gordon † gross - clinical publishing ctd chp1.pdfd marcus, d cope, a deodhar, r payne isbn 978 1...

CONNECTIVE TISSUEDISEASES

Caroline Gordon • Wolfgang L Gross

CLINICAL PUBLISHING

An Atlas of Investigation and Management

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CONNECTIVETISSUE DISEASESThis new atlas provides an illustrated guide to theinvestigation, diagnosis and management of the systemicautoimmune diseases. The authors begin with an overviewof the general principles of assessment. The main sectionsof the atlas focus in turn on specific inflammatory diseasesaffecting the connective tissues including the primarysystemic vasculitides. Information is supported by highquality colour photographs, diagnostic algorithms andtables throughout. This up-to-date visual guide to thecomplex field of connective tissue disease provides anessential tool for differential diagnosis, thus enabling more rapid and effective management of the patient with these symptoms.

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Therapeutic Strategies in RheumatologyM DohertyISBN 978 1 84692 026 4

Chronic Pain: an Atlas of Investigation and ManagementD Marcus, D Cope, A Deodhar, R PayneISBN 978 1 84692 033 2

Website: www.clinicalpublishing.co.uk

ISBN: 978 1 84692 074 5

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ordon • Gross

CLINICAL PUBLISHINGOXFORD


CONNECTIVE TISSUE

DISEASES

Caroline Gordon, MD FRCPProfessor and Consultant in Rheumatology

School of Immunity and InfectionCollege of Medical and Dental Sciences

The Medical School, University of BirminghamBirmingham, UK

Wolfgang L Gross, MD PhDMedical Director & ChairmanDepartment of Rheumatology

University of Luebeck & Clinic for Rheumatology, Bad BramstedtLuebeck, Germany

CTD final.qxp:288x230mm 9/8/11 1:25 PM Page iii

Clinical Publishing

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First published 2011

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ISBN print 978 1 84692 074 5

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Preface vii

Editors and contributors viii

Abbreviations ix

1 General approach to the assessment of patients with a suspected connective tissue disease 1ARIANE L HERRICK

Introduction 1History-taking and the assessment of symptoms 2Examination for signs of connective tissue disease 6Investigations in a patient with suspected connective tissue disease 12Conclusions 16Further reading 16

2 Systemic lupus erythematosus 17CAROLINE GORDON, JULIA U HOLLE, WOLFGANG L GROSS

Definition and pathology 17Epidemiology 17Presentation of systemic lupus 20Diagnosis and differential diagnosis 37Monitoring disease activity and distinguishing damage 38Principles of management of systemic lupus erythematosus 40Further reading 42

3 Sjögren’s syndrome 43IONA MERYON, JULIA U HOLLE, WOLFGANG L GROSS, CAROLINE GORDON

Definition, pathology, and epidemiology 43Clinical manifestations and assessment of Sjögren’s syndrome 43Classification 49Diagnosis and differential diagnosis 49Management of Sjögren’s syndrome 51Summary 52Further reading 52

Contents

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vi Contents

4 Anti-phospholipid syndrome 53IONA MERYON, JULIA U HOLLE, WOLFGANG L GROSS, CAROLINE GORDON

Definition and pathology 53Epidemiology 53Clinical presentation of anti-phospholipid syndrome 54Differential diagnosis 60Management of anti-phospholipid syndrome 61Summary 63Further reading 63

5 Idiopathic inflammatory myopathies 65IONA MERYON, JULIA U HOLLE, WOLFGANG L GROSS, CAROLINE GORDON

Definition and classification 65Epidemiology 66Clinical presentation of idiopathic inflammatory myopathy 67Diagnosis 71Course of disease 72Differential diagnosis 73Investigations 74Management of inflammatory myositis 77Summary 78Further reading 79

6 Systemic sclerosis 79PHILIP CLEMENTS, DANIEL E FURST

Definition and pathophysiology 79Epidemiology 79Presentation and assessment of systemic sclerosis 80Management of systemic sclerosis 90Further reading 93

7 The primary systemic vasculitides 95WOLFGANG L GROSS, FRANK MOOSIG

Definition and classification 95Epidemiology of primary systemic vasculitides 95Clinical manifestations and diagnosis of the systemic vasculitides 98Principles of management of the vasculitides 117Further reading 119

Index 120

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Preface

Patients that present with a connective tissue disease areoften a challenge to diagnose and treat. A connective tissuedisease is a disorder in which the tissues of the bodyconsisting of the cells and the matrix which holds themtogether are disrupted. This atlas will describe the multi -system conditions that result from inflammatory andimmune-mediated disorders that can affect all the tissues ofthe body and their management, including presentation,investigation, differential diagnosis and treatment. Systemiclupus erythematosus, Sjögren’s syndrome, anti-phospho -lipid syndrome, idiopathic inflammatory myopathies,systemic sclerosis and the primary systemic vasculitides willbe discussed in detail. These diseases are multifactorialconditions associated with a complex genetic predispositionand various, not well-understood, environmental triggersthat induce inflammatory and immune-mediated responsesdirected against components of the person’s own body. Asa result this group of diseases is known also as the systemicautoimmune diseases. This atlas will not discuss theinherited connective disorders due to genetic mutationsthat affect collagen (Ehlers–Danlos syndrome) and otherconnective tissue proteins, such as fibrillin-1 in Marfan’ssyndrome.

Patients with a systemic autoimmune connective tissuedisease can present with clinical symptoms and signs in oneor more often, several, systems of the body. Some of thesediseases affect people of certain ages and gender more oftenthan others, including children, but this atlas will focus onthe management of adult patients. These diseases are morecommon than is generally realized, cannot be cured, areassociated with considerable morbidity and still causesignificant mortality. Appropriate investigations are criticalto making the correct diagnosis so that treatment can be

tailored to the patient’s condition. It is important not onlyto recognize and treat the current disease activity, but alsoto prevent death and the development of chronic damagedue to complications of the disease and the immuno -suppressive drugs used to treat it. Treatment usuallyincludes immuno suppressive therapy and other drugsdepending on the effects of the disease on specific organs ofthe body. Principles of drug treatment will be discussed inthis atlas, but the final choice of drug and exact dosages tobe used will depend on the details of the patient’s conditionand should be planned by a physician with relevantexperience of these conditions and responsible for themanagement of the patient.

