their complications is lowerwith selective COX-2-inhibiting NSAIDs, such asrofecoxib, than nonselective NSAIDs. NSAIDs canincrease blood pressure, impair kidney function,and cause abnormal liver function tests (usuallymild), rashes, ringing in the ears, and a feeling oflightheadedness. Uncommon: Serious allergy toNSAIDs can result in anaphylaxis with bron-chospasm, urticaria, and angioedema. In a studycalled VIGOR, study patients with RA who receiveda high dose of rofecoxib (50 mg a day) had a higherrate of myocardial infarction than those whoreceived naproxen. It is not clear if this was a chancefinding or due to a protective effect of naproxen ora deleterious effect of high-dose rofecoxib.

Salagen See PILOCARPINE.

salsalate (Trade names: Argesic-SA, Disalcid,Salflex) A nonsteroidal anti-inflammatory drug(NSAID) belonging to a subgroup called nonacety-lated salicylates that differs from other NSAIDs inthat it is a weak inhibitor of cyclooxygenase (COX)enzymes that decrease the formation of inflamma-tory mediators such as prostaglandins. NSAIDs areused to treat pain and inflammation due to manycauses and for arthritis-related pain caused byrheumatoid arthritis, osteoarthritis, and bursitis.NSAIDs do not affect the progression of arthritis.


Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Uncommon: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDsare age older than 65 years, previous peptic ulceror bleeding ulcer, and treatment with a corticos-teroid. Nonacetylated salicylates are salicylates likeaspirin, but their different chemical structuremakes them behave more like COX-2-selectiveNSAIDs so that they do not inhibit platelet aggre-gation significantly and are less likely to cause seri-ous GI complications. NSAIDs can increase bloodpressure, impair kidney function, and cause ab-normal liver function tests (usually mild), rashes,ringing in the ears, and a feeling of lightheaded-ness. Serious allergy to NSAIDs can result in ana-phylaxis with bronchospasm, urticaria, andangioedema.

Sandimmune See CYCLOSPORINE.

sertraline (Trade name: Zoloft) An antidepres-sant, a class of drug commonly used to treatdepression, chronic pain, and fibromyalgia.

Side effects Common: Dizziness, insomnia ordrowsiness, dry mouth, and GI side effects such asnausea and diarrhea. Uncommon: Tremor, confu-sion, rash, sexual dysfunction, sedation, andallergy.

Solganal See GOLD INJECTIONS.

Soma See CARISOPRODOL.

sucralfate (Trade name: Carafate) An aluminumsucrose sulfate that binds to damaged areas of thestomach, coats them, and protects against pepticulcer.

Side effects Sucralfate has few side effects.Common: Constipation.

sulfasalazine (5-aminosalicylic acid (5 ASA) plus sul-fapyridine) (Trade names: Azulfidine, AzulfidineEN-tabs) A combination of a sulfonamide antibioticand a poorly absorbed salicylate that acts as a dis-

ease-modifying antirheumatic drug (DMARD) inRA. It is also used for other types of inflammatoryarthritis such as juvenile rheumatoid arthritis(JRA), Reiter’s syndrome, ankylosing spondylitis,and psoriatic arthritis. Sulfasalazine is also used totreat inflammatory bowel disease, occurring with orwithout arthritis.

Side effects Common: Rash and GI symptomssuch as nausea, vomiting, diarrhea, and cramps.Uncommon: Fever, low white blood cell count,bone marrow suppression, a peeling skin rash, he-patitis, drug-induced lupus, photosensitivity, tem-porary decrease in sperm count, and anemia.

sulfinpyrazone (Trade name: Anturane) A urico-suric that lowers serum uric acid levels by increas-ing uric acid excretion in the urine and that is usedto prevent attacks of gout.

Side effects Common: GI symptoms such asnausea and cramps, less often vomiting. Uncom-mon: Rash, itching, an allergic reaction, bringingon an attack of gout, bone marrow suppressionproblems, hepatitis, and proteinuria.

sulindac (Trade name: Clinoril) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondyli-tis, and bursitis. NSAIDs do not affect the progres-sion of arthritis.


Appendix I 319

Synvisc (Hylan GF 20) See HYALURONAN INJECTIONS.

tacrolimus (FK506) (Trade name: Prograf) Animmunosuppressive drug whose main use is to pre-vent rejection after organ transplantation.Tacrolimus is under evaluation for the treatment ofRA and appears to be similar to cyclosporine in itsmechanism of action and side effects.

tetracyclines See MINOCYCLINE.

thalidomide (Trade name: Thalomid) Thalido-mide is a sleeping tablet that was taken off the mar-ket in 1961 when it was recognized that it causedbirth defects. Recently thalidomide has been inves-tigated (under strict control) for the treatment ofmouth ulcers in patients with HIV, mouth and gen-ital ulcers in Behçet’s disease, and skin rashes ofSLE or discoid LE that have not responded to othertreatments. Thalidomide alters the immuneresponse perhaps by decreasing tumor necrosis fac-tor (TNF) production and the formation of newblood vessels (angiogenesis).

Side effects Common: Thalidomide causes seri-ous birth defects if taken during pregnancy. Nervedamage, which can be painful, severe, and perma-nent; sleepiness; constipation; rash; headaches; andedema are common. Uncommon: Low white bloodcell count.

Tolectin See TOLMETIN.

tolmetin (Trade name: Tolectin) A nonsteroidalanti-inflammatory drug (NSAID) that inhibitscyclooxygenase (COX-1 and COX-2) enzymes,decreasing the formation of inflammatory media-tors such as prostaglandins. NSAIDs are used totreat pain and inflammation resulting from a vari-ety of causes. Common indications are rheumatoidarthritis, osteoarthritis, gout, ankylosing spondyli-tis, and bursitis. NSAIDs do not affect the progres-sion of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gas-trointestinal obstruction, or bleeding. Risk factorsfor complicated peptic ulcers caused by NSAIDs

are age older than 65 years, previous peptic ulceror bleeding ulcer, and treatment with a corticos-teroid. NSAIDs can increase blood pressure,impair kidney function, and cause abnormal liverfunction tests (usually mild), rashes, ringing inthe ears, and a feeling of lightheadedness.Uncommon: Serious allergy to NSAIDs can resultin anaphylaxis with bronchospasm, urticaria, andangioedema.

Toradol See KETOROLAC.

tramadol (Trade name: Ultram) A narcotic anal-gesic that decreases pain by acting through specificopiate receptors in the brain and that is used totreat moderate-to-severe pain not controlled byacetaminophen or an NSAID.

Side effects Common: Nausea, vomiting, con-stipation, poor appetite, dizziness, feeling light-headed, and sleepiness. Uncommon: Feelingnervous or agitated, sleeping badly, seizures, anallergic reaction with urticarial rash (hives) or bronchospasm, confusion, feeling high, andaddiction.

trazodone (Trade name: Desyrel) An antidepres-sant, a class of drug commonly used to treatdepression, chronic pain, and fibromyalgia.

Side effects Common: Dizziness, drowsiness,dry mouth, and GI side effects such as nausea anddiarrhea. Uncommon: Tremor, confusion, rash,sexual dysfunction, sedation, allergy, anticholiner-gic side effects such as blurred vision, constipation,and slowness or difficulty passing urine.

Trilisate See CHOLINE MAGNESIUM SALICYLATE.

tumor necrosis factor (TNF) antagonists SeeADALIMUMAB; ETANERCEPT; INFLIXIMAB.

Tums See CALCIUM.

Tylenol See ACETAMINOPHEN.

Tylenol #3 See ACETAMINOPHEN WITH NARCOTICS.

Tylox See ACETAMINOPHEN WITH NARCOTICS.


Ultram See TRAMADOL.

valdecoxib (Trade name: Bextra) A nonsteroidalanti-inflammatory drug (NSAID) that inhibits thecyclooxygenase-2 (COX-2) enzyme, decreasing theformation of inflammatory mediators such asprostaglandins. Valdecoxib is selective for COX-2and has little effect on COX-1. Therefore it does notinhibit platelet aggregation. NSAIDs are used totreat pain and inflammation due to many causesand for arthritis-related pain caused by rheumatoidarthritis, osteoarthritis, and bursitis. NSAIDs do notaffect the progression of arthritis.

Side effects Common: GI symptoms, usuallyindigestion or heartburn, and fluid retention withankle edema. Less common: Peptic ulcers with orwithout complications such as perforation, gastroin-testinal obstruction, or bleeding. Risk factors forcomplicated peptic ulcers caused by NSAIDs are ageolder than 65 years, previous peptic ulcer or bleed-ing ulcer, and treatment with a corticosteroid. Therisk of peptic ulcers and their complications is lowerwith selective COX-2-inhibiting NSAIDs, such asvaldecoxib, than nonselective NSAIDs. NSAIDs canincrease blood pressure, impair kidney function, andcause abnormal liver function tests (usually mild),rashes, ringing in the ears, and a feeling of light-headedness. Uncommon: Serious allergy to NSAIDscan result in anaphylaxis with bronchospasm,urticaria, and angioedema. Patients allergic to sul-fonamides may have a higher risk of allergy.

venlafaxine (Trade name: Effexor) An antide-pressant, a class of drug commonly used to treatdepression, chronic pain, and fibromyalgia.

Side effects Common: Dizziness, insomnia ordrowsiness, dry mouth, and GI side effects such asnausea and diarrhea. Uncommon: Tremor, confu-sion, rash, sexual dysfunction, sedation, allergy,anticholinergic side effects such as blurred vision,constipation, and slowness or difficulty passingurine.

Vicodin See ACETAMINOPHEN WITH NARCOTICS.

Vioxx See ROFECOXIB.

Voltaren See DICLOFENAC.

Zantac See RANITIDINE.

zolpidem (Trade name: Ambien) A hypnotic(sleeping pill) used to improve sleep in conditionssuch as fibromyalgia. Zolpidem binds to the samereceptors in the brain that drugs such as diazepam(trade name: Valium) and other benzodiazepinesbind to causing sleepiness.

Side effects Common: Sleepiness, feelinghungover the next day, and headache. Uncom-mon: Dizziness, allergy, mental stimulation, confu-sion, and forgetfulness.

Zorprin See ASPIRIN.

Zostrix See CAPSAICIN.

Zyloprim See ALLOPURINOL.

Appendix I 321

Interpreting Laboratory TestsIt is important to recognize that the normal range formost laboratory tests is not rigid but is statisticallydefined. The cutoff between normal and abnormal

for many tests is calculated mathematically, usuallyso that the bottom 2.5 percent and the top 2.5 per-cent of people tested are designated abnormallyhigh or low. This means that an abnormal labora-tory result does not automatically imply that some-one has a disease. In fact, for uncommon diseasessuch as SLE, there are many more healthy peoplewith an abnormal ANA test than there are patientswith SLE.

alkaline phosphatase Similar forms of thisenzyme are found in liver and bone. An elevatedalkaline phosphatase level is found in patients withliver disease, particularly conditions such as gall-stones that obstruct the flow of bile. Any conditionthat causes bone to turn over more rapidly, forexample a fracture or PAGET’S DISEASE, will also ele-vate the alkaline phosphatase level. If it is unclearif the source of an elevated alkaline phosphataselevel is bone or liver, a bone-specific alkaline phos-phatase can be measured.

Alkaline phosphatase is a standard componentof most liver function tests (see LFTs), and an ele-vated alkaline phosphatase in an otherwise healthypatient is a common finding. This may be the firstmanifestation of Paget’s disease.

angiogram See ARTERIOGRAPHY.

anticardiolipin antibody See ANTIPHOSPHOLIPID

ANTIBODY.

anticentromere antibody Autoantibodies are anti-bodies directed against molecules within humancells, on the cell surface, or in blood or other fluids.Many of them give useful information becausethey are associated with particular diseases or man-ifestations of disease. The anticentromere antibodyhas been found in 60–95 percent of patients withCREST syndrome or limited SCLERODERMA. How-ever, the test is not very specific, and it is alsofound in a small number of patients with diffusescleroderma and other conditions.

antineutrophil cytoplasmic antibody (ANCA) In1982, an autoantibody that reacted against thecytoplasm of neutrophils was discovered. Over thesubsequent 20 years the clinical implications ofantineutrophil cytoplasmic antibodies have be-come clearer. There are two common types of anti-bodies, C-ANCA and P-ANCA, named because oftheir different staining patterns. C-ANCAs stain thewhole cytoplasm, whereas P-ANCAs cause stainingaround the nucleus (perinuclear). The most com-mon target for C-ANCA is proteinase-3 (PR3), anenzyme found in neutrophils. P-ANCAs have sev-eral targets, but the antibodies associated withrheumatic diseases are often directed against anenzyme, myeloperoxidase (MPO).

A positive C-ANCA is found in 80–90 percent ofpatients with active WEGENER’S GRANULOMATOSIS. Apositive test can sometimes occur in patients withlymphoma, cancer, infection, and other types ofvasculitis such as CHURG-STRAUSS SYNDROME. A positive C-ANCA (PR3) in a patient with classicalfeatures of Wegener’s granulomatosis confirms the diagnosis. Some clinicians believe that if the

APPENDIX IICOMMON LABORATORY AND

DIAGNOSTIC TESTS

323

C-ANCA is positive, a biopsy to prove the diagnosisunequivocally is not required. The level of C-ANCA has been studied as a way to monitor diseaseactivity and predict relapses in Wegener’s granulo-matosis. The results have been conflicting.

A positive P-ANCA test, particularly with MPOantibodies, is found in approximately 60 percent ofpatients with Churg-Strauss syndrome or micro-scopic polyangiitis. A positive P-ANCA is also foundin patients with INFLAMMATORY BOWEL DISEASE.

antinuclear antibody (ANA) Autoantibodies areantibodies directed against molecules withinhuman cells, on the cell surface, or in blood orother fluids. Antinuclear antibodies are directedagainst components of the nucleus, the part of thecell that contains DNA, and can be detected by ablood test. The ANA test can have different pat-terns, depending on how the nuclei of the cellsstain in the laboratory. These are homogeneous ordiffuse, speckled, nucleolar, and peripheral or rim.They are not specific for any illness, but some pat-terns occur more frequently with certain condi-tions. For example, a homogenous pattern is morecommon in patients with SLE.

The ANA test is positive in many patients withconnective tissue diseases, some infections, and afew normal people. It is commonly used as ascreening test for the connective tissue diseases,but although it is very sensitive (i.e., most patientswith a connective tissue disease will have a positivetest), it is not very specific (i.e., many other peoplewithout disease will also have a positive test). Apositive test therefore needs to be interpreted withcaution in conjunction with the clinical findings.

Almost all patients (99 percent) with SYSTEMIC

LUPUS ERYTHEMATOSUS have a positive ANA test, as do90 percent of SCLERODERMA patients, over 80 percentof those with SJÖGREN’S SYNDROME, and less fre-quently those with DERMATOMYOSITIS AND POLY-

MYOSITIS (60 percent), RHEUMATOID ARTHRITIS (50percent), WEGENER’S GRANULOMATOSIS and otherforms of vasculitis, infections such as HEPATITIS C andPARVOVIRUS, and patients taking certain drugs, forexample hydralazine. The ANA test is by definitionalways positive in DRUG-INDUCED LUPUS. Approxi-mately 5 percent of the normal population will havea positive ANA test, although usually at a low level.

antiphospholipid antibody Antiphospholipidantibodies were first recognized as causing a false-positive test result in early blood tests for syphilis.These antibodies are often asymptomatic and donot always result in complications. When compli-cations such as thrombosis occur in patients whohave persistently elevated levels of antiphospho-lipid antibodies, this is termed the ANTIPHOSPHOLIPID

ANTIBODY SYNDROME. Approximately 3 percent ofhealthy people have antiphospholipid antibodies,but these are often transiently positive and notassociated with disease. Treatment with somedrugs, for example chlorpromazine, quinidine, andhydralazine, can cause antiphospholipid antibod-ies. These drug-induced antiphospholipid antibod-ies, and those found in association with HIVinfection, are seldom associated with thrombosis.

The term lupus anticoagulant was coined whenit was recognized that some patients with SLE hadantibodies that apparently acted as anticoagulantsin the laboratory by prolonging tests of blood clot-ting such as the Russell viper venom time or acti-vated partial thromboplastin time. However, theterm lupus anticoagulant turned out to be a mis-nomer because the anticoagulant effects occur onlyin the test tube. These patients in fact have anincreased risk of blood clots, rather than excessivebleeding that would be the expected if the antibodyacted as an anticoagulant. It was also a misnomerbecause many people who had a positive lupusanticoagulant test did not have lupus. Theantiphospholipid antibody syndrome and the lupusanticoagulant syndrome are now known to berelated, and some patients who have an antiphos-pholipid antibody also have a positive lupus antico-agulant test. However, the overlap is not perfect,and sometimes one test is positive and the othernegative. Both tests are associated with anincreased risk of thrombosis.

Antiphospholipid antibodies bind to a substancecalled cardiolipin and are often measured as anti-cardiolipin antibodies, which may be of the IgG,IgM, or IgA subtype. The IgG and IgM subtypes aremost often associated with the antiphospholipidantibody syndrome. The results from different lab-oratories have been standardized and are usuallyreported as GPL units for IgG and MPL units forIgM. Low levels (less than 20 GPL or MPL units) of


anticardiolipin antibodies can occur with an acuteinfection and are not associated with blood clots.

arteriography (angiogram) An X ray that showsblood vessels. To obtain clear images of blood ves-sels, a dye that shows up on X ray is injected intoan artery. An arteriogram is usually performedwhen a blocked artery is suspected. For example, acoronary arteriogram is often performed in patientswith angina to see which artery in the heart isblocked and how severe the obstruction is. Arteri-ograms of abdominal and renal blood vessels areoften performed in patients with POLYARTERITIS

NODOSA. To inject dye into the arteries of the heart,gut, or kidney, a thin plastic tube (catheter) isthreaded up through the large artery in the groin(femoral artery). Newer techniques such as mag-netic resonance angiography (MRA) are less inva-sive because the dye can be injected into aperipheral vein rather than directly into the artery.

arthrocentesis See JOINT ASPIRATION.

biopsy The process of removing a small sample oftissue to examine it under the microscope or cul-ture it. A biopsy is usually performed when thediagnosis is not clear or when it is vital to make thecorrect diagnosis. A tissue sample can be obtainedfrom virtually any organ. However, if the diseaseaffects many organs, the biopsy is taken from themost accessible site that is likely to provide theanswer. For example, a skin biopsy is much easierto obtain than a lung biopsy.

Biopsies are also performed to determine howseverely a disease has affected an organ. For exam-ple, kidney biopsies are often performed in patientswith SLE not to make the diagnosis of SLE but toprovide information that helps determine what isthe best treatment.

One of the problems with performing a biopsy isthat only a small piece of tissue is obtained. This piecemay not be representative of the whole and cantherefore sometimes provide misleading information.

bone scan See RADIONUCLIDE BONE SCAN.

CBC (complete blood count) The CBC is a bloodtest that includes measurements of the white blood

cell count, platelet count, and hemoglobin orhematocrit (also known as crit).

The white blood cells fight infection. Differenttypes of white blood cell have different functions.Very important for fighting infection are the neu-trophils, also known as polymorphs or sometimesjust polys. If the neutrophil count is very low, lessthan 500 per mL (neutropenia), the risk of seriousbacterial infection is high. The most common causeof severe neutropenia is cancer chemotherapy orbone marrow transplantation.

Eosinophils are another type of white blood cell.They are elevated in patients who have an allergy,vasculitis, cancer, a parasitic infection, or a rare dis-ease such as EOSINOPHILIA MYALGIA SYNDROME.

Platelets are important for blood clotting. If a per-son has too few platelets (see THROMBOCYTOPENIA),wounds can ooze or bleed.

The hemoglobin and hematocrit are closelyrelated and measure the number and health of redblood cells. Hemoglobin is the protein in red bloodcells that enables them to carry oxygen, and thehematocrit measures the volume of red blood cells.If the hemoglobin and hematocrit are low, a personis anemic. There are many causes of anemia. It canbe caused by genetic conditions, decreased availabil-ity of raw materials, and increased loss or destruc-tion or decreased production of red blood cells.

Genetic causes of anemia One of the most com-mon genetic causes of anemia in the United States isSICKLE CELL DISEASE. Other genetic causes of anemiaare rare and usually diagnosed in childhood.

Decreased availability of raw materials Iron,folate, vitamin B12 and several other vitamins andminerals are needed for the body to make hemo-globin. If a person has a poor diet or has a gut prob-lem such as CELIAC DISEASE and is unable to absorbone or more of these nutrients, anemia will result.

Increased loss or destruction of red blood cells

Any cause of bleeding will cause anemia when theloss exceeds the ability of the body to make newred blood cells. Slow invisible blood loss, usuallyfrom the bowel, is more common than the dra-matic loss of large amounts of blood. Red bloodcells are destroyed in the spleen, and any cause ofan enlarged spleen can cause anemia.

Decreased production of red blood cells Bloodcells are manufactured in the bone marrow, and

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any disease or drug that affects the marrow candecrease production. Immunosuppressive drugssuch as CYCLOPHOSPHAMIDE can cause anemia, as canany disease that invades the bone marrow directly.

One of the most common types of anemia iscalled anemia of chronic disease. This type of ane-mia occurs in patients with RA, SLE, and otherchronic inflammatory or infective diseases. Themechanism is not clear, but it is thought thatchronic disease affects the bone marrow’s ability tomake red blood cells.

All patients with poor kidney function are ane-mic. This is because the kidneys make a hormonecalled erythropoietin that stimulates red blood cellproduction. Low levels of this hormone also con-tribute to anemia of chronic disease.

A CBC is usually checked regularly if a person istaking medicines like METHOTREXATE, CYCLOPHOS-

PHAMIDE, AZATHIOPRINE, GOLD, PENICILLAMINE, andSULFASALAZINE because they can sometimes lowerthe white cell count or the platelet count. A CBCmay also be checked occasionally if a patient is tak-ing an NSAID regularly. This is useful to do thisbecause if the patient suddenly becomes anemic, itmay be an early warning of bleeding from a stom-ach problem caused by the NSAID.

creatine kinase (CK) Also called creatine phos-phokinase or CPK, this enzyme leaks out of injuredor inflamed muscle into the bloodstream. CK leaksout of both heart and skeletal muscle and can bemeasured with a blood test. Elevated levels occurwith a heart attack and with many illnesses thataffect muscle. The types of CK released from heartand skeletal muscle can be distinguished by mea-suring subtypes.

Creatine kinase is elevated in approximately 95percent of patients with DERMATOMYOSITIS AND

POLYMYOSITIS. The test is useful both for helping makethe diagnosis and for judging response to treatment.Any muscle injury, for example an intramuscularinjection, will cause the CK to rise. Unless the injuryis severe, these elevations are minor and transient.Massive increases in CK are seen in patients withsevere muscle injury due to RHABDOMYOLYSIS.

creatinine A person’s kidney function can bechecked by measuring the creatinine level in a

blood test. It rises if the kidneys are not workingwell. A close watch is kept on the creatinine con-centration if someone is taking a drug likeCYCLOSPORINE that can decrease kidney func-tion. The creatinine level is usually checked fromtime to time in patients who are taking an NSAID,because occasionally NSAIDs can decrease kidneyfunction. The body gets rid of METHOTREXATE inthe urine, so the creatinine level is usually moni-tored from time to time in patients who are takingmethotrexate. A more exact measure of kidneyfunction is the creatinine clearance, but thisrequires that urine be collected for 24 hours, some-thing that is difficult to achieve reliably.

CRP (C-reactive protein) See ESR AND CRP.

cryoglobulins These are abnormal immunoglob-ulins that precipitate when blood is cooled to lessthan 37°C and that redissolve on warming. Thetype of immunoglobulin found is used to classifythe type of CRYOGLOBULINEMIA. Within each class ofimmunoglobulin, antibodies may be produced byone B lymphocyte and its progeny (monoclonal) ormany different unrelated lymphocytes (poly-clonal). In type I cryoglobulinemia, there is onemonoclonal immunoglobulin, usually IgM. In typeII, there is both polyclonal IgG and monoclonalIgM (usually RHEUMATOID FACTOR), and in type III,both polyclonal IgG and polyclonal IgM. Type Icryoglobulinemia is usually caused by Walden-strom’s macroglobulinemia, lymphoma, or multi-ple myeloma. Types II and III cryoglobulinemia,together referred to as mixed cryoglobulinemia,may be associated with chronic infection withhepatitis viruses B and C, lymphoma, chronic lym-phocytic leukemia, myeloma, and autoimmunediseases such as rheumatoid arthritis, Sjögren’ssyndrome, systemic sclerosis, and SLE. In somepatients there is no apparent cause, and this istermed essential mixed cryoglobulinemia.

Special preparations are needed to draw a bloodsample to test for the presence of cryoglobulins.Blood should be taken in prewarmed syringes andgiven directly to the laboratory. The amount ofabnormal cryoglobulin protein is sometimes mea-sured as a cryocrit—expressed as a percent. The cry-ocrit does not correlate very well with the severity


of symptoms but is a guide to how a patient isresponding to treatment.

CT (computed tomography) CT, also called com-puterized axial tomography (CAT), is an X ray testthat provides computer-generated images of bones,organs, and soft tissues. MRI usually provides bet-ter images of muscles, tendons, and joints than CT,but CT is often preferred when disease of the chest,abdomen, or brain is suspected. Modern computerprograms can manipulate the X-ray informationobtained to provide three dimensional pictures ofbones and joints that may help in planning difficultsurgery. Sometimes in order to obtain better defin-ition between normal and abnormal tissue, a con-trast dye is injected. This dye can cause allergies,particularly if it contains iodine, and can also affectkidney function, particularly in patients whoalready have decreased kidney function. CT scansexpose patients to a small amount of radiation andare therefore avoided during pregnancy.

