castle connolly graduate board review series

Educational Review Manual in Rheumatology

Robert G. Lahita, MD, PhD Professor of Medicine, Mount Sinai Medical SchoolVice President and Chairman of Medicine Newark Beth Israel Medical Center

Aruthur Weinstein, MD Professor of Medicine, Georgetown University Medical Center Associate Chairman, Department of Medicine and Director, Section of Rheumatology, Washington Hospital Center

4th Edition • 2007

CASTLE CONNOLLY GRADUATE BOARD REVIEW SERIES

PEDIATRIC RHEUMATOLOGY 387

Contents

1. Juvenile Idiopathic Arthritis(Juvenile Rheumatoid Arthritis)

2. Spondyloarthropathy

3. Systemic Lupus Erythematosus

4. Juvenile Dermatomyositis

5. Henoch-Schönlein Purpura (HSP)

6. Kawasaki Disease

7. Antiphospholipid AntibodySyndrome (APL)

8. Neonatal Lupus Erythematosus

9. Miscellaneous Group

10. Juvenile Scleroderma

11. References

12. Questions

PediatricRheumatology

BaluH. Athreya,MDCarlosD. Rosé,MD

1. Juvenile Idiopathic Arthritis(Juvenile Rheumatoid Arthritis)

Juvenile idiopathic arthritis (JIA) is the newnomen-clature for a group of conditions previously known asjuvenile rheumatoid arthritis in theUnited States andjuvenile chronic arthritis in Europe.1 To bring unifor-mity to the nomenclature, and to bring homogeneitywithin the subsets of this condition, the InternationalLeague ofAssociations ofRheumatologists (ILAR)proposed a new classification systemwith specificinclusion and exclusion criteria (Table 1.1).1

The age of onset, by definition, is less than 16 years,and the duration of arthritis is at least 6weeks.How-ever, since JIAis an exclusion diagnosis, one shouldlook carefully for clinical and laboratory clues forother causes. The onset by type is defined by the pat-tern of arthritis during the first 6months. Patientswithone type of onset can evolve into a different type (eg,oligoarticular pattern can become polyarticular andvice versa) after the first 6months; therefore, thecourse type also needs definition during follow-up(eg, oligoarticular onset–polyarticular course, orsystemic onset–polyarticular course).

Epidemiology

There are differences in the frequency of occurrenceof JIAin various parts of theworld. It is relatively lesscommon inAfrican-American children. Epidemio-logical studies from several countries show an inci-dence varying between 6 to 19 cases per 100,000 chil-dren at risk. In a recent survey, the prevalencewas113.4/100,000 children.2 The age of onset shows twopeaks—one between 1 and 3 years and anotherbetween 8 and 10 years. The earlier peak ismostlyseen in girlswith oligoarticular and polyarticularonset, and the later peak occursmostly in boys. Theoligoarticular variety ismore common in girls, partic-ularly in associationwith uveitis. The rheumatoid fac-tor (RF)-positive polyarticular variety ismore com-mon in girls. The systemic type is seen equally in boysand girls.

Etiology and Pathogenesis

The cause of JIAis unknown. It is a syndrome andincludes several types.Although arthritis is the com-mon feature linking them, theymay not all have thesame etiology. Recent understanding of immuno-genetics, immunopathology of inflammation, andcytokines suggests that the etiology of JIAismultifac-torial.3,4 Some of thewell-documented human leuko-cyte antigen (HLA) associations in various subtypesof JIAare listed in Table 1.2.Non-HLAgenetic asso-ciations, such as polymorphisms in proteins involvedin cytokine network, are also being intensely investi-gated. The pathogenesismay also be different in thedifferent subtypes. For example, IL-6 and IL-1 proba-bly play a greater part in the systemic variety com-paredwith the other types. Recent studies suggest thatseveral genes in polymorphs andmononuclear cellsare up-regulated in both the systemic and polyarticu-lar varieties. In addition, the relative paucity of famil-ial cases suggests that no one gene is responsible forthe initiation of this disease, but that several interact-ing genes are necessary to inherit the propensity toJIA(multigenic pattern of inheritance).

There is evidence to suggest that infections, physicaltrauma, and psychological stressmay initiate thearthritis of JIA.No specific infectious agent has beenconsistently isolated frompatientswith JIA. There isclear evidence of altered immunity in JIA.Abnormal-ities in the functions ofB-cells andT-cells have been

388 EDUCATIONAL REVIEW MANUAL IN RHEUMATOLOGY

Table 1.1

SuggestedClassification of IdiopathicArthritis of Childhood (ILAR)1

Systemic

Polyarticular RF positive

Polyarticular RF negative

Oligoarthritispersistentextended

Psoriatic arthritis

Enthesitis-related arthritis

Other:Fits no other categoryFitsmore than one category

demonstrated.However, the exactmechanismbywhich a trigger (infection, trauma, or stress) initiateschronic inflammation in a genetically susceptible hostis not clear. Current evidence points to imbalancesbetween pro-and anti-inflammatory cytokines anddefects in the innate immune system contributing tothe etiology of JIA.4

Clinical Features

The currently accepted ILARclassification (Table1.1) includes 7 subtypes based on themode of onset.Each subtype has characteristic clinical findings and apredictable course.

SystemicOnsetTypically, the child is less than 5 years oldwith highfever and rash; however, this form can be seen in allpediatric age groups and in adults. The onset is oftenexplosive.Daily fever spikes up to 40°-41°Coftenoccur during the evenings, reaching normal or belownormal in between episodes. The fever is often associ-atedwith the characteristicmacular, salmon-pink,nonpruritic rash over the trunk and extremities, oftendistributed along lines ofminor trauma. Themostimportant characteristic is its transient nature, appear-ingwith fever spikes and diminishingwhen tempera-ture settles down.Generalized lymphadenopathy andhepatosplenomegaly, togetherwith rash and fever,resemble features seen in infectious diseases. Pleuritisand pericarditismay be seen during this early acute


phase. Pericarditismay be occasionally severe enoughto cause cardiac tamponade.Anorexia,weight loss,and growth failure are some of the constitutional fea-tures seen in systemic-onset JIA.

Avery serious but unusual complication of systemic-onset JIAismacrophage activation syndrome (MAS).Occasionally, this is the presenting feature of sys-temic-onset JIA. Sudden onset of acute illness charac-terized by pancytopenia, abnormal liver function tests,and low-grade intravascular coagulation should sug-gest this diagnosis. Very high levels of ferritin andtriglycerides and a paradoxical fall in sedimentationrate are strong indicators of this diagnosis.Hemophagocytosis, if detected in the bonemarrowspecimen, is diagnostic.Mortality is as high as 50%without treatment.

Arthritismay not be seen at onset,making it difficultto diagnose systemic JIA.However,within the first 6to 8weeks, arthritis of large and small joints appears.It is symmetrical polyarthritis, involving joints of theupper and lower extremities. Almost any jointmay beinvolved, including joints of the cervical spine, sym-physis pubis, and cricoarytenoid joints. Thewrists andankles are almost always involved. Cricoarytenoidarthritismay result in acute respiratory distress and isthe one true emergency in JIA.Most children follow apolyarticular course, although a fewmay showanoligoarticular course.Usually, the systemic featuressubside over a period of 2 to 5 years. However, arthri-tis persists in over 50%of children.Uveitis is uncom-mon in this type of JIA.

PolyarticularTypeThe polyarticular subtype is defined by arthritisinvolving 5 ormore joints. This group is divided intoRF-negative andRF-positive JIA. The latter group isthe true counterpart toRF-positive arthritis in adults.

Rheumatoid factor-negative JIA, as defined by theolderAmericanCollege ofRheumatology (ACR) cri-teria, is seenwith two peaks—one in younger childrenand another in the preadolescent group.Diagnosis ofthis subtype requires the exclusion of psoriasis, pres-ence ofHLAB27, presence ofRF in the serum, andtypical systemic features. The onset is often insidious,and the extent of joint involvementmay not be fullyrecognizedwithout careful examination of all the

Table 1.2

AcceptedHLAAssociationwith JIA Subtypes

Systemic: none

Polyarticular RF positive: DR4

Polyarticular RF negative: DP3, DR5, DR8

All oligoarticular: A2, DR8, DR5, DPB1*0201

Extended oligoarticular: DR1

joints. Both large and small joints are involved, and itis often symmetrical, particularly in the young. Thecervical spine and temporomandibular joints are ofteninvolved. Systemic features are not prominent,although growth retardation, fatigue,morning stiff-ness, and low-grade fevermay be seen. Chronicuveitis is seen but less commonly than in oligoarticu-lar arthritis. Approximately 50%of childrenwithRF-negative JIAcarry antinuclear antibody (ANA) intheir serum. Fewof these childrenmay switch patternand evolve into systemic lupus erythematosus (SLE)in long-term follow-up.Asymmetric polyarthritisshouldmake one think of spondyloarthropathy.

Rheumatoid factor-positive polyarticular JIAaccounts for less than 10%of all childrenwith JIA. Itismost commonly seen in the older age group, pre-dominantly in girls, and is associatedwith erosivearthritis. The onset is often rapidwith pronouncedsystemic features such asmorning stiffness andweight loss. These children often develop subcuta-neous nodules, pulmonary disease, vasculitis, kerati-tis, and Sjögren’s syndrome,which are featuresresembling adult-onset RA.Uveitis is not common.Rheumatoid nodules are seenmostly in associationwith polyarticular disease andRF-positive status irre-spective of themode of onset. They are firm and non-tender and are located over the olecranon process andother areas subjected to pressure.Arthritis is severeand rapidly progressive, involving large and smalljoints in a symmetrical fashion. Remission is rare.

OligoarticularTypeOligoarticular type JIAis defined as arthritis involv-ing four or less joints. The earlier subclassification ofpauciarticular included type I, affectingmostly younggirls, and type II, affectingmostly older boys. Type IIpauciarthritis showing greater associationwithHLAB27 has been removed from the JIAsubset andgrouped under various names such as juvenile-onsetspondyloarthropathy or enthesitis-related arthritis orseronegative enthesopathy arthropathy syndrome(SEA).

The oligoarticular subtype is also called early onsetoligoarticular arthritis by some authorswhen the onsetis earlier than 6 years of age. This group consists ofthosewho stay on an oligoarticular course (persistentoligoarthritis) and thosewho slowly recruitmorejoints to take on a polyarticular course (extended

oligoarthritis). This conversion to a polyarticularcourse is seenmore often in childrenwith three orfour joints at onset, occurs early in the course (within1 to 3 years of onset), and is alsomore severe. Thereare also geneticmarkers associatedwith the extendedform (Table 1.2).

Classically, patientswith this type are girlswith lightcomplexionswho are less than 3 or 4 years oldwithcirculatingANA(70%-80%) and a high incidence ofuveitis. These children do not havemany systemicfeatures. The knee joint ismost commonly involved,followed by ankles and elbows.Hips are rarelyinvolved.Asymmetric involvement of thewristmaylead to advanced bone age on the affected side, andinvolvement of one kneemay result in leg-lengthinequality.When only one joint is involved, diagnosiscan be difficult tomake.

Uveitis is seen in about 20%of children in this groupand is bilateral in approximately two thirds of thepatients. Itmay precede the onset of arthritis inapproximately 10%of patients. It is often insidious,and, unlike the uveitis of spondyloarthropathy, it isasymptomatic in early stages.

Patientswith high risk for uveitis, such as thosewithANAwhose disease started before age 7 years andwho have either oligoarticular or polyarticular dis-ease, should get their eyes examined every 3 to 4months, particularlywithin the first 5 years fromdiagnosis. ChildrenwithANA-negative oligoarticularor polyarticular disease andonset of arthritis after theage of 7 years and thosewhohave had articular diseaseformore than 5years and never had uveitismaygettheir eyes examined once every 6months.Other chil-dren need eye examination once a year. Since uveitismayoccur even after arthritis has subsided, it is essen-tial to continuewith periodic eye examination for atleast 5 years after the onset of arthritis. Complicationsassociatedwith uveitis include bandkeratopathy, sec-ondary cataracts, glaucoma, and phthisis bulbi, andthey are serious in 10%-20%of the patients.

Psoriatic arthritis and enthesitis-related arthritiswillbe discussed in a later section. The other two cate-gories depicted in Table 1.1 as “fits no category” and“fitsmore than one category” are self-explanatory.


Differential Diagnosis and Investigation

The differential diagnosis of JIAdepends on the typeof arthritis at onset, pattern of joint involvement, andthe duration of arthritis at initial evaluation.

OligoarticularandMonarticularArthritisInmonarticular disease, themost important consider-ations are septic arthritis and trauma, if it is acute(Table 1.3). Lyme disease and reactive arthritismayalso be seen as acutemonarticular disease. Chronicmonarticular arthritis should raise suspicion ofchronic infections, such as tuberculosis, and localizedtumors, such as pigmented villonodular synovitis(PVNS).

Laboratory investigationsmay include examinationof the synovial fluid and, in some cases, biopsy of thesynovium, particularly inmonarticular disease. In theoligoarticular variety, CBCmay be normal and acutephase proteinsmay not be elevated.An occasionalpatientmay have IgAdeficiency. Presence ofRF sug-gests a polyarticular coursewith severe erosive dis-

ease.Antinuclear antibody is positive in about 50%ofchildrenwith oligoarticular disease and in over 80%of childrenwith oligoarticular disease of early onsetand uveitis. Antinuclear antibody positivity has lowpositive predictive value in the absence of synovitis.The actual prevalence of low-titerANAin the normalchildhood population is not known, but on the basis ofsmall studies, the frequency can be estimated to bebetween 5%and 10%.The synovial fluid shows evi-dence of inflammation (group II), with elevatedWBCcount in the range of 20-40,000/mm3with predomi-nant polymorphs. Cultures should be negative. Syn-ovial biopsy shows evidences of chronic inflamma-tion and,more importantly, excludes conditions suchas sarcoid and PVNS.

Themost characteristic abnormalities of the syn-oviumare villous hypertrophy, increased layers ofsynovial lining cells, proliferation of newblood ves-sels in the subsynovial layer, infiltrationwith lympho-cytes and plasma cells, and deposition of fibrin.

Radiological changes in early JIAinclude periarticu-lar swelling of soft tissue,widening of joint space,juxta-articular osteoporosis, and, rarely, periostealelevation.Ultrasound studies are helpful to detectfluid in the hip, shoulders, andwrists and to confirmtenosynovitis. Since permanent damage to the joint bypersistence of inflammation cannot be detected earlyby plain radiograph, and since soft tissue changesaround the jointmay be helpful to differentiate otherconditions, magnetic resonance imaging (MRI)could be used in the investigation of monarticulararthritis. Radionuclide imagingmay be helpful todetect early evidences of joint inflammation in sev-eral joints and to localize the source of inflamma-tion, particularly in young infants. In the presence ofchronic inflammation, advanced bone age andgrowth acceleration may be seen, particularly ifjoint involvement is asymmetric.

Inmonarticular arthritis, itmay be necessary to visual-ize the interior of the jointwith arthroscopy and obtainsynovial tissue for histopathology, particularly in theabsence of clinical evidence of inflammation andANA.Magnetic resonance imagingmay be helpful indetecting PVNSand hemangioma of the synovium.


Table 1.3

Differential Diagnosis ofMonarticular JIA

I. Acute

Septic arthritisOligoarticular JIASpondyloarthropathyLymediseaseLeukemiaNeuroblastomaReactive arthritisTrauma

II. Chronic

Oligoarticular JIAChronic infections (TB)Pigmented villonodular synovitisDiscoidmeniscusSynovial chondromatosisHemangioma

PolyarticularArthritisAlist of conditions to be considered in the differentialdiagnosis of polyarticular JIAis given inTable 1.4.These are chronic arthritides and do not include acutepolyarthritis commonly seen in viral and bacterialinfections,malignancy, Lyme disease, subacute bacte-rial endocarditis, and acute rheumatic fever.

Themost important investigation for classifying pol-yarticular JIAis RF. Although RF is not a sensitivetest to diagnose JIA, it is useful to classify polyartic-ular JIAinto seropositive or seronegative. Completeblood cell count often showsmicrocytic,hypochromic anemia. It may be profound in somecases, particularly in the RF-positive disease. Retic-ulocyte count, Coombs’ test, stool for occult blood,and examination of the bonemarrowmay be essen-tial to rule out other causes of anemia.WBC ismildly elevated; platelet counts are often high. Lowplatelet counts should alert physicians to look forother causes such asmalignancy and drug toxicity.Erythrocyte sedimentation rate (ESR) and C-reac-tive protein (CRP) are elevated and so are otheracute phase proteins. Antinuclear antibodymay bepresent in both subgroups and is associated withuveitis. Positive ANAand negative RF should also

alert the physician to look for evolution of the dis-ease into another rheumatic disorder such as SLE.Synovial fluid analysis and synovial biopsy are notessential for the diagnosis, although theymay beneeded to exclude other conditions such as sarcoido-sis. Imaging studies are not needed to confirm diag-nosis but may be indicated to rule out conditionssuch as leukemia presenting with polyarthritis or todetermine structural changes during long-term fol-low-up. Long-term radiological changes includemarginal erosions, joint space narrowing, subluxa-tion, ankylosis, advanced bone age, growth accelera-tion, and asymmetric growth. Pathological changesof the synovium in polyarticular JIAare the same asthose described under oligoarticular JIA.

Systemic JIABecause systemic JIAis associatedwith fever, rash,lymphadenopathy, hepatosplenomegaly, and serositis,the differential diagnosis should include infectiousdiseases,malignancy, and systemic vasculitides suchas SLE.

Childrenwith the systemic variety of JIAoften have ahighWBC, often reaching 40-50,0000/mm3. They arepredominantly polymorphonuclear. Increased bandformsmay suggest an infectious disease.When thereis predominant lymphocytosis, the differential diag-nosis should include infectionwith Epstein-Barr virusand leukemia. Platelet countsmay be increased, oftenreaching 1,000,000/cm3. Lowor low-normal plateletcount should suggest other diagnoses such asleukemia, SLE, and hemophagocytic syndrome(referred to earlier asMAS).Anemia can be profoundand difficult to treat. Erythrocyte sedimentation ratecan be very high and so canCRPand other acutephase reactants. Urinalysis is normal. Theremay bemild elevations of aspartate aminotransferase (AST)and alanine aminotransferase (ALT). Significant ele-vations should suggest other diagnoses or drug toxic-ity. Elevated lactic dehydrogenasemay suggestleukemia. Rheumatoid factormay be positive. Posi-tiveANA, if present, should alert the physician to thepossibility of other diseases such as SLE.Roentgenogramof the chestmay showpericarditis orpleuritis, or both, lymphadenopathy, and enlargedheart. Bonemarrow examination is necessary to ruleoutmalignancy and to obtain cultures inmany cases.In JIA, the bonemarrow is hypercellular but has nor-mal elements. Computed tomography (CT) scan of


Table 1.4

Differential Diagnosis of Polyarticular JIA

Polyarticular JIA

Spondyloarthropathy syndromes

Systemic lupus erythematosus

Lymedisease (early in the course)

Reactive arthritis

Viral arthritis(parvovirus, rubella, hepatitis B, Epstein-Barr virus)

Sarcoidosis

Leukemia


the abdomenmay be required to rule outmasses.Blood culturesmay be appropriate early in the courseof the disease, particularly before starting glucocorti-coid therapy.

Treatment

Themajor goals of treatment are: 1) to reduce inflam-mation, both systemic and local; 2) tomaintain func-tion; 3) to help the child and family lead as normal alife as possible; and 4) tominimize toxicity due todrug therapy.Although none of the currently availableforms of treatment can affect a cure, a combination ofcurrently available drugs used judiciously can preventpermanent joint damage and, thus, limit deformity anddisability.With the introduction ofmethotrexate(MTX) and judicial use of intra-articular glucocorti-coids and biological immunemodulators earlier in thecourse of the disease, the numbers of childrenwithjoint deformities requiring surgery and those depen-dent onwheelchairs have decreased dramatically.

Availability of effective and safemethods for con-scious sedation hasmade intra-articular injection ther-apy acceptable even for very young children.Also,with effective sedation, several joints can be injectedat the same time. Triamcinolone hexacetonide is thepreferred glucocorticoid compound.Although somechildren do not respond or respond for only a fewdays,most responses are sustained for severalmonthsto one year.

The currently accepted course ofmedical treatmentincludes the following: a) the use of nonsteroidal anti-inflammatory drugs (NSAIDs) initially; b) the use ofparenteral glucocorticoids for severe disease such aspericarditis and cricoarytenoid arthritis; c) intra-artic-ular glucocorticoids for limited joint disease; d) intro-duction ofMTXearly before joint destruction sets in;e) the use of themaximumdose ofMTX; and f) afaster timetable for the introduction of biologicalresponsemodifiers.5 Table 1.5 lists the various drugsused in the treatment of JIAand other rheumatic dis-eases and their side effects.

NonsteroidalAnti-inflammatoryDrugsThere are several classes of NSAIDs. Themost com-monly used ones are naproxen, ibuprofen, andindomethacin. Acetylsalicylic acid (aspirin) isalmost never the first choice, because it has to be

given 3 to 4 times a day and because of concernsabout Reye’s syndrome, allergy, and gastrointestinal(GI) toxicity. Serum salicylate level and liver func-tions have to bemonitored. If children on aspirin areexposed to varicella or influenza, aspirin has to bestopped. Aspirin has to be discontinued for severaldays beforemajor surgery.