Due to the variable severity of these diseases and theirmultisystem nature that may deteriorate in pregnancy,patients with an autoimmune connective tissue disease maypresent to general practioners, general physicians orinternal medicine specialists, obstetricians, intensive care orany medical or surgical specialist. The majority of patientswith these conditions are cared for long term bydermatologists, rheumatologists, and/or nephrologists, as itis the skin, joints and kidneys that are most often involved.However it should be noted that many patients developcardio-respiratory or infectious complications, includingaccelerated atherosclerosis, due to the disease and/or itstreatment. Multidisciplinary care is important and shouldinvolve the full range of allied health professionals, as wellas the relevant clinical specialists depending on the organsand systems involved.

Caroline GordonWolfgang L Gross

vii

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viii

Editors

Caroline Gordon, MD FRCPProfessor and Consultant in RheumatologySchool of Immunity and InfectionCollege of Medical and Dental ServicesThe Medical School, University of BirminghamBirmingham, UK

Wolfgang L Gross, MD PhDMedical Director & ChairmanDepartment of RheumatologyUniversity of Luebeck & Clinic for Rheumatology,

Bad BramstedtLuebeck, Germany

Contributors

Philip Clements, MD MPHProfessor of MedicineDivision of RheumatologyDavid Geffen School of Medicine at UCLALos Angeles, CA, USA

Daniel E Furst, MDCarl M Pearson Professor of RheumatologyDirector of Rheumatology Therapeutic ResearchUniversity of California in Los AngelesLos Angeles, CA, USA

Ariane L Herrick, MD FRCPProfessor of RheumatologyThe University of Manchester Manchester Academic Health Science Centre Salford Royal Hospital Salford, UK

Julia U Holle, MDDepartment of RheumatologyUniversity of Lübeck and Klinikum Bad BramstedtBad Bramstedt, Germany

Iona Meryon, MBChB MRCPDepartment of RheumatologyChelsea and Westminster Hospital NHS Foundation TrustLondon, UK

Frank Moosig, MD PhDUniversity Hospital of Schleswig-Holstein and Klinikum

Bad BramstedtBad Bramstedt, Germany

Editors and contributors

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Abbreviations

5-FDG 5-fluorodeoxyglucoseAAV ANCA-associated vasculitidesACEI angiotensin-converting enzyme inhibitorACR American College of RheumatologyALT alanine transferaseAMA anti-mitochondrial antibodyANA anti-nuclear antibodyANCA anti-neutrophil cytoplasmic antibodyAPS anti-phospholipid syndromeARB angiotensin-receptor blockerARDS acute respiratory distress syndromeAST aspartate transaminaseAZA azathioprineBMD bone mineral densityBVAS Birmingham Vasculitis Activity ScorecANCA cytoplasmic ANCACAP community acquired pneumoniaCCB calcium-channel blockerCHCC Chapel Hill Consensus ConferenceCK creatine kinaseCK-MB creatine kinase MB isoenzymeCLA cutanous (isolated) leukocytoclastic angiitisCMV cytomegalovirusCNS central nervous systemCRP C-reactive proteinCSS Churg–Strauss syndromeCT computed tomographyCV cryoglobulinaemic vasculitisCYC cyclophosphamideDEXA dual energy X-ray absorptiometryDILS diffuse infiltrative lymphocytosis syndromeDM dermatomyositis(ds)DNA (double-stranded) deoxyribonucleic acidDVT deep vein thrombosisEBV Epstein–Barr virus

ECG electrocardiogramEGD oesophago-gastroduodenostomyEMG electromyographyENA extractable nuclear antigenENT ear, nose, and throatERA endothelin receptor antagonistESR erythrocyte sedimentation rateFVC forced vital capacityGC glucocorticoidsGCA giant cell arteritisGERD gastro-oesophageal reflux diseaseGI gastrointestinalHCQ hydroxychloroquineHCV hepatitis C-associated cryglobulinaemic vasculitisHDU high dependency unitHIV human immunodeficiency virusHRCT high resolution computed tomographyHSP Henoch–Schönlein purpuraHTLV human T-lymphotrophic virusIBM inclusion body myositisIFN interferonIg immunoglobulinIIM idiopathic inflammatory myopathyIL interleukinILD interstitial lung diseaseINR international normalized ratioITP immune thrombocytopaenic purpuraIVIG intravenous immunoglobulinKD Kawasaki’s diseaseLDH lactate dehydrogenaseMAA myositis-associated autoantibodyMALT mucosa-associated lymphoid tissueMI myocardial infarctionMMF mycophenolate mofetilMPA microscopic polyangiitis

ix

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MPO myeloperoxidaseMR magnetic resonanceMRC Medical Research CouncilMS multiple sclerosisMSA myositis-specific autoantibodyMTX methotrexateNHL non-Hodgkin’s lymphomaNIH National Institutes of HealthNISP nonspecific interstitial pneumonitisNSAID nonsteroidal anti-inflammatory drugNTG nitroglycerinPAH pulmonary arterial hypertensionPAN polyarteritis nodosaPBC primary biliary cirrhosisPCR polymerase chain reactionPDE-5 phosphodiesterase-5PET positron emission tomographyPM polymyositisPMR polymyalgia rheumaticaPPI proton-pump inhibitorPR3 proteinase 3PSV primary systemic vasculitides

PVD pulmonary vascular diseaseRCT randomized controlled trialRF rheumatoid factorRV rheumatoid vasculitisRVSP right ventricular systolic pressureSGOT serum glutamic oxaloacetic transaminaseSGPT serum glutamic pyruvic transaminaseSIBO small intestinal bacterial overgrowthSLAM systemic lupus activity measureSLE systemic lupus erythematosusSPARC secreted protein, acidic and rich in cysteineSRC scleroderma renal crisisSS Sjögren’s syndromeSSc systemic sclerosisSTIR short tau inversion recovery TA Takayasu’s arteritisTGF tumour growth factorTIA transient ischaemic attackTNF tumour necrosis factorULN upper limit of normalUV ultravioletWG Wegener’s granulomatosis

Abbreviationsx

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General approach to theassessment of patientswith a suspectedconnective tissue diseaseAriane L Herrick

Chapter 1

Introduction

Connective tissue diseases including the vasculitides can bedifficult to diagnose, yet early diagnosis is essential in orderto initiate effective treatment as soon as possible, andthereby prevent/minimize tissue injury. Therefore, the keypoint is to be able to recognize the clinical features whichprompt the question ‘Could this patient have a connectivetissue disease or vasculitis?’ Early treatment can belifesaving, as exemplified by Scenarios 1 and 2.