DEXA (dual-energy X ray absorptiometry) A testused to measure bone density and thus to screenfor and diagnose OSTEOPOROSIS. In addition toDEXA there are several other ways bone densitycan be measured. These include quantitative com-puterized tomography (QCT) and quantitativeultrasound, but DEXA is the most widely usedtechnique. A DEXA test is similar to an X ray inthat it is painless and quick, but it exposes thepatient to much less radiation than a standard Xray. A DEXA report usually provides informationabout bone density at two sites where osteoporoticfractures are common, the spine and hip. Theresults are reported as a T score and a Z score.

The T score represents the relationship between aperson’s bone density and that of an average youngadult. If the T score is 2 2 it means that the person’sbone density is two standard deviations below aver-age. All people are not all exactly the same, and astandard deviation is a statistical measurement ofthe normal spread for any measurement, be itweight, height, or bone density. For anything mea-sured, height, weight, or bone density, only 2.5 per-cent of people will fall below two standarddeviations from the average. The risk of fracturealmost doubles for a decrease in bone density of one

standard deviation (i.e., a T score of -1). A T scoreabove 2 1 is regarded as normal; a score between 2 1and 2 2.5 is called osteopenia (some loss of bonemass), and a T score of 2 2.5 and below is considereddiagnostic for osteoporosis. A T score of 2 2.5 wasselected, somewhat arbitrarily, as the bone densityscore at which the risk of fracture was increasedenough for all patients to be treated for osteoporosis.Most techniques for measuring bone density reportthe result as both a T score and a Z score. The Z scorerepresents how far a person’s score is from the aver-age of other people of the same age and sex. The Zscore is not as useful as the T score for decidingwhen a person needs treatment. However, if apatient has osteoporosis with a low T score, forexample 2 3.0, and a low Z score, for example below2 1.5, this indicates that the osteoporosis is likely tobe caused by factors other than simple aging.

Guidelines from the National OsteoporosisFoundation and other authoritative bodies gener-ally recommend that a DEXA scan to screen forosteoporosis be performed in all postmenopausalwomen older than 65 years, in women who havehad a fracture, and in patients who have risk fac-tors for osteoporosis such as corticosteroid use.

DNA antibodies Autoantibodies are antibodiesdirected against molecules within human cells, onthe cell surface, or in blood or other fluids. The roleautoantibodies play and their diagnostic value vary.Many are simply markers of disease, while othersappear to play a direct role in causing disease. Anti-DNA antibodies give diagnostic and prognosticinformation and cause disease manifestations.Three types of anti-DNA antibodies can bedetected. If not otherwise qualified, the term usu-ally refers to anti-double-stranded DNA antibodies(also termed anti-dsDNA). The anti-dsDNA anti-bodies give diagnostic information in that if apatient has a positive test, he or she is very likely tohave SLE. That is, a positive test is very specific forSLE (see Glossary for explanation of specificity).About 60 percent of SLE patients are anti-dsDNApositive. These patients are at an increased risk ofdeveloping kidney disease. It is likely that com-plexes of DNA and anti-DNA antibodies play animportant role in causing glomerulonephritis,although other factors are involved.

Appendix II 327

The levels of anti-dsDNA antibodies fluctuateand tend to be higher when the disease is moreactive. They can be used to follow the course of theillness in individual patients. Attempts have beenmade to predict relapses of SLE by following thelevel of anti-DNA at regular levels. Although risinglevels do seem to predict relapse in a few patients,this has not proved reliable enough for general use.

echocardiogram An ultrasound test of the heart.The first test performed to assess the structure andfunction of the heart is usually ultrasound becauseit is noninvasive, does not expose patients to radi-ation, and is painless, quick, and relatively inex-pensive. Ultrasound is an excellent tool forassessing the structure of all three layers of theheart—the pericardium (outer lining layer), myo-cardium (heart muscle), and endocardium (heartvalves). It can diagnose a pericardial effusion (fluidin the pericardium), abnormalities of heart valvescausing them to leak, and abnormal vegetationsdue to infection (see INFECTIVE ENDOCARDITIS) orother causes such as ANTIPHOSPHOLIPID ANTIBODY

SYNDROME. An echocardiogram provides usefulinformation about how well the heart is pumping,measured as an ejection fraction. It can also beused to estimate the pressure on the right side ofthe heart (see PULMONARY HYPERTENSION).

There are two types of echocardiogram, transtho-racic and transesophageal. A transthoracic involvesthe operator moving a transducer (a flat probe aboutthe size and shape of a pack of cigarettes) on thefront of the chest. The patient is awake, and there isno pain or discomfort. A transesophageal echocar-diogram is performed by passing a small probe downthe esophagus (food pipe or gullet) and obtainingimages from a position much closer to the heart. Atransesophageal echocardiogram is similar to havingan upper GI endoscopy performed. Having a tubepassed through the mouth and down the esophagusis uncomfortable and makes patients gag and retch.Therefore the procedure is usually done under asedative. The transesophageal method provides amuch clearer view of the heart valves and is pre-ferred if infective endocarditis is suspected.

electromyography (EMG) An electromyogramcan be a useful test for confirming muscle disease

and for showing which muscles are involved. Itinvolves inserting a very fine needle into a muscleand measuring the electrical activity, both sponta-neous and on attempted contraction of the muscle.In DERMATOMYOSITIS AND POLYMYOSITIS typical find-ings of muscle irritability and low-amplitude, disor-dered impulses are found in 90 percent of patientsearly in the disease but less frequently later or inseverely affected muscles. The test can also be use-ful for diagnosing other problems that affect mus-cles such as MYASTHENIA GRAVIS. The height of thesignal reflects the response, and in myastheniaafter repeated electrical stimulation the responsedecreases in amplitude.

Nerve conduction studies are often performed atthe same time as an EMG to check that a nerveproblem is not the cause of muscle weakness.Nerve conduction studies are performed by placingtwo electrodes on the skin along a nerve. One elec-trode produces an impulse, felt as a small shock,and the other records the signal. The strength ofthe signal and the time it takes to travel betweentwo points provides information about the functionof the nerve. Nerve conduction studies are usefulfor diagnosing conditions such as CARPAL TUNNEL

SYNDROME.

An EMG and nerve conduction studies causesome discomfort. The insertion of needles intomuscles can be painful, and the small shocksadministered to study nerves are uncomfortable.

ESR and CRP The ESR (erythrocyte sedimen-tation rate, also known as sed rate) and the CRP (C-reactive protein) are two different blood teststhat are both nonspecific markers of inflammation.The ESR and CRP often, but not always, go up withinfection or inflammation and come down withsuccessful treatment.

The ESR is performed by taking a fresh bloodsample and measuring how far the red blood cellssettle in one hour in a thin, 100 mm long columnof blood in a glass tube. When there is inflamma-tion the proteins present in the blood help the redcells stick together and they sink faster. CRP is aprotein that can be measured in stored blood and istherefore more convenient to measure.

The ESR and CRP can be elevated in any type ofinflammatory arthritis, autoimmune disease, infec-


tion, or cancer. An elevated level therefore oftenindicates the presence of one of these conditions,but the finding is not specific and does not indicatea particular diagnosis. The symptoms of TEMPORAL

ARTERITIS and POLYMYALGIA RHEUMATICA can bevague, and an elevated ESR is a useful clue to thosediagnoses. A normal ESR does not exclude thepresence of an inflammatory disorder. However, anelevated ESR in a patient in whom a noninflam-matory diagnosis such as FIBROMYALGIA is suspectedis a useful indicator that the diagnosis may beincorrect.

The ESR increases a little as people age and isalso elevated by anemia, whatever the cause.

HLA-B27 The HLA-B antigens are molecules thathuman cells express on their surface. In Caucasianpopulations, approximately 10 percent of peoplehave the HLA-B27 gene. The frequency of thisgene varies widely in other populations. It almostnever occurs in the Black African population livingin the sub-Saharan desert but is found in as manyas 50 percent of Haida Indians in Canada. The pres-ence of HLA-B27 increases the likelihood of thediagnosis of ANKYLOSING SPONDYLITIS (AS) inpatients of Caucasian extraction. Because approxi-mately 10 percent of healthy people have the HLA-B27 gene, this test is of limited diagnostic valueboth in patients with features typical of AS and inthose with poorly characterized back pain.

joint aspiration The fluid removed from withinjoints by inserting a needle into the joint and draw-ing the fluid into a syringe is frequently helpful indiagnosing the type of arthritis. Once fluid hasbeen aspirated, therapeutic substances (usuallycorticosteroids) may be injected via the same nee-dle. This is discussed under the various forms ofarthritis where appropriate. Aspiration of synovialfluid is critical to the diagnosis and treatment ofINFECTIVE ARTHRITIS, important in diagnosing GOUT

and other types of arthritis caused by crystals (seeARTHRITIS), bleeding into the joint as in HEMOPHILIA

or ligament rupture, and helpful in differentiatinginflammatory from noninflammatory arthritis.Occasionally it may allow diagnosis of rare jointdiseases such as AMYLOIDOSIS. Important aspects ofthe fluid include the following.

Appearance Normal synovial fluid is clear andeither colorless or pale yellow. It is also very vis-cous. With increasing inflammation the number ofwhite cells suspended in the fluid increases, typi-cally making it turbid in REACTIVE ARTHRITIS, cloudyin gout, and like thin pus in established infection.Viscosity decreases with inflammation. This can becrudely estimated by dropping a thin string of fluidfrom the needlepoint. The longer the string of fluidis before breaking off, the greater the viscosity.Blood staining may be from the trauma of the nee-dle but, if uniform, probably indicates bleedingwithin the joint. Bleeding into a joint may be foundin trauma, destructive types of arthritis, especiallygout or pseudogout (see CALCIUM PYROPHOSPHATE

DIHYDRATE DEPOSITION DISEASE), hemophilia, antico-agulation, and PIGMENTED VILLONODULAR SYNOVITIS.Occasionally a fat layer is seen on top of the bloodaspirated from a joint, and this indicates the pres-ence of a fracture within the joint space. Smallwhite bodies in the fluid (called rice bodies) arefound in severe inflammatory arthritis, most fre-quently RHEUMATOID ARTHRITIS.

Cell count The number of cells counted undera microscope is used to separate effusions causedby inflammatory and noninflammatory types ofarthritis. By convention, less than 2,000 cells permL is noninflammatory and more is inflammatory.The type of cell present may also give information.For example, if more than 90 percent of the cellsare polymorphonuclear cells, then gout or infectivearthritis is very likely, while increasing numbers oflymphocytes are seen in rheumatoid arthritis.

Polarized light microscopy If arthritis causedby crystals is suspected, fresh fluid should be exam-ined under a polarizing microscope. Urate crystalsthat cause gout can be confidently identified in thisway, although other crystals frequently need fur-ther tests for positive identification. Although a relatively straightforward procedure, a good tech-nique and fresh fluid are required for reliableresults. Apart from the classical needle-shapedurate crystals found in gout, other crystals that maybe seen include CPPD crystals, cholesterol crystals,corticosteroid crystals (from injections), or talccrystals from the injector’s gloves.

Microbiology A Gram’s stain is usually doneimmediately if infection is suspected. This can

Appendix II 329

either show the type of organism present or some-times positively identify it. The fluid is also culturedor put into a broth or onto an agar plate that is con-ducive to bacteria growing. This is inspected overthe next five days to see if organisms are growing.These can then be further examined to identifythem and predict which antibiotics will be mosteffective. For unusual organisms such as TUBERCU-

LOSIS, special procedures and prolonged culturehave to be undertaken. Therefore, if the diagnosisis not suspected, the organism will not be found.

Special stains These are occasionally per-formed for specific purposes such as looking foramyloid material (Congo red stain) or hydroxyap-atite crystals (alizarin red).

La See SSA AND SSB

LFTs (liver function tests) No single test provides agood measure of liver function and a panel of teststhat measures different aspects of liver function, isused. Most LFT panels measure bilirubin, ALKALINE

PHOSPHATASE, albumin, total protein, AST (aspartateaminotransferase), and ALT (alanine aminotrans-ferase) concentrations.

Bilirubin levels are increased in patients whohave an increased rate of breakdown of red bloodcells (see SICKLE-CELL DISEASE) or obstruction to theflow of bile in the liver. Albumin is one of the pro-teins made in the liver. A low concentration can bedue to inability of the liver to make enough, eitherbecause dietary intake of the raw materials needed ispoor (i.e., malnutrition) or because of liver disease.Another cause of a low albumin concentration isexcessive loss of protein in the urine, as occurs withnephrotic syndrome. The concentration of total pro-tein also decreases in situations where albumin does.An elevated total protein concentration occurs whenincreased amounts of protein, usually immunoglob-ulins, are made. This can happen in many chronicinflammatory conditions such as RA and SLE (seeIMMUNE RESPONSE) and a wide range of proteins isproduced from different cell lines, sometimes calleda polyclonal increase in protein. Certain malignan-cies of B cells such as multiple myeloma cause onetype of cell to proliferate and produce a single pro-tein, called a monoclonal gammopathy.

AST and ALT are enzymes that increase whenliver cells are damaged. This can be caused by

drugs, infection (see HEPATITIS), malignancy, andautoimmune disease. LFTs, particularly AST andALT, are monitored regularly in everyone takingMETHOTREXATE and LEFLUNOMIDE. This is donebecause by keeping a careful check on the LFTs therisk of serious liver problems is reduced. LFTs, arealso checked occasionally in people taking NSAIDs,AZATHIOPRINE, and other medicines because theycan cause liver problems.

lumbar puncture A test performed to obtain asample of cerebrospinal fluid (CSF), the fluid thatsurrounds the brain and spinal cord. CSF is obtainedby inserting a needle, usually in the area of thelower back, into the space around the spinal cordand draining a few teaspoonfuls of fluid. CSF is usu-ally crystal clear and has very few cells and a lowprotein content. Inflammation caused by VASCULITIS

or cancer, for example, or infection caused bymeningitis can raise the protein and cell content ofCSF. The organism causing meningitis can often beisolated from the CSF in patients with meningitis.

lupus anticoagulant See ANTIPHOSPHOLIPID ANTIBODY.

magnetic resonance imaging (MRI) MRI evenmore than CT imaging has revolutionized the wayin which diseases and structural abnormalities areassessed and diagnosed. The implications forrheumatic diseases and orthopedic conditions havebeen profound. With the use of MRI, it is now pos-sible to obtain a three-dimensional image of almostany part of the body down to the detail of the shapeand size of blood vessels. The initial information isobtained by getting images of thin, transverse slicesthrough the area of interest. Once this informationhas been obtained it can be manipulated by thecomputer software to give considerable additionalinformation and many different views. Top of theline machines can show real-time movement.Manipulation of the signal can give informationabout the qualities of the tissues being scanned, forexample whether or not they are inflamed.

The phenomenon of nuclear magnetism is inge-niously exploited to provide this wealth of infor-mation. Atoms with an uneven number of protonsor neutrons in their nuclei have a magneticmoment. Hydrogen, present in water and fat, is themost important atom in MRI. The magnetic


moments are normally directed randomly. Thesemoments are aligned by applying a magnetic fieldacross the area of interest. This alignment is thendisturbed by a radio-frequency pulse of known fre-quency, duration, and angle. After this radio-frequency pulse the moments (usually called spins)will realign with the magnetic field. This realign-ment is termed relaxation and will be accompaniedby the emission of radio-frequency energy. Anantenna coil is used to pick up these emissions.Hundreds of these projections are acquired for eachslice. The computer then reconstructs this informa-tion into a visible image using complex formulas.

MRI provides excellent images of soft tissues andis therefore useful in studying muscles, tendons, lig-aments, joints, and other soft tissues such as brain.Although not demonstrating bone structure as wellas CT scanning, it will show inflammatory bonelesions better. MRI is not generally used to imagelungs or bowel, but virtually any other body partmay be imaged. In most situations excellent con-trast can be achieved without using any contrastmaterial (dye), thus avoiding injections and possiblereactions. When contrast material is required, suchas when examining tumors, gadolinium is used.The ability to show increased water content of tis-sues (and therefore likely inflammation) is invalu-able in certain situations in rheumatic diseases.There is no radiation and MRI has been used safelyin pregnancy, although it is still avoided in this sit-uation unless absolutely necessary.

Because time is needed to acquire the informa-tion to build up images, movement by the patientis a common cause of poor images. Very powerfulmagnets are used, and therefore all metal objectsneed to be removed both for patient safety and toprevent interference with the images. Older metalsurgical clips may contraindicate MRI. Modernclips and heart valve prostheses can usually bescanned without danger, although this should bechecked in each case. Pacemakers will be affectedby the magnetic field and special precautions needto be taken. The metal in orthopedic implants doesnot usually cause a problem.

nailfold microscopy This test examines the loopsof capillaries at the base of the nail using a power-ful magnifying glass or an ophthalmoscope. Abnor-mal loops of capillaries occur in patients with

connective tissue diseases such as scleroderma andSLE. If there is also loss of capillaries, sometimestermed capillary dropout, then the patient is morelikely to have scleroderma. Most patients with pri-mary RAYNAUD’S PHENOMENON do not develop anautoimmune disease, but a few do, and abnormalfindings on nailfold microscopy are more commonin those patients.

radionuclide bone scan This imaging techniqueinvolves injecting a radioactive substance into thepatient’s vein and then passing a gamma cameraover the patient, sometimes at a number of timepoints, to see where the substance has localized. Ithas been known since the 1920s that some radioac-tive substances would localize in bone if injectedintravenously. Many of the early substances, how-ever, were either unstable or too toxic. Tech-netium-99m-labeled phosphates were introducedin the 1970s and refined over the next few yearsinto the technetium-labeled diphosphonates, MDPand HDP, used today. The major factors that deter-mine how much technetium is taken up by boneare blood flow through the bone and osteoblasticactivity (new bone formation). Areas where thereis increased blood flow or osteoblastic activity willshow up as hot spots. Further information can begained by taking repeated images to look at themovement of the tracer over time. These radioac-tive agents are fairly weak, very stable, and almostcompletely excreted in four hours.

Technetium scans are extremely sensitive inshowing any bony injury or lesion from fractures totumors and from conditions such as PAGET’S DISEASE

and osteomyelitis. It also shows both osteoarthritisand inflammatory arthritis (see ARTHRITIS). How-ever, the scans lack the detail of CT or MRI scans.While being very sensitive for abnormalities,radionuclide bone scans do not always allow thenature of the abnormality to be determined. Theyare particularly useful for demonstrating STRESS

FRACTURES and insufficiency fractures in OSTEO-

POROSIS, where X rays are frequently normal in theearly stages. They are ideal for looking for metasta-tic bony deposits in patients with cancer since thewhole body is easily scanned in one procedure.They will demonstrate AVASCULAR NECROSIS muchearlier than X rays although not earlier than MRI.They are also used to localize areas of deep or dif-

Appendix II 331

fuse pain that can then be examined in more detailwith MRI or CT scanning.

rheumatoid factor Rheumatoid factor is an anti-body directed against immunoglobulin. The rheu-matoid factor measured by most laboratories is anIgM antibody directed against IgG. Rheumatoidfactor is usually measured to aid the diagnosis ofRA. The frequency of a positive rheumatoid factortest in patients with RA is approximately 70 per-cent but varies in different studies. A positiverheumatoid factor test can also occur in patientswith SLE (approximately 25 percent), other auto-immune diseases, and infections such as INFECTIVE

ENDOCARDITIS and HEPATITIS, cancer, and in approx-imately 5–10 percent of healthy people. This meansthat it is not a good screening test and that a posi-tive test is not diagnostic for RA. However, it is useful, particularly early in the disease, becausepatients with early RA who have a positiverheumatoid factor will tend to develop more severedisease. A positive test may therefore help in thedecision about how aggressively to treat a patient.Patients who have complications of rheumatoidarthritis affecting organs other than the joints, forexample rheumatoid nodules or lung or eye dis-ease, almost always have a positive test.

The amount of rheumatoid factor present can bemeasured in different ways but is often expressedas a titer, a measure of how much a patient’s serumcan be diluted and the test still be positive (forexample 1:40 or 1:640). A high titer, for example1:640, is much more likely to occur in RA and israre in healthy people. Changes in the titer ofrheumatoid factor are not useful for monitoringthe course of RA, and there is no reason to performthe test repeatedly.

Ro See SSA AND SSB.

Scl-70 Approximately 50 percent of patients withdiffuse SCLERODERMA develop antibodies against aprotein called topoisomerase-I (also called Scl-70).This test is positive is less than 5 percent of patientswith other autoimmune diseases and is seldompositive in healthy people. Therefore, a negativeScl-70 test does not exclude the diagnosis of diffuse

scleroderma, but a positive test suggests that it isthe likely diagnosis.

SSA and SSB These antibodies, also termed anti-Ro (SSA for SJÖGREN’S SYNDROME A) and anti-La(SSB for Sjögren’s syndrome B) are antinuclearantibodies found in patients with primary Sjögren’ssyndrome (75 percent), SLE (50 percent), andother autoimmune diseases. Anti-Ro antibodiesoccur more often than anti-La, and most patientswith anti-La antibodies also have anti-Ro. Rarelypatients with SLE have a negative ANA test and apositive test for anti-Ro antibodies. Women withanti-Ro/SSA and anti-La/SSB antibodies have anincreased chance of delivering children withNEONATAL LUPUS and an abnormal heart rhythmcalled congenital heart block. In patients with SLE,the presence of anti-SSA and anti-SSB antibodies isassociated with increased photosensitivity and arash known as subacute cutaneous lupus. The testis most often performed in pregnant women withSLE, women who have given birth to a child withheart block, and patients in whom the diagnosis ofprimary Sjögren’s syndrome is suspected.

synovial fluid analysis See JOINT ASPIRATION.

ultrasound At the simplest level, ultrasoundconsists of placing a probe against the patient’sskin. The probe then emits a pulse of sound andreceives and records its echo or echoes. Soundwaves bounce off tissue interfaces (e.g., the inter-face between fat and tendon) particularly well andwill also reflect the homogeneity (sameness) of atissue. Sound waves do not pass easily throughsolid material such as bone, and therefore, gall-stones and kidney stones will cast an echo-free

shadow behind them. A special type of ultrasoundhas been developed to measure the density ofbones. Many developments have occurred inultrasound over the past three decades, and it isnow a very sophisticated method of imaging thebody. Of all forms of imaging, ultrasound is mostdependent on the ultrasonographer. In addition tointerpreting the images obtained the ultrasonogra-pher has to use the probe to interrogate the area ofinterest.


Advantages of ultrasound compared with othermusculoskeletal imaging techniques are that it isquick, widely available, noninvasive, and fairlycheap. It is also very effective when used as a guideto needle placement when taking a biopsy or aspi-rating a collection of fluid. In musculoskeletal prac-tice, ultrasound is most frequently used to assesstendons. It demonstrates tendinitis, tears, and com-plete rupture very accurately. At the shoulder, forexample, it can also show that the ROTATOR CUFF

tendons are bunching up as the arm is lifted, thusconfirming mechanical impingement. In manycountries it has become the imaging modality ofchoice at the shoulder. Ultrasound is extremelyeffective at demonstrating BURSITIS from any cause.Increasingly ultrasound is being used to demon-strate joint effusions, and a few rheumatologistseven have portable machines in their offices toextend their examination of joints. Ultrasound isparticularly helpful in demonstrating effusions injoints that are difficult to assess clinically such asshoulders, hips, and wrists. If, for example, septicarthritis were suspected in a hip joint, the absenceof an effusion on ultrasound would virtuallyexclude that diagnosis. Although not good at imag-ing, bone ultrasound can show signs very sugges-tive of OSTEOMYELITIS.

uric acid The uric acid level in a blood test isoften elevated in patients with GOUT but is oftenmistakenly thought to be a diagnostic test for gout.The blood urate levels are not very useful in mak-ing the diagnosis during an acute attack of gout.Many people with mildly raised urate levels willnever develop gout, and 40 percent of people withacute gout will have a normal level during theattack. Most of this second group will, however,have a raised uric acid level later when the attackhas settled. The best way to diagnose gout is toidentify uric acid crystals in synovial fluid (see JOINT

ASPIRATION).

urinalysis A urinalysis is a urine test to detectblood, glucose (sugar), and protein, all of whichshould be negative. Urine is usually tested using adipstick with small squares that change color in thepresence of blood, sugar, or protein. Some dipsticks

also detect nitrite and leukocyte esterase—substancesthat indicate the presence of a urinary infection. Ifthe test for blood or protein is positive, the urine isexamined under a microscope and further tests per-formed to identify the cause. A positive test for glu-cose usually indicates a diagnosis of DIABETES

MELLITUS. However, some healthy people withoutdiabetes have an abnormally low threshold forspilling glucose into the urine.

There are many causes of an abnormal urinaly-sis, but the most common ones are menstrualblood, infections of the bladder and urinary tract,drugs, kidney stones, tumors, and autoimmunediseases affecting the kidney. Drugs such ascyclophosphamide can damage the bladder andcause blood in the urine, and gold and penicil-lamine can cause glomerulonephritis so that pro-tein leaks into the urine.

X rays Also known as radiography, X-ray imagesare often used to diagnose bone and chest diseases.X rays, a type of radiation, pass through the body,but different tissues absorb them differently. Tis-sues that absorb well, such as bone appear whiteon the image. Those that do not absorb much, suchas air, appear black. X rays are very useful for diag-nosing abnormalities of bones and joints but notvery useful for lesions in soft tissues such as mus-cles. X rays are used to help with the diagnosis andmonitoring of many rheumatic diseases. The typi-cal X ray changes of RHEUMATOID ARTHRITIS and GOUT

for example, differ, and this can be very useful formaking the correct diagnosis. Many patients withearly arthritis have normal X rays because at thisstage most of the damage occurs in the cartilage, atissue that does not show up well on X rays otherthan as space between bones. There is a lot ofresearch trying to use MRI, which provides muchmore detailed images of soft tissues such as carti-lage, to diagnose early arthritis and measure itsresponse to treatment. The advantages of X rays are that the test is quick, relatively cheap, widelyavailable, and easy to perform. The disadvantagesare that it exposes patients to a small dose of ra-diation, and is therefore avoided in pregnantwomen, and that it does not provide much detailabout soft tissues.