Naproxen is one of themost commonly usedNSAIDsbecause of its availability in liquid formulation andbecause it can be given twice a day. In addition to theusual adverse effects of all NSAIDs, a photosensitiv-ity rash,mimicking porphyria, occurs over exposedparts of the body such as the face and the hands. Thiscan be disfiguring, and children taking naproxenshould be advised to use sunscreen preparations.

Ibuprofen is also available in a liquid form, but it hasto be given 3 to 4 times a day. Indomethacin is particu-larly useful for the control of fever, serositis, andmorning stiffness. However, its effects on the centralnervous system (CNS) can be disabling.

For childrenwith severeGI intolerance, nabumetonemay be an acceptable alternative. Childrenwithplatelet abnormalitiesmay be treatedwithmagne-sium-choline trisalicylate. There is no experiencewith the use of cox-2 inhibitors in children.

Nabumetone and etodolac are effective and safe,particularly in older children when a once-a-dayregimen is considered. Miloxicam is a recent addi-tion to this list of drugs that can be given once a day.Miloxicam is available in liquid form and is rela-tively cox-2 specific.

TheNSAIDs do not prevent joint damage but do con-trol inflammation and relieve pain and stiffness.Meantime to response is approximately 4weeks. If there isno response in 6 to 8weeks, it is best to add a second-line agent. Children tolerateNSAIDs generallywell.It is best to giveNSAIDswith food to reduce gastricirritation. True ulcer secondary toNSAIDuse is rela-tively uncommon in children comparedwith adults. Itmay be necessary to giveNSAIDswith antacids orsucralfate, although their value is questionable. Skinhypersensitivity reaction, hepatotoxicity, nephrotoxi-city, andMASare some of the other known adverseeffects associatedwithNSAIDs.


yes

Figure 1.1

An approach to the pharmacologicmanagement of a patient with JRA

Continue

Continue

IncreaseMTXdose tomaximumof 50mgor 1mg/kg/wk. Use subcutaneousMTX

for doses>15mg/m2

yes

yes

yes

yes

no

no

no

no

no

no

no

yes

Pulse steroids, thenoral steroids

Add intra-articular steroids andintensify physical therapy program

Adequate response in 4weeks?

ContinueNSAID andphysicaltherapy program

Significant contractures orsynovitis in a few joints?

ChangeNSAID, intensifyphysical therapy program.


Poly, systemic


NSAIDplus physical therapy program

Blinding iridocyclitis or life-threateningsystemic illness such as pericarditis?

AddMTX10mg/m2/wk. Consider shortcourse (4-8wks) of steroids

if markeddisability or HGB,6.5

Adequate response in 3months?

Consider experimental,cytotoxic,

or combo treatment

Adequate response in 3months?

Continue

Pauci

Reproduced with permission fromGiannini EH and Cowkwell GD. Drug treatment in children with JRA: past, present andfuture. Pediatr Clin North Am. 1995;42:1104.


Table1.5

MedicationsandDosages

Medication

Dose

DailyFrequency

HowSupplied

LaboratoryMonitor

Comments

Acetylsalicylicacid

60-100

mg/kg/day

3-4individe

ddo

ses

Tablets:325mg,

ASA

levels,PT,PT

T,Watch

forsalicylism;

(aspirin)

(max:2600mg/da

y)500mg,81

mg

stool,Guiac,AST

,ALT

avoiduseinchild

with

Chewab

le:various

chickenpo

x;take

with

combinations

meals;cautionwhen

usingwith

antacids,

acetam

inop

hen,and

combining

with

other

NSA

IDs

Aurothiog

lucose

Initial:0.25mg/kg

Weeklyup

to50

mg/mLinj(+50%

CBC,U

Aevery1-2wks,

Anaph

ylactoidreactions

(Solga

nol®)

IMincrease

maintenance

dose;then

gold),10

mLvial

then

every2-4wks

may

occur.Rashescan

0.25

mg/kg

weekly

weeklyfor20do

ses;then

thereafter

besevere.Renaltoxicity;

Maintenance:

every2wks

x3do

ses,

bone

marrowtoxicity

0.75-1mg/kg/dose

every3wks

x3do

ses,

(max:50mg)

then

every4wks

Azathioprine

Initial1mg/kg/day

Onceortwiceda

ilyTablets50

mg

CBC,PltCtevery

SGOT,SP

GTevery

(Imuran

®)

bymouth;increase

1-2wks;Then:CBC,

6-12

wks.

0.5mg/kg

once

in4wks

PltC

tevery1-2months;

NOTE

:Use

only1/4to

Maintenance:

SGOT/PT

every

1/3do

seifpa

tientinon

1-3mg/kg/day

3-6months

allopu

rinol

bymouth

(continued)


Table1.5

(continued)


Medication

Dose

DailyFrequency

HowSupplied

LaboratoryMonitor

Comments

Chloram

bucil

0.1-0.2mg/kg/day

Daily

Tablets2mg

CBC

Malignancy,bo

ne(Leukeran®)

marrowsupp

ression

Cycloph

osph

amideIV

Titra

tedo

seup

toMonthlyx6,then

every

Inj100

mg,200mg,

CBC,PltCt,UA,

Conside

rthe

useof

(Cytoxan

®)

1gm

/sqm

IV3monthsfor6

doses

500mg,1g,2g

BUN,creatinine

MES

NAforpreventionof

hemorrhag

iccystitis

Cycloph

osph

amideoral

1-2mg/kg/day

Varies

25mg,50

mgtablets

Sameas

IV

d-Pe

nicillamine

Initial3mg/kg/day

Dailytofourtim

es125mg,250mg

InitialCBC,PltCt,&UA

Donottakewith

food

,(Cup

rimine®,D

epen

®)

for3

months,then

ada

ydivide

dcapsules

every1-2wks,then

milk,iron,orzinc.These

6mg/kg/day

in2

every4-6wks.C

PKcande

crease

absorption.

divide

ddo

sestoa

every6months

Can

causemyositis,

max

of10

mg/kg/day

conversion

toANA

divide

din3-4do

ses.

Max

dose:750

mg/da

y

Diclofenac

2-3mg/kg/day

divide

dTw

ice,thrice,or

25mg,50

mg,

InitialCBC,U

A,

Donotcrush

or(Voltaren®)

2-4tim

espe

rday;

fourtim

esada

y75

mg,tablets

creatinine,SG

OT;

chew

tablets

150mg/da

ymax

then

every6months

inpe

diatrics

(continued)


Table1.5

(continued)


Medication

Dose

DailyFrequency

HowSupplied

LaboratoryMonitor

Comments

Etanercept

0.4mg/kg

perdose

25mg/vial

CBConce

in6-8wks

Localreactions,

(Enb

rel®)

subc

utaneously(m

ax:

cytope

nia.Stop

ifthereis

25mg/do

se).Given

twice

anyinfection.TestforTB

aweekOR0.8mg/kg

beforetherap

y.pe

rdosesubc

utaneously

(max:50mg/do

se)

givenonce

aweek

Hydroxychloroqu

ine

Initial:3-5mg/kg/day

Dailyortwiceada

y200mgtablets

Initialretinalexam

,None

(Plaqu

enil®)

divide

d1-2tim

espe

rthen

every6months;

daytoamax

of400mg

CBCevery6months

or6mg/kg/day

Ibup

rofen

20mg-40

mg/kg/day

Threeorfour

100mg/5m

Lsusp;

InitialCBC,U

A,BUN,

May

causeasep

tic(Advil®,M

otrin

®,

Pediatric

max:

times

ada

y200mg,300mg,

creatinine,andLFTs,

meningitis

inpa

tients

Nup

rin®,

2400

mg/da

y;ad

ultm

ax:

400mg,600mg,&

then

every6months

with

SLE

Pedia-Profen

®)

3200

mg/da

y800mgtablets

Indo

methacin

1-3mg/kg/day,m

axTw

iceorthree

25mg,50

mg,75

mg,

InitialCBC,U

A,

Caution:may

increase

(Indo

cin®)

dose:150

mg/da

ytim

esada

ycapsules;75mg

creatinine,PT

,and

PTT;

methotre

xatelevels

sustainedreleasecaps;

follow-upnotneede

dif

25mg/5mLsusp

asym

ptom

atic;C

BC,

UA,and

SGOTonce

in6months

(continued)


Table1.5

(continued)


Medication

Dose

DailyFrequency

HowSupplied

LaboratoryMonitor

Comments

Methotre

xate

5-15

mg/sqm/wk,

Onceweekly

2.5mgtablets;

CBC,SGOT,andSP

GT

Stop

ifchild

develops

(Rheum

atrex®)

subc

utaneous,

25mg/mLinjection

beforestart,then

every

chickenpo

xorinfluenza.

intra

muscular,or

2wks

x2;then

every

Rarely,severelung

toxicity

bymouth

4-6wks

Methylpredn

isolone

1-2mg/kg/day

(max:

Dailyorindivide

d2mg,4mg,8mg,

BP,serumpo

tassium

Monitorw

eigh

t,BP,eye

(Med

rol®,SoluMed

rol®,

60mg);pulse

therap

ydo

seson

alternateda

ys;

16mg,24

mg,32

mg

(forcataract).Pu

lse

A-m

ethapred

®)

30mg/kg

dose

Pulsedo

semay

begiven

steroiddo

setobe

given

(max:1

g/session)

once

ada

yfor3

days

for

asIVinfusion.Followin

acutecond

itions

patientprotocol.

Nap

roxen

10mg-20

mg/kg/day,

Twiceada

y250mg,375mg,and

InitialCBC,U

A,

Advisetheuseof

(Nap

rosyn®,Aleve

®)

max

dose:1000mg/da

y500mgtablets;

creatinine,SG

OT,then

sunscreentoprevent

25mg/5m

Lsusp

every6months

pseudo

porphyria.D

onot

crushorchew

tablets.

Pred

nisone

0.14-2mg/kg/day

Dailyto

1mg,2mg,2.5mg,

CBC,BP,yearly

Take

with

food

ormilk.

(Deltasone

®,O

rasone

®)

(usualmax:60mg)

fourtim

esada

y5mg,10

mg,20

mg,

ocularexam

sAvoiduseofNSA

IDs.Use

Pred

nisolone

50mgtablets.Use

pred

nisolone

inliver

(Prelone

®)

pred

nisolone

asan

dysfunctionorwhena

oralliquid15

mg/5mL

liquidisneed

ed.

Osteopo

rosis

(continued)


Table1.5

(continued)


Medication

Dose

DailyFrequency

HowSupplied

LaboratoryMonitor

Comments

Sulfasalazine

Initial10

mg/kg/day,

Twiceada

y500mgtabletswith

orCBC,PltCtevery

May

causeorange

-yellow

(Azulifidine,zulfidine

increase

weeklyby

withoutentericcoating;

2-3wks

x3months,

discolorationofurineand

EN-ta

&S.A.S.)

10mg/kg/day

upto

250mg/5mLoral

then

every6-8wks

skin.M

aystainsoft

30mg-50

mg/kg/day.

suspension

contactlenses.Avoid

Max

pediatric:

prolonge

dexpo

sureto

2000

mg/da

y;thesun.Adm

inisterafter

Max

adult:

mealsorwith

food

.Donot

4000

mg/da

ytake

Maalox®orMylanta

®-

type

antacids.

Tolmetin(Tolectin

®)

15mg-30

mg/kg/day

Threeorfourtim

es200mg,600mgtablets;

InitialCBC,U

A,

May

take

with

food

,milk,

Max

pediatric:

aday

400mgcapsules

creatinine,andSG

OT,

orantacids.C

aution:may

30mg/kg/day;

then

every6months

increase

levelsof

Max

adult:1800

mg/da

ymethotre

xate.

Triamcinolone

5-40

mgforintra-articular

5mg/mL,20

mg/mL,&

(Aristocort®,

injectionde

pend

ingon

40mg/mLinjection

Kenacort®,

thejoint,patientag

eKenalog

®,

andweigh

tHexacetom

ide)

Ourthanks

toStuartLevine,Pharm

.D.,forthe

inform

ationinthistable.


Intra-articular InjectionsThe use of joint injectionswith triamcinolone hexace-tonide has become very popular among pediatricrheumatologistsmainly because conscious sedationbecame safer andwidely available. Patientswitholigoarticular ormonarticular diseasewho do notrespond to or tolerateNSAID therapy orwith pol-yarticular disease and an “out of phase” joint are thebest candidates. Some childrenwith early onsetoligoarthritiswhose disease lasts 1 to 2 yearsmay justrequire 2 or 3 injections during the course of the dis-ease and no oral daily systemic therapy. The jointsmore amenable to joint injection are the knee, hip,elbow,wrist, and ankle. Impeccable technique toavoid infection and fat atrophy is necessary, particu-larly for small joints such as the subtalar joint (fluoro-scopic or ultrasound guidancemay be necessary).

Disease-ModifyingAntirheumaticDrugsAfter a trialwithNSAIDs alone,more than 50%ofchildrenwill require the addition of one of the drugsfrom the category of slow-acting or disease-modify-ing antirheumatic drugs. These drugs belong to dif-ferent classes with different toxicity profiles andincludeMTX, leflunomide, cyclosporine, and sul-fasalazine.Most of these drugs have considerabletoxicity, and the response rate comparedwith that ofplacebo is not significant.Methotrexate, however,has been shown to be clearlymore effective thanplacebo at doses of 10mg/sqm/week. The toxicityprofile has also been remarkablymild. Therefore,MTX is the drug of choice for children who do notrespond to NSAIDs. It is particularly effective inextended oligoarticular disease. The experience withMTX in systemic JIAis disappointing.

Methotrexate is given orally once aweek, preferablyon an empty stomach. Some clinicians prefer startingit in subcutaneous form. The dose range is 0.5 to 1mg/kg/week or 10 to 20mg/sqm/week (maximumof25mg/week). Since absorption is variable at highdoses, it is best to giveMTXby subcutaneous injec-tion if doses greater than 15 to 20mg are needed. Folicacid given orally at 1mg/day is recommended. Beforeinitiating therapy, the family should be educated onpotential adverse effects and the need for carefulmon-itoring.Adolescent girls and boys should be coun-seled on abstinence fromalcohol and the risks of preg-nancy. Live viral vaccines and trimethoprim-contain-ing compounds for treatment of infections are con-

traindicated when patients are onMTX therapy. Themonitoring schedule forMTX toxicity shouldinclude CBC, liver function tests, serum albumin,and creatinine before and once in 4 to 6weeks afterinitiation of therapy.

Themost common adverse effects are oral ulcers andgastric symptoms. They aremild onmost occasions.Bonemarrow toxicitywith cytopenia is not common.However, in the presence of viral infections, particu-larly Epstein-Barr virus, childrenmay develop anacute illness characterized by a fall in red blood cellsand platelets associatedwith features of disseminatedintravascular coagulation and liver dysfunction.These childrenmay evolve intoMASand need closemonitoring and aggressive therapy. There are reportsof lymphoma associatedwithMTX, but, fortunately,these are very rare. Routine liver biopsy is not neededbefore initiatingMTX therapy unless there are otherrisk factors such as obesity and use of alcohol. How-ever, if there are persistent elevations of transaminase(even ifmild) duringmonitoring, liver biopsy is indi-cated. True cirrhosis is rare.

In childrenwith arthritis suggestive of spondy-loarthropathy, sulfasalazinemay be a good option.Adverse effects include persistent nausea, hypersensi-tivity reactions including pseudolymphoma syn-drome, hepatotoxicity, and bonemarrowdepression.It is best to initiate therapy at 10mg/kg/day andincrease gradually over 3 to 4weeks up to amaximumof 30 to 50mg/kg/day and up to amaximumdailydose of 2.5 g.

In childrenwith systemic JIA, and severe polyarticu-lar JIA, intravenous gammaglobulin (IV IG)may beused, although in controlled studies its effectswerefound to be no better than placebo. Considering thecost and risks of transfusion-related complications,this is not routinely recommended. Thalidomide hasbeen suggested as another possible treatment for sys-temic JIAresistant to standard treatment. High-doseglucocorticoids and cyclosporine are strongly recom-mended to treatMAS.

Indications for the use of glucocorticoids are listed inTable 1.6. Ideally, glucocorticoids should be used atthe lowest possible dose and every other day exceptwhen used for severe acute inflammatory processsuch as pericarditis or cricoarytenoid arthritis. Bolus


intravenous (“pulse”) therapy should be used for acutelife-threatening complications.

Children on long-standing glucocorticoid therapyneed closemonitoring and counselingwith focus onnutrition and special emphasis on intake of calciumsupplement, growth, blood pressure, cataract, avascu-lar necrosis, diabetes, osteoporosis, and infectiouscomplications.Diphosphonatesmay be needed totreat severe osteoporosis.

Biological immunemodulators have been recentlyintroduced for the treatment of JIA(Table 1.7). Ofthese, etanercept (Enbrel®, Amgen, ThousandOaks,CA) is the only one approved for use in JIA. Inflix-imab (Remicade®, Centocor,Horsham, PA) isapproved for use in treatingCrohn’s disease in chil-dren. Etanercept, a TNF receptor fusion protein, issuperior to any formof therapy includingMTX for thetreatment of JIA.6 It is used as a subcutaneous injec-tion twice aweek. The dose is 0.4mg/kg/dose,with amaximumof 25mg/dose. Currently,many patientsreceive a dose onceweekly at 0.8mg/kg. This is idealfor those young childrenwhowill require less than 25mg/week. The 50mg syringe is not calibrated,whichmakes it difficult to get precise dosing for thosewhoseweights demand a dose of 25 to 50mg/week. Becauseof concerns about altered immunity predisposing toserious infections, the current recommendation is to

withhold injections temporarily in the presence ofintercurrent infections (Table 1.8).

Infliximab is not approved for JIA, but small serieshave been published reporting good responses in sys-temic patients. There are short series showing efficacyof anakinra in systemic disease aswell as preliminaryinformation suggesting good efficacy of the humanizedanti-TNFmonoclonal antibody, adalimumab.

Nutrition

Childrenwith JIA, particularly thosewith systemic andpolyarticular types,may showgrowth retardationpartly due to active disease and partly due to adverseeffects of drug treatment (glucocorticoids). In addition,problems related to the temporomandibular joint andGI difficulties secondary toNSAIDs andMTX inter-ferewith adequate intake. Childrenwith JIAtend tohave diminished bone formation due to several factors,including the action of cytokines, diminished physicalactivity, poor nutrition, and effects ofmedications.Therefore, advice on good nutritional intake has to bepart of overallmanagement. Special emphasis shouldbe placed on adequate calcium supplementation, par-ticularly in children taking glucocorticoids. Regularexercise suited to the disabilities of the child is alsoessential tomaintain bonemass.

Physical andOccupational Therapy

Goals of therapy in themanagement of JIAare relief ofpain,maintenance of joint range ofmotion, preventionof deformity and contracture,maintenance of function

Table 1.6

Indications for theUse ofGlucocorticoids in JIA

Systemic

Severe systemic diseaseCricoarytenoid arthritisSevere pericarditisVasculitis associatedwith RF-positive JIAMacrophage activation syndrome (MAS)

Local

Localized joint disease (exclude infection)Uveitis

Table 1.7

Biological Agents in the Treatment of JIA

Immunoglobulins

Anti-TNF agentsEtanerceptInfliximabAdalimumab

Anti-IL1Anakinra

in activities of daily living, and adequate rest andexercise.When prescribing a therapy program, thechild’s developmental stage, family support systems,and the severity of involvement should be taken intoaccount. Goals of therapy should be realistic. Therehas to be a daily routine of therapy, and some of theexercises may have to be incorporated into dailyactivities.

Rest is rarely indicated exceptwhen the child has peri-carditis or is acutely ill. It is best to allow children toset their own limits. Participation in physical educa-tion classes should be encouraged, provided the childis allowed to perform to his or her tolerance.Activitiessuch as headstands and cartwheels are prohibitedsincemany childrenwith JIAhave c-spine andwristinvolvement. Swimming as part of a therapy programprovides range ofmotion,muscle strengthening, andaerobic exercise and is therefore ideal for childrenwith JIA.

In the presence of active inflammation, pain and stiff-nessmay be pronounced, particularly in themorning.Ahot bath in themorning followed by application ofheat to specific joints is necessary before stretchingexercises can be started. For acute pain, splinting ofthe joint in a functional position is necessary. Thesplint should be removed twice a day and the childencouraged tomove the joint asmuch as possible.Passive stretching exercises and splintingmay helpregain range ofmotion. Prone lying is helpful toreduce hip flexion contracture. Serial castingmay behelpful in the treatment of hip flexion contracture andankle tightness. Cock-up splints for thewrist and pos-terior resting splints for the knees are examples ofsplints used to prevent deformities.

Active exercise is needed to build muscle strength.Bicycling and swimming are particularly useful,since weight bearing can be avoided. The idea is togradually move frommuscle strengthening to aero-bic exercises.