Scenario 1A 55-year-old male was admitted with profound lethargyand swollen wrists, knees, and ankles, and recenthaemoptysis (he was a heavy smoker). On examination hewas pale, with synovitis of his wrists and knees (with smallknee effusions) and pitting oedema of both ankles. He wasanaemic with a haemoglobin of 99 g/l (normocytic),erythrocyte sedimentation rate (ESR) was very high at 113mm/h. Plasma biochemistry showed impaired renalfunction (urea 14.8 mmol/l, creatinine 190 μmol/l) with alow albumin at 30 g/l. Chest X-ray showed a cavitatinglesion of the left upper zone. The following day hiscreatinine had risen to 250 μmol/l. No dipstick testing ofurine had been performed on admission – 1 day later thisshowed blood and protein.

The medical registrar initially queried a paraneoplasticsyndrome with some dehydration. However, when thedipstick and repeat renal function results were seen thefollowing day, the working diagnosis was revised to aconnective tissue disease, possibly vasculitis. The renalteam performed an urgent renal biopsy and intravenousmethylprednisolone was commenced. Renal biopsy showednecrotizing glomerulonephritis, and intravenouscyclophosphamide was added to the drug regime. Initially

the renal function deteriorated further but 2 weeks laterbegan to improve. Immunology testing was positive foranti-neutrophil cytoplasmic antibody (cytoplasmic pattern,cANCA), consistent with the clinical impression ofWegener’s granulomatosis, which had been made on thebasis of a cavitating lung lesion, renal vasculitis,inflammatory arthritis, and systemic inflammation.

Scenario 2A 43-year-old female was admitted with a 3-day history ofbreathlessness and general malaise. On examination, hertemperature was 38°C, she had basal crackles, and poor airentry. Haemoglobin was 109 g/l, white blood cell count 4.9× 109/l, platelets 120 × 109/l. ESR was 45 mm/h. Chest X-ray showed widespread interstitial shadowing.

The working diagnosis was of community acquiredpneumonia (CAP). However, despite antibiotic therapy hercondition deteriorated rapidly with falling PO2 and she wastransferred to the high dependency unit (HDU). Themedical registrar who assessed the patient in the HDUnoted that she had felt tired for around 2 months, had beensuffering from mouth ulcers, and had recently begunexperiencing Raynaud’s phenomenon. An autoimmunescreen showed that she was strongly anti-nuclear antibody(ANA) positive (1/10,000) with a high titre of anti-double-stranded deoxyribonucleic acid (dsDNA) antibodies (155U/ml, reference range 0–7).

The diagnosis was revised to pneumonitis secondary tosystemic lupus erythematosus (SLE), and she was treatedwith intravenous methylprednisolone, followed later by oralprednisolone. After commencing steroids her clinicalcondition improved and the shadowing on chest X-rayresolved.

1

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Discussion of Scenarios 1 and 2Although Scenarios 1 and 2 describe patients with recentonset, fulminating illness, most patients with connectivetissue disease (including vasculitis) do not present withimmediately life-threatening illnesses, but have been unwellfor some time before a diagnosis is made. Clinical featuresare often nonspecific, especially early in the disease.Connective tissue disease should always be suspected in apatient who presents with multisystem inflammatorydisease.

The first step is to establish the diagnosis, recognizingthat many patients have overlapping features betweendifferent connective tissue diseases/vasculitides. Once adiagnosis is made, the emphasis of assessment changes. Itthen concentrates on assessment of activity and severity,and identification of new internal organ involvement.Assessment of activity and severity of the differentconnective tissue diseases is discussed mainly in thedisease-based chapters. Patients with connective tissuedisease usually need to be under long-term specialistreview, the main purpose of this being to recognize changesin disease activity and severity necessitating changes inmanagement.

History-taking and the assessment ofsymptoms

The key point is to take a full history as most tissues/organscan be affected in patients with connective tissue disease.

Presenting complaintThis may be virtually anything, examples being lethargy,breathlessness, heartburn, abdominal pain, paraesthesia,and rash.

Systemic enquiryGeneralCommon symptoms are tiredness and weight loss. Patientsmay also report fever, but it must be remembered that feverin patients with suspected or established connective tissuedisease may be due to infection, to which they may bepredisposed as a result of either the underlying disease or itstreatment. For example, infection is a major contributor tomortality in patients with SLE, who are often complementdeficient and who are frequently treated with steroidsand/or immunosuppressant drugs. These symptoms –tiredness, weight loss, and fever – are all nonspecific andoccur in malignancy and infection as well as in connectivetissue disease (Table 1.1). To complicate matters further,there are associations between certain autoimmune diseasesand malignancy; therefore, even in the patient withestablished connective tissue disease, the clinician alwaysneeds to be alert to the development of concomitantdisease.

Skin and mucous membranesRashes occur in several of the connective tissue diseases, asdescribed more fully under ‘Examination’. If a patientcomplains of a rash, always ask if it is photosensitive:classically the ‘butterfly’ rash of SLE is photosensitive.Cutaneous ulcers occur especially in systemic sclerosis(SSc), when usually the fingers or toes are affected (seebelow), and in the vasculitides. Hair loss (patchy or diffuse)occurs commonly in SLE (1.1). Mouth ulcers (1.2) occurcommonly in SLE and Behçet’s syndrome (in which genitalulcers also occur). Oral dryness is one of the mainsymptoms of Sjögren’s syndrome. Other features aredescribed in Table 1.2 and below under ‘Examination’.