Appendix II 333

Only a few resources are listed. An extensive guideis available on the Arthritis Foundation’s web site.Click on “disease center” and there, alphabetically,are all the rheumatic diseases with helpful linksand addresses. Remember, medical information onthe Internet is not always accurate and readersshould evaluate information critically.

GENERAL ARTHRITIS OR HEALTH-RELATED SITES

The American College of Rheumatology (ACR)

http://www.rheumatology.org/

This web site is mainly for health professionals butthere is a patient information page. The ACR doesnot answer medical questions about specific treat-ments, diagnoses, or symptoms. Fact Sheets: What

Is a Rheumatologist?, The Role of the Advanced Practice

Nurse, The Role of the Registered Nurse, The Role of the

Occupational Therapist, The Role of the Physical Thera-

pist, The Role of the Social Worker, The Role of Interdisci-

plinary Team Management, The Role of the Psychologist,

and The Role of the Rheumatologist are availableonline as is disease-specific information about mostcommon rheumatic conditions and links to usefulsites including organizations in countries outsidethe United States.

The Arthritis Foundation

http://www.arthritis.org/

This site is an outstanding resource for patientswith arthritis and their families. The organizationprovides books and brochures for patients witharthritis, referrals to rheumatologists in an area,and publishes a magazine, Arthritis Today. Call toll-free 800-283-7800 or go to the web site.

The web site has extensive information that isclearly written about all aspects of arthritis includ-ing surgery and drugs. The popular Drug and Sup-

plement Guides are available. Other areas coveredinclude financial planning, exercise, tips for livingwith arthritis, travel, marriage and dating, alterna-tive therapies, and specific rheumatic diseases.

International League of Associations for

Rheumatology (ILAR)

http://www.ilar.org/

This excellent web site is aimed at both doctors andpatients. Its main strength is the number of links torelated sites and disease-specific organizations.Rather than trawl through an extensive Internetsearch that produces many weird and wonderfulsites, it is often easier to go to the ILAR site andlook at their list of links. Look under “diseases” or“patient organizations.”

MedicineNet

http://www.medterms.com/script/main/hp.asp

This is a comprehensive web site that has a medicaldictionary, descriptions of arthritis-related andother illnesses, as well as information about med-ications and laboratory tests.

MedlinePlus Health Information

http://medlineplus.gov/

This web site provides is an excellent resource. It isproduced by the National Library of Medicine andhas information from the National Institutes ofHealth and other sources covering many illnesses.There are also directories of hospitals and physicians,a medical encyclopedia and dictionaries, health

APPENDIX IIIUSEFUL ARTHRITIS-RELATED WEB SITES

335

information in Spanish, as well as information aboutdrugs and links to clinical trials. There is no advertis-ing and the site does not endorse any products.There is a link to MEDLINE, the computerized,searchable database of medical literature.

National Institute of Arthritis and Musculo-

skeletal and Skin Diseases

http://www.niams.nih.gov/index.htm

This site provides unbiased health information re-garding a range of musculoskeletal illnesses.

New York Online Access to Health (NOAH)

http://www.noah-health.org/english/illness/arthritis/

This site provides information on a very largenumber of topics aimed at patients. You will prob-ably have to spend some time finding exactly whatyou need.

Well Aware

http://www.well-aware.co.uk

A web site based in the United Kingdom that pro-vides information about medical conditions, drugs,and complementary therapies. The site is compre-hensive and the information is concise and writtenin plain English. You have to log in, but it is free.The site does have advertising.

Yahoo! Health

http://health.yahoo.com/

This site has three major subdivisions: an encyclo-pedia, a drug index, and health centers. The ar-thritis and pain health center has descriptions ofrheumatic illnesses and links that provide informa-tion about laboratory tests.

RESOURCE SITES DEVOTED TO SPECIFIC TOPICS

Alexander Technique

The Alexander Techniquehttp://www.life.uiuc.edu/jeff/alextech.html

The American Society for the Alexander

Technique

http://www.alexandertech.org

Ankylosing Spondylitis

Spondylitis Association of Americahttp://www.spondylitis.org

Behçet’s Disease

Behçet’s Organization Worldwidehttp://www.behcets.org

Chiropractic Medicine

The American Chiropractic Associationhttp://www.amerchiro.org

Dietary Supplements

Food and Drug Administration Center for Food Safety and Applied Nutrition

http://www.cfsan.fda.gov/~dms/ds-savvy.html

MedlinePlus Health Information Vitamin and

Mineral Supplements

http://www.nlm.nih.gov/medlineplus/vitaminandmineralsupplements.html

National Center for Complementary and

Alternative Medicine

http://www.nccam.nih.gov/

Eosinophilia Myalgia Syndrome

National Eosinophilia Myalgia Syndrome Networkhttp://www.nemsn.org/

Fibromyalgia

American Fibromyalgia Syndrome Association http://www.afsafund.org/

Fibromyalgia Network

http://www.fmnetnews.com/

Gulf War Syndrome

Office of the Special Assistant for Gulf War Illnesseshttp://www.gulflink.osd.mil/

Hypermobility

The Hypermobility Syndrome Association (United Kingdom)

http://www.hypermobility.org/

Inflammatory Bowel Disease

Crohn’s & Colitis Foundation of America http://www.ccfa.org/

Juvenile Rheumatoid Arthritis

MedlinePlus Health Information Juvenile Rheumatoid Arthritis

http://www.nlm.nih.gov/medlineplus/juvenilerheumatoidarthritis.html

The Nemours Foundation

http://kidshealth.org/kid/health_problems/bone/juv_rheum_arthritis.html


Occupational Therapy

American Occupational Therapy Association http://www.aota.org/index.asp

Osteoporosis

National Osteoporosis Foundationhttp://www.nof.org/

Paget’s Disease

The Paget Foundationhttp://www.paget.org/

Pain

American Pain Foundationhttp://www.painfoundation.org/

American Pain Society

http://www.fmnetnews.com/

Podiatry

American Podiatric Medical Associationhttp://www.apma.org/

Podiatry Encyclopedia

http://www.curtin.edu.au/curtin/dept/physio/podiatry/encyclopedia/

Podiatry Forum

http://www.podiatrychannel.com/

Polymyositis

Myositis Association of Americahttp://www.myositis.org/

Pulmonary Hypertension

Pulmonary Hypertension Association http://www.phassociation.org/

Psoriatic Arthritis

National Psoriasis Foundationhttp://www.psoriasis.org/

Raynaud’s Phenomenon

Raynaud’s Associationhttp://www.raynauds.org/

Reflex Sympathetic Dystrophy

Reflex Sympathetic Dystrophy Syndrome Association of America

http://www.rsds.org/

Rheumatoid Arthritis

Rheumatoid Arthritis Information Networkhttp://www.healthtalk.com/rain/

Sarcoidosis

National Sarcoidosis Resource Centerhttp://www.nsrc-global.net/

Scleroderma

Scleroderma Foundationhttp://www.scleroderma.org/

Sjögren’s Syndrome

Sjögren’s Syndrome Foundationhttp://www.sjogrens.org

Systemic Lupus Erythematosus

Lupus Foundation of Americahttp://www.lupus.org/

Wegener’s Granulomatosis

Wegener’s Granulomatosis Support Grouphttp://www.wgsg.org/

Appendix III 337

Common abbreviations and medical terms.

ACR American College of Rheumatology. Anorganization representing rheumatologists in theUnited States to promote research, education, andtraining of professionals and patients (see Appen-dix III for web site address).

acromioclavicular joint A joint in front of theshoulder between the clavicle (collarbone) andacromion.

acromion (acromion process) The upper andoutermost part of the scapula (shoulder blade) thatlies above the shoulder joint socket and protects it.

acute An event that happens suddenly and usu-ally lasts only a short time. The opposite of acute ischronic.

adhesion molecules Intercellular adhesion molecule (ICAM) and vascular cell adhesion mole-cule (VCAM) are examples of receptors on cells thatallow them to attach to each other, an important ini-tial part of the immune response.

allele Alternative variants of a gene that canoccur at a particular locus.

alternative medicine (complementary medi-

cine) Unconventional medicines or treatmentsthat are not part of mainstream Western medicine.Examples include ACUPUNCTURE, BEE VENOM, COPPER

BRACELET, MAGNETS, HOMEOPATHY, herbal supple-ments, and the ALEXANDER TECHNIQUE.

ANA Antinuclear antibody test (see Appendix II).

analgesic Pain reliever.

anemia A low level of hemoglobin in the blood.Hemoglobin is the protein in red cells that carriesoxygen. Severe anemia can cause dizziness,fatigue, and lack of energy. Very severe anemia cancause heart failure (see CBC in Appendix II).

angioedema Swelling of the face, tongue, orthroat, usually caused by an allergic reaction,angiotensin-converting enzyme (ACE) inhibitors (aclass of drugs used to lower blood pressure), orrarely by hereditary or acquired abnormalities ofthe complement cascade (see COMPLEMENT).Angioedema occurs more often in patients with SLEor other autoimmune diseases.

angiogram An X ray of blood vessels (see ARTE-

RIOGRAPHY in Appendix II).

antibody Proteins made by white blood cellscalled lymphocytes. Antibodies can bind to markers,called antigens, and neutralize or destroy cells ormicroorganisms that the immune system recognizesas foreign or harmful.

anticoagulant A substance that prevents bloodfrom clotting. Two drugs often used for this pur-pose are heparin and warfarin.

antigen The target that an antibody recognizesand to which it binds. Antigens bind to specificreceptors on T cells and B lymphocytes and activatethem.

arteriogram An X ray of blood vessels (see ARTE-

RIOGRAPHY in Appendix II).

arthralgia Painful joints without swelling orwarmth.

arthritis Pain in a joint with signs of inflamma-tion such as swelling, warmth, and decreasedmovement. There are many causes of arthritis (seeARTHRITIS).

AS ANKYLOSING SPONDYLITIS.

aspiration Removing fluid, usually from a joint,by drawing it out through a needle attached to asyringe.

autoimmune disease A condition in whichthe immune system, for reasons that are poorly

GLOSSARY

339

understood, makes antibodies against its owncells, and this inappropriate immune responsedamages the body.

biopsy The removal of a small sample of tissue,for example, skin, kidney, or lung, so that it can beexamined by a histopathologist to aid diagnosis or predict prognosis more accurately (see Appen-dix II).

bone marrow suppression Bone marrow cells,precursors of the formed elements of blood, aresensitive to many immunosuppressive and anti-cancer drugs. Bone marrow suppression results ina decrease in the cellular components of blood—platelets, leukocytes (white blood cells), and ery-throcytes (red blood cells).

bursas Small sacs lined with synovial cells thatare found close to joints and tendons. Their func-tion is to facilitate smooth movement of tissues andto act as shock absorbers. Bursas can becomeinflamed (see BURSITIS).

cardiomyopathy Degeneration of heart musclethat can be caused by viral infection, drugs, someautoimmune diseases, and other muscle or heartdiseases.

CBC Complete blood count (see Appendix II).

chronic A condition that lasts for a long time,usually years. The opposite of chronic is acute.

CK Creatine kinase (see Appendix II).

CNS Central nervous system.

COX Cyclooxygenase, an enzyme regulating theformation of prostaglandins (see CYCLOOXYGENASE).

CPK Creatine phosphokinase (see CREATINE

KINASE in Appendix II).

CRP C-reactive protein (see Appendix II).

CT Computed tomography (see Appendix II).

deep-vein thrombosis (DVT) Formation of ablood clot in a deep vein, most often in the leg. Theclot can break off and eventually lodge in a bloodvessel in the lung—known as a pulmonary embolus. Predisposing factors for development of a DVT are immobilization, for example bed rest,and an increased propensity for blood to clot—ahypercoagulable state—for example the ANTIPHOS-

PHOLIPID ANTIBODY SYNDROME.

DEXA Dual-energy X-ray absorptiometry (seeAppendix II).

DIP See distal interphalangeal.

distal interphalangeal (DIP) The joints closestto the ends of the fingers.

DJD Degenerative joint disease—another termfor OSTEOARTHRITIS.

DVT See deep-vein thrombosis.

echocardiography Also known as an echo. Anultrasound of the heart used to obtain images ofcardiac chambers and valves and to estimate heartmuscle function and intracardiac pressures (seeAppendix II).

edema Accumulation of fluid in the soft tissues.

effusion Swelling of a joint caused by anincrease in the amount of synovial fluid present.

ELISA Enzyme-linked immunosorbent assay.

enthesopathy Inflammation at the point wheretendons join bone (enthesis). This is a commonsymptom of ANKYLOSING SPONDYLITIS, REITER’S SYN-

DROME, and the SPONDYLOARTHROPATHIES.

eosinophil A type of white blood cell usuallypresent in low numbers. An increase in the num-bers of eosinophils is called eosinophilia and is typ-ically caused by asthma, other allergic reactions,drugs, infection with intestinal parasites, cancer, orVASCULITIS.

ESR Erythrocyte sedimentation rate, also knownas sed rate. A nonspecific blood test that measuresinflammation (see ESR in Appendix II).

fascia Deep connective tissue made up mostly ofcollagen. Fascia lies below the skin, forming part ofthe subcutaneous tissues, and in deeper tissues sep-arates muscles and tissue planes.

fasciitis Inflammation of the fascia.

FDA Food and Drug Administration, a body ofthe U.S. government that regulates food and drugs.

generic Drugs have two names, a brand namethat the manufacturer chooses for marketing and ageneric name that represents the chemical con-stituent of the drug. For example, acetaminophenis the generic name of a well-known analgesic.Several different brands (Tylenol, Panadol, and


others) all contain the identical drug—aceta-minophen.

GI Gastrointestinal as in GI side effects, pertainingnonspecifically to any or all of the gut from mouthto anus.

glomerulonephritis Inflammation of theglomeruli, areas of the kidney where blood is fil-tered to form urine.

hematuria Blood in the urine. This may be frank

hematuria, which is visible to the naked eye, ormicroscopic hematuria, which is detected by dipsticktesting or microscopy.

hemoglobin The protein in red blood cells thatbinds and transports oxygen.

hemolysis Breakdown of red blood cells.

HLA Human leukocyte antigen—molecules onthe surface of cells that help present antigen to Tcell.

hyperpigmentation Darkening of the skin.

hypertension High blood pressure.

idiopathic A condition in which the cause is notknown.

idiosyncratic Something that occurs unpre-dictably in some individuals only. For example,hepatitis can be an idiosyncratic side effect of adrug. This means that only a few people willdevelop hepatitis when taking that drug, and whothese people are cannot be predicted.

immunocompromised A situation in which aperson’s immune system is not able to respond ade-quately to organisms and therefore increases therisk of infection. Immunosuppression is a frequentcause.

immunosuppression Suppression of theimmune system. This can occur as a result ofuncommon genetic conditions that impair antibodyformation or other components of the IMMUNE

RESPONSE. More often immunosuppression isinduced by the administration of drugs that suppresscomponents of the immune system. Immunosup-pression is often part of the therapy for autoimmunediseases. Because immunological response to foreignorganisms is also impaired, such therapy increasesthe risks of infection. Therefore immunosuppressivetreatment is always a balance between achieving

adequate suppression to control the disease andavoiding too much that will allow infections tooccur.

incidence The number of people in a populationthat are diagnosed with a condition for the firsttime within a given period of time. Incidence isusually expressed as the number diagnosed per1,000 or 100,000 population per year.

infarct Death of tissue when the blood supply iscut off or is inadequate, often because of a clot in ablood vessel (artery). Examples are stroke (cerebralinfarct) and heart attack (myocardial infarct).

inflammation A tissue response resulting frominfection, trauma, autoimmune disease and manyother noxious stimuli. Inflammation is character-ized by tissue warmth, redness, swelling, and pain.

intra-articular In or into a joint, as in an intra-

articular injection.

lesion An abnormality, usually one than can beseen directly or by using an imaging technique.

leukopenia Low total white blood cell count. Adecrease in isolated cell populations may occur, forexample lymphopenia and neutropenia.

LFTs Liver function tests (see Appendix II).

ligament Dense fibrous tissue that connectsbones.

locus The position on a chromosome where aparticular gene is found.

lymphocyte A type of white blood cell that con-tributes to the immune response. T lymphocytes(also called T cells) attack cells directly and controlother elements of the immune response, and B lym-phocytes (also called B cells) produce antibodies.

macrophage A type of cell, derived from mono-cytes circulating in the blood system, found in tis-sues and that ingests or engulfs foreign substances.It also secretes many CYTOKINES that influenceother aspects of the immune response.

MCP See metacarpophalangeal.

metacarpophalangeal (MCP) The joints form-ing the first row of knuckles closest to the wrist.

metatarsophalangeal (MTP) The joints at thebase of the toes where they join the raylike bonesof the foot (metatarsals).

Glossary 341

monarthritis Arthritis affecting one joint.

monocyte A white blood cell formed in thebone marrow that enters the bloodstream andmigrates into tissues, where it becomes amacrophage.

morbidity The consequences of an illness.

MRI Magnetic resonance imaging (see Appen-dix II).

MTP See metatarsophalangeal.

myalgia Muscle pain or achiness.

myopathy Weakness and degeneration of mus-cle without associated inflammation.

myositis Inflammation in a muscle, often associ-ated with an increase in the concentrations of mus-cle enzymes measured in a blood test.

narcotics Strong analgesics that are related tomorphine and are potentially addictive.

nephrotic syndrome A syndrome caused by aheavy leak of protein into the urine. The featuresare heavy proteinuria, edema affecting the legs andsometimes the face, and a low concentration ofprotein in the blood. Many serious kidney prob-lems, for example glomerulonephritis, can causenephrotic syndrome.

neuropathy Nerve damage that may alter sen-sation or movement in an organ or limb.

neutrophil A type of white blood cell thatdirectly ingests bacteria, antigens, or debris throughthe process of phagocytosis. Neutrophils circulateand move rapidly to areas of infection or injury.They are the major cell type found in pus. They arealso known as segmented cells (segs), polymor-phonuclear leukocytes (polys or PMNs), or granulo-cytes.

NSAID Nonsteroidal anti-inflammatory drug.

OA Osteoarthritis.

osteophyte A small spur of new bone close to ajoint. Osteophytes are typically found inOSTEOARTHRITIS.

pauciarticular arthritis Arthritis affecting afew joints, usually four or less.

pericarditis Inflammation of the pericardium, amembranous sac that encloses the heart.

peritonitis Inflammation of the peritoneum, thethin tissuelike membrane that lines the abdominalcavity.

photosensitivity Increased skin sensitivity tosunlight and other sources of ultraviolet light.

PIP See proximal interphalangeal.

placebo A Latin word meaning I shall please.Used to describe a drug or treatment that is consid-ered to be inactive. A placebo is often used to treatone group of patients in a clinical trial to see if anew treatment is more effective.

pleural effusion A collection of fluid in thespace between two layers of pleura, thin mem-branes that encase the lungs. Fluid with a low pro-tein content is a transudate and collects inconditions associated with fluid overload such asheart failure. Fluid with a high protein content iscalled an exudate and collects in inflammatoryconditions such as rheumatoid arthritis affectingthe pleura or as a result of a malignancy in thelung.

pleurisy Inflammation of the pleura, the thintissuelike membrane layer around the lungs.

pneumonitis Lung inflammation.

polyarticular Affecting many joints.

prevalence The total number of people in a pop-ulation who are affected by a condition (newlydiagnosed and previously diagnosed) at any giventime. Prevalence is usually expressed as a percent-age.

prognosis An estimate of the likely outcome ofan illness.

proteinuria Protein in the urine.

proximal interphalangeal (PIP) The jointsforming the knuckles in the middle of the fingers.

RA Rheumatoid arthritis.

range of motion The range through which ajoint can move.

remission An illness or process is inactive andno fresh damage is occurring.

resect To remove surgically.

rheumatism An old-fashioned lay term foraches and pains in and around joints.


rheumatoid factor A blood test that is oftenpositive in patients with rheumatoid arthritis (seeAppendix II).

rheumatology The study of arthritis and arthri-tis-related problems.

sacroiliac joint (SI joint) Two sacroiliac jointsjoin the spine to the pelvis. These joints are mostoften affected in ANKYLOSING SPONDYLITIS.

sensitivity The proportion of people with a dis-ease who have a positive test. For example, theantinuclear antibody (ANA) test (see Appendix II)is very sensitive and is positive in 95 percent ofpatients with SLE. A test that is both sensitive andspecific is most helpful. See specificity below.

SERM Selective estrogen receptor modulator, aclass of drugs that has some of the effects of estro-gen in some tissues. For example, RALOXIFENE hasestrogenic effects on bone but antiestrogenic effectson breast tissue.

SLE Systemic lupus erythematosus.

specificity The proportion of people withoutdisease who have a negative test result. In otherwords, if a test is positive, how strongly does it sug-gest the diagnosis of a particular disease? A test thathas many false positive results is not very specific.For example, the antinuclear antibody (ANA) test(see Appendix II), although sensitive, is not very

specific for SLE, and a positive test is found inmany healthy people. A test that is both sensitiveand specific is most helpful.

spondylitis Inflammation of the vertebrae ofthe spine.

strain Injury to soft tissues such as tendons andligaments caused by biomechanical imbalance,trauma, or overuse.

synovial fluid The fluid lining the joint cavity.

synovitis Inflammation of a joint.

synovium The thin layer of membranelike tis-sue that lines many joints and tendons.

tendon A fibrous cord that joins muscle to bone.

thrombocytopenia A low platelet count.

urticaria An raised, lumpy, itchy allergic skinrash commonly known as hives.

white blood cells (WBC) One of the cellularcomponents of blood. White blood cells (alsocalled leukocytes) initiate and regulate theimmune response. The main types of white bloodcells are neutrophils (also called granulocytes),lymphocytes, monocytes, and eosinophils. Thesecells circulate in the blood but can localize in tis-sues where inflammation is present.

WBC See white blood cells.

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Bibliography 351

Boldface page numbers indicatemajor treatment of a subject.

A

AA amyloidosis 5, 80Aβ2M amyloidosis 5abdominal aortic aneurysm, back

pain from 20ACE inhibitors. See angiotensin-

converting enzyme inhibitorsacetaminophen 297

for back pain 23for fibromyalgia 84hepatitis from 109with narcotics 297, 315NSAIDs vs. 165for osteoarthritis 171, 172for rheumatoid arthritis 231

acetate, drug metabolism and 66acetylcholine, myasthenia and 156Achilles bursitis, heel pain from

101Achilles tendinopathy, heel spur

from 101Achilles tendon 1–2

enthesitis of 9flat feet and 85rupture of 1

acid-fast bacilli (AFB), in tuberculo-sis 282

Aciphex. See rabeprazoleacitretin, for psoriasis 207acne arthralgia 2acne arthritis. See SAPHO syndromeacquired immunity 123acquired immunodeficiency syn-

drome (AIDS). See humanimmunodeficiency virus

ACR (American College ofRheumatology), definition of 339

acrodermatitis chronica atrophi-cans, from Lyme disease 148

acromegaly 2–3

carpal tunnel syndrome from 32myopathy from 160osteoarthritis from 170spinal stenosis from 258

acromioclavicular joint 246arthritis in 248–249definition of 339dislocation of 248

acromion (acromion process), defi-nition of 339

active-control clinical trial 43activity, in cognitive behavioral

therapy 45Actonel. See risedronateacupuncture 3–4

for fibromyalgia 84for osteoarthritis 172for Sjögren’s syndrome 255

acute, definition of 339acute B19-associated arthritis 188acute back pain, treatment of 22acute febrile dermatosis. See Sweet’s

syndromeacute foot strain 86ADA (adenosine deaminase), defi-

ciency of 125adalimumab 60, 297

Addison’s disease, myopathy from160

adductor tendinitis 115adenoma, in acromegaly 2adenosine deaminase (ADA), defi-

ciency of 125adenovirus 107, 288adhesion molecules, definition of

339adult-onset Still’s disease. See juve-

nile arthritisAFB (acid-fast bacilli), in tuberculo-

sis 282AIDS. See human immunodefi-

ciency virus

AL amyloidosis 5alcohol

bone mass and 177Dupuytren’s contracture and

67, 100fracture risk and 182hemochromatosis and 105hepatitis from 108hyperuricemia and 92, 95myopathy from 65, 160osteoporosis and 179psoriasis and 206rhabdomyolysis from 223sleep apnea and 255stress fractures from 261

aldolase, in myositis diagnosis 55alendronate 297–298

as bisphosphonate 26–27for osteoporosis 181, 278for Paget’s disease 187for stress fracture 261

Alexander technique 4algodystrophy. See reflex sympa-

thetic dystrophyalkaline phosphatase 174, 175,

185, 186, 323

alkaptonuria (ochronosis) 4–5, 170allele, definition of 339allergy 41, 163allogeneic bone marrow transplant

27allopurinol 95, 96, 298

alopecia, from discoid lupus lesions266

alpha interferonautoimmune disorders from 62for hepatitis B and C 48, 111for Sjögren’s syndrome 255

alpha-interferon antagonists, forBehçet’s disease 26

alphaviruses, arthritis from 287–288ALT (alanine aminotransferase), in

hepatitis 108, 110

INDEX

353

alternative medicine, definition of339

alveolitis, from myositis 56Alzheimer’s disease, inclusion body

myositis and 125Ambien. See zolpidemAmerican College of Rheumatology

(ACR), definition of 339aminoglycoside antibiotics, myas-

thenia and 157aminosalicylates, for inflammatory

bowel disease 132amitriptyline 66, 84, 192, 298

amoxicillin 150, 245amphetamines, central nervous sys-

tem vasculitis and 35amputation, brucellosis and 29amyloidosis 5–6

from AS 8carpal tunnel syndrome from 32colchicine for 80from cystic fibrosis 50from familial Mediterranean

fever 80amyopathic dermatomyositis 55amyotrophy, diabetic, myopathy

from 159ANA. See antinuclear antibodyanabolic steroids, hepatitis from 109anakinra 26, 60, 298

analgesics. See also nonsteroidalanti-inflammatory drugs(NSAIDs)

for AS 9for acromegaly 3for back pain 23for calcific tendinitis 247definition of 339for drug-induced lupus 63for erythema nodosum 72–73for fibromyalgia 84for hypermobility syndrome 120for hypertrophic pulmonary

osteoarthropathy 121for Milwaukee shoulder 155for multicentric reticulohistiocy-

tosis 156NSAIDs vs. 165for olecranon bursitis 167for Paget’s disease 186for rheumatoid arthritis 230t,

231for sickle-cell disease 250

Anaprox. See naproxenANCA. See antineutrophil cytoplas-

mic antibodyandrogenic steroids, for Felty’s syn-

drome 81anecdotal evidence, clinical trials

and 43anemia

chronic fatigue syndrome and40

definition of 339in Felty’s syndrome 81from GI bleeding 163in infective endocarditis 130in inflammatory bowel disease

132in multicentric reticulohistiocy-

tosis 156from parvovirus 188pericarditis from 190in polyarteritis nodosa diagnosis

197in rheumatoid arthritis 229in scleroderma 243in sickle-cell disease 250in SLE 269, 270

anestheticfor heel pad pain 100for Milwaukee shoulder 155for plantar fasciitis 100, 195for subtalar arthritis 101

aneurysm 45, 141angina 141, 275angioedema 163, 339angiogram. See also arteriography

in brucellosis diagnosis 29in central nervous system vas-

culitis 36definition of 339in Kawasaki disease diagnosis

142in polyarteritis nodosa diagnosis

198angiokeratoma corporis diffusum

6

angiotensin-converting enzyme(ACE) inhibitors

for myocarditis 159NSAIDs and 165plasmapheresis and 195–196in sarcoidosis diagnosis 240for scleroderma 245

ankle joint replacement 136

ankylosing spondylitis (AS) 6–9

AA amyloidosis from 5anterior uveitis and 77back pain from 20DISH and 59enthesitis in 1genetic factors in 89–90heel spur from 101hip pain from 114from inflammatory bowel dis-

ease 131juvenile spondylitis and 138knee pain from 144NSAIDs for 163scleritis and 77spinal stenosis from 258tendinitis in 256TNF antagonists for 283

Ansaid. See flurbiprofenanterior cruciate, incompetent 144anterior tarsal tunnel syndrome 88anterior uveitis 77antiarrhythmics, lupus from 61antibiotics

for brucellosis 28for cystic fibrosis 49for infective arthritis 129for infective endocarditis 130for intestinal bypass arthritis

132lupus from 61, 62for Lyme disease 148–151myasthenia and 157for olecranon bursitis 167for osteomyelitis 176for Raynaud’s syndrome 215for reactive arthritis 218for rheumatic fever 224for SAPHO syndrome 239for septic bursitis 246for sickle-cell disease 250for SLE 271tendinitis from 256tendon rupture and 1for Wegener’s granulomatosis

289, 291–292for Whipple’s disease 293

antibodies. See immunoglobulinanticancer drugs

for amyloidosis 6as DMARD 60hyperuricemia and 92in pregnancy 200–201


Raynaud’s phenomenon from214

thrombocytopenia and 278–279anticardiolipin antibody. See

antiphospholipid antibodyanticardiolipin antibody syndrome.