Children with neck involvement are encouraged touse a flat pillow or no pillow at night. During travelsin automobiles, children with c-spine disease shouldbe encouraged to use a cervical collar with a plasticinsert or a soft collar. Proper footwear is essential forchildren with arthritis of joints of the foot. Alightweight shoe that supports the ankle is useful formost children. Children withmetatarsophalangealinvolvement maywalk without a push-off andwillneed a rocker-bottom sole. Acustom-fitted shoeinsert may help children with extreme pronation orsupination deformity.

Surgery

Recent developments inmedicalmanagement havelimited the role of surgery in themanagement of JIA.In childrenwith fixed flexion contractures of the hipor knee joints, soft tissue releasesmay be necessary.Synovectomy, particularly through an arthroscope,may be indicated in childrenwithmonarticular arthri-tis that is not responsive tomedicalmanagement andhas resulted in significant impairment in jointmotion.Itmay also be useful in a childwith polyarticulararthritis responding tomedicalmanagement butwhohas limitation of function because of pain or synovialhypertrophy in a single joint.


Table 1.8

Guidelines During theUse of BiologicalAgents to Treat JIA

PPD testing (sometimes chest radiograph) is routinebefore initiating therapy

PPD ismandatory in high-risk groups

Watch for reactivationof TBsoonafter starting therapy

Should not be started in patients with active infections

Cautionwhen using in patients with recurrentinfections and immunodeficiencies

Should bediscontinued in patients withmoderate tosevere infections

Closelymonitor patients on these agents if theydevelop infections

RoutineCBConce in 6 to 8weeks

Replacement of hip and knee jointsmay be necessaryin childrenwith advanced erosive disease and jointdestruction. Themost important indication for jointreplacement surgery is pain. Important considerationsin themanagement of children undergoing surgeryinclude the following:

1. Proper preparation of the child and the family on thegoal to be accomplished (expected results)

2. Evaluation of blood counts, renal function, liverfunctions

3.Roentgenogramof the c-spine andwarninganesthesiologists

4.Assessment ofmouth opening (temporomandibularjoint)

5.Adjustments of the glucocorticoid dose

6.Discontinuation ofNSAIDs as appropriate

7. Reviewof the exercises that the childwill be askedto perform after surgery

8. Earlymobilization

Family Counseling andGeneral Care

Juvenile idiopathic arthritis is a chronic diseasewith acourse characterized by exacerbations and remissions.Therefore, it is important to educate the family and thechild and help them lead as normal a life as possible.Juvenile idiopathic arthritismay involvemany organsystems. Eye involvement and joint diseasemay inter-ferewith schoolwork and social activities. There hasto be coordinated carewith adequate communicationbetween the primary physician, consultants, the fam-ily, and the school personnel. Since communityresources have to be available, developing outreachservices andworkingwith community agencies areessential components of care of childrenwith JIAandother chronic diseases.

Prognosis/Outcome (Table 1.9)

Mortality is less than 1%-2% inmost parts of theworld. In Europe,where amyloidosis ismore com-mon, themortality rate is higher. Amyloidosis, infec-tion (related to drug therapy), andMASare themajorcauses of death.

Recent studies have shown that after 10 years of fol-low-up, almost 50%of childrenwith systemic onset,45%of childrenwith polyarticular onset, and 30%-


Table 1.9

Course of Arthritis and Prognosis

Onset Course Outcome

Polyarthritis RF seropositive PoorANApositive Good: Switch to systemic lupus erythematosusRF/ANAnegative Variable

Oligoarthritis ANApositive UveitisExtendedpauciarthritis Poor/erosivePersistent pauciarthritis Good

Systemic Oligoarthritis GoodPolyarthritis Poor

50%of childrenwith oligoarticular onset have activearthritis. Radiological evidence of arthritiswith jointspace narrowing or erosion occurs in almost twothirds of the patientswithin 2.5 years of onset, evenwhen treatment is started early. These datamaychangewith the current trend to useMTXand intra-articular steroids earlier in the course of the diseaseand the use of biological immunemodulators.

Earlier studies showed that almost one-third of chil-drenwith JIAfor 10 years ormorewere in Stein-brocker functional classes III and IV. In childrenwithsystemic-onset JIA, steroid dependency and highplatelet counts at 6months after the onset of the dis-ease have been shown to predict poor prognosis.Among thosewith polyarticular JIA, childrenwithRFpositivity, early involvement of the joints of the handsand feet, involvement of the hips, and joint erosionshave theworst functional outcome.Among thosewiththe oligoarticular type, almost 98%are in functionalclasses I and II, and half of themdo not need anymed-ications after a year of therapy.However, for approxi-mately 25%of these patients, the disease tends torecur even into adult life, and for approximately 20%,the disease tends to evolve into an extended pattern.

Recent studies utilizing functional measurement andquality of life measurement scales show that long-term outcome is generally favorable for mostpatients with JIA.7 In spite of issues related tochronic illness, chronic pain, and eye problems,many of them complete college, are gainfullyemployed, and have a family.

One of themost important developments in the fieldof pediatric rheumatology is the development of vali-dated scales tomeasure outcome.8 Themost com-monly used ones are theCore Set Criteria for

Improvement (Table 1.10) and theChildhoodVersionof theHealthAssessment Scale (C-HAQ). TheC-HAQ is a disease-specific scale formeasurement offunctional status. This scale iswidely used for tworeasons: it is adapted from the adult version (HAQ)and therefore useful for following a patient fromchildhood to adulthood, and it has been validated andtranslated into several languages. TheC-HAQcanalso be used as one component of theCore Set Crite-ria. Criteria for inactive disease both on and off treat-ment are in the development phase.


Table 1.10

Core Set Criteria for Improvement in JIA

Improvement is defined as at least 30% improvementfrombaseline in 3 of the 6 following core set variables,with nomore than one of the remaining variablesworsening by greater than 30%:

PhysicianGlobal Assessment (disease activity)

Parent/Patient Global Assessment (disease activity)

Functional ability (C-HAQ)

Number of joints with active arthritis

Number of joints with limited range ofmovement

Erythrocyte sedimentation rate

2. Spondyloarthropathy

The concept of seronegative spondyloarthropathy(SSp) was developed to describe conditions charac-terized by chronic arthritis, axial skeleton involve-ment, absence of RF andANAin the serum, familialaggregation, and association with B27.9 Conditionsdescribed in the earlier literature as HLAB27-related arthritis, oligoarticular JIAtype II, and SEAsyndrome fall within this category. Specific diseasessuch as inflammatory bowel disease (IBD)-relatedarthritis, Reiter’s syndrome, psoriatic spondy-loarthropathy, and juvenile ankylosing spondylitis(JAS) also belong in this category. In the newerILAR classification, several of these conditions arelisted under the name enthesitis-related arthritis(ERA). The exact relationship between juvenile SSp(JSSp) and the conditions included under the newclassification is unclear.1

Epidemiology

The following facts apply to childrenwith JSSp, asdefined before the introduction of the ILARclassifica-tion. Incidence and prevalence vary fromcountry tocountry, and evenwithin a country, often reflecting thefrequency ofHLAB27 in the population. The ratio ofJIAto JSSp is between 1.5 to 3:1.As a group, theseconditions occurmore in boys than in girls except forpsoriatic arthritis. Onset occurs around age 10 years.There is a strong associationwithHLAB27; this ishighest for JAS (82%-95%).Among the subtypes ofB27, B27.05 is themost common in JAS.Additionalgenetic factors predisposing to JAS include HLADRB1.08, HLADPB1.0301, and non-MHC geneLMP2.

Pathology and Pathogenesis

The pathological changes seen in the synoviumarethe same as those seen in JIA, although the inflamma-tionmay bemore acute. The differentiating feature isthe inflammation of the periarticular tissues, tendons,and entheses. In addition, up to 75%of patientswithSEAsyndrome and JAS shownonspecific inflamma-tory changes in the colon and the terminal ileum, evenin the absence of abdominal symptoms.Arthritis inassociationwith IBDand reactive arthritis (ReA) isseen followingGI and genitourinary infections. Thefollowing factors suggest thatmany of these condi-tions are triggered by infectious agents in a geneticallysusceptible host: relationshipwith severalMHCand

non-MHCantigens, the existence ofmolecularmimicry between several bacterial antigens andHLAB27 antigen, demonstration of bacterial antigens inthe joints of patientswithReAand existence ofCD4+, andHLAB27 restrictedT lymphocytes reactivewith products of enteric bacteria in the synoviumofpatientswithReA.Ankylosing spondylitis (AS)-likedisease,which develops only in a nonsterile environ-ment in theB27 transgenic rat, is a powerful finding infavor of this hypothesis.

Other investigations suggest that the assembling ofthe B27molecule with the putative peptide pro-duces an unstable complex in the reticulo-endothe-lial system, which in turn elicits a stress reaction andconcomitant expanded inflammatory response.None of the studies is specific for the pediatric formof the disease.

Juvenile Ankylosing Spondylitis (JAS)

Diagnostic criteria developed for adultswithAS(Table 2.1)when applied to childrenwill result in grossunderdiagnosis because sacroiliac changes take sev-eral years to develop.However, diagnosing JAS in theabsence of sacroiliac changesmay result inmislabel-ing ofmany children.Actual numbers of childrenwithtrue JASare low.Approximately 10%of the adultswithAShad their disease onset in childhood.

Clinical FindingsIn JAS, peripheral arthritis precedes axial arthritis bymanyyears.Night pain,morning stiffness, and lowbackpain are relieved bymovement.Asymmetricarthritis involving joints of the lower extremity is com-mon.Early or isolated involvement of the hip jointmaybe seen (rare in JIA). Enthesitis, particularly at theinsertions of tendoachilles and plantar fascia,maybedisabling. Tenderness at the sacroiliac joints andrestricted range ofmotion of the spinemaybe demon-strated longbefore radiological changes become evi-dent.Among the extra-articular features, acute iritis isrelativelymore common, and aortic regurgitation, api-cal pleural thickening, and cardiac conduction defectsare less common in children.

LaboratoryFindingsEvidence of inflammation, such as elevated sedimen-tation rate and anemia of chronic illness,maybe seen.HLAB27 is seen in over 90%of patients. Characteris-


tic radiological changes described in adults are rarelyseen. Themost common findings in children areapparent widening of the joint space and sclerosisaround the sacroiliac joints on plain radiographs. Thevalue of other imagingmodalities has not been estab-lished in pediatrics. If doubts arise, CT scan orMRI,or both,may be used.

TreatmentMedications to control inflammation and physicaltherapy to relieve pain andmaintain function are thecornerstones of management of children with JAS.Treatment should start with one of the NSAIDs.Indomethacin and naproxen are themost commonlyprescribed drugs; however, some childrenmay nottolerate indomethacin. If NSAIDs are not effective,sulfasalazine should be added (Table 1.5). If sul-fasalazine is started, children should bemonitoredfor cutaneous rash, bonemarrow toxicity, and hepa-

totoxicity. Occasional doses bymouth of glucocorti-coidsmay be needed, particularly in the presence ofsevere enthesitis. Recently, etanercept and inflix-imab have emerged as the treatments of choice forAS. There are anecdotal reports of their usefulness inthe pediatric age group.

In the pediatric age group, local injectionwith gluco-corticoid is not routinely used for the treatment ofplantar fasciitis. Custom-made orthotics for shoes andphysicalmodalities of therapy, such as heat and cold,may be used to relieve pain. Exercises to stretch theback and expand the chest and good sitting posture areother essential elements of a physical therapy pro-gram. In addition, providing psychosocial support isessential to help the child and family live as normal alife as possible. Sincemost of these children are in theadolescent age group, psychosocial counselingbecomes necessary.

Enthesitis-RelatedArthritis

In the new classification schema, ERAis a separatecategory (Table 2.2). Enthesitis-related arthritis defi-nitely includes JAS andSEAsyndrome, and probablyincludes IBD-related arthropathy and reactivearthropathy, but does not include psoriatic arthritis.Themost important clinical characteristics of ERAareonsetmost commonly in the preadolescent or adoles-cent age groups,male preponderance, oligoarticularor polyarticular arthritis predominantly in the lowerextremities, asymmetric joint involvement, enthesitis,and a strong associationwithHLAB27. Systemic fea-tures are not prominent, although somemay have sig-nificantweight loss. Lumbosacral symptoms andsigns are not commonly present. Onsetmay be pre-ceded by infection of theGI or genitourinary tract.Rashmay be present depending on associated condi-tions (Reiter’s syndrome).Acute iritis has a signifi-cant associationwith this subtype.

Laboratory studies should includeCBCandmeasure-ment of acute phase reactants, determination ofRForANA(to show their absence) andHLAB27 (to showits presence), and imaging studies as needed.Culturesof theGI andgenitourinary tracts and endoscopicinvestigations of theGI tractmaybe needed if there aresymptoms suggestive of involvement of these organs.Follow-up should includemonitoring for evolution


Table 2.1

Diagnostic Criteria forAnkylosing Spondylitis

Diagnostic criteria for AS

Limitation of lumbar spinemotion in 3 planes

Pain or a history of pain at dorsolumbar junctionof spine

Limitation of chest expansion to 2.5 cmor less

Definite AS

Grade 3-4 –Bilateral sacroiliitis on radiography plusone criterion

Grade 3-4 –Unilateral or grade 2 bilateral sacroiliitisplus criterion 1 or criteria 2 and 3

Probable AS

Grade 3-4 –Bilateral sacroiliitis and noclinical criteria


into JASorCrohn’s disease. The evolution to spondy-loarthropathy occurs in one-third to two-thirds ofpatients according to different series.

Reactive Arthritis (ReA)

Reactive arthritis is defined as acute onset of arthritisoccurring 1 to 6weeks after an infection of theGI orgenitourinary tract. If it is associatedwith urethritisand conjunctivitis, the termReiter’s syndrome isapplied. Symptoms and signs clear over a period ofmonths to 1 or 2 years in some butmay evolve intoASor chronic peripheral arthritis.

Clinical FindingsIn children, ReAoften follows intestinal infection.Most of the time, these symptoms are resolved by thetime the rheumatic symptoms are present. It is impor-tant to take a good epidemiological history to establishexposure at school or during recreational activitiesand to document episodes of enteric infection in the

recent pastwithin the patient’s household. Themostcommonorganisms are Salmonella typhimurium,Shigella flexneri, Campylobacter jejuni, Yersiniapseudotuberculosis, andYersinia enterocolitica. Theclinical features of arthritis are similar to those seen inall of the SSp syndromes.Dysuria and sterile pyuriamay suggest the presence of urethritis. Conjunctivitis,and sometimes uveitis, are seen,which are both acutein onset. Keratoderma blennorrhagicum is a rare find-ing in children.

LaboratoryFindingsIn addition to routine blood counts, appropriate cul-tures of urethra, cervix, conjunctiva and of the stoolare essential, althoughmost of the time stool culturesobtained after resolution of diarrheal episodes are notvery helpful. The value of serology is still debated.Electronicmicroscopy of the synoviumand analysisof the synovial fluid using polymerase chain reactionto look for infectious agents are still experimental.Efforts should bemade to culture some of the fastidi-ous organisms associatedwithReA. Synovial fluidculturesmay be needed to rule out septic arthritis.

TreatmentTreatment of the infection (if appropriate) and the useofNSAIDs are effective inmost cases.

IBD-Associated Arthritis

Both ulcerative colitis andCrohn’s diseasemay beassociatedwith arthritis. Arthritismay be peripheralor axial. Peripheral arthritis ismore common and isseen in close associationwith the onset or flare ofinflammation in the gut. It usually involves largejoints, is asymmetric, and is nonerosive.Axial arthri-tis does not correlatewith IBDactivity but is associ-atedwith the presence ofHLAB27. There is greaterincidence of IBD-associated arthritis inmales. Inflam-matory bowel disease should be suspectedwhenarthritis occurs in associationwith growth retardation,unexplained anemia, and unexplained fevers orabdominal pain.Growth retardation is themostimportant systemic feature. Cutaneousmanifestationsincluding erythema nodosumand pyoderma gan-grenosumcan be seen.Uveitis is rare. There are sev-eral reports of an association between celiac diseaseand arthritis.

Table 2.2

Enthesitis-RelatedArthritis

Definition

Arthritis and enthesitis OR

Arthritis or enthesitis with at least 2 of the following:• Sacroiliac joint tenderness or inflammatoryspinal pain, or both

• Presence of HLAB27• Family history in at least first- or second-degreerelative ofmedically confirmedHLAB27-relateddisease

•Anterior uveitis that is usually associatedwithpain, redness, or photophobia

•Onset of arthritis in a boy after 8 years of age

Exclusions

Psoriasis confirmedby a dermatologist in at least onefirst- or second-degree relative

Presence of systemic arthritis

Laboratory InvestigationsIn addition to routine investigations, stool for occultblood, contrast studies of theGI tract, endoscopy (ifthere are symptoms), andmeasurement of antineu-trophil cytoplasmic antibody (ANCA)may help insome cases. IgAantibodies to tissue transglutaminaseare of diagnostic value in celiac disease provided thepatient does not have IgAdeficiency.

TreatmentTreatment of the primary disease is themost impor-tant step. TheNSAIDsmay be added to controlarthritis, although some of these drugsmay aggravatecolitis. Use of infliximab has been, perhaps, the sin-glemost encouraging advance in the treatment ofCrohn’s disease and its extra-intestinal complica-tions. Etanercept has not been effective. Adalimumabhas been found effective in the treatment of patientswho did not respond to therapywith infliximab.Morerecently, this biological agent has been used success-fully as the initial therapy for Crohn’s disease. Inulcerative colitis,MTX can be effective to controlintestinal and extra-intestinal disease. Sometimes,controlling the intestinal diseasewith sulfasalazine orother non-absorbablemedicationsmay control thejoint disease; however, most of the time, the arthriticsymptoms need specific therapy. The arthritis ofceliac diseasemay improvewith dietarymanipula-tion. TheNSAIDsmay elicit or worsen intestinalflares in patients with colitic arthritis and, therefore,should be usedwith caution.

Psoriatic Arthritis

Juvenile psoriatic arthritis (JPsA) is a separate subsetof JIAin the new classification. Thismay be difficultto diagnose because the rash often does not appear formany years after the onset of arthritis. The incidencein childhood is unknown; it occursmore often in girlsthan in boys andmay be seen at any age (even in 1 to 2year olds). HLAB27 is associatedwith the occurrenceof sacroiliitis. Approximately 50%of childrenwithJPsAhave no, or verymild, skin diseasewhen arthritisoccurs; however, certain characteristics of arthritisshould suggest this possibility. These characteristics

include acute inflammatory arthritis, involvement ofjoints of the fingers and toeswith tenosynovitis(sausage digit), and asymmetric oligoarthritis. Othersubtypes of arthritis described in adults are not com-monly seen in children. Cervical spine involvement iscommon, but sacroiliac joint involvement is uncom-mon.Nail pitting and skin rash,when seen, are char-acteristic. Chronic uveitismight also be seen.Antinu-clear antibodiesmay be present in some childrenwithJPsA. Table 2.3 lists the ILARcriteria for the classifi-cation of JPsA.

TreatmentMost children respond to treatmentwith one of theNSAIDs. In some patients, glucocorticoids andMTXmay be needed. Some clinicians prefer sulfasalazine.Etanerceptmay be another good option for both thejoint and skin disease.


Table 2.3

ILARCriteria for Psoriatic Arthritis

Arthritis andpsoriasisOR

Arthritis and at least one of the following:DactylitisNail pitting or onycholysisFamily history of psoriasis in a first-degree relative

Exclusions

Presence of rheumatoid factor

Presence of systemic juvenile idiopathic arthritis

Presence of family history ofHLAB27-associated disease

Onset of arthritis in a boywithHLAB27 afterthe age of 6 years

autoantibodies thanwith the clinical expression of thedisease.Defects in the formation and clearance ofimmune complexes are strongly linked to the patho-genesis of SLE.

Clinical Features

The onset of SLEmay be acute or insidious. Initialmanifestationmay involve only one organ system,such as the kidney or theCNS, inwhich case diagno-sis is difficult.Most commonly it involvesmore thanone system, such as the skin and the joints, followedbymucosa and the kidney.Generalized nonspecificfeatures such as fever, fatigue, andweight loss are uni-versal. Fever and lymphadenopathy aremore com-mon in children than in adults. Occasionally, signifi-cant growth retardationmay precede the onset ofother signs and symptoms in children. Serositisinvolving pleura, pericardium, and peritoneum,especiallywhen it involves all of these surfaces(polyserositis), is a characteristic feature of SLE.

MusculoskeletalArthralgia andmyalgia are seen in themajority ofchildrenwith SLE.Arthritis of SLE is classicallypolyarticular in nature and involves small and largejoints symmetrically. Itmay be intermittent ormigra-tory.Often the pain is out of proportion to theswelling, though erosive arthritis is uncommon.Occa-sionally, children diagnosed as having JIAmay switchover to a clinical spectrum resembling SLE. Tenosyn-ovitis, particularly around thewrist,may be seen inchildhoodSLE.Myositiswith generalized pain andtenderness is often seen in childrenwith severe sys-temic vasculitis and acute presentation.

Skin andMucosaSkinmanifestations of SLEmay be classified aslesions specific and nonspecific for SLE (Table 3.1).Clinical features of these lesions are similar to thoseseen in adults.