General approach to the assessment of patients2

Manifestations (may occur separately or in Differential diagnoses to be consideredany combination)

Fatigue/tiredness/malaise Infection

Fever Connective tissue disease

Weight loss Vasculitis

Enlarged lymph nodes Malignancy (including lymphoma)

Table 1.1 Nonspecific manifestations of connective tissue disease or vasculitis


Raynaud’s phenomenonThis occurs commonly in connective tissue disease,especially in SSc, in which it is rare not to have Raynaud’s.The classic episodic colour changes of the fingers (white,then blue/purple, then red) occur typically in response tocold exposure or to stress (1.3). In Scenario 2, the point ofinterest about the Raynaud’s phenomenon was that it hadcommenced only recently: patients with primary(idiopathic) Raynaud’s phenomenon typically develop thisin their teens or early 20s. When Raynaud’s phenomenonoccurs in patients with underlying connective tissue disease

General approach to the assessment of patients 3

SLEPhotosensitive (‘butterfly’) rash

Alopecia

Mouth ulcers

APSLivido reticularis

Systemic sclerosisScleroderma

Digital pitting/ulceration

Telangiectases

Calcinosis

DermatomyositisFacial rash (‘heliotrope’) with periorbital oedema

Gottron’s papules

Periungal erythema

VasculitisSplinter haemorrhages and nailfold infarcts

Purpura

Oral and genital ulcers in Behçet’s syndrome

Cutaneous ulcers

Table 1.2 Typical skin manifestations in connective tissue disease

1.1 Diffuse alopecia in a patient with systemic lupus

erythematosus.

1.2 Aphthous mouth ulcer. (Courtesy of Dr. M.

Pemberton.)

it can progress to irreversible tissue injury with ulceration,scarring, or gangrene. Worrying features in the history are apersistent fingertip discoloration and the development ofdigital ulceration.

MusculoskeletalInvolvement of the musculoskeletal system is common(Table 1.3). Patients with connective tissue disease oftenhave arthralgia. They may also develop an inflammatoryarthritis with joint pain, swelling, and stiffness. Proximal



1.3 Raynaud’s phenomenon in a patient with

undifferentiated connective tissue disease:

several of the digits are cyanosed.

JointsPain (arthralgia)

Early morning stiffness

Joint line tenderness

Joint swelling (synovial hypertrophy +/- effusion)

Reduced range of movement

MusclesPain (myalgia)

Early morning stiffness

Proximal muscle tenderness

Proximal muscle weakness

Table 1.3 Musculoskeletal symptoms and signs in connective tissue disease or vasculitis

Cardiac manifestationsPericarditis

Pericardial effusion

Angina

Arrhythmias

Cardiac failure

Valvular heart disease

Pulmonary manifestationsPleurisy

Pleural effusion

Pulmonary embolism

Pneumonitis

Lung fibrosis

Haemoptysis

Table 1.4 Some examples of cardiorespiratory manifestations of connective tissue disease or vasculitis

muscle pain and weakness occur in inflammatory muscledisease: the patient has difficulty getting out of bed or outof a chair, especially first thing in the morning. Proximalmuscle weakness may also be a side-effect of chronic use ofcorticosteroids.

CardiorespiratoryA number of different forms of heart or lung involvementmay occur including pulmonary fibrosis, pneumonia,pulmonary embolism (especially in those with anti-phospholipid syndrome [APS]), pericardial effusion,valvular heart disease or (especially in SSc) arrhythmia(Table 1.4). Therefore, all cardiorespiratory symptomsshould be asked about if not volunteered, includingbreathlessness, chest pain, and oedema. Patients withconnective tissue disease, especially SLE, are at increased

Upper gastrointestinal tractMucosal ulceration

Acid reflux

Dysphagia

Lower gastrointestinal tractAbdominal pain

Change in bowel habit

Blood loss in stools

Table 1.5 Some examples of gastrointestinal symptoms of connective tissue disease or vasculitis by region


risk of coronary artery disease and should therefore bespecifically asked about symptoms.

GastrointestinalGastrointestinal (GI) features are often not recognized asbeing due to connective tissue disease or vasculitis (Table1.5). Swallowing difficulty, often with reflux symptoms, isvery common in patients with SSc who may experience awide range of GI symptoms including alteration in bowelhabit: diarrhoea may reflect bacterial overgrowth, andconstipation, colonic dysmotility. Abdominal pain can(rarely) be caused by mesenteric ischaemia, which canoccur in patients with vasculitis.

RenalAnkle swelling has a long differential diagnosis but includesnephrotic syndrome, which can occur for example in SLE.

NeuropsychiatricAs with the other organ systems, almost any symptom canoccur in patients with connective tissue disease. SLE can beassociated with involvement of peripheral, central, andautonomic nervous systems as well as with cognitiveimpairment and psychiatric disturbance (Table 1.6). Animportant point is that neuropsychiatric features can occurnot only as a primary manifestation of connective tissuedisease but also indirectly: for example, as a result ofhypertension, uraemia, infection, coagulation problems (asin APS), or as a result of drug treatment, especially withcorticosteroids. Paraesthesia is a common feature inpatients with connective tissue disease and can have manycauses, for example, peripheral neuropathy or (in the upper

limb) carpal tunnel syndrome. Many patients withconnective tissue diseases, as with other chronic diseases,become depressed.

EyesThe commonest symptom is of dry, gritty eyes, occurring inpatients with Sjögren’s syndrome. Eye dryness can beconfirmed using Schirmer’s tear test (1.4).


Region ManifestationsPeripheral nervous system Paraesthesia in distribution of a nerve, e.g. median nerve

Weakness in distribution of a nerve, e.g. ulnar nerve

Central nervous system Psychosis

Seizures

Hemiplegic stroke

Transverse myelitis

Autonomic nervous system Postural hypotension

Table 1.6 Some examples of neuropsychiatric manifestations of connective tissue disease or

vasculitis by region

1.4 Schirmer’s test. In this case showing satisfactory

wetting of the filter paper.


Drug historyA detailed drug history is important because:• Connective tissue disease (especially SLE and small

vessel vasculitis) can be a side-effect of certain drugs. Forexample, minocycline can cause SLE or vasculitis.

• Drugs used in the treatment of connective tissue diseasemay cause side-effects which are difficult to distinguishfrom active disease. For example, methotrexate maycause pneumonitis and several immunosuppressantsmay cause pancytopenia.

Two common clinical dilemmas are:1 A patient with dermatomyositis complains of increasing

muscle weakness. Is this active disease despite steroids(necessitating an increase in dosage) or is it steroid-related myopathy (necessitating a reduction in dosage)?