See antiphospholipid antibodysyndrome

anticentromere antibody 323

anticholinesterases, for myasthenia157–158

anticoagulantsfor antiphospholipid antibody

syndrome 11for Behçet’s disease 26cholesterol emboli syndrome

and 38definition of 339hemarthrosis from 102for myositis ossificans 160NSAIDs and 165in plasmapheresis 195for pulmonary hypertension

210anticonvulsants, lupus from 61antidepressants

chronic fatigue syndrome and41

for fibromyalgia 84for Gulf War syndrome 97for hypermobility syndrome

120metabolism of 192myasthenia and 157

anti-double-stranded DNA anti-body, in SLE 264–265

antigenin autoimmune disorders 263definition of 339in immune response 123–124in SLE treatment 274

antiglomerular basement mem-brane disease. See Goodpasture’ssyndrome

antihistone antibodies, in SLE diag-nosis 264

antihypertensives, lupus from 61anti-inflammatory drugs. See nons-

teroidal anti-inflammatory drugs(NSAIDs)

anti-LKM, in autoimmune hepatitis108

antimalarials 9, 272, 310

anti-Mi-2, in myositis 56, 57antineutrophil cytoplasmic anti-

body (ANCA) 323–324

in Churg-Strauss syndromediagnosis 42

in drug-induced lupus diagnosis62

in vasculitis diagnosis 287in Wegener’s granulomatosis

diagnosis 289, 290antinuclear antibody (ANA) 324

in autoimmune disorders 123in autoimmune hepatitis diag-

nosis 108complement and 46drug-induced lupus and 61, 62in inclusion body myositis diag-

nosis 126in mixed connective tissue dis-

ease diagnosis 155in overlap syndrome diagnosis

183in pauciarticular juvenile arthri-

tis diagnosis 137, 138in scleroderma diagnosis 241,

243in SLE diagnosis 264

antioxidant vitamins, for arthritistreatment 59

antiphospholipid antibody 264,268, 324–325

antiphospholipid antibody syn-drome 10–11

livedo reticularis from 147pregnancy and 202in SLE diagnosis 270thrombocytopenia and 279thrombosis and 269

antiplatelet antibodies, in thrombo-cytopenia 123

anti-PM-scl, in myositis 56, 57antipsychotics, lupus from 61antireflux drugs 155, 183antirejection drugs, as DMARD 60antirheumatic drugs, lupus from

61anti-ribosomal P protein antibody,

in SLE diagnosis 264anti-RNP antibody, in SLE diagnosis

264anti-Sm antibody, in SLE diagnosis

264anti-SRP, in myositis 56, 57

antisynthetase antibodies 56, 57antithrombotic agents, for

Kawasaki disease 142antithyroid drugs, lupus from 61anti-TNF drugs. See tumor necrosis

factor antagonistsantituberculous drugs 92, 129anti-U1-RNP, in myositis 56antiviral drugs 111, 113aortic aneurysm, abdominal, back

pain from 20aortic valve, leaking of 45apitherapy. See bee venomApley’s grinding test 154apophysitis, calcaneal 100–101arachidonic acid 48–49arboviruses, arthritis from 287–288arcade arthritis 280Aredia. See pamidronatearteriogram, definition of 339arteriography 275–276, 325

arteritis, Takayasu’s 275

arteritis, temporal 77, 198,276–278

arthralgiain autoimmune hepatitis 108definition of 339drug-induced 63from eosinophilia myalgia syn-

drome 69from erythema migrans 148in Gulf War syndrome 97from hepatitis B 110from hepatitis C 112HIV and 117–118hypermobility and 138from infective endocarditis 130in mixed connective tissue dis-

ease 155in overlap syndrome 183in scleroderma 242in SLE 266from Sweet’s syndrome 262from system onset juvenile

arthritis 137arthritis 11–13. See also specific types

in autoimmune hepatitis 108bee venom for 25from Behçet’s disease 25from brucellosis 28carpal tunnel syndrome from

32celiac disease and 34

Index 355

arthritis (continued)

classifications of 12 (See also spe-

cific classes)common variable immunodefi-

ciency and 125copper bracelet for 46from cystic fibrosis 49definition of 339diagnosis of 12from dialysis 58drug-induced 63from drug-induced lupus 62erythema nodosum and 72exercise for 75–76heat for 99from Henoch-Schönlein purpura

107in hepatitis C 113HIV and 117–118in hypermobility syndrome 120ice for 123infective arthritis from 127from Lyme disease 149magnets for 153in mixed connective tissue dis-

ease 155in multicentric reticulohistiocy-

tosis 156from myositis 54osteoarthritis from 170in polyarteritis nodosa 197from polymyalgia rheumatica

199prevalence of 12in Reiter’s syndrome 217in relapsing polychondritis 221in rheumatic fever 224from rubella 237from rubella vaccine 285, 286in sarcoidosis 240in scleroderma 242from sickle-cell disease 250silicone implants and 250–251from Sjögren’s syndrome 252in SLE 266in spondyloarthropathy 260treatment of 13, 14t

from Whipple’s disease 292in wrist 293–294

arthritis, acne. See SAPHO syn-drome

arthritis, acute B19-associated 188arthritis, arcade 280

arthritis, bacterial 127–128. See also

infective arthritisarthritis, crystal-induced. See cal-

cium pyrophosphate dihydratedeposition disease

arthritis, enteropathic 49–50, 69

arthritis, fungal 127–129arthritis, gonococcal 128arthritis, infective 126–129. See

infective arthritisback pain from 20in children 143from diabetes 58with glenohumeral arthritis 248hip pain from 114from HIV 118from infective endocarditis 130from joint injection 133–134osteoarthritis from 170osteomyelitis and 175SAPHO syndrome as 239from sickle-cell disease 250in SLE 266

arthritis, intestinal bypass 132

arthritis, juvenile 136–139

anterior uveitis and 77B19 and 188bone marrow transplant for 27joint replacement for 136knee pain from 143Lyme disease and 147NSAIDs for 163pericarditis from 190subtalar arthritis from 101synovectomy for 262TNF antagonists for 283in wrist 293–294

arthritis, neuropathic 161–162

from diabetes 58with glenohumeral arthritis 248hepatitis C and 112

arthritis, psoriasis and psoriatic114, 203–209

back pain from 20carpal tunnel syndrome from

32in children 138de Quervain’s tenosynovitis in

53foot pain and 85hip pain from 114from HIV 118hyperuricemia and 92

knee pain from 144olecranon bursitis in 167tendinitis in 256TNF antagonists for 283treatment of 206–209

arthritis, reactive 215–219. See also

Reiter’s syndromeback pain from 20from BCG vaccine 281, 286enthesitis in 1foot pain and 85hip pain from 114from HIV 117joint replacement for 136knee pain from 144Lyme disease as 149from rubella vaccine 285, 286SAPHO syndrome as 239

arthritis, rheumatoid (RA). See

rheumatoid arthritisarthritis, septic. See infective arthri-

tisarthritis, subtalar, heel pain from

101arthritis, viral 287–288

arthritis-dermatitis syndrome, fromhepatitis B 110–111

arthritis mutilans 205arthrocentesis. See joint aspirationarthrodesis 13

for flat feet 85for osteoarthritis 173for rheumatoid arthritis 227for spinal stenosis 259for subtalar arthritis 101vs. joint replacement 136

arthroplasty. See joint replacementarthroscopy and arthroscopic sur-

gery 13–15

for abnormal meniscus 154for Baker’s cyst 24in biceps tendinitis diagnosis

247for hemarthrosis 102for infective arthritis 129for meniscal tears 143, 154for osteochondritis dissecans

174in pigmented villonodular syn-

ovitis diagnosis 194for plica syndrome 143for rotator cuff syndrome 237in shoulder pain diagnosis 247


in SLAP lesions diagnosis 248for synovectomy 262for synovial chondromatosis

144Arthrotec. See diclofenacartificial tears 254, 298–299

AS. See ankylosing spondylitisascites 110, 112Ascriptin. See choline salicylateaseptic necrosis. See avascular

necrosisaspartate aminotransferase (AST),

in hepatitis 108, 110aspergillosis, opportunistic infection

by 168aspiration 339. See also joint aspira-

tionaspirin 299

for antiphospholipid antibodysyndrome 11

COX-2-selective drugs and 164COX enzymes inhibited by 49gout and 95for hypertension 273hyperuricemia and 92joint replacement surgery and

135for juvenile arthritis 138for Kawasaki disease 142liver disease from 269as nonselective NSAIDs

162–163for polyarteritis nodosa 198for polymyalgia rheumatica 200for Raynaud’s phenomenon

215for temporal arteritis 278

assistive devices 15

for AS 9occupational therapy and 167in osteoarthritis treatment 172

AST. See aspartate aminotransferaseasthma, from Churg-Strauss syn-

drome 41–42Atharva-Veda 17atherosclerosis

central nervous system vasculitisand 35

cholesterol emboli syndromecaused by 38

corticosteroids and 200in diabetes mellitus 57gout and 94

in polyarteritis nodosa 198in SLE 269–270, 273

atrial myxoma 16

atrophic gastritis, in SLE 268audiological testing, in Paget’s dis-

ease diagnosis 186auranofin 299

as DMARD 60for hepatitis C arthritis 113for rheumatoid arthritis 232

aurothioglucose, as DMARD 60autoantibodies

in autoimmune disorders 123in myositis 56in neonatal lupus 161in SLE 264–265

autoimmune disorders. See also der-matomyositis and polymyositis

antigens in 263bone marrow transplant for 27celiac disease and 34chronic fatigue syndrome and 40complement and 46cryoglobulinemia from 47definition of 339–340drug-induced 62hepatitis from 108immune response in 123in multicentric reticulohistiocy-

tosis 156photopheresis for 193primary immunodeficiencies

and 124autoimmune hemolytic anemia 62,

269autoimmune hepatitis 108–109,

252autoimmunity. See immune

responseautologous bone marrow transplant

27autonomic nerve dysfunction, in

reflex sympathetic dystrophy 219avascular necrosis (AVN) 16–17

with glenohumeral arthritis 248hip pain from 114from HIV 118of lunate 293from sickle-cell disease 250from SLE 266

AVN. See avascular necrosisaxial skeleton, inflammation of. See

spondyloarthropathy

Ayurvedic medicine 17

azathioprine 299–300

for AS 9for autoimmune hepatitis 108for Behçet’s disease 26as DMARD 60for gout 96for Henoch-Schönlein purpura

108herpes zoster and 113–114for inclusion body myositis 126for inflammatory bowel disease

132liver disease from 269for myasthenia 158for myositis 56for polyarteritis nodosa 198for polymyalgia rheumatica 200for psoriatic arthritis 207, 208for pyoderma gangrenosum

diagnosis 212for reactive arthritis 219for relapsing polychondritis 222for sarcoidosis 240for Sjögren’s syndrome 255for SLE 272for temporal arteritis 278TPMT variants and 192vaccination and 285for Wegener’s granulomatosis

291–292

AZT (zidovudine), myositis from119

Azulfidine. See sulfasalazine

B

B19. See parvovirusbacillus Calmette-Guérin (BCG)

vaccinereactive arthritis from 216, 286rheumatic disease from 63for tuberculosis 281

back pain 19–24

from AS 8causes of 19–21cognitive behavioral therapy for

45culture and 19diagnosis of 21in hypermobility syndrome 119from infective endocarditis 130manipulation for 176from osteoporosis 178

Index 357

back pain (continued)

prevalence of 19from spinal stenosis 258symptoms of 21treatment of 22–23from tuberculosis 282

back school, for back pain 23

baclofen, for reflex sympatheticdystrophy 219

bacterial arthritis 127–128. See also

infective arthritis

Baker’s cyst 24–25, 145

Bantu siderosis 103

Barmah virus, arthritis from 288

B cells. See B lymphocytes

BCG (bacillus Calmette-Guérin)vaccine

reactive arthritis from 216, 286rheumatic disease from 63for tuberculosis 281

Becker’s muscular dystrophy,myopathy from 159

bee venom 25

Behçet’s disease 25–26

central nervous system vasculitisfrom 35

erythema nodosum and 72posterior uveitis and 77TNF antagonists for 283

Bell’s palsy, in Lyme disease 148Benemid. See probenecidbenzbromarone, for gout 95, 96benzodiazepines, for back pain 23benzylpenicillin, for Whipple’s dis-

ease 293beta2-glycoprotein, in antiphospho-

lipid antibody syndrome 10beta2-microglobulin, in dialysis

58beta2-microglobulin amyloidosis

5beta-amyloid protein 125beta-blockers 204, 214Bextra. See valdecoxibBible cysts 89biceps tendinitis 247biceps tendon rupture 247. See also

shoulder painbiofeedback, for fibromyalgia 84biologicals (biologic agents) 26, 60biomechanical abnormalities, in

rehabilitation exercise 75

biopsy 325

in autoimmune hepatitis diag-nosis 108

definition of 340in Felty’s syndrome diagnosis 81in Goodpasture’s syndrome

diagnosis 91in hemochromatosis diagnosis

104in Henoch-Schönlein purpura

diagnosis 107–108in hepatitis C diagnosis 113in inclusion body myositis diag-

nosis 126in lung disease diagnosis 228in Lyme disease diagnosis 149in multicentric reticulohistiocy-

tosis diagnosis 156in myocarditis diagnosis

158–159in myopathy diagnosis 159in myositis diagnosis 55, 160in osteomalacia diagnosis 174in osteosarcoma diagnosis 182in Paget’s disease diagnosis 186in pigmented villonodular syn-

ovitis diagnosis 194in polyarteritis nodosa diagnosis

196, 197–198in polymyalgia rheumatica diag-

nosis 199in pulmonary hypertension

diagnosis 210in pyoderma gangrenosum diag-

nosis 211in rheumatoid vasculitis diagno-

sis 235in SAPHO syndrome diagnosis

239in sarcoidosis diagnosis 240in scleroderma diagnosis 243in Sjögren’s syndrome diagnosis

253, 254in Sweet’s syndrome diagnosis

262in temporal arteritis diagnosis

277in tuberculosis diagnosis 282in Wegener’s granulomatosis

diagnosis 290in Whipple’s disease diagnosis

292

bipartite patella 143, 190bisphosphonates 26–27

for AS 9for myositis ossificans 160osteomalacia from 174for osteoporosis 64, 181, 278for Paget’s disease 186–187for reflex sympathetic dystrophy

219for stress fracture 261

black heel, heel pain from 101bladder cancer, reactive arthritis

and 216blastomycosis, erythema nodosum

and 72bleomycin, Raynaud’s phenomenon

from 214blind loop syndrome 242, 245blood

abnormalities in, in SLE 269in bowel motions 163–164removal of, for hemochromato-

sis 105blood pressure

atherosclerosis and 269in chronic fatigue syndrome 40with NSAIDs 164pregnancy and 270sleep apnea and 255in Takayasu’s arteritis 275

blood tests. See also specific types

in Lyme disease diagnosis149–150

in myasthenia diagnosis 157in osteomalacia diagnosis 175in osteomyelitis diagnosis 176in osteosarcoma diagnosis 182in Paget’s disease diagnosis 185,

186in polyarteritis nodosa diagnosis

197in rheumatoid arthritis diagnosis

230in rubella diagnosis 237in scleroderma diagnosis 243in sickle-cell disease diagnosis

250in Wegener’s granulomatosis

diagnosis 290blood transfusions 103, 105, 250bloody old shoulders. See Milwau-

kee shoulder


B lymphocytesin humoral immunity 124myasthenia and 156in SLE 265

body bulk, hyperuricemia and 92bone fractures

osteoporosis and 178in Paget’s disease 186PEMF for healing 153reducing risk of 182stress 260–261wrist pain from 293

bone marrowhemochromatosis and 103hyperactive 250in sickle-cell disease 250suppression of, definition of

340bone marrow transplantation

27–28

for primary immunodeficiency125

for scleroderma 245for SLE 274

bone mass 177, 179, 273bone resorption 177, 185bone scan. See radionuclide bone

scanbone spur 28

bosentan, for pulmonary hyperten-sion 211

Bouchard’s nodes 28, 170boutonniere deformity 227bradykinin, plasmapheresis and

195–196breast implants 250–251bromocriptine 3, 273bronchoalveolar lavage, in sclero-

derma diagnosis 244bronchoscope 55, 244brucellosis 20, 28

Budd-Chiari syndrome 269Buerger’s disease 28–29

bumetanide 63, 92bunions, in adults 87burns, severe, immunodeficiency

and 124bursas, definition of 340bursitis 29

in Achilles tendon 2in hallux valgus 87hip pain from 114

joint injection for 133knee pain from 144–145NSAIDs for 163

bursitis, Achilles, heel pain from101

bursitis, olecranon 167

bursitis, prepatellar 202–203

bursitis, septic 245–246

bursitis, subacromial 248bursitis, subcalcaneal, heel pain

from 100bursitis, trochanteric 114–115, 281

Butazolidin. See phenylbutazone

C

calcaneal apophysitis 100–101calcaneal fractures, heel pain from

101calcaneus, pain at. See heel paincalcification, from myositis 54calcific tendinitis 247, 256calcinosis, in scleroderma 243calcipotriene, for psoriasis 206calcitonin 300

for osteoporosis 181for Paget’s disease 186–187for stress fracture 261

calcitriol, for osteomalacia 175calcium 300

in bone 177elevated concentration of (See

hypercalcemia)level of, myopathy from 160osteomalacia and 174, 175for osteoporosis 179–180, 278

calcium carbonate 300calcium citrate 300calcium lactate 300calcium phosphate dibasic 300calcium pyrophosphate dihydrate

deposition disease (CPPD) 31–32

in acromegaly 3calcific tendinitis from 256carpal tunnel syndrome from

32hemarthrosis from 102from hemochromatosis 103hip pain from 114from hypophosphatemic rickets

121osteoarthritis from 170prepatellar bursitis from 203

spinal stenosis from 258in wrist 293–294

camptodactyly 32

cancellous bone 177cancer. See also malignancies

back pain from 20chemokines and 37chronic fatigue syndrome and

40in dermatomyositis 54–55hip pain from 114magnets and 153microscopic polyarteritis and


tosis 156Paget’s disease and 186pericarditis from 190Sweet’s syndrome and 261thrombocytopenia and 278–279treatment for, hemochromatosis

and 103candidate gene approach 89cane, assistance from 15capsaicin 171, 300

captopril, vasculitis from 64, 286carbon tetrachloride, hepatitis from

109cardiomyopathy 65, 340cardiovascular complications 8,

164carditis 149, 224carisoprodol 300

carpal tunnel syndrome (CTS)32–34

in acromegaly 3from amyloidosis 5from diabetes 58from dialysis 58manipulation for 176wrist pain from 294

cartilage 34, 169, 221cataracts, corticosteroids and 77catecholamines, in meditation 154cauda equina syndrome, from AS

8causalgia. See reflex sympathetic

dystrophyCBC (complete blood count) 279,

325–326

CC chemokines 37CD4 lymphocytes 118, 124

Index 359

ceftriaxone, for Lyme disease 150cefuroxime, for Lyme disease 150Celebrex. See celecoxibcelecoxib 300–301

heart attack and 164for osteoarthritis 172as selective COX-2 inhibitors 163

celiac disease 34–35, 174Cellcept. See mycophenolate mofetilcellular immunity 124, 265central nervous system, in choles-

terol emboli syndrome 38–39central nervous system vasculitis

35–36

cephalosporins 62, 64, 286cephazolin, for infective arthritis

129cerebrospinal fluid (CSF)

in central nervous system vas-culitis 36

in Guillain-Barré syndromediagnosis 159

in Kawasaki disease diagnosis142

cerivastatin, myositis from 65cervical spine, joint replacement

and 134–135cevimeline 301

Charcot’s joint. See neuropathicarthritis

cheirarthropathy, diabetic 57chemokines 36–37, 251chemonucleolysis, for back pain 24chemotherapy

in bone marrow transplant 27efflux transporters and 66–67immunodeficiency caused by

124for osteosarcoma 182

chicken pox 113, 168children

abnormal meniscus in 154arthritis in (See juvenile arthritis)foot pain in 85–86infective arthritis in 143inflammatory bowel disease in

138Kawasaki disease in 141–142knee pain in 143psoriasis and psoriatic arthritis

in 138Reiter’s syndrome in 138

SLE in 138vasculitis in 138

chiropractic medicine 37–38

chlorambucil 301

for Behçet’s disease 26for multicentric reticulohistiocy-

tosis 156for polyarteritis nodosa 198for Wegener’s granulomatosis

291chloroquine. See hydroxychloro-

quine and chloroquine phosphatechloroquine phosphate. See hydrox-

ychloroquine and chloroquinephosphate

chlorpromazineantiphospholipid antibodies

from 10autoimmune disorders from 62hepatitis from 109

cholesterolatherosclerosis and 269in multicentric reticulohistiocy-

tosis 156cholesterol emboli syndrome

38–39, 147cholestyramine, leflunomide and

201choline magnesium salicylate 301

choline salicylate 301–302

chondrocalcinosis 31–32, 171chondroitin sulfate. See glu-

cosamine and chondroitin sulfatechondromalacia patellae 144, 190chorea, in SLE 267chorea, Sydenham’s, in rheumatic

fever 224Christmas disease. See hemophiliachronic, definition of 340chronic back pain 22chronic fatigue syndrome 39–41

cognitive behavioral therapy for45

Gulf War syndrome and 97hypnosis for 121

chronic foot strain 86chronic inflammatory demyelinat-

ing polyneuropathy, plasmaphere-sis for 196

chronic lymphocytic leukemia,cryoglobulinemia from 47

Churg-Strauss syndrome 35, 41–43

cimetidine 160, 302

ciprofloxacinlupus flares from 62rheumatic disease from 63for scleroderma 245

circinate balanitis, from reactivearthritis 217

cirrhosisfrom hemochromatosis 103from hepatitis B 109, 110from methotrexate 208in Sjögren’s syndrome 252,

253cisapride 245, 302

citrate, in plasmapheresis 195claudication

in brucellosis 28–29intermittent, in diabetes mellitus

57neurogenic, from spinal stenosis

258in Takayasu’s arteritis 275

claw foot, in children 85clinical trial 43–44

for AS 9for acupuncture 4for B19 and rheumatoid arthritis

188–189for celecoxib 164for diet 58–59for fibromyalgia 82for Gulf War syndrome 97for inclusion body myositis 126for Kawasaki disease 142limitations of 43for PEMF 153for photopheresis 193for plasmapheresis 196for scleroderma 241