Raynaud’s phenomenon is seen in approximately15%-25%of childrenwith SLE andmay lead to gan-grene of the fingertips. SevereRaynaud’s phe-nomenon and sclerodactyly, however, should suggestoverlapping syndromes.

Shallow irregular ulcers of the oralmucosa are oftenmultiple andmay involve the hard palate, soft palate,


3. Systemic Lupus Erythematosus

Systemic lupus erythematosus in children is amultisys-temautoimmunedisorderwithvaried clinicalmanifes-tations andepisodesof remission andexacerbations.10

Epidemiology

Approximately 15%of all cases of SLEoccur in thepediatric age group. The incidence is approximately0.5 per 100,000, and the prevalence rate variesdepending on race and sex. The female-to-male ratiois approximately 4.5:1. It is uncommonbefore the ageof 5 years, and the frequency increaseswith age. Themajority of cases of SLE seen in children are in theadolescent age group, andAfrican-American andAsian girls show the highest prevalence.

Etiology and Pathogenesis

The cause of lupus is unknown and is probablymulti-factorial. Exposure to infections, physical agents suchas ultraviolet light, drugs, and stress has been noted inassociationwith the onset of SLE.Hormonal factorshave also been shown tomodulate immune responseand play a part in diseasemanifestation and exacerba-tion.One ormore of these factorsmay precipitate anautoimmune process in a genetically susceptible host.

Familial clustering and the incidence in twins suggestgenetic susceptibility to SLE. Twenty-four percent ofmonozygotic twins develop SLE, comparedwith 2%of dizygotic twins. The concordance rate inmonozy-gotic twins is also small. However, the greater thantenfold difference in the incidence betweenmono- anddizygotic twins is similar to other autoimmune dis-eases, suggesting that both genetic and nongeneticfactors are important. At least 6 different loci on chro-mosomes 1, 2, 4, 6, and 16may contribute to geneticsusceptibility to SLE.

Additional evidence for genetic contribution to the eti-ology is the association between inherited deficiencyof complement components, specifically homozygousC2 andC4, and SLE. Polymorphisms in cytokines andFc receptors, abnormality of�-cell function, anddefects in apoptosis have been implicated in the patho-genesis of SLE.Also, there is an associationwithHLADR3 inAmericanwhites of European extractionandHLADR2 inAmericans ofAfrican-Caribbeandescent. It appears that specificHLAgenes aremoreclosely associatedwith the production of specific


uvula, and the buccalmucosa and are relatively pain-less. Nasal ulcers are commonbut perforation is rarein children.

HeartApproximately 30%-42%of childrenwith SLEdevelop cardiac disease. Pericarditis andmyocarditisare themost commonmanifestations. Signs andsymptoms are similar to those in adults. Other cardiacabnormalities include valvular disease and coronaryartery disease.Valvular diseasemay be due to aninfectious process (opportunistic infection) or to thedisease process itself (Libman-Sacks). Aclinicallysignificantmurmurmay be present. Lesions ofLibman-Sacks can be demonstrated by echocardiog-

raphy.Myocardial perfusion studies have demon-strated segmental abnormalities in childrenwith SLEin the absence of clinical symptoms.

LungPleuropulmonary disease is less common in childrenthan in adults, particularlymassive pleural effusions,shrinking lung syndrome, diffuse pulmonary infil-trates, and pulmonary hypertension.However, pul-monary infections superimposed onSLE are commonandmay precipitate a flare. Pleuritis, acute pneumoni-tis, and pulmonary hemorrhage are commonly associ-atedwith childhoodSLE. Pulmonary function abnor-malities characterized by diffusion defects and evi-dence of restrictive lung disease are common andmaybe seen evenwith normal radiological appearance.

Gastrointestinal TractGastrointestinalmanifestations are not diagnostic ofSLE and include serositis, vasculitis of the intestinesresulting in acuteGI bleeding, perforation of the vis-cera, and pancreatitis. Both acute pancreatitis andGIhemorrhagemay be related to the disease or to gluco-corticoid treatment. In children, protein-losingenteropathy andmalabsorption syndromemay be thepresentingmanifestations of SLE.

Abdominal pain is a common symptom in children.Involvement of intra-abdominal tissues and organs bythe disease itself; adverse effects of drugs used to treatSLE; incidental, common conditions such aspyelonephritis and appendicitis; and emotional factorsin response to a chronic conditionmay allmanifest asabdominal pain. Judicial investigations are essential tolook for themost common andmost urgent causes ofthis common symptom.

Lymphatic SystemGeneralized lymphadenopathy is common in chil-dren with SLE. Some children withmassive lym-phadenopathy and hepatosplenomegalymay initiallysee an oncologist before being referred to a rheuma-tologist. Exclusion ofmalignancy is obviouslyessential before using glucocorticoids andimmunosuppressors.

Nervous SystemNeuropsychiatricmanifestations of SLE includeheadache, seizure,mood and cognitive disorders,movement disorders, psychosis, and disorders of the

Table 3.1

CutaneousManifestations AssociatedWithSystemic Lupus Erythematosus in Children

Specific lesions

Localized facial (malar) erythema

Annular, polycyclic (submacular cutaneous)

Widespread erythema

Discoid lupus (localized: generalized)

Lupus profundus

Bullous lesions

Nonspecific lesions

Raynaud’s phenomenon

Livedo reticularis

Dermal vasculitis

Subcutaneous nodules

Alopecia


spinal cord and peripheral nervous system. Problemsof decidingwhen these signs and symptoms are due toSLE andwhen they are secondary to other causes,such as infection or adverse effects of therapy, aresimilar to those experienced in adults.

Headache is a common complaint andmay be due tomultiple causes, though headache, evenwithout asso-ciated evidences of intracranial pathology, requiresinvestigation if it is persistent (for over 1 or 2 days)and is not responsive to analgesics. It is essential torule out opportunistic infections, hypertension, and allother causes of increased intracranial pressure. Fun-doscopic eye examinationmay reveal papilledema,cotton-wool spots, and hemorrhages. Since hyperten-sive retinopathy and diabetic retinopathy are uncom-mon in children, differential diagnosis is relativelyeasy.Other abnormalitiesmay include retinal arteryocclusion due to vasculitis.

Seizure is one of themost commonmanifestations ofSLE (approximately 10% to 20%). Itmay be seen asthe presentingmanifestation, often resulting in treat-mentwith anticonvulsants for a year or two beforeSLE is diagnosed.Under this circumstance, it is oftendifficult to determinewhether the SLEwas druginduced orwhether the initial seizurewas due toCNSdisease secondary to SLE.

Chorea is themost commonmovement disorder inchildren, and, at present, themost common cause ofchorea in theWesternHemisphere is SLE (not acuterheumatic fever). Cranial and peripheral neuropathiesand transversemyelitis do occur in children but not ascommonly as in adults.

Psychosis (characterized by loss of short-termmem-ory and hallucinations) and seizure are themost com-monmanifestations. Slowdeterioration in school-workmay occasionally be the presenting evidence ofCNS lupus, but other causes of school failure, such assubstance abuse and depression, aremuchmore com-mon and should be excluded before considering thediagnosis of SLE. Emotional lability, anxiety, anddepressionmay occur because of the child’s responseto a devastating chronic illness. Cosmetic defects dueto the skin disease and glucocorticoid therapy oftenprecipitate serious behavioral problems, particularlyin the adolescent age group, leading tomajor depres-sion and noncompliancewith therapy.

KidneyRenal disease at the onset of SLE ismore common inchildren than in adults.11 It is characterized by protein-uria, hematuria, and cylindruria.Othermodes of pre-sentation include hypertension, renal failure,nephrotic syndrome, or asymptomatic protein-uria/hematuria. Renal disease of SLE, however, isoften asymptomatic, and renal histologymay beabnormal even if urinalysis is normal. Therefore, rou-tine urinalysis of freshly voided urine (includingmicroscopy) and assessment of renal function are anessential part of routinemanagement of childrenwithSLE.Histopathological classification of lupus nephri-tis is the same in children as in adults.12 Diffuse prolif-erative glomerulonephritis (DPGN) (class IV) is themost commonly diagnosed subgroup and is associ-atedwithmore severe disease and bad prognosis.Other less common renalmanifestations includehematuria (secondary to drug-induced cystitis), reno-vascular hypertension, and renal vein thrombosis.

BloodHematological abnormalities are less common in chil-dren than in adults. Anemia is themost commonabnormality and is often related to chronic illness.However, reticulocyte count andCoombs’test shouldbe evaluated in all childrenwith SLE to excludehemolysis. Leukopeniawith absolute lymphocytecount less than 1,500 is characteristic of active dis-ease. Leukocytosis (even in the normal range)may beevidence of infection or prior therapywith glucocorti-coids. Band forms of over 10%-15%should alsomake one suspect infection. Thrombocytopeniaoccurs in less than 20%of patients at presentation.Childrenmay have antiplatelet antibodywithout lowplatelet count. Themost common coagulation abnor-mality is prolonged PTTsecondary to associatedlupus anticoagulant. This is often associatedwithincreased risk of thrombosis. The PTandPTTareboth prolonged in the presence of other antibodiesagainst coagulation factors, and the risk of bleeding ishigh in these children.

EndocrineThemost important association is the presence ofantithyroid antibodies,whichmay be seen in up to40%of childrenwith SLE.Hashimoto’s thyroiditismay be the presentingmanifestation of SLE in chil-dren.Delay in the onset ofmenstruationmay occur as

part of the disease or secondary to chronic glucocorti-coid therapy. Steroid-induced diabetesmellitus isanother important comorbidity.

Diagnosis

Systemic lupus erythematosus should be consideredin the differential diagnosis of any childwithmulti-systemdisease, particularly ifANAis positive. Thedata set developed by theACR (Table 3.2) ismeant tobe used for classification purposes and to selectpatients for clinical therapeutic studies. In one studyfromBrazil, the older criteria of 1982were applied to103 childrenwith SLE and 101 childrenwith otherrheumatic diseases.When 4 of 11 criteriawere set asthe requirement for diagnosis, the sensitivitywas 96%and specificitywas 100%.Evenwhen the limitwasset at 3 criteria, sensitivitywas 100%and specificitywas 97%. In actual clinical settings, the diagnosis ofSLE can bemadewith as few as 2 or 3 criteria pro-vided other conditions have been excluded and sero-logical evidence of autoimmunity is present.

Laboratory Features

Antinuclear antibody is themost sensitive test for thediagnosis of SLE, but it is nonspecific. The actualprevalence of low titerANAin the normal childhoodpopulation is not known; small studies show that thefrequency can be estimated to be between 5%and10%.Nonspecific elevation ofANAmay be seen fol-lowing viral infections, Lyme disease, andmalignan-cies. Antinuclear antibodymay be positive in certainsubtypes of JIA, scleroderma, dermatomyositis,mixed connective tissue disease, and Sjögren’s syn-drome.An occasional childwith SLEwho isANAnegativemay have SSAor SSB antibodieswhen acomplete profile is obtained.

Antibodies to double-strandedDNAare pathog-nomonic of SLE and are almost always elevated inactive disease.Antibodies to Smare very specific butare seen in approximately 30%of childrenwith SLE.High titer antibody to double-strandedDNAcorre-lateswith active disease and nephritis and can be usedtomonitor therapy.

Antihistone antibodies are seen in drug-inducedlupus. The drugsmost commonly associatedwithlupus in children are anticonvulsants, antithyroid

medications, andminocycline (commonly used totreat acne).

Initial laboratory investigations of childrenwith SLEshould include total hemolytic complement to iden-tify childrenwith deficiency of complement compo-nents. C3 andC4 aremeasured serially tomonitorcourse of disease and response to therapy.

ElevatedESR, anemia, and low serumalbumin arecommon in active SLE and are useful tomonitor thecourse of the disease. Few clinicians routinely obtainCRPandESRand use acute elevation ofCRPas evi-dence of infection.

In addition to these general investigations, specificstudiesmay have to be obtained depending on theorgan system involved.All patients should have achest radiograph to look for cardiac and pulmonaryabnormality.Other appropriate investigationsmayinclude electrocardiogram (EKG), echocardiogram,and pulmonary function studies. Skin biopsy is rarelyneeded for the diagnosis of SLE.

Baseline renal studies should include urinalysis;serum levels of blood urea nitrogen, creatinine, andalbumin; and 24-hour urine collection for protein andcreatinine clearance.Abnormal urinalysis alone in thepresence of elevated anti-DNAand lowC3 is pathog-nomonic for lupus nephritis. Indications for renalbiopsy are outlined in Table 3.3.

It is difficult to establish the diagnosis ofCNS lupusby laboratorymethods.However, analysis of the cere-brospinal fluid (CSF) is essential to rule out oppor-tunistic infections by bacteria and fungi. TheCSFfindingsmay be normal ormay showelevated proteinand pleocytosis. Asepticmeningitis is characterizedby pleocytosis,mostlymononuclear. Elevated pres-surewithout alterations in protein or cells is observedwith pseudotumor.Measurements of complementlevels inCSF are not clinically practical or useful. Inup to 70%of children, electroencephalogram resultsmay be abnormalwith diffuse slowing throughout.Focal changes are less common.BothCTscan andMRImay help exclude infarction and hemorrhage.Magnetic resonance imaging is the preferredmode ofinvestigation of suspected neuropsychiatric lupus. Itmay be normal or reveal edema, atrophy, or focallesions in thewhitematter secondary to vasculitis.



Table 3.2

1997Update of the 1982AmericanCollege of RheumatologyClassification Criteria forSystemic Lupus Erythematosus

Item Definition

Malar rash Fixed erythema, flat or raised, over themalar eminences, sparing thenasolabial folds

Discoid rash Erythematous raised patcheswith adherent keratotic scaling and follicularplugging; atrophic scarringmay occur in older lesions

Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history orphysician observation

Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observedby a physician

Nonerosive arthritis Involving 2 ormore peripheral joints, characterized by tenderness, swelling,or effusion

Pleuritis or pericarditis a. Pleuritis—convincing history of pleuritic pain or rub heard by a physician orevidence of pleural effusion

ORb. Pericarditis—documented by electrocardiogramor rub heard by aphysician or evidence of pleural effusion

Renal disorder a. Persistent proteinuria >0.5 gmper day or >3+ if quantitation not performedORb.Cellular casts—maybe red cell, hemoglobin, granular, tubular, ormixed

Neurologic disorder a. Seizures—in the absence of offending drugs or knownmetabolicderangement, eg, uremia, ketoacidosis, or electrolyte imbalance

ORb. Psychosis—in the absence of offending drugs or knownmetabolicderangement, eg, uremia, ketoacidosis, or electrolyte imbalance

(continued)


Newer techniques of evaluation of brain function suchas PETscan are notwidely available and have notbeen evaluated adequately in children.

Plain radiographs of the bones and jointsmay beneededwhen fracture, infection, or avascular necrosisis suspected. Children on long-term steroid therapyshould have aDEXAscan tomeasure bone densityonce every 2 years.

Therapy

Management of SLE in children should include gen-eral supportive care and specific anti-inflammatory orimmunosuppressive therapy, or both.

General SupportiveCareCounseling. This includes education of the family,child (if appropriate), and other caregivers (includingschoolteachers) to help the child lead as normal a lifeas possible.

Advice onnutrition, skin care, exercise, and rest.The child should be encouraged to participate inschool and extracurricular activities to his or her toler-ance and according to the activity of disease. It is bestto encourage them to understand their disease andtake appropriate precautions such as the use of sun-screen for outdoor activities. Sunscreenswith an SPFequal to or greater than 15 should be used on all sun-exposed areas. Sunscreenswith awater base are ideal

Table 3.2 (continued)

1997Update of the 1982AmericanCollege of RheumatologyClassification Criteria forSystemic Lupus Erythematosus

Item Definition

Hematologic disorder a. Hemolytic anemiawith reticulocytosisORb. Leukopenia <4,000/mm3 onmore than or equal to 2 occasionsORc. Lymphopenia <1,500/mm3 onmore than or equal to 2 occasionsORd. Thrombocytopenia <100,000/mm3 in the absence of offending drugs

Immunologic disorder a. Anti-DNA: antibody to nativeDNA in abnormal titerORb. Anti-Sm: presence of antibody to Smnuclear antigenORc. Positive finding of antiphospholipid antibodies based on:1) an abnormal serum level of IgGor IgManticardiolipin antibodies2) apositive test result for lupus anticoagulant usinga standardmethod,OR3) a false-positive test result for at least 6months and confirmedbyTreponemapallidum immobilization or fluorescent treponemal antibodyabsorption test

Positive antinuclear antibody An abnormal titer of antinuclear antibody by immunofluorescence or anequivalent assay at any point in time in the absence of drugs

FromHochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemiclupus erythematosus.Arthritis Rheum. 1997;40(9):1725.


for use on the face, and thosewith an alcohol base forthe rest of the body. Reapplication after swimming orsweating is indicated. Adolescent girls withsevere skin problems and scarring and pigmentarychanges may require cosmetic preparations to maskthese skin lesions.

Good general nutrition is essential. In addition, chil-dren and family should receive education on salt-restricted, low-caloric dietwhen receiving glucocorti-coids. Children receiving long-termglucocorticoidsshould learn about supplementationwith high-potas-siumdiets and high-calciumdiets. They should beencouraged to take 1 g to 1.2 g calcium supplements aday. They should be encouraged to take part in regularexercise activities to their tolerance and encouraged totake periods of rest, particularlywhen the disease isactive. Childrenwith severe anemia,myocarditis, andhypertension should obviously be restricted, althoughthey need not be kept on strict bed rest.

Well-child issues. Growth and development, antici-patory guidance, and immunization require extraattention. In addition to routine immunizations, chil-drenwith SLE should receive immunization againstpneumococcus (because of their functional asplenia)and yearly immunizations against influenza viral

infection. Children on glucocorticoids and immuno-suppressives should not receive live virus vaccines.

Recognition and prompt treatment of secondaryproblems such as infections. Although fever in chil-drenwith SLE is as likely to be due to community-acquired infection as in normal children, all feversshould be taken seriously, particularly in those on glu-cocorticoids and immunosuppressives.Also, an inter-current infectionmay precipitate a flare of SLE.Therefore, it is best to take appropriate culturesincludingCSF (if appropriate) and chest radiographsbefore treatment. If necessary, cultures should beobtained and treatment startedwith both broad-spec-trum antibiotics and glucocorticoids until the fevercan be attributed to infection or flare, or both.

Hypertension. This is a major cause of morbidity inchildren with SLE, and adequate management ofhypertension should be a major part of generalmanagement.

Minimizing adverse effects of drug therapy. Thisincludes efforts tominimize adverse effects of gluco-corticoids such as the use of alternate-day steroid ther-apy and steroid-sparing agents, low-sodiumdiet, andcalcium supplementation.Adverse effects of “bolus”therapywith cyclophosphamide should beminimizedwith the use of intravenous hydration for 24 hours,MESNA, anti-emetics, cycling therapy duringmiddleofmenstrual cycle, carefulmonitoring of nadirWBCcount, and readjusting the dose of cyclophosphamideaccordingly. Experiencewith the use of agents toblock release of gonadotropins in the adolescent agegroup is limited.

Recognition of flare early and aggressive treatmentare also important.

Specific Treatment for SLE

Treatment of SLEhas to be tailored to individualneeds depending on severity of the disease and organsystem involved.

Mild disease characterized by fever, rash,myalgia,and arthritis early in the course of or during early flarecan bemanagedwithNSAIDs. Commonly usedNSAIDs and their doses are listed in Table 1.5. It isbetter to avoid acetylsalicylic acid because of its sig-

Table 3.3

Indications for Renal Biopsy in Children

Childwith nephrotic syndrome inwhom it isdifficult to differentiate between class IV andclass V nephritis

Child inwhom there is rapid deterioration ofrenal function in the presence of high-doseglucocorticoid therapy

Child inwhom there is a suspicion of scarring of thekidney (as an aid to stopping aggressive therapy)

Entry into clinical therapeutic trials

Used with permission fromMalleson PN. The role of renalbiopsy in childhood onset systemic lupus erythematosus:a viewpoint.Clin Exp Rheumatol. 1989;7(5):563-566.


nificant adverse effects on theGI tract and liver andibuprofen because of a potential for precipitatingasepticmeningitis-like syndrome.

Moderately active disease characterized by persistentfever, painful arthritis,myositis, pleuritis, andmildvasculitic rash is best treatedwithmoderate doses ofprednisone (1mg/kg/day equivalent). Hydroxy-chloroquinemay be added to this regimen if skin dis-ease is a significant problem. The starting dose is 5-6mg/kg/day up to amaximumdose of 400mg/day andthen reduced to 3-5mg/kg/day after 2months. Chil-dren requiring hydroxychloroquine should get theireyes examined every 6months. Topical steroidsmaybe used for short periods of time, but they should beusedwith caution for facial lesions. Topicaltacrolimus is also effective. Formild skin diseasewithout systemic features, hydroxychloroquine alonemay be adequate. Resistant dermatitismay be treatedwith other antimalarials (quinacrine) or dapsone.