2 A patient with SLE on azathioprine (or anotherimunosuppressant) develops pancytopenia. Is this activeSLE (necessitating an increase in dosage) or is itazathioprine-related bone marrow toxicity (necessitatinga reduction in dosage)?

In both these examples, a careful history andexamination, backed up by appropriate investigations,should indicate whether the drug treatment should beincreased or reduced.

Family historyThere is likely to be a genetic component to most of theconnective tissue diseases, although the absolute risk tofamily members is small. For example, although the singlemost important risk factor for SSc is a positive familyhistory, the risk for each family member is less than 1%.Perhaps more important to the clinician is the anxietygenerated by the family history: the patient with tiredness isconcerned because his/her mother had SLE, or the patientwith Raynaud’s phenomenon is concerned because his/hermother had SSc. These fears/anxieties should not beunderestimated.

Social historySmoking causes vascular injury, and therefore should bestrongly discouraged in patients with connective tissuediseases who often already have a compromisedvasculature. Details about occupation, housing, and socialsupport are important to establish (as in other chronicdiseases) whether or not a patient is able to work, and thelevel of home support, as these parameters are often majorcontributors to quality of life.

Examination for signs of connectivetissue disease

A full examination is required for the same reason as a fullhis tory: these are multisystem diseases and (in patients withestablished connective tissue disease or a vasculitis) drugsused in their treatment may cause a wide range of adverseeffects.

Systemic enquiryGeneralExamine the temperature chart. As stated above, fever canbe a manifestation of connective tissue disease. Manypatients are anaemic and therefore pale. Lymphadenopathyis described in connective tissue disease but is uncommon,therefore other causes should also be considered (Table1.1). In the patient with parotid gland enlargement,consider Sjögren’s syndrome (1.5).

Skin and mucous membranesThe skin and mucous membranes should always be examinedcarefully because these can often give clues to an underlyingconnective tissue disease. Typical skin manifestations of thedifferent connective tissue diseases are summarized in Table1.2. While these have been listed by disease, it should berecognized that the skin and mucous membraneabnormalities overlap between diseases and so these are oftenfalse distinctions. For example, digital ischaemic ulcers canoccur in SLE, SSc, and in the vasculitides.• SLE. While the typical rash is facial (‘butterfly’) (2.2A,

B) and photosensitive, more chronic lesions occur indiscoid (2.6, 2.7A) and subacute cutaneous lupuserythematosus (1.6). Alopecia, which may be scarringespecially in discoid lupus (2.9), and mouth ulcers arealso common. Mouth ulcers are a common side-effect ofimmuno suppressant drugs and so this possibility shouldbe considered where relevant.

• APS. This diagnosis should be considered in patientswith livedo reticularis (1.7).

• SSc. This is associated with many different cutaneousmanifestations:

– Skin thickening (scleroderma). Scleroderma proximal tothe metacarpophalangeal joints is the major classificationcriterion for SSc and its development often leads to thediagnosis. Skin thickening usually begins in the fingers(sclerodactyly [1.8]), feet, and face and then mayprogress proximally especially in those with the diffusecutaneous subtype. It must be remembered, however,that scleroderma occurs in conditions other than SSc andit is important to differentiate SSc from, for example,generalized morphoea (1.9) or eosinophilic fasciitis.



1.7 Livedo reticularis.

The rash is more

obvious over the left

knee than the right.


1.5 Right-sided

parotid gland

enlargement in a

patient with

Sjögren’s

syndrome

secondary to SSc.

1.6 Subacute

cutaneous lupus

erythematosus.

1.8 Sclerodactyly. The skin is

thickened, giving rise to flexion

contractures of the fingers.

1.9 Generalized

morphoea, most

marked over the

thorax posteriorly

where the skin is

thickened, tight, and

shiny. This is not

SSc: the patient did

not have Raynaud’s

phenomenon and the

skin thickening did

not commence

distally.


– Digital ulceration/ischaemia. An underlying connectivetissue disease should always be suspected when a patientwith good peripheral pulses presents with digital ulcersor ischaemia, because the pathology is likely to involvethe digital arteries and/or the microvessels. Digital ulcerstend to occur at the fingertips in patients with limitedcutaneous SSc (1.10) and over the proximal and distalinterphalangeal joints in patients with diffuse cutaneousdisease (1.11). Digital ulcers can become infected andsevere digital ischaemia can progress to gangrene (1.12).Digital pitting (1.13) is one of the three minorclassification criteria of SSc and reflects chronic digitalischaemia.

– Telangiectases (1.14). If accompanied by othercharacteristic symptoms and signs, for example,Raynaud’s phenomenon, these should make one suspectSSc.

– Calcinosis. Subcutaneous calcinosis (1.15) should alsoalways make one query an underlying diagnosis of SSc(1.16).

• Dermatomyositis. This diagnosis may be suspected fromthe typical rash, which commonly affects the face (some -times with heliotrope discoloration and periorbital oedema,5.5A, B), neck and upper back, the extensor aspects of thehands (Gottron’s papules, 5.6A, B), elbows, and knees,and the periungal areas. Dermato myositis is associatedwith marked abnormalities of the nailfold capillaries, whichcan sometimes be seen with the naked eye (1.17A, B).

• Vasculitis. Typical features pointing to an underlyingvasculitis include splinter haemorrhages, nailfoldinfarcts, a purpuric rash (1.18, 1.19A, B) and vasculiticulcers (1.20A, B, 1.21). If any of these are observed,then this should prompt a search for evidence ofvasculitis elsewhere, for example renal vasculitis. Asalready mentioned, digital ischaemia and mouth ulcers(1.2) can also occur in the vasculitides. Becausevasculitis can occur as part of other multisysteminflammatory diseases, for example in patients withrheumatoid arthritis and SLE, it is important always tobe on the alert for signs of vasculitis because these mightinfluence management (1.21).


1.10 Infected fingertip ulceration in a patient with limited

cutaneous SSc.

1.11 Ulceration over the extensor surface of the middle

finger proximal interphalangeal joint in a patient with

diffuse cutaneous SSc. There is marked sclerodactyly

with contractures.

1.12 Digital tip ulcer which has progressed to gangrene in

a patient with SSc.