Clinoril. See sulindacclofibrate, myopathy from 160clotting factor, for hemophilia 106clubbing 121, 130clubfoot, in children 86coal tar, for psoriasis 206cocaine


myopathy from 65–66, 160rhabdomyolysis from 223

coccidiomycosis, erythemanodosum and 72


codeine 302

acetaminophen with 297metabolism of 66, 192for osteoarthritis 172for rheumatoid arthritis 231

Cogan’s syndrome 44–45

cognitive behavioral therapy 45–46

for back pain 23for chronic fatigue syndrome 41for fibromyalgia 84for Gulf War syndrome 97for hypermobility syndrome 120

colchicine 302–303

for amyloidosis 6for back pain 23for Behçet’s disease 26for CPPD 32for familial Mediterranean fever

80for gout 91, 95, 96for gout attack 94myopathy from 65, 160for pyoderma gangrenosum

diagnosis 212for relapsing polychondritis 222for SAPHO syndrome 239for scleroderma 245

cold. See also icefor gout attack 94in osteoarthritis treatment

171–172in physical therapy 194Raynaud’s phenomenon and

213–214colitis. See inflammatory bowel dis-

easecollagen 303

function of 169in Goodpasture’s syndrome 90homocystinuria and 116in hypermobility syndrome 119in osteoarthritis 169in relapsing polychondritis 221

Colles’ fractures 178, 293colon cancer, back pain from 20combined immunodeficiencies

124–125common peroneal nerve, damage

to, foot pain from 87–88common variable immunodefi-

ciency (CVID) 125communication, assistive devices

for 15complement 46, 123, 264, 265,

270–271complementary medicine, defini-

tion of 339complete blood count (CBC) 279,

325–326

complex regional pain syndrome.See reflex sympathetic dystrophy

component proteins 46compression fracture, from osteo-

porosis 178computer tomography scans. See CT

scansconcentrative meditation 153concentric isotonic exercise 74conjunctivitis 76

HIV and 118from psoriatic arthritis 205from reactive arthritis 217from Reiter’s syndrome 217from Sweet’s syndrome 262

connective tissue diseaseB19 and 189Raynaud’s phenomenon in 213relapsing polychondritis and

221Sweet’s syndrome and 261tendinitis in 256

constrained prosthesis 135contiguous spread, in osteomyelitis

175continuous passive motion (CPM)

machine 136continuous positive airway pressure

(CPAP) 223, 255contraceptives, oral, hepatitis from

109contracture, diabetic 57–58controlled clinical trial 43cookbook acupuncture 4copper bracelet 46

core decompression, for avascularnecrosis 16–17

corneal opacities, from angioker-atoma corporis diffusum 6

coronary artery disease, inacromegaly 3

cortical bone 177corticosteroids 46, 303

for AS 9for acromioclavicular joint

arthritis 249for amyloidosis 6for anterior uveitis 77for antiphospholipid antibody

syndrome 11for atherosclerosis 270for autoimmune hepatitis 108avascular necrosis and 16for back pain 23for Baker’s cyst 24, 145for Behçet’s disease 26for biceps tendinitis 247bone resorption and 177for calcific tendinitis 247for carpal tunnel syndrome 33cataracts and 77for central nervous system vas-

culitis 36Churg-Strauss syndrome and

41, 42–43for Cogan’s syndrome 45for CPPD 32for cryoglobulinemia 48for de Quervain’s tenosynovitis

53for DISH 59for drug-induced lupus 63for Dupuytren’s contracture 67for enthesitis 1for eosinophilia myalgia syn-

drome 70for eosinophilic fasciitis 70for eosinophilic myositis 71for epicondylitis 72for erythema nodosum 73for fibromyalgia 84for ganglion 89for Goodpasture’s syndrome 91for gout attack 94for hallux rigidus 87for heel spur 102for Henoch-Schönlein purpura

108for hepatitis B vasculitis 111for hepatitis C arthritis 113immunodeficiency caused by

124for inclusion body myositis 126for inflammatory bowel disease

132for intestinal bypass arthritis

132

Index 361

corticosteroids (continued)

joint injection of 133for juvenile arthritis 138for Kawasaki disease 142Milwaukee shoulder and 155for mixed connective tissue dis-

ease 155for multicentric reticulohistiocy-

tosis 156for myasthenia 158for myocarditis 159myopathy from 65, 160,

266–267for myositis 56for olecranon bursitis 167for osteoarthritis 171, 173osteonecrosis from 64osteoporosis from 64, 177, 179,

278for overlap syndrome 183for palindromic rheumatism

187for pericarditis 191for plantar fasciitis 100, 195for polyarteritis nodosa 198for polymyalgia rheumatica 200for posterior calcaneal bursitis

100for posterior uveitis 77in pregnancy 201for prepatellar bursitis 203psoriasis and 204, 206for psoriatic arthritis 207psychosis and 267for pyoderma gangrenosum

diagnosis 212for reactive arthritis 218–219for reflex sympathetic dystrophy

219for relapsing polychondritis 222rheumatic disease from 63for rheumatic fever 224for rheumatoid arthritis 230t,

233for rheumatoid vasculitis 235for rotator cuff syndrome 236for SAPHO syndrome 239for sarcoidosis 240for scleritis 77, 228for scleroderma 245for Sjögren’s syndrome 255for SLE 266–267, 272for spinal stenosis 259

stress fractures and 261for subacromial bursitis 248for subtalar arthritis 101for Sweet’s syndrome 262for Takayasu’s arteritis 276for temporal arteritis 277–278for tendinitis 257tendon rupture and 1for thrombocytopenia 279for trigger finger 280–281for trochanteric bursitis 281tuberculosis and 281vaccination and 285for vasculitis 287for Wegener’s granulomatosis

291–292cortisol 154, 177COX. See cyclooxygenaseCOX-1 inhibitors 162COX-2 inhibitors 94, 162COX-2-selective drugs 163, 164,

171, 172, 231. See also cyclooxy-genase

Coxsackie viruses 107, 160CPAP (continuous positive airway

pressure) 223, 255CPM (continuous passive motion)

machine 136CPPD. See calcium pyrophosphate

dihydrate deposition diseasecranial arteritis. See temporal arteri-

tisC-reactive protein (CRP). See ESR

and CRPcreatine kinase 326

in eosinophilic myositis 71in myositis diagnosis 55, 160in scleroderma 243

creatine phosphokinasein inclusion body myositis diag-

nosis 126in myasthenia diagnosis 157in rhabdomyolysis diagnosis

223creatinine 290, 326

CREST syndrome. See sclerodermaCrohn’s disease. See enteropathic

arthritis; inflammatory boweldisease

CRP (C-reactive protein). See ESRand CRP

crush fracture, from osteoporosis178

crutches 15, 16cryoglobulinemia 46–48

from hepatitis C 112microscopic polyarteritis with

197plasmapheresis for 196Raynaud’s phenomenon from

214cryoglobulins 326–327

crystal-induced arthritis. See cal-cium pyrophosphate dihydratedeposition disease; gout

CSF. See cerebrospinal fluidCTS. See carpal tunnel syndrome

(CTS)CT (computer tomography) scans

327

in hemochromatosis diagnosis104

in myasthenia diagnosis 157in myositis diagnosis 55in osteochondritis dissecans

diagnosis 173in osteosarcoma diagnosis 182in Paget’s disease diagnosis 186in relapsing polychondritis diag-

nosis 222in scleroderma diagnosis 244in spinal stenosis diagnosis 258in stress fracture diagnosis 261in Wegener’s granulomatosis

diagnosis 290Cuprimine. See penicillamineCushing’s disease, myopathy from

160CVID (common variable immunod-

eficiency) 125CXC chemokines 37cycling, as exercise 76cyclobenzaprine 84, 304

cyclooxygenase (COX) 48–49, 162,340

cyclophosphamide 304

for Behçet’s disease 26in bone marrow transplant 27for central nervous system vas-

culitis 36for Churg-Strauss syndrome

42–43for Cogan’s syndrome 45for cryoglobulinemia 48for Felty’s syndrome 81for Goodpasture’s syndrome 91


for Henoch-Schönlein purpura108

for hepatitis B vasculitis 111herpes zoster and 113–114immunodeficiency caused by

124for inclusion body myositis 126intravenous 291for multicentric reticulohistiocy-

tosis 156for myositis 56for polyarteritis nodosa 198in pregnancy 201–202for relapsing polychondritis 222for rheumatoid vasculitis 235for scleroderma 244, 245for Sjögren’s syndrome 255for SLE 272–273for temporal arteritis 278for thrombocytopenia 279thrombocytopenia from 279vaccination and 285for vasculitis 287for Wegener’s granulomatosis

291–292cyclosporine 304

for autoimmune hepatitis 108for Behçet’s disease 26for Cogan’s syndrome 45as DMARD 60herpes zoster and 114hyperuricemia caused by 95–96for inclusion body myositis 126metabolism of 66for myasthenia 158for myositis 56myositis from 65PgP and 67for psoriasis 207for psoriatic arthritis 207, 208for pyoderma gangrenosum

diagnosis 212for relapsing polychondritis 222rheumatic disease from 64for rheumatoid arthritis 232for sarcoidosis 240for scleroderma 245for Sjögren’s syndrome 255for SLE 273

CYP (cytochrome P450) superfam-ily 66, 192

cystic fibrosis 49–50

cystitis 290

cytochrome P450 (CYP) superfam-ily 66, 192

cytokines 26, 50–51. See also

chemokinescalcium crystals and 31in cellular immunity 124for cryoglobulinemia 48rheumatic disease from 63in rheumatoid arthritis patho-

genesis 226SLE and 264

cytomegalovirusarthritis from 288central nervous system vasculitis

from 35polyarteritis nodosa diagnosis

and 196posterior uveitis and 77Sjögren’s syndrome and 251SLE and 265

Cytotec. See misoprostolCytoxan. See cyclophosphamide

D

dactylitis, from sickle-cell disease 250danazol 273, 304–305

Danocrine. See danazoldapsone 305

for pyoderma gangrenosumdiagnosis 212

for relapsing polychondritis 222for SLE 273

Darvocet. See acetaminophen, withnarcotics

Daypro. See oxaprozindeafness 185, 223deconditioning, fibromyalgia and

81–82deep peroneal nerve, compressed,

foot pain from 88deep vein thrombosis (DVT)

in antiphospholipid antibodysyndrome 11

Baker’s cyst and 24, 145definition of 340estrogen and 181from joint replacement surgery

135degenerative disc disease 59, 257degenerative joint disease (DJD).

See osteoarthritisdehydroepiandrosterone (DHEA)

273, 305

dementia, in Lyme disease 148Demerol. See meperidinedemyelinating polyneuropathy,

chronic inflammatory 196Depen. See penicillamineDepoMedrol. See corticosteroidsdepression 82, 84–85, 267. See also

antidepressantsde Quervain’s tenosynovitis 53, 294dermatomyositis and polymyositis

53–57

malignancy associated with 159myocarditis in 158in overlap syndrome 183plasmapheresis and 196Raynaud’s phenomenon in 213rhabdomyolysis from 223from SLE 266

desferrioxamine, for hemochro-matosis 105

DEXA (dual-energy X-ray absorp-tiometry) 327

dexamethasone 201, 303dexfenfluramine, pulmonary

hypertension from 209dextropropoxyphene7, for

osteoarthritis 172DHEA (dehydroepiandrosterone)

273, 305

diabetes mellitus 57–58

in acromegaly 2atherosclerosis and 269carpal tunnel syndrome from 32celiac disease and 34DISH and 59Dupuytren’s contracture and

67, 100frozen shoulder and 114, 248gout and 94from hemochromatosis 103, 104immunodeficiency caused by

124neuropathic arthritis from 162NSAIDs and 165osteomyelitis and 175

diabetic amyotrophy, myopathyfrom 159

diabetic cheirarthropathy 57dialysis 5, 58, 91diarrhea

from angiokeratoma corporisdiffusum 6

in Gulf War syndrome 97

Index 363

diarrhea (continued)

from scleroderma 242from Whipple’s disease

292–293diclofenac 305–306

as COX-2 inhibitors 163for fibromyalgia 84for gout attack 94

Didronel. See etidronatediet 58–59, 92, 95dietary supplements, for arthritis

treatment 59diffuse idiopathic skeletal hyperos-

tosis (DISH) 58, 59–60, 258diffuse infiltrative lymphocytosis

syndrome (DILS) 118diffuse scleroderma 240, 241–242diffusion, of drugs 66diflunisal 306

digoxin 67, 159dihydropyridine, for Raynaud’s

phenomenon 215DILS (diffuse infiltrative lymphocy-

tosis syndrome) 118diltiazem 160, 210dinner fork deformity 227DIP (distal interphalangeal) 205, 340dipyridamole, for Kawasaki disease

142Disalcid. See salsalatediscoid lupus lesions 266disease-modifying antirheumatic

drugs (DMARDs) 60

approach to 231choosing 232combinations of 232–233effectiveness of 233for hepatitis C arthritis 113joint replacement surgery and

135for juvenile arthritis 138with NSAIDS 162for psoriatic arthritis 207for reactive arthritis 219for rheumatoid arthritis 230t,

231–233TNF antagonists vs. 283

DISH (diffuse idiopathic skeletalhyperostosis) 58

distal interphalangeal (DIP)definition of 340psoriatic arthritis in 205rheumatoid arthritis in 227

distal interphalangeal joint replace-ment 136

dithranol, for psoriasis 206diuretic

for carpal tunnel syndrome 33hyperuricemia and 92lupus from 61for myocarditis 159myopathy from 160NSAIDs and 165rheumatic disease from 63–64

DJD (degenerative joint disease).See osteoarthritis

DMARDs. See disease-modifyingantirheumatic drugs

DNA antibodies 327–328

Dolobid. See diflunisaldouble-blind clinical trials 43dowager’s hump 178doxepin 306

doxycycline. See also minocyclinefor brucellosis 28for Gulf War syndrome 97for Lyme disease 150, 151

d-penicillamine. See penicillaminedressing, assistive devices for 15Dressler’s syndrome 190driving, assistive devices for 15drug(s), during pregnancy

200–201drug-induced hepatitis. See hepati-

tis, drug-induceddrug-induced immunodeficiency

124drug-induced lupus 60–63, 190drug-induced myopathy 159–160drug-induced rheumatic disease

63–66

drug metabolism 66, 191–192,201

drug therapy, pharmacogenetics in191–193

drug transport 66–67

dual-energy X-ray absorptiometry(DEXA) 327

Duchenne’s muscular dystrophy,myopathy from 159

Dupuytren’s contracture 67

CPPD and 32diabetes and 57heel pain from 100

Duragesic. See fentanylDVT. See deep vein thrombosis

dystrophic change, in reflex sympa-thetic dystrophy 219

E

ear, in relapsing polychondritis 221Easprin. See aspirinEaton-Lambert syndrome, myopa-

thy from 159eccentric isotonic exercise 74echocardiogram 328

definition of 340in hemochromatosis diagnosis

104in infective endocarditis diagno-

sis 130in Kawasaki disease diagnosis

142in pericarditis diagnosis 191in relapsing polychondritis diag-

nosis 222Ecotrin. See aspirinedema 70, 340Edrophonium, in myasthenia diag-

nosis 157education

in fibromyalgia treatment 84in osteoarthritis treatment

171in SLE treatment 271in Wegener’s granulomatosis

treatment 291EEG. See electroencephalogramefflux transporters 66–67effusion, definition of 340Ehlers-Danlos syndrome 119Elavil. See amitriptylineelbow joint replacement

135–136elbow pain. See olecranon bursitiselectrocardiogram

in hemochromatosis diagnosis104

in infective endocarditis diagno-sis 130

in myositis diagnosis 55in pericarditis diagnosis 191in rheumatic fever diagnosis

224electroencephalogram (EEG)

in fibromyalgia trials 82in myocarditis diagnosis 158in SLE diagnosis 271


electromyography (EMG) 328

in inclusion body myositis diag-nosis 126

in myasthenia diagnosis 157in myopathy diagnosis 159in myositis diagnosis 55, 160

electrotherapeutic modalities, inphysical therapy 194

elemental diets, for arthritis treat-ment 58–59

ELISA. See enzyme-linkedimmunosorbent assay

embolus, from avascular necrosis 16EMG. See electromyographyENA (extractable nuclear antigen)

155, 251Enbrel. See etanerceptencephalitis, from Behçet’s disease

25endocarditis

infective (See infective endo-carditis)

in myocarditis 158in rheumatic fever 224

endocrine disorders, myopathyfrom 160

endomyocardial biopsy, inmyocarditis diagnosis 158–159

endoscopy, in inflammatory boweldisease diagnosis 132

endothelin receptor antagonist, forscleroderma 245

endurance, in muscle conditioning74

enteropathic arthritis 49–50, 69

enthesitisfrom AS 7of Achilles tendon 1, 9heel spur from 101HIV and 117–118in hypermobility syndrome

119from reactive arthritis 217in spondyloarthropathy 260

enthesopathydefinition of 340from inflammatory bowel dis-

ease 131in pauciarticular juvenile arthri-

tis 137entrapment neuropathy, in carpal

tunnel syndrome 32

environmentin autoimmune hepatitis 108inflammatory bowel disease and

131in myositis 53–54in temporal arteritis 276

enzyme-linked immunosorbentassay (ELISA)

in cryoglobulinemia diagnosis 48in hepatitis C diagnosis 113in HIV diagnosis 117in Lyme disease diagnosis

149–150eosinophil, definition of 340eosinophilia myalgia syndrome

41–42, 69–70

eosinophilic fasciitis 32, 70

eosinophilic myositis 71

epicondylitis 71

epilepsy, Dupuytren’s contractureand 67, 100

episcleritis 76–77epoprostenol, for pulmonary

hypertension 210–211Epstein-Barr virus

arthritis from 288in chronic fatigue syndrome 39rheumatoid arthritis from 225Sjögren’s syndrome and 251SLE and 265vasculitis and 286

ergot preparations, Raynaud’s phe-nomenon from 214

erosive osteoarthritis 170erythema ab igne, from heat 99erythema infectiosum 188erythema marginatum, in rheu-

matic fever 224erythema migrans, from Lyme dis-

ease 148, 149erythema nodosum 72–73

from Behçet’s disease 25from cystic fibrosis 49from inflammatory bowel dis-

ease 131panniculitis from 187in relapsing polychondritis 222from sarcoidosis 239–240from Sweet’s syndrome 262Takayasu’s arteritis in 275

erythrocyte sedimentation rate. See

ESR and CRP

erythroderma, exfoliative dermatitiswith 204

erythromycinhepatitis from 109lupus flares from 62PgP and 67for scleroderma 245

erythropoietin 26esomeprazole 306

esophageal dysmotility, in sclero-derma 243

ESR (erythrocyte sedimentationrate) and CRP (C-reactive pro-tein) 328–329

definition of 340in familial Mediterranean fever

diagnosis 80in inflammatory bowel disease

diagnosis 132in juvenile arthritis diagnosis


tosis diagnosis 156in osteosarcoma diagnosis 182in polyarteritis nodosa diagnosis

197in polymyalgia rheumatica diag-

nosis 199in reactive arthritis diagnosis

218in relapsing polychondritis diag-

nosis 222in rheumatic fever diagnosis

224in rheumatoid arthritis diagnosis

229in Sjögren’s syndrome diagnosis

254in SLE diagnosis 270in Sweet’s syndrome diagnosis

262in temporal arteritis diagnosis

277estrogen. See also selective estrogen

receptor modulatorbone resorption and 177erythema nodosum and 72osteoporosis and 177, 180–181in SLE 264

etanercept 26, 60, 232, 283,306–307

ethambutol, hyperuricemia and 92

Index 365

etidronate 27, 307

osteomalacia from 174for osteoporosis 181, 278for Paget’s disease 187

etodolac 307

etretinate, for psoriatic arthritis208

Evista. See raloxifeneEvoxac. See cevimelineexclusion diets, for arthritis treat-

ment 59exercise 73–76

for back pain 23bone resorption and 177for calcific tendinitis 247for chronic fatigue syndrome 41for fibromyalgia 84for flat feet 85for Gulf War syndrome 97for metatarsalgia 86for myositis 57for osteoarthritis 171–172for osteoporosis 179in physical therapy 193–194for reflex sympathetic dystrophy

219rehabilitative 73–75, 236, 249for spinal stenosis 259

exfoliative dermatitis with erythro-derma 204

explosive strength, in muscle con-ditioning 74

extracorporeal phototherapy. See

photopheresisextractable nuclear antigen (ENA)

155, 251eye problems 76

in AS 7–8in acromegaly 2–3in Behçet’s disease 25in hydroxychloroquine 272in Lyme disease 148in myasthenia 157in pauciarticular juvenile arthri-

tis 137–139in polyarteritis nodosa 197in psoriatic arthritis 205in reactive arthritis 217in relapsing polychondritis

221–222in rheumatoid arthritis 228in sarcoidosis 240

in Sjögren’s syndrome 251, 252in SLE 267in spondyloarthropathy 260in temporal arteritis 277in Wegener’s granulomatosis

290

F

Fabry’s disease, angiokeratoma cor-poris diffusum and 6

facioscapulohumeral muscular dys-trophy, myopathy from 159

familial Mediterranean fever (FMF)79–80

AA amyloidosis from 5genetic factors in 89pericarditis from 190

famotidine 307

faradic stimulation, in physicaltherapy 194

fascia, definition of 340fasciitis, definition of 340fasting, for rheumatoid arthritis 58fat, inflammation of. See panniculitisfat embolus, from avascular necro-

sis 16fatigue

in autoimmune hepatitis 108in chronic fatigue syndrome

39–41from eosinophilia myalgia syn-

drome 69from erythema migrans 148in Gulf War syndrome 97from hepatitis B 110from Lyme disease 150in myasthenia 157from system onset juvenile

arthritis 137fat metabolism, myopathy from

160faucets, long-levered, for joint pro-

tection 134FDA, definition of 340feeding, assistive devices for 15Feldene. See piroxicamfelodipine, for Raynaud’s phenome-

non 215Felty’s syndrome 80–81, 228, 279fenfluramine, pulmonary hyperten-

sion from 209fenoprofen 307–308

fentanyl 308

ferritin 104, 138fever

from familial Mediterraneanfever 79–80

in relapsing polychondritis221–222

from system onset juvenilearthritis 137

fever, rheumatic. See rheumaticfever

fibrillin, in hypermobility syndrome119

fibroblasts, in scleroderma 241fibromyalgia 81–85

acupuncture for 4cognitive behavioral therapy for

45Gulf War Syndrome and 97hepatitis C and 112from HIV 119Lyme disease and 150manipulation for 176silicone implants and 250–251

fibrositis. See fibromyalgiafifth disease 188Finkelstein’s test 53FK506. See tacrolimusflat feet

in children 85in hypermobility syndrome 120from plantar fasciitis 99pronation and 195

flavivirus 111Flexeril. See cyclobenzaprineflexibility

of Achilles tendon 1heat and 99in rehabilitation exercise 75

flexural psoriasis 204fludarabine, for myositis 56fluorescein, in Sjögren’s syndrome

diagnosis 254fluoride 181–182, 255fluoxetine 308

flurbiprofen 308

FMF. See familial Mediterraneanfever

folic acid (folate) 308

folinic acid 308

foot drop, from Churg-Strauss syn-drome 42


foot pain 85–88, 93. See also heelpain; plantar fasciitis

foot strain 86. See also plantar fasci-itis

Fosamax. See alendronatefractures. See bone fracturesfrostbite 88

frozen shoulder 114, 219, 248functional exercise, in rehabilita-

tion exercise 75fungal arthritis 127–129fungal infection, opportunistic

168furosemide 63, 92fusion, of joints. See arthrodesis

G

gabapentin 309

gallium scan, in myositis diagnosis55

gammaglobulin 309

gamma interferon, for scleroderma245

ganglion 32, 89

gangrenein antiphospholipid antibody

syndrome 11from brucellosis 28in cholesterol emboli syndrome

39in cryoglobulinemia 47from infective endocarditis 130in polyarteritis nodosa 197from Raynaud’s phenomenon

214gastrointestinal (GI) system

definition of 341NSAIDs side effects in 163–164in scleroderma 240, 242, 243,

245in Sjögren’s syndrome 253in SLE 268in spondyloarthropathy 260

G-CSF (granulocyte colony stimu-lating factor) 27

gemfibrozil, myopathy from 160generic, definition of 340–341genetic factors 89–90. See also

heredityin autoimmune hepatitis 108in familial Mediterranean fever

79

in Felty’s syndrome 80in immunodeficiency 124in inflammatory bowel disease

131in juvenile spondylitis 137in osteoarthritis 169in Paget’s disease 185in polymyalgia rheumatica

198–199in psoriasis 203in pulmonary hypertension

209in rheumatoid arthritis 225in SAPHO syndrome 239in sickle-cell disease 249–250in Sjögren’s syndrome 251in SLE 263–264

genome wide scan 89German measles. See rubellaGH. See growth hormonegiant cell arteritis. See temporal

arteritisGI (gastrointestinal) system

definition of 341NSAIDs side effects in 163–164in scleroderma 240, 243, 245in Sjögren’s syndrome 253in SLE 268in spondyloarthropathy 260

glenohumeral arthritis 248glenohumeral joint 246glenohumeral joint instability 249glomerulonephritis 8, 156, 341. See

also kidney functionglucocorticoids. See corticosteroidsglucosamine and chondroitin sul-

fate 173, 309

glucuronide, drug metabolism and66

gluten, sensitivity to 34gluteus medius muscle, tendinitis at

115glycogen metabolism, myopathy

from 160GM-CSF (granulocyte-macrophage

colony stimulating factor) 81gold. See auranofingold injections 232, 309

golfer’s elbow. See epicondylitisgonococcal arthritis 128gonococcal tenosynovitis, carpal

tunnel syndrome from 32

Goodpasture’s syndrome 90–91,

196gout 91–96, 92t

bursitis from 29carpal tunnel syndrome from 32drug-induced 63–64foot pain and 85with glenohumeral arthritis 248hemarthrosis from 102hip pain from 114infective arthritis and 128NSAIDs for 163olecranon bursitis in 167prepatellar bursitis from 203from sickle-cell disease 250spinal stenosis from 258tendinitis in 256uric acid and 58

grab rails 15granular lymphocytes, large 81,

123–124granulocyte colony stimulating fac-

tor (G-CSF) 27granulocyte-macrophage colony

stimulating factor (GM-CSF) 81griseofulvin, autoimmune disorders

from 62ground glass appearance 244growth factors, for Felty’s syn-

drome 81growth hormone (GH), in

acromegaly 2Guillain-Barré syndrome

myopathy from 159plasmapheresis for 196in SLE 267

Gulf War syndrome 96–97

Guttate psoriasis 204

H

HAART (highly active antiretroviraltherapy), for HIV 117

Hahnemann, Samuel 116hallux rigidus 87hallux valgus, in adults 86–87halothane, hepatitis from 109hand contractures, in diabetes mel-

litus 57–58hand joint replacement 136HBeAg (hepatitis B e antigen) 111HBsAg (hepatitis B surface antigen)