More severe disease characterized by vasculitic rash(with infarction), pleural and pericardial effusion,pneumonitis,myocarditis, hemolytic anemia, throm-bocytopenia,most neurological problems, andglomerulonephritis are best treated with a high doseof prednisone (2mg/kg/day) orally or parenterallydepending on the acuity and severity. In acute dis-ease or in the presence of a rapidly declining clinicalcondition, it is best to usemethylprednisone as intra-venous bolus (“pulse steroid therapy”). The dose is30mg/kg (max 1g) dissolved in 50-100ml of 5%D/Wand given as a bolus over 45minutes to 1 hour.Vital signs, particularly blood pressure, should bemonitored every 10 to 15minutes during the infu-sion. In children with severe hypertension, it is saferto avoid this approach, but, if it is necessary, itshould be usedwith caution and the dose should beinfused over 1 to 2 hours.

Focal andmesangial glomerulonephritismay betreatedwith prednisone alone at 0.5 to 1mg/kg/dayfor 2 to 4months followed by gradual tapering of thedose. Currently, treatment of diffuse glomeru-lonephritis includes both glucocorticoids and intra-venous cyclophosphamide.

Intravenous cyclophosphamide is given as bolusdoses according toNIHprotocol or one of the vari-ants. Although not curative, this formof therapy prob-

ably delays the onset of permanent renal failure. Thisformof therapy also reducesmorbidity such as infec-tions and bladder toxicity comparedwith oral therapy.However, long-term effects on fertility and onco-genicity are of concern.During this therapy,WBC isto bemonitored and the dose adjusted tomaintain theWBCcount during the secondweek after infusionbetween 3000 and 4000mm3.

The current trend in the treatment ofDPGNof SLEseems to be the induction of therapywith intravenousbolus cyclophosphamide once amonth for 6months,followed bymaintenance therapy using azathioprineormycophenolate.13

Chlorambucil ormycophenolate can be used for chil-drenwith TypeVnephritis not responding to steroidtherapy or if the adverse effects of steroids are at unac-ceptable levels. In a childwith end-stage renal dis-ease, particularly if biopsy shows extensive scarringwithminimal inflammation, it is best to stop usingimmunosuppressives.

The drug of choice for significant and recurrentthrombocytopenia is IV IG. The total dose is 1 g/kggiven once a day for 2 to 3 days. It is given in additionto glucocorticoids, and the response is often rapid.This is also helpful in the treatment of hemolytic ane-mia, but to a lesser extent.

For rapidly progressivemultisystemdisease, the useof plasmapheresis is justified, although clinical stud-ies have not shownbenefits.

Oneother agent thatmaybeof use in childrenwithSLEismycophenolatemofetil, both as a steroid-sparingagent and formaintenance therapy.There are reports onthe use of stemcell transplantation for the treatment ofsevereSLEnot responding to standard therapy.14Moreprotocol-driven studies are needed before the indica-tion so that efficacy and safety can be determined.

Blocking TNF action with biological immunemodu-lators is not a favored approach because these agentshave been shown to induce the formation of ANAand anti-DNAantibodies. There are anecdotalreports of the use of anti-CD20 antibody (rituximab)in severe SLEwith favorable response. Experiencewith autologous bonemarrow transplantation is alsolimited in children.


Course and Prognosis

Mortality in childhoodSLEhas improved consider-ably since the 1970s,mainly because of early recogni-tion of the disease, recognition ofmilder disease, theavailability and better use of antibiotics and immuno-suppressives, and improved critical care techniques.Recent studies have shown a 10-year survival of 85%.Predictably, renal andCNS involvement are associ-atedwith significantmorbidity and death; however,infection is the leading immediate cause of death inchildrenwith SLE.

With improved survival, there is an increase inmor-bidity due to both chronicity and complications oftherapy.Adverse effects due to drug therapy are amajor cause ofmorbidity. Infections due to commonorganisms and opportunistic infections are particu-larly common in children on prolonged glucocorti-coid therapy.11,15 Fungal infections and infectionswithresistant organisms often result in death.Noninfec-tious complications of drug therapy include cataracts,growth retardation,weight gain, diabetes, pancreati-tis, hypertension, avascular necrosis, and osteoporosisrelated to glucocorticoids; bonemarrow suppression,ovarian failure, pancreatitis, and hemorrhagic cystitisdue to immunosuppressive therapy; andGI bleedingand renal failure secondary toNSAID therapy.

Long-term and permanent organ damage to the kid-neys results in chronic renal failure in amajority ofthe children over a period of 10 to 15 years andmayrequire renal dialysis and transplantation. Chronicbrain damagemay lead to severe psychiatric dys-function and organic brain syndrome requiring insti-tutionalization. Another major morbidity is the earlyonset of atherosclerosis and associated cardiovascu-lar problems.

MeasurementToolsSeveral new clinicalmeasurement tools are availabletomonitor patientswith SLE.Originally developedfor use in adults, some of themhave been tested inchildren and some have beenmodified.Validationstudies are still in progress. Until pediatric-specificmeasures (DiseaseActivity andDiseaseDamageIndex) are available, it appears that SLEDAI andSLICCmay be used tomonitor childrenwith SLE.

4. Juvenile Dermatomyositis

Juvenile dermatomyositis (JDM) belongs to a groupof idiopathic inflammatorymuscle disorders (IIM)characterized by chronic inflammation of themuscle,characteristic rash, and onset before the age of 16years.16,17 Idiopathic inflammatorymuscle disordersinclude several conditions such as polymyositis andgranulomatousmyositis, which are not common inchildhood. Juvenile dermatomyositis is separatedfromadult-onset dermatomyositis because of agreater degree of vascular inflammation and thrombo-sis and greater and unique associationwith calcinosisand lipodystrophy. Patientswith JDMare rarelyknown to developmalignancy. Polymyositis has theclinical features resulting frommuscle inflammation,but there is no rash, and the pathology is differentfromdermatomyositis.

Pathogenesis and Etiology

Muscle pathology is characterized by infiltrationwith DR + B cells and CD4 + T cells. Perivascularinfiltration with inflammatory cells in the muscle,endothelial damage of small vessels, vascularocclusion in the absence of inflammatory compo-nent, and the deposition of membrane attack com-plex in the vessel wall suggest an immune-medi-ated injury. Increased frequency of JDM in childrenwith DQAI.0501>DR3>B8 suggests a genetic com-ponent to the illness. Recent evidence suggests that anabnormality in the TNF-alpha 2 genemay be associ-atedwith chronicity. Extensive efforts have notuncovered any relationship to specific environmen-tal agents. Presence of ANAin over 50% of childrenwith JDM, association with several muscle-specificantibodies, and association of JDMwith immunedeficiency diseases such as X-linked hypogamma-globulinemia and enterovirus infection suggest thatimmune dysregulation in a genetically susceptiblehost is responsible for this condition. Studies usinggene array techniques have shown that several genesassociated with IFN alpha are overexpressed inJDM.Microchimerism is another possiblepathogenicmechanism.

Epidemiology

Peak incidence of the disease occurs between 5 and 14years of agewith slight predominance in girls.Although there is no definitive evidence for seasonalincidence, a prospective case control study showed


increased recognition of the symptoms in summermonths, probably because of exacerbation of the rash.No known environmental agent has been associateddefinitivelywith JDM.

Clinical Features

Juvenile dermatomyositis is characterized by inflam-mation of proximal muscle groups with weaknessand typical skin changes. Onset may be acute orinsidious. Acute generalized pain and fatigue arevery common andmay precede the onset of rash andweakness. Rashmay precede or occur in associationwithmuscle disease. Rarely, the typical rashmayoccur without clinically recognizablemuscle disease(amyopathic dermatomyositis/dermatomyositis sinemyositis). In these patients, further investigationsmay reveal subclinical muscle disease (enzyme ele-vations orMRI abnormality).

Early in the course of the disease, particularlywithacute onset, edema of the eyelidsmay be seen in addi-tion to erythema and rash over sun-exposed areas ofthe body.Violaceous discoloration of the eyelids(heliotropic rash), when seen, is characteristic ofJDM.TheV-sign and rash over shawl area asdescribed in adults are also seen in childrenwith anti-MI2 antibodies. Erythematous patches over the exten-sor aspects of the small joints of the fingers, elbows,and knee jointsmay be nodular or plaque-like(Gottron’s lesions) becoming atrophic during recov-ery.Vasculitic lesionswith a central necrotic areamaybe seen, particularly over the eyelids, axilla, and chestwall. Occasionally, the lesions ulcerate. Such vas-culitic lesions are associatedwith severe disease andbleeding from theGI tract.

Althoughmyositis-specific antibodies andmyositis-associated autoantibodies are seen less commonly inchildren, the phenotypes are similar to those seen inadults. For example, antisynthetase antibody associ-ated disease is characterized by acute onset, severemyositis, and pulmonary fibrosis. Anti-MI 2 anti-body-associated disease runs amilder coursewithrash over theVof the neck and the shawl area. Signalrecognition particle-associated JDM is often acutewith severe course and cardiac involvement.

Myositis is characterized by pain in themuscles andbyweakness. Proximalmuscles are involved, result-

ing in signs and symptoms such as inability to climbstairs, sit up in bed from a lying position, get up fromthe floor, comb hair, etc.More severe involvementmay result in total immobility, dysphonia, nasalvoice, nasal regurgitation, choking on food, and res-piratory distress. Swallowing difficulties may resultin aspiration pneumonia. Severe involvement of res-piratorymuscles and interstitial lung disease lead toreduced vital capacity and fall in DLCO. Althoughsignificant myocarditis is rare, conduction abnor-malities may be seen on EKG. Examination of theeyemay show retinal exudates and vasculitis. Pol-yarticular arthritis involving large and small jointsmay be seen at the onset.

Two commonly associated complications are subcuta-neous calcification and lipodystrophy. Subcutaneouscalcification is seen often after the acute phase is over,particularly in thosewith severe disease and thosewith delay in treatment. Calcificationmay be of dif-ferent types, from small areas of calcification over fin-gertips to tumoral calcinosis. These lesionsmay elicitan inflammatory response by themselves ormay getinfected leading to cellulitis and pyogenic deep-tissueinfections such as pyomyositis. Extensive subcuta-neous calcification (exoskeleton-like deposition)maylead to respiratory compromise and severe disability,confining such patients towheelchairs. The associa-tionwith lipodystrophy is intriguing. Theremay beassociated acanthosis and insulin resistance in somechildren, but the exactmechanism is not known.

Laboratory Features

Blood counts are often normal exceptwhen there issignificantGI bleeding or an infection.Acute phasereactants are often elevated. But themost importantabnormalities are related to themuscle disease.Mus-cle-related enzymes released into the circulation suchasCK,AST,ALT, and aldolasemay be elevated. It isbest to evaluate 2 or 3 of these enzymes because theprobability of only one of thembeing elevated is low.Changes inCKdo not strictly correlatewith diseaseactivity. It often rises before clinical flare and comesdownbefore clinical improvement. Aldolase does notnormalize for prolonged periods. Insertional irritabil-ity, spontaneous activity at rest, and bizarre high fre-quency discharges are seen on electromyogram(EMG). This is one of themajor investigations rou-tinely recommended for the diagnosis of JDM, but it


is a painful procedure and is not specific. Ifmuscles areinvolved in a patchymanner, EMGmaybenormal.Magnetic resonance imaging of themuscle hasbecome an excellent tool for the initial diagnosis andfollow-upof patientswith JDMandpolymyositis. Inaddition,MRI is an ideal tool to select the appropriatemuscle for biopsy. For these reasons, the authors preferMRI toEMGexceptwhenneurological disease is sus-pected.Magnetic resonance imaging of the affectedmuscles shows increased signal intensity inT2-weighted images, indicative of edemaof the tissues.

Biopsy of themuscle shows degeneration, necrosis,and regeneration ofmyocytes; perivascular atrophyof type I and II fibers; and perivascular round cellinfiltrationmostly with T-cells andmacrophages. Inchildren, early changes occur in the endothelium ofthe small vessels, resulting in vascular occlusion.

This endothelial damagemay be reflected by ele-vated vWF antigen in circulation. In the presence oftypical rash, typical proximal muscle involvement,and enzyme elevation, biopsymay not be necessarytomake the diagnosis.

Myositis-specific antibodies are those directed againstvarious enzymes andRNAs involved in protein syn-thesis. These include aminoacyl RNAsynthetase(JO1, PL-12, PL-7), signal recognition particle, andMI 2.Approximately 30%-40%of adults and 10%ofchildrenwith IIMhave these antibodies.Othermyosi-tis-associated autoantibodies such asU1-RNP,U2-RNP, and fibrillarin are also seen in patientswho havemyositis as a component of an overlap syndrome.These are seen in approximately 25%of adults and10%of childrenwith IIM.Clinical associations ofmyositiswith these antibodies are shown inTable 4.1.

Table 4.1

Myositis-Specific Autoantibodies (MSA)

Myositis-specific autoantibodies

Anti-signal recognition particle Very acute onset, polymyositis, myonecrosis on biopsy, responds poorly totherapy, needs cytotoxic agents

Anti-MI2 V-sign, shawl sign, respondswell to therapy, goodprognosis

Myositis-associated autoantibodies

Anti-UI RNP Overlap syndrome,mixed connective tissue disease

Anti-PM/Scl Scleroderma andmyositis, Raynaud’s phenomenon, calcinosis

Anti-Ku Scleroderma,myositis overlap syndrome

Anti-U2RNP Scleroderma,myositis overlap syndrome

Anti-U3RNP Scleroderma,myositis overlap syndrome

Anti-Annexin Juvenile dermatomyositis


Diagnosis

Criteria for the diagnosis of JDMare given inTable4.2.Differential diagnosis of the rash should includeSLE, overlap syndromes, psoriasis, and photosensi-tive eruptions.Muscleweakness requires differentia-tion fromnoninflammatorymyopathies, particularlydrug-inducedmyopathies,muscular dystrophy, andmetabolic and endocrine diseases such as hypothy-roidism.Acutemyositis has tobedifferentiated fromviral, bacterial (Borrelia), andparasitic (Toxo)myositis.

Treatment

Inmild tomoderate cases, glucocorticoids (pred-nisone at 1-2mg/kg/day) are given orally for 6 to 8weeks until there is clinical improvement and returnofmuscle-derived enzymes to normal. Because delayin initiating treatment is clearly associatedwith

greatermorbidity,many clinicians prefer startingearly aggressive treatment. Intravenousmethylpred-nisone as “pulse” therapy is indicated for the treat-ment of severemyositis, particularly if there is palatalweakness and involvement of the respiratorymuscles.Thismay have to be given every day or every otherday for 3 doses.Oral therapy (prednisone 2mgkg/day) is continued simultaneously.After theenzymes settle down, oral glucocorticoid therapy isslowly tapered andmaintained at as low a dose as pos-sible. It is not unusual for the full course of steroidtherapy to last 6months to 2 years.When the gluco-corticoid dose is tapered, if the disease flares or if thepatient develops unacceptable side effects, a second-line agent has to be added.Of those,MTX is the pre-ferred agent, although there are reports of benefit frommany other agents, particularly cyclosporine and IVIG. Intravenous gammaglobulinmay be particularlyuseful in an acute setting. In patientswho haveGIinvolvement and cutaneous ulcers (ulcerative JDM)with severe vascular disease, pulse cyclophos-phamidemay be used.

Some clinicians prefer starting therapywith both glu-cocorticoids andMTX to reduce the need for pro-longed steroid therapy and consequent adverseeffects. Hydroxychloroquine is useful to treat thecutaneousmanifestation andmay be added to any oneof the other agents (Table 4.3). Since bone demineral-ization is amajor problem in childrenwith JDM, sup-plemental calcium and vitaminD should be given.However, caution is indicated if the child is demobi-lizing calcium fromdystrophic calcification. Experi-encewith the use of biological agents is limited andnot encouraging.

There is no acceptable treatment for dystrophic calci-fication and lipodystrophy. Early treatment of JDMhas been shown to reduce the severity and incidenceof these complications.Acute inflammation associ-atedwith calciumdepositionmay respondwell tocolchicine.Antibiotic therapymay be needed forassociated bacterial infection. Surgical removalmaybe necessary if calciumdeposits are nodular and inter-ferewith function (eg, calcium in the gluteus).

Table 4.2

Criteria Used for Diagnosis ofJuvenile Dermatomyositis

Symmetric weakness of the proximalmusculature

Characteristic cutaneous changes consisting ofheliotrope discoloration of the eyelidswith periorbitaledemaand an erythematous, scaly rash over thedorsal aspects of themetacarpophalangeal andproximal interphalangeal joints (Gottron’s papules)

Elevation of the serum level of one ormore of theskeletalmuscle enzymes: creatine kinase, aspartateaminotransferase, lactic dehydrogenase, andaldolase

Electromyographic demonstration of thecharacteristics ofmyopathy anddenervation

Muscle biopsy showing histologic evidence ofnecrosis and inflammation


Physical therapymeasures are essential in theman-agement of JDM.During the active phase, passiverange ofmotion, proper positioning, avoidance ofaspiration, andmaintenance of good nutrition shouldbe the focus.After the acute phase is over andmusclepain has disappeared, the therapy program shouldprogress gradually from active range ofmotion, iso-metric exercises to isotonic and resistive exercises.Efforts to reduce contracturemay require the use ofsplints. Itmay take severalmonths to years to improveendurance, andmost children seem to have someresidualmuscleweakness.

Prognosis

With the institution of early aggressive therapy andbetter management of complications, mortality hasbeen reduced considerably and long-term survival isgreater than 90%. Approximately one-third ofpatients with JDM have a monocyclic course. Oth-ers have a chronic, continuous, or polycyclic coursewith severe morbidity, including calcinosis, con-tractures, growth retardation, cosmetic problems,and adverse effects of therapy. Anewly recognizedlong-termmorbidity is secondary lipodystrophywith its associated cosmetic andmetabolic prob-lems. Indicators of poor prognosis are severe dis-ease at onset, ulcerative disease, calcification, inter-stitial lung disease, delay in therapy, and associationwith Jo1 and signal recognition particle.

Table 4.3

DrugsUsed in the Treatment of Juvenile Dermatomyositis

Primary

Prednisone Oral 1-2mg/kg/day (see text for details)

“Pulse”methylprednisone 30mg/kg as a bolus (max: 1 g)

Sunscreen At least SPF 15

Hydroxychloroquine 5-7mg/kg/day (max: 400mg)

Secondary

Methotrexate 0.4-1mg/kg/week subcutaneous, intravenous, or oral (not intramuscular)

Intravenous gammaglobulin 1 g/kg/dose x 2 days once amonth for 3-6months

Azathioprine 1-2mg/kg bymouth daily

Cyclosporine 2.5-5mg/kg/day divided into two doses;monitor blood level

Cyclophosphamide 500-1,000mg/sqm intravenously as infusion,monthly


5. Henoch-Schönlein Purpura (HSP)

Henoch-Schönlein purpura (HSP) is a vasculitic syn-drome characterized by non-thrombocytopenic pur-pura, colicky abdominal pain, arthritis, and nephri-tis.18,19 It occursmost commonly in school-aged chil-dren (range 2-11 years;mean 4 years) and is seenequally in boys and girls. Henoch-Schönlein purpurais seenmore often in thewinter and springmonths.

Etiology

Ahistory of upper respiratory infection is often presentpreceding the onset ofHSP, suggesting an infectiousetiology.However, no specific infectious agent hasbeen consistently associatedwith the onset. Cases fol-lowingvaccination and exposure to drugs or specificfood items suggest an allergic andhypersensitivity eti-ologyofHSP. Some recurrent formsofHSPmay fol-low infectionwith beta hemolytic streptococcus.


Serum IgAlevels are often elevated in childrenwithHSP.Characteristic pathology ofHSPis leukocyto-clastic vasculitis of the skin, kidney, andGI tract.Evenmore characteristic is the deposition of IgAandC3 in the small vessels of the skin and kidney, sug-gesting that this disease is an IgA-mediated vasculitis.

Clinical Manifestations

The classical clinical triad of palpable purpura, col-icky abdominal pain, and arthritis in school-aged chil-dren is easy to diagnose.However, over 50%of chil-drenwithHSPoften presentwith symptoms otherthan purpura.When arthritis or abdominal symptomsprecede the characteristic rash, diagnosis is difficult.Classification criteria forHSPsuggested by theACRare not relevant in children because one criteriondefines the age (<20 years) and one other (skinbiopsy) is rarely needed tomake the diagnosis.

The characteristic rash ofHSPis seen in 100%of chil-dren, although not at the onset (only 50%). Palpablepurpura is seen over the buttocks and lower extremi-ties. Itmay also be seen over the trunk and upperextremities but rarely over the face.Urticarial, ery-themamultiform-like, and ecchymotic lesions arealso commonly seen.Another characteristic feature ismigrating edema seen commonly over the scalp, face,sternum, and extremities. It is particularly common in

infants and young children. The edemamay involvethe scrotumalso. This is different from the testicularswelling caused by vasculitis. The arthritis ofHSPusually involves large joints andmay precede the rashby several days. The swelling is typically periarticular.

Themost commonGI symptom is colicky abdomi-nal pain.Most commonly, rash occurs before theonset of visceral symptoms, but occasionallyabdominal symptoms precede the rash by days orevenweeks. The painmay be severe and associatedwith vomiting. Stool is positive for occult blood inmore than half the cases. Frank hematemesis ormelena is less common. Sudden onset of severe painor suddenworsening of abdominal painmay indicatebowel infarction, intussusception, or pancreatitis.Intussusception occurs in less than 5% of patients. Itis typically ilio-ileal as opposed to the ileocolic vari-ety seen in children without HSP.