1.13 Digital pitting (demonstrated in the finger on the left

side of the image) in a patient with SSc.

1.14 Telangiectases in a patient with SSc.

1.15 Calcinosis of the thumb.

1.16 Several clinical features of SSc: cyanosis of the

middle and ring finger, digital pitting of the middle finger,

a calcinotic nodule of the pulp of the ring finger,

telangiectases, and amputation of the index finger (this

was due to severe digital ischaemia).

1.17A: Periungal erythema in a patient with probable

early dermatomyositis. Dilated capillaries can be seen

with the naked eye, as well as being well demonstrated

with capillary microscopy (B).

A

B



1.18 Purpuric

rash of the lower

limbs. Histology

showed

leucocytoclastic

vasculitis.

A

B

1.19A: Purpuric rash in a patient with Henoch–Schönlein

purpura; B: histology of a skin biopsy from the patient

shown in (A) shows superficial vessels surrounded and

infiltrated by neutrophil polymorphs along with

karyorrhectic debris. There is vascular damage with red

blood cell extravasation. Magnification ×10. (Courtesy of

Dr. L. Jamieson.)

A B

1.20A: Vasculitic ulcers, the most obvious one being over the lateral aspect of the midfoot. There is also a vasculitic rash

of the left leg and ischaemic change of the right 5th toe; B: histology of one of the ulcers of the patient shown in

(A) shows a dense leucocytoclastic neutrophilic infiltrate involving both large and small vessels leading to fibrinoid

necrosis of the vessels as well as necrosis of the epidermis and striking papillary dermal oedema. Magnification

×4. (Courtesy of Dr. L. Jamieson.)


MusculoskeletalThere are a large number of possible findings onmusculoskeletal examination (Table 1.3), underscoring theneed for a careful assessment in all patients in whomconnective tissue disease is either confirmed or suspected.In inflammatory arthritis there is usually warmth,tenderness, and swelling (1.22). As with the skin, thecharacteristic musculoskeletal findings are consideredunder disease subheadings but again, this is a falsedistinction as there is considerable overlap in the possiblemanifestations between diseases.• SLE. This is in the differential diagnosis in patients,

especially young women, presenting with aninflammatory arthritis. There may be reversibledeformities of the fingers.

• SSc. Contractures occur especially in patients withdiffuse cutaneous disease (1.8). Patients with earlydiffuse disease may have friction rubs, for example at theknees and ankles.

• Inflammatory muscle disease. Pointers to the diagnosisare proximal muscle weakness and tenderness.

As a final point, fibromyalgia can occur in patients withconnective tissue disease so if a patient has multiple tenderpoints then this diagnosis should be considered.

CardiorespiratoryKey points to look for in patients with suspected or provenconnective tissue disease are shown in Table 1.4 andinclude:

• Raised blood pressure. This may reflect renalinvolvement or concomitant ‘essential’ hypertension.Either way, it is imperative that the blood pressure bewell controlled. Hypertension in a patient with SSc maymay occur in ‘scleroderma renal crisis’, which is amedical emergency; therefore, the blood pressure mustbe checked in any patient with SSc who develops newsymptoms such as headache or new breathlessness.

• A loud pulmonary component to the second heartsound, suggesting pulmonary hypertension.

• Basal crackles, suggesting pulmonary fibrosis.

GastrointestinalKey points to look for include signs of weight loss,abdominal tenderness (which can occur in SLE-relatedserositis or in patients with mesenteric ischaemia), andabdominal distension (which can occur in patients with SScand episodes of pseudo-obstruction secondary to smallbowel involvement).

Nervous systemConnective tissue diseases can give rise to a wide spectrumof neurological signs reflecting how peripheral, central, andautonomic nervous systems can all be involved (Table 1.6).Points to highlight are as follows:• If a patient has signs of mononeuritis multiplex, consider

whether he/she might have vasculitis.• Peripheral neuropathy (which may be asymptomatic)

may be a feature of several of the connective tissuediseases.


1.21 Vasculitic ulcer in a patient with Wegener’s

granulomatosus. The sutures mark the site of the biopsy.

1.22 Swelling of the dorsum of the hand and wrist due to

arthritis in Henoch–Schönlein purpura. This is the same

patient as in Figure 1.19.


• Trigeminal neuropathy, clinical features of whichinclude impaired sensation in the distribution of one ormore branches of the trigeminal nerve, may be thepresenting feature of connective tissue disease.

• Meningitis should always be suspected in the unwellpatient with SLE, for example with drowsiness andpyrexia. The immediate concern is bacterial meningitis,although aseptic meningitis can also occur in SLE.

EyesAbnormalities include redness in the patient withconjunctivitis or uveitis (for example in Behçet’s disease),abnormalities of the sclera in vasculitis, and proptosis inWegener’s granulomatosis. The fundi should be examinedif there is any possibility of retinal vasculitis, for example inthe patient with SLE, in whom cotton wool exudates maybe found.

Investigations in a patient with suspectedconnective tissue disease

As a generalization, investigations are indicated to:• Inform diagnosis. Some investigations are highly specific

for different connective tissue diseases. For example, adiffuse cANCA staining is very suggestive of Wegener’sgranulomatosis. The finding of histological vasculitis willconfirm a suspected diagnosis and may give confidence tothe clinician that immunosuppressant therapy is justified.

• Monitor disease activity. Monitoring of the acute phaseresponse (ESR and/or C-reactive protein [CRP]) isstandard practice in assessing disease activity/treatmentresponse in most of the connective tissue diseases. Incertain connective tissue diseases, monitoring levels ofcertain specific autoantibodies can also be useful (forexample cANCA in Wegener’s granulomatosis or anti-double-stranded DNA [dsDNA] antibodies in patientswith SLE).

Because connective tissue diseases, including thevasculitides, are often complex and multisystem, a largenumber of investigations may be required in any oneindividual, firstly at the time of diagnosis, and secondly inthe monitoring of disease activity/severity and in thedocumentation of the degree of involvement (if any) of thedifferent internal organs. Therefore, it is not possible to givea comprehensive list of all the investigations which might berequired, nor of all the possible abnormalities. This sectionwill give a summary of some of the tests which are mostfrequently requested/helpful. Most patients with a proven

or suspected diagnosis of connective tissue disease will, onpresentation, require the following investigative ‘work-up’:• A full blood count.• A biochemical profile.• Assay of an acute phase reactant, usually the ESR or

CRP.• Dipstick testing of urine, and microscopy of urine.• Immunology testing, including ANA.• A chest X-ray.• Other tests as clinically indicated.