111

Index 367

headachesin central nervous system vas-

culitis 35in erythema migrans 148fibromyalgia and 83in Lyme disease 148in SLE 267in temporal arteritis 277

heartinfection in (See infective endo-

carditis)inflammation of (See carditis;

myocarditis)in Kawasaki disease 141in Lyme disease 148–149in myositis 54in relapsing polychondritis 221in rheumatic fever 223, 224in sarcoidosis 240in scleroderma 242in Sjögren’s syndrome 253in SLE 268

heart attack. See myocardial infarc-tion

heart blockin Lyme disease 148–149in neonatal lupus 161, 202,

270in Sjögren’s syndrome 253

heart diseasearthritis and 13pericarditis from 190pulmonary hypertension from

209in SLE 268TNF antagonists and 283

heart failurefrom acromegaly 3from amyloidosis 5from hemochromatosis 103,

104, 105from infective endocarditis

130from Lyme disease 149from myocarditis 158, 159NSAIDs and 165from plasmapheresis 195from polyarteritis nodosa 197from pulmonary hypertension

210sleep apnea and 255from Takayasu’s arteritis 275TNF antagonists and 283

heat 99

for acromioclavicular jointarthritis 249

for back pain 23for Dupuytren’s contracture 67for osteoarthritis 171–172in physical therapy 194

Heberden’s nodes 170heel cord. See Achilles tendonheel pad, painful 100heel pain 99–101. See also plantar

fasciitisheel spur 59, 101–102

height, loss of, from osteoporosis178

hemangioma, hemarthrosis from102

hemarthrosis 102, 106hematogenous spread, in

osteomyelitis 175hematological disease, common vari-

able immunodeficiency and 125hematoma 106hematuria, definition of 341hemochromatosis 102–105

blood transfusion and 105CPPD caused by 31genetic factors in 89osteoarthritis and 170, 171

hemodialysis 32, 58hemoglobin 249–250, 341hemolysis, definition of 341hemophilia 105–107

genetic factors in 89hemarthrosis from 102synovectomy for 262–263

Henoch-Schönlein purpura (HSP)107–108

heparin-induced thrombocytopenia(HIT) 278, 279

heparinsfor Behçet’s disease 26cholesterol emboli syndrome

and 38low-molecular weight 11, 135osteoporosis from 64

hepatitis 108

arthritis from 225chronic fatigue syndrome and

40from drug-induced lupus 62

hepatitis, autoimmune 108–109,

252

hepatitis, drug-induced 109

hepatitis A, polyarteritis nodosadiagnosis and 196

hepatitis B 109–111

acupuncture and 4cryoglobulinemia from 47Henoch-Schönlein purpura from

107polyarteritis nodosa diagnosis

and 196vaccine for 63, 285, 286vasculitis and 286

hepatitis B e antigen (HBeAg) 111hepatitis B surface antigen (HBsAg)

111hepatitis C 111–113

acupuncture and 4cryoglobulinemia from 47pyoderma gangrenosum and

211Sjögren’s syndrome and 251SLE and 265vasculitis and 286

hepatocellular carcinoma 111heredity. See also genetic factors

in Dupuytren’s contracture 100in hemochromatosis 102in myositis 53–54

heroincentral nervous system vasculitis

and 35myopathy from 160

herpes virusesarthritis from 288central nervous system vasculitis

from 35Henoch-Schönlein purpura from

107vasculitis and 286

herpes zoster 20, 113–114

heterotopic ossification, from hipreplacement 9

HFE protein, hemochromatosis and102

HHC. See hemochromatosishidebound skin, in scleroderma

241high chair, for joint protection 134highly active antiretroviral therapy

(HAART), for HIV 117high-velocity thrust 38hip pain 114–115

hip replacement 136


histiocytes, in multicentric reticulo-histiocytosis 156

histoplasmosis, erythema nodosumand 72

HIT (heparin-induced thrombocy-topenia) 278

HIV. See human immunodeficiencyvirus

HLA 115. See also genetic factorsin celiac disease 34definition of 341in inflammatory bowel disease

132in rheumatoid arthritis 225in SLE 264in Takayasu’s arteritis 275

HLA-B27 329

in ankylosing spondylitis 6–7in psoriatic arthritis 203in reactive arthritis 216–217in spondyloarthropathy 260

HLA-B51, Behçet’s disease and 25HMG coenzyme reductase

inhibitors, myositis from 64holistic therapy. See Ayurvedic

medicinehomeopathy 115–116

homocystinuria 116

homogentisic acid oxidase, defi-ciency of. See alkaptonuria

hormonesin acromegaly 2bone resorption and 177osteoporosis and 177, 180–181,

278in SLE 264

housemaid’s knee 145, 203housewife’s knee. See prepatellar

bursitishousework, assistive devices for 15HPOA. See hypertrophic pulmonary

osteoarthropathyHPOA (hypertrophic pulmonary

osteoarthropathy) 121

HPV-B19. See parvovirusHSP. See Henoch-Schönlein purpuraHTLV1, polyarteritis nodosa diagno-

sis and 196human immunodeficiency virus

(HIV) 116–119

arthritis from 225central nervous system vasculitis

from 35

chemokines and 37hemophilia and 106immunodeficiency from 124psoriasis and 203, 204pyoderma gangrenosum and

211Sjögren’s syndrome and 251tuberculosis and 281vasculitis and 286

human parvovirus B19, Henoch-Schönlein purpura from 107

humoral immunity 124hyalgan. See hyaluronan injectionshyaluronan injections 171, 173,

309

hyaluronans, joint injection of 133hyaluronate. See hyaluronan injec-

tionshyaluronic acid. See hyaluronan

injectionshydralazine

antiphospholipid antibodiesfrom 10

lupus from 61myopathy from 160

hydrocodone 172. See also aceta-minophen, with narcotics

hydrocortisone 303. See also corti-costeroids

hydroxyapatite crystals 154–155,248

hydroxychloroquine and chloro-quine phosphate 310

as antimalarial 9as DMARD 60for hepatitis C arthritis 113for HIV-associated arthritis 118myopathy from 65, 160, 267for myositis 57for palindromic rheumatism

187in pregnancy 201psoriasis flares from 204for psoriatic arthritis 208for rheumatoid arthritis 232for sarcoidosis 240for Sjögren’s syndrome 255for SLE 272

hydroxyurea 54, 250Hylan GF 20. See hyaluronan injec-

tionshypercalcemia, in acromegaly 3hyperlipidemia, gout and 94

hypermobilityin acromegaly 2arthralgia and 138flat feet and 85osteoarthritis from 170at patella 189

hypermobility syndrome 119–120

glenohumeral joint instabilityfrom 249

from homocystinuria 116stress fractures from 261

hyperostosis, in SAPHO syndrome239

hyperparathyroidismfrom dialysis 58myopathy from 160osteoporosis from 178

hyperpigmentation, definition of341

hypersensitivity vasculitis. See vas-culitis

hypertensionin acromegaly 2definition of 341gout and 94from NSAIDs 49in polyarteritis nodosa 198in scleroderma 245in SLE 273

hypertension, pulmonary 209–211,

210t

in pregnancy 201in scleroderma 240, 242, 243,

245in SLE 268

hyperthyroidism 160, 178hypertrophic pulmonary

osteoarthropathy (HPOA) 50,119, 121

hyperuricemiacauses of 92–93drug-induced 63–64gout and 91kidney disease from 93

hyperviscosity syndrome 47, 196hypnosis 84, 121

hypophosphatasia 174hypophosphatemic rickets 121

hypothyroidismcarpal tunnel syndrome from

32CPPD caused by 31myopathy from 160

Index 369

hypothyroidism (continued)

osteoporosis and 178pericarditis from 190polymyalgia rheumatica and 200

I

IBD. See inflammatory bowel dis-ease

IBM. See inclusion body myositisibuprofen 310

aspirin and 163COX enzymes inhibited by 49,

163for fibromyalgia 84for gout attack 94

ice 123

for acute foot strain 86for biceps tendinitis 247for calcific tendinitis 247for de Quervain’s tenosynovitis

53for enthesitis 1for osteoarthritis 172for reactive arthritis 219for tendinitis 257

idiopathic, definition of 341idiopathic thrombocytopenic pur-

pura. See thrombocytopeniaidiosyncratic, definition of 341idiosyncratic hepatitis 109IgA antibodies 107, 216IgA deficiency 125IgG antibodies

in Lyme disease diagnosis 149in parvovirus diagnosis 188in rubella diagnosis 237

IgM antibodiesin Lyme disease diagnosis 149in parvovirus diagnosis 188in rubella diagnosis 237

iliopsoas muscle, tendinitis at 115imagery, in cognitive behavior ther-

apy 45imipramine 84, 310

immune response 123–124

fibroblasts and 241inflammatory bowel disease and

131in Kawasaki disease 141in SLE treatment 274

immunocompromised, definition of341

immunodeficiency 124–125

immunoglobulincryoglobulinemia and 46–48deficiency of 125definition of 339direct damage by 265in humoral immunity 124in parvovirus diagnosis 188polyarteritis nodosa diagnosis

and 196in Sjögren’s syndrome 251, 254SLE and 264–265types of 124

immunoglobulin, intravenous(IVIG) 309. See also gammaglobu-lin

for Guillain-Barré syndrome159

for inclusion body myositis 126for Kawasaki disease 142for myasthenia 158for myositis 56for polyarteritis nodosa 198for pyoderma gangrenosum

diagnosis 212for Sjögren’s syndrome 255for SLE 273for thrombocytopenia 279for Wegener’s granulomatosis

292immunoglobulin antibodies, in

Lyme disease diagnosis 149immunoglobulin replacement ther-

apy. See intravenous immunoglob-ulin

immunomodulator 158, 212immunosuppression

for autoimmune hepatitis 108for Behçet’s disease 26in bone marrow transplant 27for central nervous system vas-

culitis 36for Churg-Strauss syndrome

42–43for Cogan’s syndrome 45for cryoglobulinemia 48definition of 341for eosinophilic fasciitis 70for Goodpasture’s syndrome 91for hepatitis B vasculitis 111herpes zoster and 113–114immunodeficiency caused by

124for inclusion body myositis 126

infective arthritis from 127for inflammatory bowel disease

131for mixed connective tissue dis-


tosis 156for myocarditis 159for myositis 56olecranon bursitis and 167opportunistic infections with

167–168osteomyelitis from 175for overlap syndrome 183with plasmapheresis 196for posterior uveitis 77for psoriasis 207for relapsing polychondritis 222for scleritis 77for scleroderma 245scleroderma and 241for temporal arteritis 278for thrombocytopenia 279thrombocytopenia and 278–279vaccination and 285for vasculitis 287

Imuran. See azathioprineincidence, definition of 341inclusion body myositis (IBM)

125–126

Indocin. See indomethacinindomethacin 9, 94, 310

infarct, definition of 341infection

with common variable immun-odeficiency 125

in Felty’s syndrome 80hemochromatosis and 104Henoch-Schönlein purpura from

107hepatitis from 108immunodeficiency and 124infective arthritis from 127myositis from 160osteomyelitis from 175pericarditis from 190reactive arthritis from 216rheumatoid arthritis from 225in SLE 271, 274Sweet’s syndrome and 261TNF antagonists and 283in Wegener’s granulomatosis

289, 290–291


infection, nosocomial 168infection, opportunistic 167–168

cyclophosphamide and 291in SLE 274

infectious arthritis. See infectivearthritis

infective arthritis 126–129

back pain from 20in children 143from diabetes 58with glenohumeral arthritis 248hip pain from 114from HIV 118from infective endocarditis 130from joint injection 133–134osteoarthritis from 170osteomyelitis and 175SAPHO syndrome as 239from sickle-cell disease 250in SLE 266

infective endocarditis 129–130

inflammation, definition of 341inflammatory bowel disease (IBD)

130–132

in children 138enteropathic arthritis and 69erythema nodosum and 72pyoderma gangrenosum and

211scleritis and 77Sjögren’s syndrome and 253SLE and 268Sweet’s syndrome and 261Takayasu’s arteritis in 275TNF antagonists for 283

inflammatory polyarthritis, fromhepatitis C 112

inflammatory tendinitis 256infliximab 311

as biological 26for Crohn’s disease 132as DMARD 60for heart failure 283for rheumatoid arthritis 232,

283for SAPHO syndrome 239

influenza, myositis from 160injectable gold 309

innate immunity 123–124insecticides, Gulf War syndrome

and 96insoles, for hallux valgus 87insulin, in diabetes mellitus 57

interdigital nerves, stretched, footpain from 88

Interferon-α

for hepatitis C 113rheumatic disease from 63

Interleukin-1 (IL-1) 51Interleukin-2 63, 125Interleukin-4 (IL-4) 51Interleukin-6 (IL-6) 51Interleukin-10 (IL-10) 51intermittent claudication, in dia-

betes mellitus 57interstitial fibrosis, from rheuma-

toid arthritis 228interstitial keratitis 45intestinal bypass arthritis 132

intra-articular, definition of 341intra-articular joint injection 133intravenous immunoglobulin (IVIG)

309. See also gammaglobulinin Guillain-Barré syndrome 159for inclusion body myositis 126for Kawasaki disease 142for myasthenia 158for myositis 56for polyarteritis nodosa 198for pyoderma gangrenosum

diagnosis 212for Sjögren’s syndrome 255for SLE 273for thrombocytopenia 279for Wegener’s granulomatosis

292intussusception, from Henoch-

Schönlein purpura 107iodine, erythema nodosum and 72iritis, from psoriatic arthritis 205iron, in hemochromatosis 102–103irritable bowel syndrome,

fibromyalgia and 83isokinetic exercise 74isometric exercise 74isoniazid, for tuberculosis 282isotonic exercise 74isradipine, for Raynaud’s phenome-

non 215IVIG. See intravenous immunoglob-

ulin

J

JA. See juvenile arthritisJaccoud’s arthritis, in SLE 266

jaundicefrom hepatitis B 110from hepatitis C 112in sickle-cell disease 250

joint aspiration 329–330

for hemarthrosis 106for infective arthritis 129for olecranon bursitis 167in reactive arthritis diagnosis

218for septic bursitis 246

joint fusion. See arthrodesisjoint injection 133–134, 233joint mice. See loose bodiesjoint protection 134, 167, 171–172joint replacement 134–136

for AS 9for acromegaly 3for avascular necrosis 17for hemophiliacs 106infective arthritis from 127for osteoarthritis 169, 171, 173for rheumatoid arthritis 233

Jones criteria, for rheumatic fever224

jumper’s knee 145juvenile arthritis (JA) 136–139

anterior uveitis and 77B19 and 188bone marrow transplant for 27joint replacement for 136knee pain from 143Lyme disease and 147NSAIDs for 163pericarditis from 190subtalar arthritis from 101synovectomy for 262TNF antagonists for 283in wrist 293–294

juvenile hemochromatosis 102juvenile rheumatoid arthritis. See

juvenile arthritisjuvenile spondylitis 137–138

K

Kaposi’s sarcoma, methotrexateand 118

Karelin fever, arthritis from 288Kawasaki disease 141–142

Keinbock’s disease 293Kenalog. See corticosteroidskertoderma blenorrhagicum, from


Index 371

ketamine, for fibromyalgia 84ketoconazole 65, 66ketoprofen 311

ketorolac 311

kidney diseaseanti-dsDNA antibody and 264arthritis and 13from hyperuricemia 93NSAIDs and 165osteomalacia from 174plasmapheresis and 196pregnancy and 270from reactive arthritis 219rheumatiod arthritis and 228in scleroderma 242, 245in Sjögren’s syndrome 253in SLE 267

kidney failurefrom amyloidosis 5from angiokeratoma corporis

diffusum 6in atherosclerosis 269from Goodpasture’s syndrome

90–91from Henoch-Schönlein purpura

108from homocystinuria 116myopathy from 160from rhabdomyolysis 223in SLE 274tendon rupture and 1in Wegener’s granulomatosis

290kidney function

in cholesterol emboli syndrome38, 39

in Churg-Strauss syndrome 42in Henoch-Schönlein purpura

107immunodeficiency and 124NSAIDs and 49, 165in polyarteritis nodosa 197in relapsing polychondritis 222in rhabdomyolysis 119, 223in scleroderma 240in Sjögren’s syndrome 253in Wegener’s granulomatosis

290kidney infection, back pain from

20Kineret. See anakinraknee pain 142–145, 189–190. See

also meniscal tears

knee replacement 136Koebner phenomenon 204

L

La. See SSA and SSBlaboratory tests, interpreting 323lactate, in meditation 154lactate dehydrogenase, in myositis

diagnosis 55laminectomy, for back pain 24lamivudine, for hepatitis B and C

111lansoprazole 312

for GI complications 164for osteoarthritis 172for scleroderma 245

large granular lymphocytes 81,123–124

lateral epicondylitis 71lavage, bronchoalveolar, in sclero-

derma diagnosis 244lavage, for osteoarthritis 171, 173lead, exposure to, hyperuricemia

and 92leflunomide 312

as DMARD 60hepatitis C and 113hepatitis from 109in pregnancy 201for psoriatic arthritis 207for rheumatoid arthritis 232for SLE 274for Wegener’s granulomatosis

292leprosy, erythema nodosum and

72Lesch-Nyhan syndrome 92lesions

definition of 341from dermatomyositis 54from erythema migrans 148from Lyme disease 148in multicentric reticulohistiocy-

tosis 156nerve, foot pain from 87–88in polyarteritis nodosa 197from pyoderma gangrenosum

211from rheumatoid vasculitis 235in SLE 266in tuberculosis 281

Leucovorin. See folinic acid

leukemiacryoglobulinemia from 47hemarthrosis from 102juvenile arthritis and 138microscopic polyarteritis with

197polymyalgia rheumatica and

200pyoderma gangrenosum and

211leukocytes, polymorphonuclear, in

innate immunity 124leukocytoclastic vasculitis. See vas-

culitisleukopenia, definition of 341leukotriene receptor antagonists,

Churg-Strauss syndrome and 41leuprolide 273levodopa 62, 92levofloxacin, rheumatic disease

from 63LFTs (liver function tests) 330

ligament, definition of 341ligament injuries, at knee 144–145limb girdle muscular dystrophy,

myopathy from 159limited scleroderma 240, 242–243lipomas, carpal tunnel syndrome

from 32lipopolysaccharides, in reactive

arthritis 216livedo reticularis 147

from antiphospholipid antibodysyndrome 10

from cholesterol emboli syn-drome 38

in polyarteritis nodosa 197in relapsing polychondritis 222in SLE 266

liver, inflammation of. See hepatitisliver cancer 105, 109, 111liver disease

hepatitis C and 112osteomalacia from 174in SLE 269

liver failurefrom hemochromatosis 105from hepatitis B 110myopathy from 160

liver functionhemochromatosis and 103immunodeficiency and 124in juvenile arthritis 138


NSAIDs and 165in polyarteritis nodosa 197in sarcoidosis 240in Sjögren’s syndrome 253

liver function tests (LFTs) 277, 330

liver transplant, for hepatitis B 111localized myasthenia 157locomotion, assistive devices for

15locus, definition of 341lodestone 153Lodine. See etodolacLöfgren’s syndrome 72, 240loose bodies 15, 147

Looser’s zones 114Lortab. See acetaminophen, with

narcoticslovastatin, myositis from 64low-molecular weight heparins 11,

135L-tryptophan, eosinophilia myalgia

syndrome and 69lumbar puncture 36, 271, 330

lungin Goodpasture’s syndrome

90–91in myositis 54in polyarteritis nodosa 197sarcoidosis in 239in Sjögren’s syndrome 252–253in Wegener’s granulomatosis

289–290lung cancer

frozen shoulder and 248hypertrophic pulmonary

osteoarthropathy caused by121

pericarditis from 190lung disease

arthritis and 13Dupuytren’s contracture and 67pulmonary hypertension from

209from rheumatoid arthritis 228in scleroderma 240, 242, 243,

245in Sjögren’s syndrome

252–253in SLE 268

lupus. See systemic lupus erythe-matosus

lupus, drug-induced 60–63, 190lupus, neonatal 161

lupus anticoagulant. See antiphos-pholipid antibody

lupus profundus 187Lyme disease 147–151

carpal tunnel syndrome from32


myocarditis from 158lymphocytes

definition of 341granular, in Felty’s syndrome

81myasthenia and 156in polymyositis 53in psoriasis 203

lymphokines. See cytokineslymphoma


common variable immunodefi-ciency and 125

cryoglobulinemia from 47–48photopheresis for 193polymyalgia rheumatica and

200in Sjögren’s syndrome 253

lymphopenia, in SLE 269lymphoproliferative disease, in Sjö-

gren’s syndrome 253lysosomal storage diseases, angiok-

eratoma corporis diffusum and 6

M

macrophages 124, 341magnesium, level of, myopathy

from 160magnesium choline salicylate. See

choline magnesium salicylatemagnetic resonance imaging (MRI)

330–331

in arteriography 276in back pain diagnosis 22in Baker’s cyst diagnosis 24in biceps tendinitis diagnosis

247in calcific tendinitis diagnosis

247in central nervous system vas-

culitis diagnosis 36in hemochromatosis diagnosis

104in infective arthritis diagnosis 128

in meniscal tear diagnosis 154in myositis diagnosis 55in osteoarthritis diagnosis 171in osteochondritis dissecans

diagnosis 173in osteomyelitis diagnosis 176in osteosarcoma diagnosis 182in Paget’s disease diagnosis 186in pigmented villonodular syn-

ovitis diagnosis 194in reactive arthritis diagnosis

218in relapsing polychondritis diag-

nosis 222in rheumatoid arthritis diagnosis

229–230in rheumatoid psoriatic arthritis

diagnosis 205in rotator cuff syndrome diagno-

sis 236in Sever’s disease diagnosis 101in shoulder pain diagnosis 247in SLAP lesions diagnosis 248in SLE diagnosis 271in spinal stenosis diagnosis 258in stress fracture diagnosis 261in tendinitis diagnosis 256in trochanteric bursitis diagnosis

281magnets 153, 172major histocompatibility complex

(MHC) 115malaria, quinine for 116malignancies. See also cancer;

osteosarcomain dermatomyositis 54–55, 56hemarthrosis from 102herpes zoster and 113myopathy from 159primary immunodeficiencies

and 124in Sjögren’s syndrome

251–252malnutrition, immunodeficiency

and 124manipulation. See also chiropractic

medicinefor back pain 22–23in osteopathy 38, 176in physical therapy 194

march fracture 87, 261Marfan’s syndrome 119massage 22–23, 86

Index 373

Maxwell’s law 153McArdle’s disease, myopathy from

160McKenzie exercises 23McMurray’s grinding test 154MCP (metacarpophalangeal) 204,

341MDR (multidrug resistance) 192mechanical back pain 20mechanic’s hands, from dermato-

myositis 54meclofenamate sodium 312

Meclomen. See meclofenamatesodium

medial epicondylitis 71medicine, alternative, definition of

339medicine, complementary, defini-

tion of 339meditation 153–154

melphalan, for amyloidosis 6meningitis, from Behçet’s disease

25meniscal tears 154

in adults 144arthroscopic surgery for 15in children 143

menopause 103, 177meperidine 231, 312

mercaptopurine, for inflammatorybowel disease 132

mesalamine, for inflammatorybowel disease 132

Mesmer 153mesna 273, 312

metabolic disorderscarpal tunnel syndrome from 32CPPD caused by 31myopathy from 160

metabolic syndrome, DISH and 59metacarpophalangeal (MCP) 204,

226–227, 341metatarsalgia, in adults 86metatarsophalangeal (MTP) 204,

341metatarsus varus, in children

85–86methocarbamol 312–313

methotrexate 313

for AS 9for Behçet’s disease 26for Cogan’s syndrome 45as DMARD 60

hepatitis C and 113hepatitis from 109herpes zoster and 113–114for inclusion body myositis 126joint replacement surgery and

135Kaposi’s sarcoma and 118for myositis 56NSAIDs and 165for polyarteritis nodosa 198for polymyalgia rheumatica

200in pregnancy 201for psoriasis 207for psoriatic arthritis 207, 208for pyoderma gangrenosum

diagnosis 212for reactive arthritis 219for rheumatoid arthritis 232rheumatoid nodules and 234for SAPHO syndrome 239for sarcoidosis 240for scleroderma 244for SLE 273for Takayasu’s arteritis 276for temporal arteritis 278TNF antagonists vs. 283for Wegener’s granulomatosis