In a recent population-based study ofHSPin 270 chil-dren, 20%had renal involvement during the acuteattack.Microscopic hematuria or hematuriawith pro-teinuriawere themost common abnormalities. Long-termpersistent renal disease occurred in approxi-mately 1%.This ismore common in childrenwhohave severe nephritis or nephrotic features at the ini-tial presentation.On biopsy, renal changes range fromminimal changes to severe crescentic glomeru-lonephritis. Immunofluorescence studies revealglomerular deposits of IgA,C3, and properdin.

Less commonmanifestations ofHSPinclude pul-monary hemorrhage, pancreatitis, vasculitis of testic-ular vessels, hemorrhagic cystitis, and involvement oftheCNS and peripheral nervous system.

Laboratory Findings

Diagnosis ofHSPis not based on laboratory studies.The only exception is the need to establish a normalplatelet count. Hemoglobin andwhite cell counts areoften normal. Platelet countsmay be increased, partic-ularly in associationwithGI bleeding. TheESRmayshowmild elevation. Routine urinalysismay showhematuria or proteinuria, or both, but no casts. Occultblood is often detected on examination of the stool.Serum IgAlevel is normal or elevated.Ultrasonogra-phymay be helpfulwhen intussusception is sus-pected. Radiographic features on barium studies char-


acteristic ofHSPinclude thumb-printing in the regionof the duodenum, “picket-fence” appearance in theregion of the jejunum, and “coil-spring” appearanceof intussusception. In patientswith atypical features,ANCAshould be obtained to rule out other vasculiticdisorders.

If platelet counts are low,HSPis ruled out. Differen-tial diagnosis should include all conditions associatedwith purpura, arthritis, and abdominal pain, andmaybe a difficult task. This is a particular problemwhenarthritis or abdominal pain, or both, occur before thecharacteristic rash.Acute abdomen, acute rheumaticfever, intussusception,Kawasaki disease (KD), drugreactions,meningococcemia, and torsion of the testisare some of the conditions that have to be considered.Recurrent bouts ofHSPare known to occur for peri-ods over 6months.However, this should triggerinvestigations to rule out other vasculitic disorders,particularly if there are atypical features.

Treatment

Henoch-Schönlein purpura is a self-limiting disease inmost situations.Analgesics orNSAIDs, or both,maybe used to control joint pain. Intravenous hydrationmay be needed in an acutely ill childwith abdominalpain and poor oral intake. In childrenwith severe col-icky abdominal pain, a short course of glucocorticoidsfor 3 to 5 days gives dramatic relief. However, thereare no good studies to support the use of glucocorti-coids routinely. Symptomsmayflare after discontinu-ation of steroids. In this situation, some authorsmayuse glucocorticoids for 2 to 3weeks. Childrenwithmicroscopic hematuria andmild proteinuria do notrequire any treatment, but childrenwith a nephritic ornephrotic picture should be treatedmore aggressively.For thosewith severe renal involvement,more aggres-sive therapymay be needed including the use of intra-venous “pulse” glucocorticoids, azathioprine, orcyclophosphamide, or a combination of the three.

All childrenwithHSPshould bemonitored closelywith routine urinalysis once aweek during the first 2to 3months. Subsequent follow-upwill depend on theseverity of the initial presentation and should includeurinalysis andmeasurement of blood pressure.

Prognosis

Prognosis is excellent in most situations. The ill-ness usually lasts for 6 to 8 weeks with “showers”of new skin lesions. Recurrences may be seen up to2 years after the initial attack. Proteinuria of greaterthan 1 g/day, nephrotic syndrome, and crescenticglomerulonephritis in more than 50% of glomeruliare associated with poor renal outcome.


6. Kawasaki Disease

Kawasaki disease is an acute systemic illness ofyoung children characterized by fever, exanthem,conjunctival injection, cervical adenitis, and swellingof the hands and feet. It is a systemic vasculitic syn-dromewith a tendency to involve coronary arteries.20,21

Epidemiology

Kawasaki disease is a disease of young childrenwith80%of cases occurring before the age of 4 years and50%of cases in children younger than 2 years. Boysare affectedmore than girls (1.5 to 1). It is aworld-wide disease, but childrenwith Japanese andKoreanancestry are at the greatest risk. Before 1987, therewere community-wide outbreaks at intervals of 3 to 5years, but there have been none since then.Kawasakidisease is reportedmost often duringwinter andspring. The overall rate ofKDamong siblingswasnoted to be 2.1%, comparedwith 0.19% in the generalpopulation for children between the ages of 0 to 4years. Approximately 3%-5%of childrenwithKDexperience a recurrence.

Etiology

The clinical features and the cyclic nature of epi-demics suggest an infectious etiology. However,extensive investigations have ruled out many com-mon infectious agents including retroviruses as thecause of KD. Recent studies suggest that anunknown toxin with superantigen characteristicssuch as the TSST-1may be responsible for initiatingan abnormal immune response. There is no docu-mented correlation with drugs, insect vectors, orother environmental agents.

Clinical Features

Signs and symptomsofKDevolve over days toweeks.Someof the symptoms (eg, conjunctival injection)maybe transient, lasting for less than a day.All of theclassic featuresmaynot be present at any one time.Also,manyof the featuresmaybemild or unapparent,particularly in infants less than 9months of age. Inolder children, atypical presentations such as retropha-ryngeal enlargement of lymphnodes are common.

There are three phases in the evolution of clinical fea-tures. The acute febrile phase lasts for 7 to 14days andis characterized byhigh fever, conjuctival injection,

rash, lymphadenopathy, intense erythemaof thetongue and lips, and swelling of the hands and feet.Fever starts abruptlywithout prodrome, is remittent innature, ranges up to 41°C, and could persist for 10 to12days (if untreated).Conjunctival injection is diffuseand is associatedwith photophobia but is not exuda-tive. The rash can be of almost any type including pso-riasiform, but it has classically diffuse, erythematosusmacules or plaqueswith slightly raisedmargins. Itmaybe urticarial. The rash involves the trunk, extremities,and face. Intense erythemaof the perineum followedbypeeling is characteristic.Vesicular or pustularrashes are not characteristic ofKS, but cutaneous vas-culitis (palpable purpura) can be seen.

Lymphadenopathy ofKD is characteristically a singlelarge node or groupof nodes in one side of the neck.Firm indurated edemaof the hands and feet resemblingserumsickness is often seen during this phase. Thechild is often irritable andmay also have diarrhea ormild hepatic dysfunction.

The subacute phase is characterized by arthritis, peel-ing of the skin, thrombocytosis, andmyocardial dys-function and is seen usually 10 to 24days after theonset of illness.Arthritismaybe acute andpolyarticu-lar involving large and small joints in the early phase.When it occurs after thefirst fewdays, it is oftenoligoarticular.Knee and ankle joints are often affectedwith large effusions. Synovial fluid cell counts are highin the early phase (>100,000/mm3).Desquamation ofthe skin can be dramatic, and casts of entire toes andfingersmaybe shed. Perineal and subungual desqua-mation is typical forKD.Somechildrenmayhaveepisodes of skin peeling for several years after anattack ofKD.These episodes often followanupperrespiratory infection. Thrombocytosismaybe seen asearly as 5 days after the onset of fever, but, by day11,almost allwill have platelet counts ofmore than450,000/mm3. Sterile pyuria and asepticmeningitismay also be seen during these 2weeks.

The classic feature ofKD is coronary arteritiswith itsconsequences such asmyocardial infarction.How-ever, a spectrumof abnormalitiesmaybe seen.Myocarditis is seen in the acute phase.Almost all chil-drenwill have tachycardia,with over 50%showingabnormal cardiac rhythm.Pericardial effusion andmitral insufficiencymaybe shownby echocardiogra-phyduring thefirstweekof illness.Mild tomoderate


Diagnosis

Diagnosis ofKD is clinical because there is no singlediagnostic laboratory test. TheCenters forDiseaseControl Criteria for the diagnosis ofKDare listed inTable 6.1. Thesewere developed for epidemiologicalcase definition and classification, and some childrenmay not fulfill these classical criteria.

Fever persistent for at least 5 days (unless IV IGwasused before the fifth day) together with at least 4 ofthe 5 remaining criteria is considered to be diagnos-tic of KD. Fever for more than 2 days together withonly 4 of the other criteria can be diagnosed as KDwhen coronary aneurysm is recognized by 2Dechocardiogram or coronary angiography. Otherdiagnoses have to be excluded. This list includesscarlet fever, toxic shock syndrome, febrile viral dis-eases, and hypersensitivity reactions. It is alsoimportant to note that irritability is an important non-specific feature of this syndrome.

congestive failuremaybe seen in approximately 20%of children during the acute phase. Prolongation of theP-R interval andfirst-degree heart block can be seen onEKG.Coronary artery abnormalities are seen usuallyduring the secondweekof illness.

During the convalescent phase lasting 6 to 8weeksafter the onset, fever subsides, rash gets less pro-nounced, the arthritis also clears slowly, andmyocardi-tis improves, although thrombocytosis and elevatedESR linger. This is the timewhen established compli-cations progress, and theremaybe reboundof clinicalfeatures.Aneurysmsofmedium-sized vessels andmyocardial disease secondary to coronary involve-mentmaybe seen several years later.

CoronaryArteryDisease

Acharacteristic feature of coronary arteritis is thedevelopment of coronary artery aneurysm, reachingpeak severity and incidence in thefirst 4 to 6weeks ofillness. Significant coronary artery diseasewasreported in up to 25%of childrenwithKDbefore theintroduction of IVIG therapy.Mortality in thesepatientswas 2%.Although these percentages aremuchsmaller, a fewchildren develop transient dilatation ofcoronary arteries even after IVIG therapy and about1%develop giant aneurysms.Those at highest risk forthis complication are boyswith onset at less than 1year of age; thosewith recurrence andpersistence ofinflammation even after IVIG; and thosewith lowserumalbumin, high totalWBC, andhighCRP.Although angiographicallymore than 50%of theseaneurysms regress during thefirst year, subclinicalendothelial damagemaypersist, resulting in coronaryartery disease later in life. There is increased risk ofthrombotic or stenotic obstruction resulting in cardiacdysfunction,myocardial infarction, and suddendeathin thosewith persistence of aneurysm.Themostimportant predictor of nonresolution of coronaryaneurysm is the size of the initial lesion.Giantaneurysmsdefined as thosewith amaximumdiameterofmore than 8mmusually progress to persistent coro-nary disease. It is precisely the incidence of these giantaneurysms that is dramatically decreased by early ther-apywith IVIG.

Table 6.1

Criteria for Diagnosis of Kawasaki Disease

Fever formore than 5 days (4 days if treatment withintravenous gammaglobulin was given) AND

Four of the following, not explained by anotherdisease process:

• Polymorphous exanthema•Bilateral conjunctival injection•Changes in lips and oral cavity: reddening of lips,strawberry tongue, diffuse injection of oral andpharyngealmucosa

•Changes in peripheral extremities: erythema,edemaof the hands and feet, periungualdesquamation

•Cervical lymphadenopathywith at least one nodelarger than 1.5 cm in size


It is key to know that childrenwith illness not fulfill-ing the above criteria have developed coronaryaneurysm, necessitating the concept of incompleteKD. Some have had only 2 features and still devel-oped coronary artery disease. This occurs in approxi-mately 10%-20%and ismore common in youngerinfants. An elaborate algorithmhas been developed todealwith these atypical presentations.21 In atypicalcases, demonstration of uveitis, gallbladder hydrops,sterile pyuria, or asepticmeningitismay help tomakea diagnosis and start treatment. Early in the course ofthe disease, observation for 24 hours to look for evolu-tion of specific symptomsmay help.

OnceKD is considered to be a serious possibility,there is an urgent need to treatwith IV IG.However,IV IG is expensive and is notwithout adverse reac-tions. Therefore, there are concerns about overdiag-nosing atypicalKD.Kawasaki himself suggests adefinitive diagnosis ofKDon the basis of 5 criteria outof 6 (not emphasizing fever) and possibleKD if 4 of 6features are present togetherwith objective evidenceof coronary aneurysm. It is obvious that clinical judg-ment is essential in infantswith febrile or evenafebrile illness characterized by rash and peeling. Car-diac investigations and treatmentwith IV IGmay benecessary in such situations. The diagnosismay bedelayed in older children and adolescentswho showmoreGI symptoms such as abdominal pain, vomiting,diarrhea, andweight loss, and in thosewith acute sur-gical abdomen as the presentingmanifestation.

Complications

Myocardial infarction is themost important complica-tion early in the disease.Although coronary artery dis-ease is themost dreaded feature ofKD, othermedium-sized vessels including the brachial, femoral,and hepatic arteriesmay be involvedwith aneurysmformation.

Hydrops of the gall bladdermay be seen in the acutephase and recognized clinically and confirmed byultrasonography. Some children, particularly infants,may develop peripheral gangrene.Mild hepatitis andurethritis are self-limiting.

Treatment

Intravenous gammaglobulin at 2 g/kg infused over 10to 12 hours in a single dose is the treatment of choice.This treatment is indicated even for childrenwho areseen after the tenth day of illness if they have persis-tent fever or persistent evidence of systemic inflam-mation or show coronary artery disease on echocar-diogram.Measles and varicella vaccines should notbe given for 11months after a dose of IV IG.

In addition, acetylsalicylic acid is started at 20 to 25mg/kg/dose at 4 doses a day. This dose is reduced toone dose of 81mg a day after the child has beenafebrile for at least 2 to 3 days. If the child is onhigh-dose aspirin, serum salicylate levels and liverfunction tests should be monitored to avoid risks ofReye’s syndrome. Aspirin should be discontinued ifthe child develops varicella or influenza during thefollow-up phase.

Approximately 10%of childrenwithKDwill notrespond to initial treatmentwith gammaglobulin. Ifthe fever persists for 48 hours ormore after initialtherapy or if it recurs, a second dose of IV IG is rec-ommended. If children do not respond to a seconddose, it is reasonable to use pulse doses ofmethylprednisolone (30mg/kg as a bolus,with amaximumof 1 g) once a day for 1 to 3 days. These childrenwillalso require further investigations to rule out othertypes of vasculitides and to document the severity ofcardiovascular involvement. Therapywithcyclophosphamidemay have to be considered. Thereare no available data from controlled studies on theuse of TNF inhibitors in the treatment ofKD, but theyhave been used in resistant cases.

Recommendations for long-termmanagement arebased on relative risks for complications of coronarydisease. The need formedications, restriction of phys-ical activity, and frequency of follow-up are outlinedin Table 6.2.


Table 6.2

Risk Stratification to Plan Follow-up of ChildrenWhoHadKawasaki Disease

Pharmacological Follow-up andTherapy Physical Activity Diagnostic Testing Invasive Testing

Risk Level I (no coronary artery changes at any stage of illness)

Nonebeyond 1st No restrictions beyond Cardiovascular risk None recommended6-8weeks 1st 6-8weeks assessment, counseling

at 5-y intervals

Risk Level II (transient coronary artery ectasia disappearswithin 1st 6-8weeks)

Nonebeyond 1st No restrictions beyond Cardiovascular risk None recommended6-8weeks 1st 6-8weeks assessment, counseling

at 3- to 5-y intervals

Risk Level III (1 small-mediumcoronary artery aneurysm/major coronary artery)

Low-dose aspirin For patients <11 y old, Annual cardiology follow-up Angiography, if(3-5mg/kg aspirin no restriction beyond 1st with echocardiogram+ noninvasive testper day), at least until 6-8weeks; patients 11-20 y ECG, combinedwith cardio- suggests ischemiaaneurysm regression old, physical activity guided vascular risk assessment,documented by biennial stress test, counseling; biennial stress

evaluation ofmyocardial test/evaluation ofmyocardialperfusion scan; contact or perfusion scanhigh-impact sportsdiscouraged for patientstaking antiplatelet agents

(continued)


Table 6.2 (continued)

Risk Stratification to Plan Follow-up of ChildrenWhoHadKawasaki Disease

Risk Level IV (�1 large or giant coronary artery aneurysm, ormultiple or complex aneurysms in samecoronaryartery, without obstruction)

Long-termantiplatelet Contact or high-impact Biannual follow-upwith 1st angiography attherapy andwarfarin sports should be avoided echocardiogram+ECG; 6-12moor sooner if(target INR 2.0-2.5) or because of risk of bleeding; annual stress test/ clinically indicated;low-molecular-weight other physical activity evaluationofmyocardial repeatedangiographyheparin (target: recommendations guided perfusion scan if noninvasive test,antifactor Xa level by stress test/evaluation of clinical, or laboratory0.5-1.0U/mL) should myocardial perfusion findings suggestbe combined in scan outcome ischemia; electivegiant aneurysms repeat angiography

under somecircumstances

Risk Level V (coronary artery obstruction)

Long-term low-dose Contact or high-impact Biannual follow-upwith Angiographyaspirin; warfarin or sports should be avoided echocardiogramandECG; recommended tolow-molecular-weight because of risk of bleeding; annual stress test/evaluation address therapeuticheparin if giant other physical activity ofmyocardial perfusion scan optionsaneurysmpersists; recommendations guidedconsider use of by stress test/myocardial�-blockers to reduce perfusion scan outcomemyocardial O2consumption

Permission requested fromNewburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-termmanage-ment of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis,and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics.2004;114(6):1708-1733.


Prognosis

Kawasaki disease is an acute, self-limiting diseaseexcept for its tendency to induce coronary vasculitiswith serious sequelae. In Japan, themortality rate hasdecreased from2% in the 1970s before the currenttreatmentmethodswere introduced to 0.1%.Risk ofcoronary aneurysm, particularly the giant aneurysms,has been loweredwith the use of IV IG.However,evenwith IV IG, risk of coronary aneurysms is high(5%) in infants less than 1 year of age.As indicatedearlier, themajority of aneurysms detected in the first2 to 3weeks of the disease regress by one year. How-ever, even these patients are at risk for coronary arterydisease in their young adult life.

7. Antiphospholipid AntibodySyndrome (APL)

Antiphospholipid antibody syndrome in children ischaracterized by several clinicalmanifestations sec-ondary to vascular thrombosis (Table 7.1) and thepresence of circulating antiphospholipid antibodies(APL) or lupus anticoagulant (Lac), or both. Recur-rent fetal loss also has to be taken into account in theadolescent and young adult age groups. Preliminarycriteria for the classification ofAPLsyndrome22 areoutlined in Table 7.2. It is important to remember thatthese are classification criteria, not diagnostic criteria.Adiagnosticwork-up forAPLsyndrome should beundertaken in childrenwith unexplained venous orarterial thrombosis, particularly if they are recurrent.23

CirculatingAPLantibodies have been shown inpatientswith juvenile rheumatoid arthritis, acuterheumatic fever, insulin-dependent diabetesmellitus,andHIV infection.However, these are rarely associ-atedwith vascular thrombosis. Asignificant numberof both adults and childrenwith SLE carryAPLorLac, or both.When one of these rheumatic diseases isassociatedwith thrombosis and circulatingAPL, it isclassified as secondaryAPLsyndrome.Childrenwhodo not fulfill the criteria for the diagnosis of SLEorone of the other rheumatic diseases are considered tohave primaryAPLsyndrome.

Approximately 20%-80%of patientswith childhoodSLE carryAPLand 10%-60%showLac. Presence ofLac ismore closely associatedwith thrombosis. Itappears thatAPLandLac are separate antibodiesdirected at discrete antigens in complexwith phos-pholipids. Beta 2-glycoprotein I (B2GP1) is requiredfor the binding ofAPLto cardiolipin in primaryAPLsyndrome,whereas theAPLs seen in infectious dis-eases andVDRLtests areB2GP1-independent. Simi-larly, Lac activity requires the presence of prothrom-bin as an associated antigen. Thus, it appears thatAPLmeasures phospholipids in complexwithB2GP1 bythe enzyme-linked immunosorbent assay (ELISA)method,whereas Lac is a functionalmeasure of activ-ity of prothrombin-associated antiphospholipids.

Clinical Features

Signs and symptomsmay vary depending on theorgan and the type of vessel (artery or vein) involved.Themost commonpresentations ofAPLsyndrome inchildren are deep venous thrombosis of the lowerextremities, pulmonary embolism, and thrombosis of


Table 7.1

Major Vaso-OcclusiveManifestations Associatedwith AntiphospholipidAntibodies in 50Children

Vessel ClinicalInvolved Manifestations

Veins

Limbs Deep vein thrombosisSuperficial vein thrombosis

Large Veins Superior or inferior vena cavathrombosis

Lungs Pulmonary thromboembolismPulmonary hypertension

Skin Livedo reticularis

Brain Cerebral venous sinus thrombosis

Adrenal glands Addison’s disease

Liver Budd-Chiari syndrome(Large vessels)

Liver Hepatomegaly, enzymeelevation(Small vessels)

Eyes Retinal vein thrombosis

Reprinted from Ravelli A, Martini A. Antiphospholipid antibody syndrome in pediatric patients. RheumDis Clin North Am.1997;23(3):657-676. With permission from Elsevier.