The broad principles will be discussed here.

TestsHaematologyPatients with active connective tissue disease typically havea normochromic normocytic anaemia, a slightly raisedplatelet count, and a raised ESR. However, this is not trueof patients with ‘primary’ APS (i.e. not associated with aconnective tissue disease such as SLE) and SSc, which arenot usually associated with a major inflammatorycomponent. A high ESR in the patient with SSc shouldmake one query whether there is an overlap with anotherconnective tissue disease, or whether there is an additionalpathology such as infection or malignancy.

Active SLE may be associated with a fall in thehaemoglobin, white cell count, and/or platelet count. Aproportion of patients with SLE develop autoimmunehaemolytic anaemia. Thrombocytopenia occurs in APS.Eosinophilia occurs in Churg–Strauss syndrome.

It is essential to monitor the full blood count in patientson immunosuppressive therapy. A fall in any of thecomponents of the blood count should alert the clinician tothe possibility of drug toxicity. As already discussed above,a common clinical dilemma is the patient with SLE andpancytopenia. Bone marrow examination may be helpful.

Blood biochemistry• Blood biochemical profile. This should always be

checked. Many patients with connective tissue diseasehave renal or (less frequently) hepatic involvement whichmay be asymptomatic.

• CRP. This is typically raised in active inflammation,although not usually elevated in SLE unless there isserositis. Therefore, a raised CRP in the patient withSLE should always prompt the clinician to look forunderlying infection.

• Muscle enzymes. These should always be checked if aninflammatory muscle disease is suspected. Creatinephosphokinase is most commonly used in diagnosis and



monitoring: blood levels may be very high onpresentation with polymyositis. Circulating levels ofaldolase, transaminases, and lactate dehydrogenase mayall be high in patients with muscle inflammation.

• Globulins. Hypergammaglobulinaemia (polyclonal) maybe seen especially in patients with Sjögren’s syndrome.

UrineAll patients with a suspected or proven diagnosis ofconnective tissue disease should have dipstick testing ofurine. So often this simple test is omitted or delayed(Scenario 1) yet an abnormal dipstick may be the first clueto renal involvement. Glomerulonephritis can occur in SLEor the vasculitides. Dipstick testing may then show proteinand/or blood, and microscopy of urine an active sedimentwith white and red blood cells and casts. If renal


SLE• Anti-dsDNA antibodies. Highly specific for SLE. Titre

can be a useful measure of disease activity. However,

not sensitive: many patients with SLE do not

demonstrate anti-dsDNA antibodies

• Anti-Sm antibodies. Specific, not sensitive

• Anti-Ro and anti-La antibodies (associated with

Sjögren’s sydrome as below). Not sensitive. Both

these autoantibodies are associated with the neonatal

lupus syndrome and so women of childbearing age

with either of these antibodies need to be advised

accordingly and ideally should have prepregnancy

counselling

Sjögren’s syndrome• Anti-Ro and anti-La antibodies

APS• Anti-cardiolipin antibodies. Low levels of anti-cardiolipin

antibodies occur in a number of other clinical situations

(e.g. infection) and so this finding is not specific

SSc• Anti-centromere antibodies (in limited cutaneous

disease). Specific, but not sensitive

• Anti-topoisomerase (anti-Scl-70) antibodies (in diffuse

cutaneous disease, with an association with

pulmonary fibrosis). Specific, but not sensitive

• Anti-RNA polymerase I and III antibodies (in diffuse

cutaneous disease, with an association with renal

involvement). Specific, but not sensitive

Inflammatory muscle disease• Anti-Jo-1 antibodies (associated with lung fibrosis).

Specific, not sensitive2

• Anti-PM-Scl antibodies (associated with SSc overlap)

Vasculitis• cANCA (associated with Wegener’s granulomatosis).

Antibody is usually to proteinase 3. Specific, not

sensitive

• Perinuclear ANCA (pANCA). Less specific than cANCA

for vasculitis. Antibody is usually to myeloperoxidase

Overlap syndromes• U1 RNP antibodies. This antibody must, by definition,

be present for the diagnosis of mixed connective

tissue disease

1This list is not comprehensive but includes the

autoantibodies currently most useful to the practising

clinician. For example, a large number of different

autoantibodies are now recognized to be associated

with inflammatory muscle disease2A number of other anti-synthetase antibodies are now

recognized. Anti-Jo-1 is the one most commonly found

Table 1.7 Autoantibody associations with connective tissue diseases1

involvement is suspected, then a urine sample should besent for estimation of protein/creatine ratio and forcreatinine clearance.

ImmunologyThe connective tissue diseases are associated withcirculating autoantibodies and as already stated these canbe useful in diagnosis. Also, in individual connective tissuediseases, particular autoantibodies are associated withcertain phenotypes. For example, in patients with SSc, anti-centromere antibody is highly specific (but not sensitive) forthe limited cutaneous disease subtype whereas anti-topoisomerase (anti-Scl-70) is specific (but not sensitive)for the diffuse cutaneous subtype. Some of theautoantibody associations with the different connectivetissue diseases are listed in Table 1.7.


If a patient presents with what could be a connective tissuedisease (e.g. fever, rash, splinter haemorrhages, anaemia, anda raised ESR), one or more of the following immunologicaltests are indicated, depending on the clinical context:• ANA. This is a nonspecific test but useful in screening.

Over 95% of patients with SLE are ANA positive. Thehigher the titre, the more likely the patient is to have anautoimmune disease: an ANA titre of 1/1,600 is muchmore likely to be clinically relevant than a titre of 1/100.

• Antibodies to dsDNA. These should be assayed if theANA is positive and the patient is suspected of havingSLE. The level of anti-dsDNA antibodies can be a usefulmeasure of disease activity.

• Antibodies to specific antigens. These are more disease-specific than the ANA. Some useful disease/auto -antibody associations are listed in Table 1.7. As ageneralization, most of the disease-specific auto -antibodies are not sensitive, i.e. many patients with thedisease do not have the autoantibody.