291–292methoxsalen, for psoriasis

206–207methoxypsoralen, in photopheresis

193methyldopa, autoimmune disorders

from 62methylprednisolone 303

for myositis 56for polyarteritis nodosa 198for rheumatoid arthritis 233

metoclopramide, for scleroderma245

MHC (major histocompatibilitycomplex) 115

Miacalcin. See calcitoninmicrognathia, from juvenile arthri-

tis 138microscopic polyarteritis, in pol-

yarteritis nodosa 197midodrane, for Sjögren’s syndrome

255migraine 83, 267Milwaukee shoulder 154–155

mindfulness meditation 153–154

minocycline 313

as DMARD 60for rheumatoid arthritis 232for scleroderma 245

miscarriage, from antiphospholipidantibody syndrome 10

misoprostol 313

for GI complications 164for osteoarthritis 172in pregnancy 201

mitochondrial function, abnormal,myopathy from 160

mixed connective tissue disease155

in overlap syndrome 183pericarditis from 190Sjögren’s syndrome from 252

monoarthritis 149, 342monoclonal immunoglobulin, in

Sjögren’s syndrome 251monocytes 123–124, 342mononeuritis multiplex 42, 235mononucleosis 160, 225montelukast, Churg-Strauss syn-

drome and 41morbidity, definition of 342morphea. See sclerodermamorphine 192, 231, 313

Morton’s neuroma 88Morton’s syndrome 87motor reeducation, in muscle con-

ditioning 74Motrin. See ibuprofenmouth problems, in Sjögren’s syn-

drome 252MRI. See magnetic resonance imag-

ingMTP (metatarsophalangeal) 204,

341mucocutaneous lymph node syn-

drome. See Kawasaki diseasemulticentric reticulohistiocytosis

156

multidirectional instability, fromshoulder dislocation 249

multidrug resistance (MDR) 192multinucleate giant cells, in multi-

centric reticulohistiocytosis 156multiple myeloma

AL amyloidosis from 5cryoglobulinemia from 47–48in Sjögren’s syndrome 251

mumps, arthritis from 288


muscle conditioning 73–75, 120muscular dystrophies, myopathy

from 159musculoskeletal disorders, exercise

and 73musculoskeletal foot pain 85–87mushrooms, hepatitis from 109myalgia

definition of 342from eosinophilia myalgia syn-

drome 69from erythema migrans 148from familial Mediterranean

fever 80in Gulf War syndrome 97from Sweet’s syndrome 262from system onset juvenile

arthritis 137myasthenia gravis 156–158, 159,

196mycophenolate mofetil 313–314

for gout 96for inflammatory bowel disease

132for SLE 273for Wegener’s granulomatosis

292myelitis, transverse, in SLE 267myeloma 47, 251myoadenylate deaminase defi-

ciency, myopathy from 160myocardial infarction


in atherosclerosis 269estrogen and 180–181frozen shoulder and 248from homocystinuria 116in Kawasaki disease 141NSAIDs and 164in polyarteritis nodosa 197in SLE 274in temporal arteritis 277

myocarditis 158–159

in neonatal lupus 161in rheumatic fever 224in scleroderma 242in SLE 268

myochrysine. See gold injectionsmyoglobin 55, 119, 223myopathy 159–160

definition of 342drug-induced 64–66

from osteomalacia 174polymyalgia rheumatica and 200from SLE 266–267

myositis 160. See also dermato-myositis and polymyositis; inclu-sion body myositis (IBM)

definition of 342drug-induced 64–66hepatitis C and 112from HIV 119in mixed connective tissue dis-

ease 155polymyalgia rheumatica and

200Sjögren’s syndrome from 252

myositis-associated antibodies 56myositis ossificans 160

N

nabumetone 314

nailfold microscopy 331

Nalfon. See fenoprofenNaprelan. See naproxenNaprosyn. See naproxennaproxen 314

COX enzymes inhibited by 49,163

for gout attack 94heart attack and 164

narcoticsacetaminophen with 297, 315for back pain 23definition of 342for osteoarthritis 171, 172–173for rheumatoid arthritis 231

natural killer cell. See large granularlymphocytes

negative thoughts, in cognitivebehavior therapy 45–46

neonatal lupus 161, 202, 270Neoral. See cyclosporineneostigmine, for myasthenia 157nephrotic syndrome 5, 342nerve damage 148, 197nerve entrapment, wrist pain from

294nerve lesions 87–88, 221–222nerve root decompression, for back

pain 23–24nerve root pain 21nervous system complications 25,

253neurasthenia. See Gulf War syndrome

neurogenic claudication, fromspinal stenosis 258

neurological disease, in SLE 267neuromuscular disorders, myopa-

thy from 159Neurontin. See gabapentinneuropathic arthritis 161–162

from diabetes 58with glenohumeral arthritis 248hepatitis C and 112

neuropathyin acromegaly 2–3definition of 342from eosinophilia myalgia syn-

drome 70in Gulf War syndrome 97heat and 99in Lyme disease 148peripheral 58, 253

neutropenia 165, 269neutrophil 124, 342neutrophil count, in Kawasaki dis-

ease diagnosis 141–142Nexium. See esomeprazolenifedipine 210, 215nitric oxide, for pulmonary hyper-

tension 211nitrogen bubbles, from avascular

necrosis 16nitroglycerin ointment 215, 314

nittropaste. See nitroglycerin oint-ment

nizatidine 314

nocardiosis, opportunistic infectionby 168

nodal osteoarthritis 170nomifensine, autoimmune disor-

ders from 62nonconstrained prosthesis 135nonselective NSAIDs 162–163,

171, 172nonsteroidal anti-inflammatory

drugs (NSAIDs) 162–165

for AS 9for acromegaly 3for acromioclavicular joint

arthritis 249for acute foot strain 86for back pain 22–23for Baker’s cyst 24for biceps tendinitis 247for bursitis 145for calcific tendinitis 247

Index 375

nonsteroidal anti-inflammatorydrugs (continued)

for carpal tunnel syndrome 33COX enzymes inhibited by 49for CPPD 32for cystic fibrosis 50for de Quervain’s tenosynovitis

53for drug-induced lupus 63for enthesitis 1for episcleritis 77for erythema nodosum 73for fibromyalgia 84for gout attack 94, 95for hepatitis C arthritis 113hepatitis from 109for HIV-associated arthritis 118for hypermobility syndrome

120for hypertrophic pulmonary

osteoarthropathy 121inflammatory bowel disease and

131, 132for intestinal bypass arthritis

132joint replacement surgery and

135for juvenile arthritis 138liver disease from 269for Lyme disease 150for Milwaukee shoulder 155for mixed connective tissue dis-


tosis 156for olecranon bursitis 167for osteoarthritis 172for overlap syndrome 183for Paget’s disease 186for palindromic rheumatism

187for polymyalgia rheumatica

200in pregnancy 201for prepatellar bursitis 203for psoriatic arthritis 207for reactive arthritis 219for reflex sympathetic dystrophy

219for relapsing polychondritis 222for rheumatic fever 224for rheumatoid arthritis 230t,

231

for rotator cuff syndrome 236for rubella 237for SAPHO syndrome 239for sarcoidosis 240side effects of 163–165for Sjögren’s syndrome 255for SLE 272for spinal stenosis 259for subtalar arthritis 101for Sweet’s syndrome 262for tendinitis 257for trigger finger 280–281

Norflex. See orphenadrine citratenorfloxacin, rheumatic disease from

63nortriptyline 66, 192, 315

nose, in relapsing polychondritis221

nosocomial infection 168NSAIDs. See nonsteroidal anti-

inflammatory drugsnucleoside analogs, for HIV 117

O

OA. See osteoarthritisobesity

gout and 93–94osteoarthritis and 169sleep apnea and 255

obstructive sleep apnea. See sleepapnea

occupation 170, 214occupational therapy 167, 172ochronosis. See alkaptonuriaOckelbo disease, arthritis from 288ocreotide, for scleroderma 245octreotide 3, 255ofloxacin, tendon rupture and 1oil fires, smoke from, Gulf War syn-

drome and 96olecranon bursitis 167, 245–246oligoarthritis 204oligoarticular reactive arthritis 217omeprazole 315

for GI complications 164for scleroderma 245

O’nyong-nyong, arthritis from 287open-label clinical trials 43opportunistic infection 167–168,

274, 291oral contraceptives, hepatitis from

109organic brain syndrome, in SLE 267

organ transplantgout and 95–96hyperuricemia and 92–93sarcoidosis from 239

orphenadrine citrate 315

orthoses 167, 171–172orthostatic intolerance, in chronic

fatigue syndrome 40orthotics

for back pain 23in osteoarthritis treatment

171–172in podiatric treatment 196for subtalar arthritis 101

Orudie. See ketoprofenOruvail. See ketoprofenOs-cal. See calciumOsgood-Schlatter’s disease 143osteoarthritis (OA) 168–173

in acromegaly 2with acromioclavicular joint

arthritis 248acupuncture for 4from alkaptonuria 5arthroscopic surgery for 15in back pain 20Baker’s cyst from 24, 145bone spur from 28Bouchard’s nodes from 28carpal tunnel syndrome and 33cartilage in development of 34cause of 169–170CPPD caused by 31diagnosis of 170–171from foot strain 86from frostbite 88genetic factors and 90with glenohumeral arthritis 248gout and 93hallux rigidus from 87from hemochromatosis 103hip pain from 114in hypermobility syndrome 120joint injection for 133joint replacement for 134–136knee pain from 144manipulation for 176meniscal tears and 154NSAIDs for 163PEMF for 153polymyalgia rheumatica and

199–200risk factors for 169–170


splints for 259symptoms of 170tarsal coalition from 86treatment of 171–173vitamin C for 59in wrist 294

osteocalcin, in Paget’s disease diag-nosis 186

osteochondritis dissecans 15, 143,173–174

osteolysis, clavicle 249osteomalacia 174–175

back pain from 20drug-induced 64hip pain from 114hypophosphatemic rickets and

121stress fractures from 261

osteomyelitis 175–176

from BCG vaccination 286in children 143from diabetes 58from sickle-cell disease 250spinal stenosis from 257–258

osteonecrosis. See avascularnecrosis

osteopath 38, 176

osteophytes 20, 342osteoporosis 176–182

from AS 8in acromegaly 2–3back pain from 20bisphosphonates for 26calcaneal fractures and 101cause of 177–178corticosteroids and 278from cystic fibrosis 50drug-induced 64from heparin use 11hip pain from 114homocystinuria and 116medication for 180–182osteoarthritis and 170from reflex sympathetic dystro-

phy 219stress fractures from 261temporal arteritis and 278treatment for 179–182

osteosarcoma 182, 186osteotomy, for osteoarthritis 171,

173ovarian cancer, in dermatomyositis

54–55, 56

overflow diarrhea 242overlap syndromes 182–183

mixed connective tissue disease155

myositis in 160pericarditis from 190polymyositis from 54Raynaud’s phenomenon in

213oxaprozin 315

oxycodone 297, 315

OxyContin. See oxycodone

P

Paget’s disease 185–187

back pain from 20bisphosphonates for 26hip pain from 114osteosarcoma and 182spinal stenosis from 258stress fractures from 261

paincold and 123in fibromyalgia 82–83heat and 99magnets for 153in osteoarthritis 170

painful heel pad 100painkillers. See analgesicspalindromic rheumatism 187

palmoplantar psoriasis 204Pamelor. See nortriptylinepamidronate 316

for AS 9for Paget’s disease 187for stress fracture 261

pancreatic disease, panniculitisfrom 187–188

pancreatitisback pain from 20in Sjögren’s syndrome 253SLE and 268

panniculitis 187–188, 266pantoprazole 172, 316

Paracelsus 116paraplegia, in Lyme disease 148paraproteinemia, Raynaud’s phe-

nomenon from 214parathyroid hormone, for osteo-

porosis 181paroxetine 316

parson’s knee 145

parvovirus 188–189

arthritis from 225polyarteritis from 196SLE and 265vasculitis and 286

PAS stain, in Whipple’s diseasediagnosis 292–293

patella, bipartite, in children 143patellofemoral disorders 15, 143,

189–190

pauciarticular arthritis, definition of342

pauciarticular juvenile arthritis137

PCR. See polymerase chain reactionPellegrini-Stieda disease 145PEMF. See pulsed electromagnetic

fieldspencil in cup 206penicillamine 316

as DMARD 60myasthenia caused by 156myopathy from 160myositis from 65polymyositis from 54for psoriatic arthritis 208for Raynaud’s phenomenon

244for rheumatoid arthritis 232

penicillinautoimmune disorders from 62erythema nodosum and 72for Lyme disease 150metabolism of 66for rheumatic fever 223, 224vasculitis from 64, 286

peptic ulcers, from NSAIDs 49peptidoglycans, in reactive arthritis

216Percocet. See acetaminophen, with

narcoticspercutaneous discectomy, for back

pain 24pericardial friction rub 191pericarditis 190–191

definition of 342in Lyme disease 149in mixed connective tissue dis-

ease 155in myocarditis 158in overlap syndrome 183in rheumatic fever 224from rheumatoid arthritis 228

Index 377

pericarditis (continued)

in scleroderma 242in SLE 268from system onset juvenile

arthritis 137peripheral neuropathy 58, 253peripheral vascular disease 57,

269peritendinitis, of Achilles tendon

1peritoneal dialysis 58peritonitis 79–80, 342personal hygiene, assistive devices

for 15Perthes disease, osteoarthritis from

170pes cavus, in children 85pethidine. See meperidineP-glycoprotein (PgP) 66–67, 192PgP (P-glycoprotein) 66–67, 192phagocytic cells, in innate immu-

nity 123–124pharmacogenetics 66, 191–193

phenylbutazone 9, 94, 316

phenylpropanolamine, centralnervous system vasculitis and 35

phenytoinmyasthenia and 157myopathy from 160vasculitis from 64, 286

phlebotomy, for hemochromatosis105

phosphate 121, 174, 175phosphorus, level of, myopathy

from 160photopheresis 192, 245photosensitivity 266, 271, 342phototherapy, for psoriasis

206–207physical therapy 193–194

for AS 9for acromegaly 3for back pain 22heat in 99for hypermobility syndrome

120ice in 123for inclusion body myositis 126for incompetent anterior cruci-

ate 144for reflex sympathetic dystrophy

219vs. occupational therapy 167

pigmented villonodular synovitis(PVS) 194

carpal tunnel syndrome from 32hemarthrosis from 102knee pain from 144synovectomy for 263

pilocarpine 316

PIP. See proximal interphalangealpiroxicam 94, 163, 316–317

pituitary gland, in acromegaly 2placebo, definition of 342placebo-control clinical trial 43plantar fasciitis 99–100, 194–195

Plaquenil. See hydroxychloroquineplasmapheresis 195–196

for cryoglobulinemia 48for Goodpasture’s syndrome 91for myasthenia 158for relapsing polychondritis 222for TTP 279

pleasant imagery, in cognitivebehavior therapy 45

pleural effusion, definition of 342pleurisy

in autoimmune hepatitis 108definition of 342from familial Mediterranean

fever 79–80in mixed connective tissue dis-

ease 155in overlap syndrome 183from rheumatoid arthritis

227–228plica syndrome 143plyometric exercise 74PMR. See polymyalgia rheumaticapneumatosis intestinalis 242pneumocytosis infection, oppor-

tunistic 168, 291pneumonitis 268, 342podiatrist 196

Pogosta disease, arthritis from 288polyarteritis nodosa 196–198


Churg-Strauss syndrome and42

hepatitis B vasculitis and 110hepatitis C and 112

polyarthritis, common variableimmunodeficiency and 125

polyarthritis, inflammatory, fromhepatitis C 112

polyarticular, definition of 342polyarticular juvenile arthritis 137polycythemia, Raynaud’s phenome-

non from 214polymerase chain reaction (PCR)

in hepatitis C diagnosis 113in HIV diagnosis 117in Lyme disease diagnosis 149in tuberculosis diagnosis 282in Whipple’s disease diagnosis

292–293polymorphonuclear leukocytes, in

innate immunity 124polymyalgia rheumatica (PMR)

198–200, 277polymyositis. See dermatomyositis

and polymyositispolyvinyl chloride, Raynaud’s phe-

nomenon from 214Poncet’s disease 282popliteal cyst. See Baker’s cystposterior calcaneal bursitis, heel

pain from 100posterior cruciate, torn 144posterior tibial nerve, compressed,

foot pain from 88posttraumatic sympathetic dystro-

phy. See reflex sympathetic dys-trophy

potassium, level of, myopathy from160

potentisation 116Pott’s disease 281–282power, in muscle conditioning 74prednisolone. See corticosteroidsprednisone 303. See also corticos-

teroidsfor amyloidosis 6for autoimmune hepatitis 108for Behçet’s disease 26for carpal tunnel syndrome 33for myositis 56osteoporosis from 64for palindromic rheumatism

187for polyarteritis nodosa 198for polymyalgia rheumatica 200in pregnancy 201for SLE 272for Sweet’s syndrome 262for temporal arteritis 277–278for Wegener’s granulomatosis

291


preeclampsia, in pregnancy 202pregnancy 200–202

erythema nodosum and 72loss of, from antiphospholipid

antibody syndrome 10NSAIDs and 165rheumatoid arthritis in 225rubella in 237SLE in 270, 271in Sydenham’s chorea in 224Wegener’s granulomatosis in

291prepatellar bursitis 202–203,

245–246prevalence, definition of 342primary amyloidosis 5primary immunodeficiencies

124–125probenecid 95, 317

procainamide 61, 160procollagen carboxyterminal pep-

tide, type I 186pro-drugs 66, 191–192prognosis, definition of 342progressive systemic sclerosis. See

sclerodermapromoter variants 192–193pronation, plantar fasciitis and

100, 194propoxyphene, acetaminophen

with 297proprioception

for hypermobility syndrome 120in rehabilitation exercise 75splints for 259

proptosis, in Wegener’s granulo-matosis 290

Propulsid. See cisapridepropylthiouracil, vasculitis from 64prosorba column 317

prostacyclin, for Raynaud’s syn-drome 215

prostaglandins 48–49, 210prosthesis, constrained vs. noncon-

strained 135protease inhibitors 67, 117Protein A Immunoadsorption Col-

umn. See prosorba columnprotein-losing enteropathy, in SLE

268proteinuria, definition of 342prothrombin, in antiphospholipid

antibody syndrome 10

Protonix. See pantoprazoleproton pump inhibitors 164, 245,

317

proximal interphalangeal (PIP) 204definition of 342replacement of 136rheumatoid arthritis in 226–227

proximal myopathy, from osteoma-lacia 174

Prozac. See fluoxetinepseudogout. See calcium pyrophos-

phate dihydrate deposition diseasepseudo-Lyme disease 149pseudolymphoma, in Sjögren’s syn-

drome 253psoriasis and psoriatic arthritis

203–209

back pain from 20carpal tunnel syndrome from

32in children 138de Quervain’s tenosynovitis in

53foot pain and 85hip pain from 114from HIV 118hyperuricemia and 92knee pain from 144olecranon bursitis in 167tendinitis in 256TNF antagonists for 283treatment of 206–209

psychiatric disease, in SLE 267ptosis, from myasthenia 157pulmonary embolus 11, 135pulmonary hemorrhage, in SLE

268pulmonary hypertension 201,

209–211, 210t

in scleroderma 240, 242, 243,245

in SLE 268pulsed electromagnetic fields

(PEMF) 153pulseless disease. See Takayasu’s

arteritispump bumps, heel pain from 101purines, hyperuricemia and 92, 95pustules, in SAPHO syndrome 239PUVA therapy, for psoriatic arthritis

208PVS. See pigmented villonodular

synovitis

pyoderma gangrenosum 211–212

pyrazinamidehyperuricemia and 92rheumatic disease from 64for tuberculosis 282

pyridium cross-linked peptides, inPaget’s disease diagnosis 186

pyridostigmine 96, 157pyridoxine, for homocystinuria

116

Q

Qi, in acupuncture 3–4quinacrine, for SLE 272quinidine

antiphospholipid antibodiesfrom 10

autoimmune disorders from62

thrombocytopenia from 279quinine 116, 279quinolone antibiotics 1, 63

R

RA. See rheumatoid arthritisrabeprazole 317

for GI complications 164for osteoarthritis 172for scleroderma 245

radiation, immunodeficiencycaused by 124

radiation therapy, for pigmentedvillonodular synovitis 194

radiculopathy. See back painradiochemical synovectomy 263radioisotope scan 55, 101radionuclide bone scan 331–332

in infective arthritis diagnosis128

in osteomyelitis diagnosis 176in Paget’s disease diagnosis 186in reflex sympathetic dystrophy

diagnosis 219in rheumatoid arthritis diagnosis

229radiotherapy

for AS 9for acromegaly 3for osteosarcoma 182

raloxifene 317

randomized clinical trials 43range of motion, definition of 342ranitidine 317–318

Index 379

rash. See also erythema nodosum;lesions; livedo reticularis; pyo-derma gangrenosum

in autoimmune hepatitis 108from Behçet’s disease 25from cholesterol emboli syn-

drome 38from cystic fibrosis 49drug-induced 62from eosinophilia myalgia syn-

drome 70from familial Mediterranean

fever 80from gonococcal arthritis 128in Gulf War syndrome 97from Henoch-Schönlein purpura

107from hydroxychloroquine 272from Kawasaki disease 141in leukocytoclastic vasculitis

286from Lyme disease 148in mixed connective tissue dis-

ease 155neonatal lupus and 161, 270from NSAIDs 163, 165in overlap syndrome 183from psoriasis 205in relapsing polychondritis 222in rheumatic fever 224from rheumatoid vasculitis

235from rubella 237from sarcoidosis 240in SLE 266in Sweet’s syndrome 261–262from system onset juvenile

arthritis 137in vasculitis 287in Wegener’s granulomatosis

290Raynaud’s phenomenon 213–215

in cryoglobulinemia 47ice treatment and 123in mixed connective tissue dis-

ease 155from myositis 54in overlap syndrome 183in pulmonary hypertension 210in scleroderma 240, 241, 243,

244from Sjögren’s syndrome 252

reachers, for joint protection 134

reactive arthritis 215–219. See also

Reiter’s syndromeback pain from 20from BCG vaccine 281, 286enthesitis in 1foot pain and 85hip pain from 114from HIV 117joint replacement for 136knee pain from 144Lyme disease as 149from rubella vaccine 285, 286SAPHO syndrome as 239

recombinant-based immunoblotassay (RIBA)

in cryoglobulinemia diagnosis48

in hepatitis C diagnosis 113red meat, iron in 105referred pain 115, 143–144, 145reflex sympathetic dystrophy 67,

88, 219–220

rehabilitation exercise 73–75, 236,249

Reiter’s syndrome 217. See also

reactive arthritisanterior uveitis and 77in children 138HIV and 117–118

Relafen. See nabumetonerelapsing polychondritis 77,

221–223

relaxationin cognitive behavior therapy

45in exercise 76meditation for 153–154

relaxin, for scleroderma 244–245Remicade. See infliximabremission, definition of 342resect, definition of 342respiratory tract 221, 289rest

for acute foot strain 86for biceps tendinitis 247for bursitis 145for calcific tendinitis 247in cognitive behavior therapy

45for epicondylitis 72for gout attack 94for olecranon bursitis 167for osteolysis, clavicle 249

for stress fracture 261for subtalar arthritis 101for tendinitis 257

retinoid, for psoriasis 207reverse transcriptase inhibitors, for

HIV 117Reye’s syndrome 138rhabdomyolysis 223

from drug-induced myositis 65from HIV 119myositis from 160

rheumatic disease. See also rheuma-toid arthritis (RA)

genetic markers of 115opportunistic infection with

168overlap syndromes of 182–183palindromic rheumatism and

187pericarditis from 190pregnancy and 200–202

rheumatic disease, drug-induced63–66

rheumatic fever 223–224

infective endocarditis and 129myocarditis from 158NSAIDs for 163

rheumatism, definition of 342rheumatism, palindromic 187

rheumatoid arthritis (RA)225–234. See also rheumatic disease

AA amyloidosis from 5antimalarials for 9antiphospholipid antibody syn-

drome caused by 10B19 and 188–189Baker’s cyst from 24, 145bone marrow transplant for 27bursitis from 29carpal tunnel syndrome from

32cause of 225–226conjunctivitis and 76cryoglobulinemia from 47de Quervain’s tenosynovitis in

53diagnosis of 228–230disease caused by 226fasting for treatment of 58Felty’s syndrome from 80foot pain and 85genetic factors in 90, 115


infective arthritis from 127interleukin-1 and 51joint injection for 133joint replacement for 134–136knee pain from 144leukocytoclastic vasculitis with

286Lyme disease and 149medical costs associated with

11–12microscopic polyarteritis with

197myasthenia and 156NSAIDs for 162, 163olecranon bursitis in 167osteoarthritis from 170osteoporosis and 177palindromic rheumatism and

187pericarditis from 190photopheresis for 193placebo-controlled studies on 43plantar fasciitis and 100plasmapheresis and 196polymyalgia rheumatica and

199pregnancy and 201–202prepatellar bursitis from 203pronation and 195pyoderma gangrenosum and

211Raynaud’s phenomenon in

213rehabilitation exercise for 73scleritis and 77Sjögren’s syndrome and 251,

252stress fractures from 261subtalar arthritis from 101symptoms of 226–228, 226t

synovectomy for 262tai chi chuan for 275tendinitis in 256TNA-α and 50TNF antagonists for 283treatment of 230–233, 230t

trigger finger in 280in wrist 293–294

rheumatoid factor 332

in autoimmune disorders 123in autoimmune hepatitis diag-

nosis 108cryoglobulinemia and 47

definition of 343in Felty’s syndrome 80in hepatitis C diagnosis 112in infective endocarditis diagno-

sis 130in polyarteritis nodosa diagnosis

197in polyarticular juvenile arthritis

137in reactive arthritis diagnosis 218in rheumatoid arthritis diagnosis

229rheumatoid nodules and 234in Sjögren’s syndrome diagnosis

254rheumatoid nodule 234

DMARD use and 231heel pain from 101in rheumatoid arthritis 227for scleritis 228

rheumatoid psoriatic arthritis204–205

rheumatoid vasculitis 235

rheumatologist 235

rheumatology, definition of 343Rheumatrex. See methotrexaterhinitis, from Churg-Strauss syn-

drome 42RIBA. See recombinant-based

immunoblot assayribavirin, for hepatitis C 48ribonuclear protein antibody

(RNP), in mixed connective tissuedisease 155, 183

rickets. See osteomalaciarickets, hypophosphatemic 121

Ridaura. See auranofinrifampin 28, 282risedronate 318

as bisphosphonate 27for osteoporosis 181, 278for Paget’s disease 187for stress fracture 261