Vessel ClinicalInvolved Manifestations

Arteries

Brain Stroke, transient ischemic attacks

Kidney

Large vessels Renal artery thrombosis

Small vessels Renal thromboticmicroangiopathy

Limbs Ischemia, gangrene

Heart Myocardial infarction

Liver Hepatic infarction

Gut Mesenteric artery thrombosis

Spinal cord Transversemyelopathy


Table 7.2

Preliminary Criteria for the Classification of theAntiphospholipid Syndrome*

Clinical Criteria

1. Vascular thrombosis:One ormore clinical episodes of arterial, venous, or small-vessel thrombosis in any tissue or organ.Thrombosismust be confirmedby imaging or Doppler studies or histopathology, with the exception ofsuperficial venous thrombosis. For histopathologic confirmation, thrombosis should be present withoutsignificant evidence of inflammation in the vessel wall.

2. Pregnancymorbidity:A)Oneormoreunexplaineddeathsof amorphologically normal fetusat or beyond the10thweekofgestation,

with normal fetalmorphologydocumentedbyultrasoundorbydirect examinationof the fetus, orB)One ormore premature births of amorphologically normal neonate at or before the 34thweek of gestation

because of severe preeclampsia or eclampsia, or severe placental insufficiency, orC) Three ormore unexplained consecutive spontaneous abortions before the 10thweek of gestation, with

maternal anatomic or hormonal abnormalities andpaternal andmaternal chromosomal causes excluded.

In studies of populations of patients who havemore than one type of pregnancymorbidity, investigators arestrongly encouraged to stratify groups of subjects according to A, B, or C above.

Laboratory Criteria

1. Anticardiolipin antibody of IgGor IgM isotype, or both, in blood, present inmediumor high titer, on 2 ormoreoccasions, at least 6weeks apart, measured by a standardized enzyme-linked immunosorbent assay for B2-glycoprotein I-dependent anticardiolipin antibodies.

2. Lupus anticoagulant present in plasma, on 2 ormore occasions at least 6weeks apart, detected according tothe guidelines of the International Society on Thrombosis andHemostasis (Scientific Subcommittee on LupusAnticoagulants/Phospholipid-Dependent Antibodies), in the following steps:A) Prolongedphospholipid-dependent coagulation demonstrated on a screening test, eg, activated partial

thromboplastin time, kaolin clotting time, dilute Russell’s viper venom time, dilute prothrombin time,Testarin time.

B) Failure to correct the prolonged coagulation time on the screening test bymixingwith normal platelet-poorplasma.

C) Exclusion of other coagulopathies, eg, factor VIII inhibitor or heparin, as appropriate.

Definite antiphospholipid antibody syndrome is considered to be present if at least one of the clinical criteria andone of the laboratory criteria aremet.

* No exclusions other than those contained within the above criteria are needed. However, because of the likelihood thatthrombosis may bemultifactorial in patients with antiphospholipid antibody syndrome, the workshop participantsrecommend that a) patient populations being studied should be assessed for other contributing causes of thrombosis,and b) such populations should be stratified according to identifiable or probable risk factors, eg, age or comorbidities.Specific limits were not placed on the interval between the clinical event and the positive laboratory findings. However, itwas the view of many at the workshop that a) information about such intervals should be assessed when relevant, and b)the relatively strict definition of laboratory criteria (including the requirement that results again be positive on repeat testsperformed at least 6 weeks after the initial test) would help to exclude antiphospholipid antibody positively that representsan epiphenomenon to the clinical events.

FromWilsonWA, Gharavi AZ, Koike T, et al. International consensus statement on preliminary classification criteria fordefinite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum.1999;42(7):1309-1311.


cerebral vessels. Deep venous thrombosismay beaccompanied by pulmonary embolism. Pulmonaryembolism should be considered in childrenwith SLEandAPLsyndromewho develop cough, dyspnea, andchest pain. CatastrophicAPLsyndrome characterizedby respiratory distress syndrome, thrombocytopenia,andmulti-organ failure due towidespread thromboticevents has been reported in children.

Pregnancy-associated events such as unexplaineddeath, premature delivery, and recurrent spontaneous,unexplained abortionsmay be seen in the adolescentperiod, and young girlswithAPLsyndrome needcounseling on sexual and pregnancy-related issues.

Among the other conditions associated with APLsyndrome, thrombocytopenia is themost important.Less commonly associated conditions includechorea, Libman-Sacks endocarditis, aseptic necrosisof the femoral head, and Tourette’s syndrome.Antiphospholipid antibodies have been shown tocross the placenta and be associated with thrombosisin the neonatal period.

Laboratory Studies

Antiphospholipid antibodies aremeasured utilizingtheELISAmethod, andLac ismeasured utilizing sev-eralmethods listed in Table 7.2. Immunoassays tomeasure antibodies to beta 2 glycoprotein 1 and pro-thrombin are not universally available.

Treatment23,24

PatientswithAPLsyndromewithout any history ofthrombosis do not require prophylactic treatment.They need education to reduce other risk factors, suchas smoking and use of contraceptives. If such individ-uals undergo surgery or prolonged immobilization,subcutaneous heparinmay be considered to reducethe risk of venous thrombosis. The recurrence rate ofthrombosis in a childwith an initial attack isunknown.However, childrenwith one thromboticevent associatedwithAPLsyndrome should receiveanticoagulation immediatelywith heparin followedbywarfarin tomaintain an INRof 2 to 2.5 for 6months. Long-termmaintenancewithwarfarin tomaintain INRbetween 1.5 and 2.0may be safer thanhigh-dosewarfarin.More recently, introduction oflowmolecularweight heparin hasmade themanage-

ment of these children less risky, although studies toprove efficacy are lacking. In the presence of catas-trophicAPLsyndrome, treatmentwith glucocorti-coids, cyclophosphamide, and plasmapheresis is indi-cated in addition to the anticoagulant therapy.


8. Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is characterizedby several typical clinical features and the presence ofcirculatingmaternal autoantibodies.25-27 Themostimportant clinical features are: 1) erythematous, annu-lar cutaneous lesions; 2) complete congenital heartblock (CCHB); and 3) hemocytopenia.More recently,neonatal giant cell hepatitis has been added to this listof associations.

Pathogenesis

Neonatal lupus erythematosus is caused by thetransplacental passage ofmaternal autoantibodies,particularly in the first trimester during the formationof the cardiac conduction system. Pregnantwomenwhose sera contain anti-SSA(Ro) and anti-SSB (La)antibodies have a higher risk of having a childwithNLE. These antibodies are directed at two separateSSAproteins (52Kd and 60Kd) and to one SSB (48Kd) protein. The combination of antibodies to 52Kd-Ro and 48Kd-La seems to be highly correlatedwithCCHB.Although these antibodies are present in thesera of 85%ofmotherswhose fetuses are affected,only 2%of all newborns ofmotherswith these anti-bodies have congenital heart block. In addition, therecurrence rate in subsequent pregnancies is less than20%. Identical twins are discordant for congenitalheart block. Therefore, it appears that these specificantibodies are essential for the development of con-genital heart block but not sufficient. It appears thatcongenital heart block results fromdefective repairand fibrosis of the conduction tissue from injurycaused bymaternally transmitted antibodies.

On the basis of data from a large national registry, itappears that 28%ofmothers of babieswith congenitalheart block and 35%ofmothers of babieswithNLEare asymptomatic at the time of delivery of theaffected baby.Approximately 15%-25%hadSjögren’s syndrome or SLE. Fifteen percent to 25%had undifferentiated autoimmune disease. Severalothers developed one of these conditions during thesubsequent follow-up period.

Maternally transmitted antibodies disappear over sev-eralweeks tomonths.Clinicalmanifestations related tothe skin and formedelements of thebloodalso resolvespontaneously following thenatural disappearanceof

maternal antibodies.Theone exception isCCHB,which is a permanent lesiondue to an inflammatoryreaction in theAVnodeandneighboring tissues.

Clinical Features

Cutaneous lesions of NLE are rarely seen at birth butusually within several hours to days after birth (meanage at detection is 6 weeks). They are annular, ery-thematous scaly plaques and involve sun-exposedareas such as the scalp, the face in a peri-orbital dis-tribution, and arms, but may also involve the diaperarea. These lesionsmay continue to appear for sev-eral weeks tomonths but not beyond 6months ofage. The lesions tend to be transient (mean durationof 17weeks) and heal without scarring inmost cases.However, hyperpigmentation, telangiectasia, atro-phy, and pitting of the skinmay be seen as residualfindings in some cases.

Themost serious and important feature ofNLE isCCHB.Ninety percent of isolatedCCHB is due totransmitted antibodies from an asymptomaticmother.Most patients have third-degree heart block at presen-tation. It is signaled by the sudden onset of fetal brady-cardia. If not recognized and treated, the lesionsprogress to cause fetal congestive heart failure andhydrops fetalis. Even incompleteAVblockmayprogress postnatally. Rarely do children presentwithheart block after the neonatal period. Less consequen-tial forms of conduction abnormalities such as sinusblock, prolongedQ–T interval, and first-degree heartblock also have been reported. Intrauterine death inCCHB is estimated to be between 25%and 35%.

Thrombocytopenia and leukopenia,when present, areseen at birth and persist for severalweeks tomonths.They are often asymptomatic, although petechiae andGI hemorrhagemay occur. Thrombocytopenia is notassociatedwith antiplatelet antibodies butwith anti-Ro antibodies.

Neonatal hepatitis and cholestatic jaundicemay alsobelong to the spectrumof clinical features associatedwithNLE. They often occur togetherwith cutaneous,hematologic, or cardiac lesions ofNLE, butmay alsooccur as isolated phenomena.



Skin lesions show epithelial basal cell damage,mononuclear infiltrate, and IgGdeposits. In the heart,myocarditis and fibrosis of the conduction system tar-geting theAVnodes are themajor features. Immunedeposits have been demonstrated in themyocardiumincluding IgG, complement, and fibrin.Anti-52KDand anti 60KD-Ro antibodies have been eluted fromthe heart of an affected infant, suggesting amajor rolefor this antibody in the pathogenesis ofNLE.

Treatment

Complete congenital heart block is a permanentlesion, and almost all infants will require pacemakerplacement. All pregnantmothers at risk for CCHBshould havemeasurement of antibodies to Ro and La(with specificity) and should be closelymonitoredwith fetal echocardiography.27 If evidence of fetalbradycardia ormyocarditis, or both, is detected, treat-ment ofmothers with dexamethasone (4mg per dayorally) for 2 to 6weeks is indicated. Oral sympath-omimetic has also been tried. The infant should bedelivered as soon as possible, and a cardiac pace-maker should be inserted immediately after birth.Becausemostmothers who deliver infants withCCHBdo not necessarily deliver subsequent babieswith CCHB, and because aggressive treatment withdexamethasone and plasmapheresis throughout preg-nancy is associatedwith risks for themother and thefetus, this treatment is not recommended.

Skin lesions in the infant resolvewithout scarring,and therefore, no specific treatment is needed. Themother and child should be instructed to avoid sunexposure. Topical application ofmild corticosteroidcreammay hasten the clearing but is rarely indicated.Treatment is not necessary for thrombocytopeniaunless there is pronounced reduction in platelets andhemorrhagic features. If necessary, glucocorticoidtherapy for 2 to 3weeksmay be used.

Prognosis

Cutaneous and hematologic features due tomater-nally transmitted antibodies resolve over a fewweeks to a fewmonths, correlating with the half-lifeof these passively transferred antibodies. Completecongenital heart block is a permanent lesion, and themortality rate is high. There are recent reports ofSLE and other autoimmune diseases later in life inchildren who have hadNLE.


9. Miscellaneous Group

Afewother areas of importance in pediatric rheuma-tology include arthropathies seen in associationwithvarious syndromes, immunodeficiencies, and heredi-tary periodic fevers.

SyndromicArthropathy

When an arthropathy is seen in associationwith adefined syndrome, it is best not to classify it as JIA,because JIAis a specific condition and an exclusiondiagnosis. In addition, arthropathymay be non-inflammatory in several syndromes.28We suggest thata congenital or familial arthropathy be considered inthe differential diagnosis of arthritis if one ormore ofthe following features are seen:

•More than one member of the family (particularlysiblings) has arthritis, short stature, or growthretardation

• The child has 2 ormore dysmorphic features

• The patient’s serumdoes not showANAorRF

•There is no systemic evidence of inflammation(normal sedimentation rate and hemoglobin) orsynovial inflammation (normal synovial cell count,noninflammatory synovial biopsy)

Some examples of syndromes associatedwitharthropathy are listed in Table 9.1.

Immunodeficiency andArthritis

Avariety of rheumatic disorders (SLE, dermato-myositis, vasculitis) have been shown to be associatedwith specific immunodeficiencies, andmany immun-odeficiencies are associatedwith excessive levels ofautoantibodies. The clinical features of rheumatic dis-eases seen in associationwith immunodeficiencies aresimilar to those seen in immunocompetent children. Itis a good practice tomeasure immunoglobulin levelsand total hemolytic complement (CH50) during ini-tial work-up of definite rheumatic diseases in chil-dren. IgAdeficiency has been seen in associationwithJIA-like arthritis, SLE, scleroderma, and JAS.Com-plement deficiencymay be seen in associationwithSLE, discoid lupus erythematosus, Sjögren’s syn-drome, polymyositis, HSP, and vasculitis. Thestrongest association iswith SLE. Therefore, CH50

should bemeasured in the initialwork-up for SLE,particularly in children diagnosed before the age of 5years and in thosewith a strong family history.Otherimmune deficiencies and associated rheumatic condi-tions are listed in Table 9.2.

Periodic Fever Syndromes

One of themost dramatic developments in pediatricrheumatology in the past 8 years has been the identifi-cation of genes responsible for some of the hereditaryperiodic fever syndromes. Periodic fever is defined as3 ormore attacks of unexplained fever occurring atleast 7 days apart over a period of 6months. Commoncauses of periodic fever syndromes are given inTable9.3.Obviously, one needs to exclude infectious andanatomic causes aswell as immunodeficiencies in any

Table 9.1

SomeSyndromesAssociatedWith Arthropathy

Blau syndrome Polyarticular arthritis,granulomatous arteritis, uveitis

Cystic fibrosis Episodic polyarthritis,hypertrophic osteoarthropathy

DiGeorge Polyarticular arthritis,syndrome immunodeficiency,

hypocalcemia, cardiacanomalies

Down syndrome Polyarticular arthritis, congenitalheart disease, gastrointestinalanomalies, hypotonia

Farber’s disease Polyarthritis, nodular periarticularswellings,mental retardation

Lowe syndrome Contracture of joints,mentalretardation, renal tubulardysfunction, cataracts

Turner syndrome Arthritis, short stature,lymphedema,webbed neck


childwith recurrent attacks of fever. Of the remainingcauses, periodic feverwith adenitis, pharyngitis, andaphthous stomatitis (PFAPA) and hereditary periodicfevers have attracted the attention of clinical investi-gators in the past fewyears.29

PFAPAis one of the commonest causes of recurrentfebrile episodes in children. This condition usuallystarts before the age of 5 years. The febrile attacksoccur at very regular intervals of 22 to 26 days and lastfor about 5 to 7 days. Shallow aphthous ulcers occur

over the buccalmucosa and the pharynx. The pharynxis red andmay showulcers but no exudate. The cervi-cal nodes are enlarged but not lymph glands in otherlocations.Arthralgiamay be seen, but not true arthritis.During the attacks, the totalWBC is increased (a cru-cial difference fromcyclic neutropenia), andESRandCRPare elevated. Cultures are negative. In betweenattacks, the child iswell and grows normally, and theacute phase response settles down.Asingle dose ofprednisone (1mg/kg) at the onset of the attackwillabort the attack inmany cases andmay be diagnostic.In patientswho do not respond to this therapy, smalldoses of prednisonemay be used for 2 or 3 days as longas the attacks are not too frequent. Cimetidinemayhelp reduce the frequency of attacks. The role of tonsil-lectomy is not established. The prognosis is excellentbecausemost children stop getting these episodesbefore they reach adolescence.

Hereditary periodic fevers are recognized by the fol-lowing features: recurrent bouts of unexplainedinflammatory episodes involving serosal tissue, skin,and other systems; familial history; associationwithamyloidosis; and absence of abnormalities of thehumoral immune system andT-cell functions. Theseconditions are also included under the rubric of autoin-flammatory syndromes. Table 9.4 lists the clinical fea-tures of these syndromes. Treatment is specific for

Table 9.2

ImmuneDeficiency andArthritis

Immune AssociatedDeficiency Syndrome

Chronic Systemic lupusgranulomatous erythematosus (SLE), discoiddisease lupus erythematosus

Chediak-Higashi SLE-like diseasedisease

Complement SLEdeficiency(C1q, C1r, C1s,C1 INH,C4, C8)

C2 SLE, Henoch-Schönleinpurpura, vasculitis, juvenileidiopathic arthritis (JIA)

Wiscott-Aldrich Arthritis, vasculitissyndrome

Nezelof syndrome Arthritis, SLE

IgAdeficiency SLE, JIA

Common variable Arthritisimmunodeficiency

X-linked Arthritisgammaglobulinemia

Table 9.3

Causes of Recurrent Fever in Children

Infections, eg,Brucella, Borrelia, Spirillum,Plasmodium, Leishmania

Anatomic defects, eg, pulmonary, urinary tract

Immunodeficiencies: congenital and acquired

Rheumatic diseases: systemic lupus erythematosus,Behcet’s syndrome, relapsing polychondritis

Other: inflammatory bowel disease, PFAPA

Hereditary periodic fever syndromes


Table9.4

SummaryofC

linicalFindingsAssociatedwithHereditaryPeriodicFevers

Clinical

Manifestation

FMF

FCAS

MWS

CINCA/NOMID

TRAPS

HIDS

Durationofattacks

12-72hr

12-24hr

2-3da

ysContinuous

Often>7da

ys3-7da

ys

Cutaneous

Erysipeloiderythema

Cold-indu

ced

Urticaria-like

Urticaria-like

Migratoryrash,

Nonmigratory

urticaria-like

rash

rash

unde

rlyingmyalgia

maculop

apularrash

onrash

trunk,limbs;urticaria

Abd

ominal

Peritonitis,constipation

Nausea

Sometimes

Uncom

mon

Peritonitis,diarrhea,

Severepa

in,vom

iting

,>diarrhea

abdo

minalpa

inorconstipation

diarrhea

>constipation,

rarelype

ritonitis

Pleural

Freq

uent

Notseen

Rare

Rare

Freq

uent

Rare

Arth

ropa

thic

Monarthritis,

Polyarthralgia

Polyarthralgia,

Epiphysealovergrow

th,

Arth

ralgia,arth

ritis

Symmetric

polyarthritis,

occasionallyprotracted

oligoarth

ritis

contractures,intermittent

inlargejoints

arthralgia

inknee

orhip

orchronicarthritis

Ocular

Rare

Conjunctivitis

Conjunctivitis,

Conjunctivitis,

Conjunctivitis,

Rare

episcleritis

uveitis,visionloss

periorbitalede

ma

Neurologic

Heada

che

Heada

che

Sensorineural

Headache,deafness,

Rare

Heada

che

deafness

asep

ticmeningitis,

mentalretarda

tion

(continued)


Table9.4

(continued)

SummaryofC

linicalFindingsAssociatedwithHereditaryPeriodicFevers

Clinical

Manifestation

FMF

FCAS

MWS

CINCA/NOMID

TRAPS

HIDS

Lymph

/spleen

Splenomeg

aly

Notseen

Rare

Ade

nopa

thy,

Splenomeg

aly

Cervicalade

nopa

thy

>lymph

adenop

athy

hepa

tosplenomeg

aly

>lymph

adenop

athy

Vasculitis

HSP

,polyarte

ritis

Notseen

Notseen

Occasional

HSP

,lym

phocytic

Cutaneous

vasculitis,

nodo

savasculitis

rarelyHSP

Amyloido

sis

Variableriskde

pend

ing

Rare

Occurs

May

developina

Occurs

Rare

onMEF

V,SA

Age

notype

s,in~25%

portion

ofpa

tients

in~10%

familyhistory,ge

nder,

reaching

adulthood

compliancewith

treatment

CINCA/NOMID,chronicinfantile

neurolog

iccutaneousandarticularsynd

rome,also

calledneonatalonsetm

ultisysteminflammatorydisease;FCAS,fam

ilialcoldautoinflamma-

torysynd

rome;FM

F,familialMed

iterraneanfever;HIDS,hyperimmunog

lobulinem

iaDwith

periodicfeversyndrome;HSP,H

enoch-Schönleinpurpura;MWS,M

uckle-Wellssyn-

drome;TR

APS,tum

ornecrosisfactorreceptor-associated

periodicsynd

rome.