• Cryoglobulins. These are proteins that precipitate whencold, and can occur in connective tissue disease andvasculitis, infections (particularly hepatitis C), ormalignancy. Cryoglobulins may be monoclonal (inwhich case myeloma or another haematologicalmalignancy should be suspected), polyclonal, or ‘mixed’.

• Testing for APS. Testing for both lupus anticoagulant (afunctional assay which measures the ability of a patient’sserum to prolong in vitro measures of clotting) and anti-cardiolipin antibodies should be requested if a patient issuspected of having an APS. This is because one testmay be negative but the other positive.

Other investigationsThese will be indicated according to the clinical picture.However, some general points can be made.

Investigation of suspected muscle inflammationThe muscle enzymes should be checked as above. Other testsare: electromyography (EMG), muscle biopsy, and magneticresonance (MR) scanning (1.23A, B). An important clinicalpoint is that a normal muscle biopsy does not exclude thediagnosis of inflammatory muscle disease because themyositic process is patchy and may be missed on biopsy.

Investigation of suspected vasculitisThe ‘gold standard’ investigation is biopsy, as appearancesmay be diagnostic. Sometimes the histological appearanceswill point to a specific type of vasculitis. For example, anecrotizing granulomatous vasculitis affecting small andmedium vessels would be highly suggestive of Wegener’s

granulomatosis. The site of the biopsy will depend upon theclinical scenario. For example, renal biopsy was indicated inScenario 1 because of the renal impairment and thehaematuria and proteinuria. Other common biopsy sites areskin, sural nerve, temporal artery (if temporal arteritis issuspected), and muscle. Angiography may also play a keyrole in the diagnosis and assessment of vasculitis. Forexample, if a diagnosis of vasculitis is suspected in a patientwith abdominal pain, then the finding of aneurysms and/orvascular occlusions on mesenteric angiography may pointto a diagnosis of polyarteritis nodosa. Newer techniques,including MR and computed tomographic (CT)angiography, which are less invasive than conventional (X-ray) angiography, are now used in the monitoring of large-vessel vasculitis such as Takayasu’s arteritis.

Investigation of the patient with Raynaud’sphenomenonIn the patient with primary (idiopathic) Raynaud’sphenomenon, there should be no symptoms or signssuggestive of an underlying connective tissue disease. Inaddition, the ANA should be negative or present in low titreonly (<1/100), the ESR should be normal, and the nailfoldcapillaries should be normal. Nailfold capillaroscopy isbelieved to be the investigation best predictive of underlyingconnective tissue disease, abnormal capillaries (1.24A, B)conferring a relative risk of an underlying SSc (or‘scleroderma’)-spectrum disorder in the order of 13.

Other investigations to identify presence and degreeof internal organ involvementIt is not possible to provide a comprehensive list, as themultisystem and heterogeneous nature of the connectivetissue diseases means that almost any investigation might berequired. Some challenging and relatively common clinicalscenarios are as follows:• Investigation of breathlessness in a patient with SLE or

other connective tissue disease. The differentialdiagnosis is extensive, but investigations will include achest X-ray (1.25, 1.26), pulmonary function tests withtransfer factor, an electrocardiogram (ECG) (1.27), anechocardiogram (to include estimation of the pulmonaryartery pressure), and most likely a high-resolution CTscan of the thorax.

• Investigation of weight loss in a patient with SSc or otherconnective tissue disease. Weight loss is oftenmultifactorial and has several possible causes.Investigation in the patient with SSc should includechecking for bacterial overgrowth with hydrogen and[14C] labelled breath test.




A B

1.23 MR images showing myositis. A: T1-weighted image shows the replacement of the posterior muscle groups with

fat, fat atrophy; B: STIR image shows the muscle as patchy high signal, indicating an increase in the muscle water

content (oedema). (Courtesy of Dr. C. Hutchinson.)

A B

1.24 Normal (A) and abnormal (B) capillaroscopy in a patient with SSc, showing dilated loops and (left side of image)

giant capillaries and areas of haemorrhage.

1.25 Chest X-ray showing basal shadowing (pulmonary

fibrosis) in a patient with SLE.

1.26 Chest X-ray showing pericardial effusion in a patient

with SSc. The patient was breathless and the pericardial

effusion was drained.


• Investigation of lethargy in a patient with connectivetissue disease. A common clinical dilemma is to decidehow far to pursue the symptom of fatigue, which is oneof the main symptoms of connective tissue disease andyet which can have other causes. It is not possible togeneralize, but it is important to remember that patientswith autoimmune connective tissue disease have anincreased prevalence of thyroid disease over the generalpopulation, and are often anaemic via a variety ofpossible mechanisms. The key is a careful clinicalassessment.

Conclusions

Assessment of patients with connective tissue diseasesincluding the vasculitides is complex. Even once a diagnosisis made, the disease course is often unpredictable and forthat reason most patients will require long-term follow-up,often involving more than one specialist. A detailed historyand examination, backed up by relevant investigations, arekey factors in defining the problem at any one point in timeso that an appropriate management strategy may befollowed. Any new symptom or sign must be pursued. Evenif not directly attributable to the underlying connectivetissue disease, any comorbidity and its treatment mayimpact on the patient, underscoring the need for a holisticapproach to investigation and management.


Further reading

Cutolo M, Grassi W, Matucci Cerinic M (2003).Raynaud’s phenomenon and the role of capillaroscopy.Arthr Rheum 11:3023–30.

Kumar TS, Aggarwal A (2010). Approach to a patient withconnective tissue disease. Indian J Paediatr 77:1157–64.

LeRoy EC, Medsger TA (1992). Raynaud’s phenomenon:a proposal for classification. Clin Exp Rheumatol10:485–8.

McLuskey P, Powell RJ (2004). The eye in systemicinflammatory diseases. Lancet 364:2125–33.

Solomon DH, Kavanaugh AJ, Schur PH (2002). Evidence-based guidelines for the use of immunological tests:antinuclear antibody testing. Arthr Rheum (Arthr CareRes) 47(4):434–44.

1.27 ECG in a breathless patient with an SSc/myositis overlap, showing

supraventricular tachycardia.


gordon † gross - clinical publishing ctd chp1.pdfd marcus, d cope, a deodhar, r payne isbn 978 1...

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