Rituxan. See rituximabrituximab 318

RNP (ribonuclear protein anti-body), in mixed connective tissuedisease 155

Ro. See SSA and SSBRobaxin. See methocarbamolrofecoxib 318

COX enzymes inhibited by 49for gout attack 94

heart attack and 164for osteoarthritis 172as selective COX-2 inhibitors 163

role-playing, in cognitive behaviortherapy 46

rose bengal stain, in Sjögren’s syn-drome diagnosis 254

Ross river virus, arthritis from287–288

rotator cuff syndrome 235–237,

247RSD. See reflex sympathetic dystro-

phyrubella 237

arthritis from 225myositis from 160vaccine for 63, 285, 286vasculitis and 286

runner’s knee 145

S

SAA (serum amyloid A) 5sacroiliac joint (SI joint), definition

of 343Salagen. See pilocarpinesalicylic acid, for psoriasis 206saliva stimulation 254–255salsalate 318–319

Sandimmune. See cyclosporineSAPHO syndrome 2, 239

sarcoidosis 239–240

back pain from 20erythema nodosum and 72foot pain and 85pericarditis from 190posterior uveitis and 77pyoderma gangrenosum and

211sausage digits 118

from inflammatory bowel dis-ease 131

from psoriatic arthritis 205from reactive arthritis 217

scaphoid, fractured 293scapula 246scapular pain 249Schirmer’s test 252sciatica 20SCID (severe combined immunode-

ficiency) 125scientific acupuncture 4scintigraphy, in Sjögren’s syndrome

diagnosis 254

Index 381

Scl-70 243, 332

scleritisabout 77from rheumatoid arthritis 228in Wegener’s granulomatosis

290sclerodactyly, in scleroderma 243scleroderma 240–245

antiphospholipid antibody syn-drome caused by 10

bone marrow transplant for 27carpal tunnel syndrome from 32cause of 241cryoglobulinemia from 47diagnosis of 243–244in mixed connective tissue dis-

ease 155myocarditis in 158myositis in 160in overlap syndrome 183pericarditis from 190photopheresis for 193polymyositis from 54pulmonary hypertension and

209Raynaud’s phenomenon in 213silicone implants and 250–251Sjögren’s syndrome from 252symptoms of 241–243

screening, for hemochromatosis 104scurvy, hemarthrosis from 102SEA. See seronegative enthesopathy

and arthritis syndromesecondary amyloidosis 5second metatarsal bone, stress frac-

ture of 87segmental spinal dysfunction,

fibromyalgia and 82–83selective COX-2 inhibitors. See also

cyclooxygenaseas NSAID 163, 164for osteoarthritis 171, 172for rheumatoid arthritis 231

selective estrogen receptor modula-tor (SERM) 180–181, 343

sensitivity, definition of 343septic arthritis. See infective arthritisseptic bursitis 245–246

septicemia, microscopic polyarteritisand 197

SERM (selective estrogen receptormodulator), definition of180–181, 343

seronegative enthesitis andarthropathy 7

seronegative enthesopathy andarthritis (SEA) syndrome 137

serositis 62, 267–268serotonin, in fibromyalgia 82sertraline 319

serum amyloid A (SAA) 5sesamoiditis, in adults 87severe combined immunodeficiency

(SCID) 125Sever’s disease 100–101sex hormones. See also estrogen;

testosteronebone resorption and 177hemochromatosis and 104osteoporosis and 177, 180–181in SLE 264

sexual abuse, fibromyalgia and 81shell shock. See Gulf War syndromeshingles 113. See also herpes zostershoulder dislocation 249shoulder-hand syndrome. See reflex

sympathetic dystrophyshoulder joint replacement 135shoulder pain 246–249. See also

Milwaukee shoulder; rotator cuffsyndrome

arthroscopic surgery for 15from diabetes 58

shrinking lung 268sialometry, in Sjögren’s syndrome

diagnosis 254sicca syndrome 76, 108. See also

Sjögren’s syndromesickle-cell disease (sickle-cell ane-

mia) 249–250

avascular necrosis and 16hemochromatosis and 103osteomyelitis and 175vaccination and 285

SI joint. See sacroiliac jointsildenafil, for pulmonary hyperten-

sion 211silicone implants 250–251

simple low-back pain 21simvastatin, myositis from 64Sinding-Larsen-Johansson syn-

drome 143single nucleotide polymorphisms

(SNPs) 89sinus, in Wegener’s granulomatosis

289

Sjögren’s syndrome 251–255

antiphospholipid antibody syn-drome caused by 10


common variable immunodefi-ciency and 125

conjunctivitis and 76cryoglobulinemia from 47hepatitis C and 112from HIV 118microscopic polyarteritis with 197in SLE 268

skin 240–245, 290. See also lesions;rash

SLAP lesions 247–248slapped cheek syndrome 188SLE. See systemic lupus erythe-

matosussleep, fibromyalgia and 82sleep apnea 2–3, 40, 255

slim disease 119smoke, from oil fires, Gulf War syn-

drome and 96smoking

atherosclerosis and 269bone mass and 177brucellosis from 28Dupuytren’s contracture and 67inflammatory bowel disease and

131osteoporosis and 179Raynaud’s phenomenon and

214rheumatoid arthritis and 225SLE and 271Wegener’s granulomatosis and

291SNPs (single nucleotide polymor-

phisms) 89sodium, level of, myopathy from

160sodium hyaluronate, joint injection

of 133soft-tissue arthritis-related prob-

lems 255–257

soft tissue injections, for back pain22–23

soldier’s heart. See Gulf War syn-drome

Solganal. See gold injectionsSoma. See carisoprodolsomatization 39


specificity, definition of 343spinal cord, lesions in, foot pain

from 87spinal curvature, from osteoporosis

178spinal pathology, back pain from

21–22spinal stenosis 24, 257–259

spirochete 147spirometry 55, 222spleen, in SLE 269splenectomy

for Felty’s syndrome 81for thrombocytopenia 279vaccination and 285

splints 259–260

for carpal tunnel syndrome 33for de Quervain’s tenosynovitis

53for epicondylitis 72for hallux valgus 87for joint protection 134occupational therapy and 167for reactive arthritis 219for tendinitis 257for trigger finger 280–281

spondylitisdefinition of 343psoriatic arthritis and 205from reactive arthritis 217

spondylitis, ankylosing. See anky-losing spondylitis

spondylitis, juvenile 137–138spondyloarthropathy 260. See also

psoriasis and psoriatic arthritis;reactive arthritis

anterior uveitis and 77heel spur from 101HLA-B27 and 6from inflammatory bowel dis-

ease 131plantar fasciitis and 100, 195

spondylolisthesis 257spondylosis, degenerative, spinal

stenosis from 257SSA and SSB 332

in neonatal lupus 161pregnancy and 270in SEL diagnosis 264in Sjögren’s syndrome 251, 253

statin drugsfor cholesterol emboli syndrome

39

myopathy from 160myositis from 64rhabdomyolysis from 223

stem cell transplant, for SLE 274stenosing tenosynovitis 256sternoclavicular hyperostosis. See

SAPHO syndromesternoclavicular joint 246–247steroids. See corticosteroidssteroids, anabolic, hepatitis from

109Still, Andrew Taylor 176Still’s disease. See also juvenile

arthritisNSAIDs for 163pericarditis from 190TNF antagonists for 283

strain, definition of 343strength, in muscle conditioning 74streptococcal infections

erythema nodosum and 72Henoch-Schönlein purpura from

107myositis from 160psoriasis from 204rheumatic fever from 223

streptomycin 28, 293stress

in Gulf War syndrome 96inflammatory bowel disease and

131psoriasis and 204

stress fracture 87, 260–261

stretchingfor AS 8for clubfoot 86for Dupuytren’s contracture 67for enthesitis 1for epicondylitis 72in exercise 76for fibromyalgia 84for myositis 57

strokein atherosclerosis 269in cholesterol emboli syndrome

38–39frozen shoulder and 248from homocystinuria 116from infective endocarditis 130reflex sympathetic dystrophy

and 219in relapsing polychondritis

221–222

in SLE 267, 274sleep apnea and 255in Takayasu’s arteritis 275

ST segments, in pericarditis diagno-sis 191

subacromial bursitis 248subacute cutaneous lupus erthe-

matosus (SCLE) 266subcalcaneal bursitis, heel pain

from 100substance P levels, in fibromyalgia

82subtalar arthritis, heel pain from

101sucralfate 319

Sudeck’s atrophy. See reflex sympa-thetic dystrophy

sulfasalazine 319

for AS 9as DMARD 60for hepatitis C arthritis 113hepatitis from 109for HIV-associated arthritis 118inflammatory bowel disease and

132in pregnancy 201for psoriatic arthritis 207–208for reactive arthritis 219for rheumatoid arthritis 232for SAPHO syndrome 239

sulfate, drug metabolism and 66sulfinpyrazone 95, 319

sulfonamideserythema nodosum and 72lupus flares from 62myopathy from 160thrombocytopenia from 279vasculitis from 64, 286

sulindac 94, 319

sun protection, for SLE 271superficial peroneal nerve, trapped,

foot pain from 88superficial thrombophlebitis 26, 29surgery

for AS 9for Achilles tendinitis 2for Achilles tendon rupture 1for acromioclavicular joint dislo-

cation 248for avascular necrosis 16–17for back pain 23–24for Baker’s cyst 24–25for biceps tendinitis 247

Index 383

surgery (continued)

bowel, enteropathic arthritis and69

for brucellosis 29for bunions 87for calcaneal fractures 101for calcific tendinitis 247for carpal tunnel syndrome 34for claw foot 85for clubfoot 86for de Quervain’s tenosynovitis

53for DISH 59for Dupuytren’s contracture 67for Felty’s syndrome 81for flat feet 85for ganglion 89for hallux rigidus 87for hallux valgus 87heart, from rheumatic fever

224for heel spur 102hemarthrosis from 102for incompetent anterior cruci-

ate 144for infective arthritis 129for infective endocarditis 130for Kawasaki disease 142for loose bodies 147for meniscal tears 154for metatarsalgia 86for Milwaukee shoulder 155for myasthenia 158for olecranon bursitis 167for osteoarthritis 171, 173for osteolysis, clavicle 249for osteomyelitis 176for osteosarcoma 182for pigmented villonodular syn-

ovitis 194for plantar fasciitis 195for prepatellar bursitis 203for pulmonary hypertension 211for pyoderma gangrenosum

diagnosis 212for Raynaud’s syndrome 215for reflex sympathetic dystrophy

219for rheumatoid arthritis 227for rotator cuff syndrome

236–237for septic bursitis 246for sesamoiditis 87

for shoulder dislocation 249for SLAP lesions 248for sleep apnea 255for spinal stenosis 259splints following 259–260for Takayasu’s arteritis 276for tarsal coalition 86for tendinitis 257transsphenoidal, for acromegaly

3for trigger finger 280–281for wrist pain 293

surgical synovectomy 262–263Sweden, back pain in 19Sweet’s syndrome 261–262

Sydenham’s chorea, in rheumaticfever 224

synovectomy 262–263

for Baker’s cyst 25for hemophiliacs 106for Lyme disease 150for pigmented villonodular syn-

ovitis 194synovial chondromatosis 144, 263synovial fluid. See also joint aspiration

in arthritis diagnosis 12in Baker’s cyst 24definition of 343in infective arthritis diagnosis

128–129in osteoarthritis 169in pigmented villonodular syn-

ovitis diagnosis 194synovitis 239, 343synovium

definition of 343function of 262in rheumatoid arthritis patho-

genesis 226Synvisc. See hyaluronan injectionssyphilis 35, 162syringomyelia, neuropathic arthritis

from 162systemic lupus erythematosus

(SLE) 263–274. See also drug-induced lupus

antimalarials for 9antiphospholipid antibody syn-

drome caused by 10avascular necrosis and 16B19 infection and 189bone marrow transplant for 27carpal tunnel syndrome from 32

cause of 263–266central nervous system vasculitis

from 35in children 138common variable immunodefi-

ciency and 125complement and 46conjunctivitis and 76cryoglobulinemia from 47diagnosis of 270–271drug-induced (See drug-induced

lupus)flares in, drug-induced 62genetic factors and 90HIV and 118leukocytoclastic vasculitis with

286in mixed connective tissue dis-

ease 155myasthenia and 156myocarditis in 158myositis in 160osteoporosis and 177in overlap syndrome 183palindromic rheumatism and

187panniculitis from 187pericarditis from 190photopheresis for 193plasmapheresis and 196polymyositis from 54pregnancy and 202pulmonary hypertension and

209pyoderma gangrenosum and

211Raynaud’s phenomenon in 213scleritis and 77silicone implants and 250–251Sjögren’s syndrome from 252Takayasu’s arteritis in 275thrombocytopenia from 279treatment of 271–274

systemic lupus erythematosus dis-ease activity index (SLEDAI) 271

systemic onset juvenile arthritis(Still’s disease) 137

systemic sclerosis. See scleroderma

T

tacrolimus 56, 132, 320

tai chi chuan 275

tailor’s bunion 87


Takayasu’s arteritis 275–276

talipes equinovarus, in children 86tamponade 191tarsal coalition, in children 86tarsal tunnel syndrome 276

TB. See tuberculosisT cells. See T lymphocytestelangiectasia, in scleroderma 243temporal arteritis 77, 198,

276–278

tendinitis. See also soft-tissue arthri-tis-related problems

in Achilles tendon 1–2in adductor muscles 115from diabetes 58drug-induced 63hip pain from 115joint injection for 133knee pain from 145NSAIDs for 163from reactive arthritis 217with rotator cuff syndrome

235–236tendon rupture and 1trochanteric bursitis and 281in wrist 294

tendinitis, biceps 247tendinitis, calcific 247tendinopathy, Achilles, heel spur

from 101tendon

definition of 343rupture of 1structure of 256

tennis elbow. See epicondylitistenosynovitis, de Quervain’s 53,

294tenosynovitis, gonococcal 32, 128tenosynovitis, stenosing 256tenoxicam, for gout attack 94Tensilon test, for myasthenia 157terbinafine, autoimmune disorders

from 62testosterone, osteoporosis and

177–178, 180tetracycline 28, 245. See also

minocyclineTetrahydrofolate. See folinic acidthalassemia, hemochromatosis and

103thalidomide 26, 201, 320

therapeutic plasma exchange. See

plasmapheresis

therapy, acupuncture 3–4

therapy, cognitive behavioral45–46

therapy, occupational 167

therapy, physical 193–194

for AS 9for acromegaly 3for back pain 22heat in 99for hypermobility syndrome

120ice in 123for inclusion body myositis 126for incompetent anterior cruci-

ate 144vs. occupational therapy 167

therapy, tai chi chuan 275

thiazideshyperuricemia and 92myopathy from 160rheumatic disease from 63vasculitis from 64, 286

thiopurine methyltransferase(TPMT) 192

thoracic outlet, Raynaud’s phenom-enon and 214

thromboangiitis obliterans. See

Buerger’s diseasethrombocytopenia 278–279


antiplatelet antibodies in 123definition of 343drug-induced 62in neonatal lupus 161from rubella 286SLE and 270, 273

thrombophlebitis 26, 29, 222thrombosis

from antiphospholipid antibodysyndrome 10–11

from avascular necrosis 16in Guillain-Barré syndrome 159from Henoch-Schönlein purpura

107liver disease and 269in SLE 268, 270in temporal arteritis 277, 278

thrombosis, deep vein (DVT)in antiphospholipid antibody

syndrome 11Baker’s cyst and 24, 145definition of 340

estrogen and 181from joint replacement surgery

135thrombotic thrombocytopenic pur-

pura (TTP) 278, 279thromboxane, formation of 48–49thymus, in myasthenia 156, 158thyroid disorders

carpal tunnel syndrome from32

celiac disease and 34chronic fatigue syndrome and

40common variable immunodefi-

ciency and 125CPPD caused by 31frozen shoulder and 248myasthenia and 156myopathy from 160Sjögren’s syndrome and 252,

253temporal arteritis and 277

thyrotoxicosis. See hyperthyroidismTIAs (transient ischemic attacks), in

cholesterol emboli syndrome38–39

ticks 147–148ticlopidine, for Kawasaki disease

142tilt test, in chronic fatigue syn-

drome diagnosis 40tissue type. See HLAT lymphocytes

in cellular immunity 124myasthenia and 156in SLE 265

TNA-α. See tumor necrosis factoralpha

TNF antagonists. See tumor necrosisfactor antagonists

Tolectin. See tolmetintolmetin 320

tophi 93, 234Toradol. See ketorolactorn cartilage. See meniscal tearstoxic hepatitis 109toxic oil syndrome 69, 70toxoplasmosis 77, 160TPMT (thiopurine methyltrans-

ferase) 192trabecular bone 177tracheotomy, for relapsing poly-

chondritis 222

Index 385

tramadol 172, 231, 320

transcutaneous electrical nervestimulation (TENS) 194

transferrin saturation, inhemochromatosis diagnosis 104

transfusions, blood 103, 250transient ischemic attacks (TIAs)

38–39transport, assistive devices for 15transsphenoidal surgery, for

acromegaly 3transverse myelitis, in SLE 267trazodone 320

trepostinil, for pulmonary hyper-tension 211

triamcinolone 303trichinella, myositis from 160trichloroethylene, eosinophilic

fasciitis and 70trigger finger 58, 256, 280–281

trigger point acupuncture 4Trilisate. See choline magnesium

salicylatetrimethoprim/sulfamethoxazole

291–292, 293trochanteric bursitis 114–115, 281

troponin I, in myositis diagnosis 55troponin T, in myositis diagnosis 55T score, in osteoporosis diagnosis

179TTP (thrombotic thrombocytopenic

purpura) 278, 279tuberculin skin test 282tuberculosis (TB) 281–282

AA amyloidosis from 5back pain from 20carpal tunnel syndrome from

32central nervous system vasculitis

from 35erythema nodosum and 72frozen shoulder and 248hip pain from 114infective arthritis from 127–129in multicentric reticulohistiocy-

tosis 156opportunistic infection by 168osteomyelitis from 175sarcoidosis and 239spinal stenosis from 258tendinitis in 256TNF antagonists and 283

tumor necrosis factor alpha (TNA-α) 50–51

tumor necrosis factor antagonists(TNF antagonists) 282–283. See

also adalimumab; etanercept;infliximab

for AS 9for Behçet’s disease 26for inflammatory bowel disease

132pharmacogenetics and 193for psoriatic arthritis 207, 208for rheumatoid arthritis 232for scleroderma 245tuberculosis and 281for Wegener’s granulomatosis

292Tums. See calciumTylenol. See acetaminophenTylenol #3. See acetaminophen,

with narcoticsTylox. See acetaminophen, with

narcotics

U

ulcerfrom Behçet’s disease 25in cholesterol emboli syndrome

39in cryoglobulinemia 47from NSAIDs 164skin (See lesions)

ulcerative colitis. See inflammatorybowel disease

Ultram. See tramadolultrasound 332–333

for biceps tendinitis 247in calcific tendinitis diagnosis

247for epicondylitis 72in Felty’s syndrome diagnosis 80in myocarditis diagnosis 158in neonatal lupus diagnosis 161in physical therapy 194in rheumatoid arthritis diagnosis

229in rotator cuff syndrome diagno-

sis 236in scleroderma diagnosis 244in serositis diagnosis 267–268in shoulder pain diagnosis 247in tendinitis diagnosis 256in trigger finger diagnosis 280in trochanteric bursitis diagnosis

281

uncontrolled clinical trials 43undifferentiated connective tissue

disease. See overlap syndromesunsaturated fatty acids, for arthritis

treatment 59uptake transporters 66–67uranium, depleted, Gulf War syn-

drome and 96urate, in gout 91, 92t

urate-lowering therapy, for gouttreatment 94–95

urate oxidase, for gout 96uremia, pericarditis from 190urethritis 118, 217uric acid 58, 91, 234, 333

uricase, gout and 91uricosuric drugs, for gout 95urinalysis 290, 333

urine hydroxyproline, in Paget’sdisease diagnosis 186

urticariadefinition of 343from ice application 123from NSAIDs 163in relapsing polychondritis 222in SLE 266

uveitisabout 77from inflammatory bowel dis-

ease 131from pauciarticular juvenile

arthritis 137–139from reactive arthritis 219

V

vaccination 285–286

Gulf War syndrome and 96for hepatitis B 111for Lyme disease 151rheumatic disease from 63in SLE treatment 271splenectomy and 81

valdecoxib 163, 321

valproic acid, myopathy from 160vancomycin, for infective arthritis

129varicella virus 35, 288varicella zoster virus. See herpes

zostervascular disease 6, 57, 269vasculitis 286–287, 286t. See also

specific types

atrial myxoma and 16in autoimmune hepatitis 108


avascular necrosis and 16from Behçet’s disease 25–26cause of 286in children 138from cystic fibrosis 50drug-induced 64, 286in eye 77in Felty’s syndrome 80from hepatitis B 110–111hepatitis C and 112from herpes zoster 114from HIV 118myocarditis in 158opportunistic infection with

168panniculitis from 187plasmapheresis and 196in relapsing polychondritis

221–222scleritis and 77Sjögren’s syndrome and 252,

253in SLE 267, 268TNF antagonists for 283

vasculitis, central nervous system35–36

vasoconstrictors, central nervoussystem vasculitis and 35

vasodilatorsfor brucellosis 29for myocarditis 159for pulmonary hypertension

210veganism, for arthritis treatment

59vegetarianism, for arthritis treat-

ment 59Velcro, as assistive device 15venesection, for hemochromatosis

105venlafaxine 321

Vicodin. See acetaminophen, withnarcotics

vincristine, myopathy from 160Vioxx. See rofecoxibviral arthritis 287–288

virus. See specific viruses

viscosupplements. See hyaluronaninjections

vision loss, in acromegaly 2–3vitamin C

for alkaptonuria 5deficiency of (See scurvy)iron absorption and 105

for osteoarthritis 59for reflex sympathetic dystrophy

219vitamin D 174, 175, 179–180, 278Voltaren. See diclofenac

W

Waldenstrom’s macroglobulinemia,cryoglobulinemia from 47–48

walker, assistance from 15walking, as exercise 76walking stick 134, 172warfarin

for antiphospholipid antibodysyndrome 11

for Behçet’s disease 26cholesterol emboli syndrome

and 38metabolism of 192NSAIDs and 165in pregnancy 201for pulmonary hypertension

210warm up, in exercise 76water, exercise in 76, 194WBC. See white blood cellsWeber-Christian disease, panniculi-

tis from 187wedge fracture, from osteoporosis

178Wegener’s granulomatosis 289–292


Churg-Strauss syndrome and41–42

scleritis and 77weight loss

in osteoarthritis treatment171–172

for plantar fasciitis 100, 195from polyarteritis nodosa 197for sleep apnea 255from system onset juvenile

arthritis 137in urate-lowering therapy 95

Western blot 117, 149wheelchair, assistance from 15Whipple’s disease 292–293

white blood cells (WBC)definition of 343in photopheresis 193in SLE 269, 270

winter’s heel, heel pain from 101work hardening, for back pain 23

wrist joint replacement 136wrist pain 293–294

wrist splint, for joint protection134

X

xanthelasma, in multicentric reticu-lohistiocytosis 156

X rays 333

in acromioclavicular joint arthri-tis diagnosis 249

in biceps tendinitis diagnosis247

in calcific tendinitis diagnosis247

in DISH diagnosis 59in gout diagnosis 94in hemochromatosis diagnosis

104in hip pain diagnosis 114in hypertrophic pulmonary

osteoarthropathy diagnosis121

in infective arthritis diagnosis129

in inflammatory bowel diseasediagnosis 132

in juvenile arthritis diagnosis138

in meniscal tears diagnosis 154in multicentric reticulohistiocy-

tosis diagnosis 156in myasthenia diagnosis 157in myositis diagnosis 55in neuropathic arthritis diagno-

sis 162osteoarthritis and 170, 171in osteochondritis dissecans

diagnosis 173in osteolysis, clavicle, diagnosis

of 249in osteomalacia diagnosis

174–175in osteomyelitis diagnosis 176in osteoporosis diagnosis

178–179in osteosarcoma diagnosis 182in Paget’s disease diagnosis 185,

186in patellofemoral disorders diag-

nosis 189in pigmented villonodular syn-

ovitis diagnosis 194

Index 387

X rays (continued)

in psoriatic arthritis diagnosis205–206

in pulmonary hypertensiondiagnosis 210

in reactive arthritis diagnosis 218in reflex sympathetic dystrophy

diagnosis 219in rheumatoid arthritis diagnosis

229in rotator cuff syndrome diagno-

sis 236in SAPHO syndrome diagnosis

239in sarcoidosis diagnosis 240

in scleroderma diagnosis 244in serositis diagnosis 267–268in Sever’s disease diagnosis 101in shoulder pain diagnosis 247in spinal stenosis diagnosis 258in stress fracture diagnosis 261in synovial chondromatosis

diagnosis 144in tendinitis diagnosis 256in tuberculosis diagnosis 282in Wegener’s granulomatosis

diagnosis 290in Whipple’s disease diagnosis

293in wrist pain diagnosis 293

Z

zafirlukast, Churg-Strauss syn-drome and 41

Zantac. See ranitidinezidovudine (AZT) 119, 160zolpidem 321

Zorprin. See aspirinzoster. See herpes zosterZostrix. See capsaicinZ score, in osteoporosis diagnosis

179Zyloprim. See allopurinol


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