Permission

requested

from

:Brydges

S,A

threya

B,K

astnerDL.Periodicfeversyndromes

inchildren.In:C

assidyJT,PettyRE,LaxerR,Linsley

CB,eds.TextbookofPed

iatric

Rheum

atolog

y.5thed

.Philadelphia:Elsevier;2005:660.

these conditions. Colchicine is the treatment of choicefor familialMediterranean fever. Etanercept is thetreatment of choice for tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and anakinrafor the cryopyrinopathies. There is no specific treat-ment for the hyperimmunoglobulinemiaD syndrome.Glucocorticoids and anakinra have been usedwithsome success.Anewly redefined pediatric granulo-matous arthritis syndrome should be considered inthis group, although it is not a periodic fever. Thefamilial formof the disease (calledBlau syndrome,described byBlau in 1985) and the sporadic form(knownuntil recently as early onset or juvenile sar-coidosis) are identical. They are characterized byearly onset of an icthyosiform rash, polyarthritis,panuveitis, and sarcoid-like granulomas in the syn-ovium, dermis, and sometimes conjunctiva. It hasbeen recently demonstrated that the disease (bothfamilial and sporadic form) is associatedwithmuta-tions in theNACHT/NODdomain ofCARD-15. It isinteresting to note that thesemutationsmay affectfunctioning of the innate immune system.

10. Juvenile Scleroderma

The scleroderma group of disorders in childhood ischaracterized, as in adults, by exaggerated collagendeposition in the affected tissueswith fibrosis andhardening of the skin. The term scleroderma is used todenote the entire group of diseases associatedwithcutaneous sclerosis and is subdivided into two generalcategories: localized and systemic.30-32 The clinicalfeatures of the localized and systemic forms are simi-lar for themost part in adults and children except forthe differences listed in Table 10.1.

Localized Scleroderma

Localized scleroderma (LS), also called focal sclero-derma, is themost commonvariety in children. It isnot a homogeneous disease and displaysmarked clini-cal and pathologic heterogeneity. Localized sclero-dermamay be subdivided into “morphea” and “linearscleroderma,” based on the characteristics of thelesion.Arecently proposed classification uses thetermmorphea for the entire group32 and subdivides itinto several categories (Table 10.2). The early lesionsare circumscribed patches of induration of the skin.When the lesions involve 1 or 2 sites and the pathol-ogy is confined to skin and superficial adipose tissue,they are called guttate or plaquemorphea dependingon the type of lesion. The lesionsmay occur over the


Table 10.1

Adult andChildhood Scleroderma

Children Adults

Linear scleroderma Verycommon Lesscommon

Limitedvariety of Rare Commonsystemic scleroderma

Renal diseaseof Uncommon Commondiffuse systemic

Small bowel disease Lesscommon Common

Arthropathy Lesscommon Common

Renal crisis Rare Common

face, trunk, and extremities. Active lesions often havea violacious border. These lesionsmay become hardand atrophic,with pigment changes.When the lesionsaffectmore than 2 anatomic sites or individualplaques become confluent, the condition is calledgeneralized morphea.When the lesions and theunderlying sclerotic process take on a linear pattern,mostly along the extremities, it is called linear mor-phea or linear scleroderma. The process mayinvolve deeper tissues all the way to the bone. Thistype of scleroderma is called en coupe de sabrewhen it involves the face and the scalp. Deepmor-phea also involves deeper tissues similar to linearscleroderma but does not follow a linear pattern anddoes not involve deeper organs and viscera. How-

ever, very rarely, patients with morphea evolve intoa systemic variety or one of the other connective tis-sue diseases. Not uncommonly, morphea and linearscleroderma coexist in the patient.

EpidemiologyIn a recent epidemiological study fromOlmstedCounty inMinnesota, the incidence rate adjusted forage and sexwas found to be 2.7/100,000 population.Prevalencewas estimated at 50/100,000 by age 15years. Approximately one-third of cases ofmorpheaare diagnosed in the pediatric age group. It ismorecommon in girls. There is no known associationwithHLAantigen, and familial cases are rare.Mean age ofonset is between 5 to 10 years.

LaboratoryFeaturesBlood counts are often normal except for peripheraleosinophilia. Antinuclear antibody is present in theserumof approximately 40%of childrenwith speck-led or nucleolar pattern. Rheumatoid factormay alsobe seen in some patients. There is often generalizedhypergammaglobulinemia.Other antibodies shown tobe present in the sera of childrenwith linear sclero-derma include those directed against ssDNA, dena-turedDNA, histone,HMGprotein, and Scl 70. Ele-vated levels of s IL-2Rhave also been reported in LS.In the presence of facial and scalp lesions,MRI of thehead and brain is indicated because of the knownassociationwith cerebral lesions.

PathologyHomogenization of collagen bundles is the funda-mental change in all these types. The epidermis isoften normal or atrophic, but the dermis showshomogenization of collagen, decrease in the numberor size of appendages, and perivascular inflammatoryinfiltrate. The depth of involvement is important insubdividing the various categories ofmorphea.

DifferentialDiagnosisAtrophic and circumscribed skin lesionsmay be seenin other conditions such as phenylketonuria, por-phyria cutanea tarda, and lichen sclerosis et atrophi-cus. Eosinophilic fasciitis and its relationship to local-ized sclerodermamay lead to confusion in diagnosis.


Table 10.2

Classification ofMorphea

PlaquemorpheaMorphea en plaqueGuttatemorpheaAtrophoderma of Pasini andPieriniKeloidmorphea (nodularmorphea)(Lichen sclerosus et atrophicus)

Generalizedmorphea

Bullousmorphea

LinearmorpheaLinearmorphea (linear scleroderma)En coupde sabre

Progressive hemifacial atrophy

DeepmorpheaSubcutaneousmorpheaEosinophilic fasciitisMorphea profundaDisabling panscleroticmorphea of children

Permission requested from Peterson LS, Nelson AM,SuWP. Classification of morphea (localized scleroderma).Mayo Clin Proc. 1995;70(11):1068-1076.

TreatmentThere is no proven remedy for LS. Topical and intra-lesional therapywith glucocorticoidsmay be used formilder and superficial lesions for short periods. Ifthere is active fasciitis, a trialwithmoderate doses ofglucocorticoids orally is recommended.

Although no controlled studies have been done, cur-rent opinion favors the early treatment of lesions, par-ticularly if they are of the linear scleroderma type andif they are deep, spreading rapidly, and involve theface and scalp. In the early edema phase, beforehardening takes place, a combination of d-penicil-lamine orMTX and glucocorticoids has been foundto be useful. More recently, MTX has become thedrug of choice because of the ease of administrationand lesser toxicity profile.33 Glucocorticoids areused during the early edema phase for 3 to 6 monthsand d-penicillamine orMTX is continued for 3 to 6months after lesions stabilize. If d-penicillamine isused, careful monitoring is essential to recognizeadverse effects such as myasthenia, bone marrowsuppression, and renal damage.Monitoring forMTX toxicity is similar to that followed in the treat-ment of JIA. Physical therapy including the use ofstatic and dynamic splints will be needed to slow thecontracture andmaintain range of motion.

PrognosisInmost children, the lesions regress spontaneouslyover a period of 3 to 5 years, leaving an atrophic orpigmented area (except in panscleroticmorphea).With early treatment, secondary problems such ascontracturesmay beminimized. Linear sclerodermainvolving deeper tissuesmay cause arrest of growth ofone limb, resulting in cosmetic, functional, and psy-chological problems. Facial involvementmay causeserious psychosocial problems, and cosmetic surgerymay be needed in some children.

Systemic Scleroderma (SSc)

In adults, systemic scleroderma (SSc) is divided intotwo subsets: diffuse cutaneous involvement (diffusecutaneous SSc) and limited cutaneous involvement(limited SSc, previously known as theCRESTsyn-drome). The diffuse variety is characterized by sym-metric andwidespread thickening of skin affecting theproximal and distal portions of the extremities, face,and trunk; early appearance of visceral involvement

(lungs,GI tract, and the kidneys); and the presence ofantiScl 70 and anti-RNApolymerase I, II, and III anti-bodies. The limited cutaneous SSc variety is charac-terized by symmetrical involvement of the skin,which is restricted to the distal aspects of the extremi-ties and the face andwhich displays slowprogression(overmany years and decades); prominent Raynaud’sphenomenon; and often severe andwidespread subcu-taneous calcifications. In this subset of SSc, there isoften a distinctive involvement of the lungs and liver,and the presence of anti-centromere (kinetochore)antibodies is considered to be a highly specific sero-logicalmarker.

In children, the diffuse cutaneous type is themostcommonvariety. The limited cutaneous type isextremely uncommon, probably because of the veryslow evolution of the disease over several decades.

EpidemiologySystemic scleroderma is relatively uncommon inchildhood and accounts for less than 10%of allpatientswith this type.Almost all childhood patientsbelong to the diffuse cutaneous type.Age of onset isoften in later childhood (older than 8 years). It occurswith equal frequency in boys and girls at youngerages. In older children, girls outnumber boys. Thereare occasional reports of familial cases. The associa-tion betweenHLA-II antigens and SSc is related toclinical subtypes and the associated autoantibodies.

Etiology andPathogenesisThe pathogenesis of SSc is unknown. Epidemiologi-cal, clinical, and pathological features of the diseasesuggest a role for environmental agents, genetics,immunological alterations, alterations in collagenmetabolism, and abnormalities in themicrovascula-ture and endothelium. There is an increased interest inthe role of various cellular elements includingmastcells and of cytokines involved in the fibrotic process.It is postulated that immune cells turn on autocrinesignals that facilitate the proliferation and persistenceof fibroblastswith an abnormal phenotype committedto high level of collagen production. The similaritybetween graft-versus-host disease (GVHD) and scle-roderma has long been recognized. This similarity,togetherwith the observation that fetal hematopoieticcellsmay be detected in the circulation ofwomen upto 27 years postpartum, led to the hypothesis that SScmay be aGVHDcaused by activated fetal cells.


Although the pathogenesismay be similar betweenadult-onset and childhood-onset scleroderma, it is notknownwhether differences in the stage ofmaturationof the immune systemor age-related differences in thefunctional responses of the endothelium and themicrovasculaturemay affect the pathogenesis or theclinicalmanifestations in pediatric cases.

Clinical FeaturesEarly skin changes consist of puffiness of fingers,hands, and feet due to nonpitting edema. Thesechanges spread proximally.Afterweeks tomonths,this is replaced byfibrosis and sclerosis of the skin.The skin becomes hard,woody, and adherent todeeper structures. This is particularly prominent in thehands and fingers and the face. The tightness andthickening prominent in the dorsumof the distal digitscauses acrosclerosis. There is limitation of range ofmotion of fingers leading to “prayer sign.” The facebecomes expressionless, with tight puckered lips andinability to open themouth. Later still there is atrophyof the skin resulting in shiny appearance of the skinand prominent venousmarkings and telangiectasia.Pigmentary changes of the skin and subcutaneous cal-cificationmay be seen at this stage. Pitting of the fin-gertips and loss of pulp are characteristic of SSc.

Raynaud’s phenomenon is common in SSc andmaybe the presenting manifestation. Microvascularchanges in the nail-bed capillaries associated withRaynaud’s phenomenon are highly indicative ofSSc, particularly if ANAis also positive. Character-istic nail-bed capillary changes include areas of“drop-out” of capillaries, prominent loops, and newformation of capillaries.

Next to the skin, theGI tract is themost commonlyaffected system. Esophageal dysmotility, particularlyinvolving the lower third of the esophagus, is themostcommon abnormality.Decreased lower esophagealsphincter pressuremay result in reflux esophagitis.Involvement of the small intestinemay lead tomalab-sorption, bacterial overgrowth, and intestinal obstruc-tion. Involvement of the distal intestinemay lead tosevere constipation. Fibrosis of the conduction systemof the heartmay lead to arrhythmia. Rarely,myocardi-tis and pericarditismay be seen. Congestive failuremay be seen associatedwithmyocardial fibrosis orpulmonary hypertension. Pulmonary hypertensionoften secondary to interstitial lung disease is insidious

in onset. Physical examination and chest radiographdo not correlate well with pulmonary functionabnormalities. Chest radiographmay show a bibasi-lar interstitial pattern. High-resolution CT scan andnuclear medicine studies aremore sensitive in recog-nizing early changes in the lung. Restrictive patternand decreased diffusion capacity are themost com-mon abnormalities in pulmonary function tests.Occasionally, an obstructive or small airway diseasemay be seen.

Fortunately, renal involvement is not as common as inadultswith SSc. Scleroderma renal crisiswithmalig-nant hypertension is themost commonpresentation.Symmetric polyarthritis,myopathy, cranial neuropa-thy, and Sjögren’s syndrome are other associatedproblems seen in childrenwith SSc.

LaboratoryFindingsTheCBC is often normal except for anemia sec-ondary tomalabsorption and eosinophilia. Hyper-gammaglobulinemia and the presence ofRF andANAsuggest alterations in humoral immunity.AntiScl 70 antibody (topoisomerase), seen in approxi-mately 20%-40%of patients, is associatedwith thediffuse type, and pulmonary disease and anticen-tromere antibody correlatewith the limited variety.The PM/Scl antibody is seen in associationwith over-lap syndrome.AnEKGmay showvarious degrees ofheart block, ventricular hypertrophy, and evidence ofpulmonary hypertension. Radionuclide scansmayshowmyocardial perfusion defects and reduced con-tractility. Pulmonary function abnormalities com-monly seen in SSc have been outlined earlier. In thepresence of renal failure, the glomerular filtration ratewill be altered and plasma renin levels increased.

The serological profile in childhoodSSc is similar tothat seen in adults. In the diffuse variety, elevated lev-els of anti-Scl 70 antibodymay be seen.Anti-Scl 70antibodiesmay be seenwith limited SSc in contrast toadultswith this subset of SScwho usually displayanti-centromere antibodies. It should be emphasizedthat all of these studies are limited because of thesmall number of patients, inclusion of patents at vari-ous stages of the disease, and variation in themethod-ology employed for their assessment.


PathologyEarly lesions include hyalinization of the vessel walland proliferation of the endothelium. Perivascularinfiltrationwith T-cells, plasma cells, andmacrophages affecting the deep dermis and subcuta-neous tissue is also seen at this stage. Later, increasein collagen content of the dermis occurs, resulting inthinning of the epidermis and atrophy of the retepegs. The lower two-thirds of the esophagus showreplacement of the smoothmuscle by atrophic tissue,and there is infiltration ofmononuclear cells into lam-ina propria andAuerbach’s plexus. Fibrosis of car-diacmuscle and diffuse alveolar and interstitial fibro-sis of the lung are characteristic of SSc. Concentricintimal proliferation of the interlobar and arcuatearteries is amajor feature of renal involvement. Thereis no true vasculitis.

ManagementGeneral supportivemeasures include education of thefamily and advice on nutrition and protection againstexposure to cold.Generalized skin care such as theuse of emollients, and a good physical therapy pro-gram to prevent contractures should be emphasized.There is no proven specific therapy for the treatmentof childhood scleroderma.Of the available therapies,the only onewith any scientific validity is d-penicil-lamine.Use of prednisone in combinationwith d-penicillamine early in the course of skin disease isuseful. However, prednisone should be used, if at all,with extreme caution in the systemic variety andshould not be used in the presence of renal involve-ment.Methotrexate is usedmore frequently, althoughthere is no definite evidence for its superiority overd-penicillamine. In addition, there is the concernabout pulmonary toxicity associatedwithMTX.Theuse of d-penicillaminemay also benefit some patientswith pulmonary disease. In the presence of severe pul-monary diseasewith active inflammation, aggressivetherapywith glucocorticoids and cyclophosphamidemay be needed. Colchicine, hydroxychloroquine,MTX, cyclosporine, and azathioprine have been usedbased on anecdotal experience.

MildRaynaud’s phenomenon ismanagedwith simplemeasures to protect against exposure to cold andtrauma.Mild tomoderateRaynaud’s phenomenonmay bemanagedwith biofeedback in some children.

Formore serious problems, oral nifedipine is the drugof choice. It is started in lowdoses at bedtime andincreased gradually if it is tolerated. Intravenous ilo-prost has been used in a few childrenwith peripheralgangrene. The role of biological agents and bonemar-row transplantation is not clear. Sympathectomy isrecommended for intractableRaynaud’s phenomenonwith gangrene.

Renal vascular hypertension is treatedwithACEinhibitors. Reflux due to loss of lower esophagealsphincter and esophagealmobility ismanaged by rec-ommending upright posture, particularly after eatingand during sleep and the use of cisapride andH2blocker. If signs ofmalabsorption develop, nutritionalsupplementationwill have to be recommended.

PrognosisThe skin disease and contracturesmay cause both cos-metic and functional problems.However, the diseasemay stabilize and the skinmay even soften over sev-eral years. Visceral involvementmay progresswithconsequences such asmalabsorption and growthretardation, cardiac arrhythmias and heart failure, pul-monary hypertension, severe reflux, gangrene ofextremities, and renovascular hypertension. Commoncauses of death are cardiac and pulmonary. Renaldeaths are uncommon comparedwith adultswith SSc.


11. References

1. PettyRE, SouthwoodTR,Manners P, Baum J,GlassDN,Goldenberg J,HeX,Maldonado-Cocco J,Orozco-Alcala J, PieurAM, Suarez-AlmazorME,WooP. International League ofAssociations forRheumatology classification ofjuvenile idiopathic arthritis: second revision,Edmonton, 2001. JRheumatol. 2004;31(2):390-2.

2. AnderssonGareB. Juvenile arthritis—whogetsit, where andwhen?Areviewof current data onincidence and prevalence.ClinExpRheumatol.1999;17:367-374.

3. MurrayKJ,MoroldoMB,Donnelly P, PrahaladS, PassoMH,Giannini EH,GlassDN.Age-spe-cific effects of juvenile rheumatoid arthritisassociatedHLAalleles.Arthritis Rheum.1999;42(9):1843-1853.

4. SullivanKE. Inflammation in juvenileidiopathic arthritis.Pediatr ClinNorth Am.2005;52(2):335-357.

5. Hashkes PJ, LaxerRM.Medical treatment ofjuvenile idiopathic arthritis. JAMA.2005;294(13):1671-1684.

6. LovellDJ,Giannini EH,ReiffA,CawkwellGD, SilvermanED,Nocton JJ, Stein LD,GedaliaA, IlowiteNT,WallaceCA.Etanerceptin childrenwith polyarticular juvenile rheuma-toid arthritis.NEngl JMed. 2000;342(11):763-769.

7. Prahalad S, PassoMH.Long-termoutcomeamong patientswith juvenile rheumatoid arthri-tis.Front Biosci. 1998;3:e13-22.

8. DuffyC.Measurement of health status, func-tional status, and quality of life in childrenwithjuvenile idiopathic arthritis: clinical science forthe pediatrician.Pediatr ClinNorth Am.2005;52(2):359-372, v.

9. Burgos-VargasR, Pacheco-TenaC,Vasquez-Mellado J. Juvenile-onset spondy-loarthropathies.RheumDisClinNorth Am.1997;23(3):569-598.

10. Benseler SM, SilvermanED. Systemic lupuserythematosus.Pediatr ClinNorth Am.2005;52(2):443-467, vi.

11. Cameron JS. Lupus nephritis in childhood andadolescence.Pediatr Nephrol. 1994;8(2):230-249.

12. Weening JJ,D’AgatiVD, SchwartzMM,Seshan SV,AlpersCE,AppelGB, et al. Theclassification of glomerulonephritis in systemiclupus erythematosus revisited. JAmSocNephrol. 2004;15(2):241-250.

13. ContrerasG, PardoV, LeclercqB, LenzO,TozmanE,O’NanP,RothD. Sequential thera-pies for proliferative lupus nephritis.NEngl JMed. 2004;350(10):971-980.

14. BarronKS,WallaceC,WoolfreyCEA,LaxerRM,HirschR,HorwitzM, Siegel J, FilipovichL,WulffraatN, PassoM,Rider LG.Workshopreport on autologous stem cell transplantationfor pediatric rheumatic diseases. JRheumatol.2001;28(10):2337-2358.

15. Lacks S,White P.Morbidity associatedwithchildhood systemic lupus erythematosus.JRheumatol. 1990;17(7):941-945.

16. PachmanLM. Juvenile dermatomyositis: patho-physiology and disease expression.Pediatr ClinNorth Am. 1995;42(5):1071-1098.

17. Compeyrot-Lacassagne S, FeldmanBM.Inflammatorymyopathies in children.PediatrClinNorth Am. 2005;52(2):493-520.

18. Saulsbury FT.Henoch-Schönlein purpura inchildren. Report of 100 patients and reviewofthe literature.Medicine (Baltimore).1999;78(6):395-409.

19. Szer IS.Henoch-Schönlein purpura:when andhow to treat. JRheumatol. 1996;23(9):1661-1665.

20. Burns JC,GlodeMP.Kawasaki syndrome.Lancet. 2004;364(9433):533-544.


21. Newburger JW,TakahashiM,GerberMA,GewitzMH,Tani LY,Burns JC, et al. Diagnosis,treatment, and long termmanagement ofKawasaki disease: a statement for health profes-sionals from theCommittee onRheumaticFever, Endocarditis andKawasakiDisease.Council onCardiovascularDisease in theYoung,AmericanHeartAssociation.Pediatrics. 2004;114(6):1708-1733.

22. WilsonWA,GharaviAZ,KoikeT, LockshinMD,BranchDW,Piette JC,BreyR,DerksenR,Harris EN,HughesGR,Triplett DA,KhamashtaMA. International consensus statement on pre-liminary classification criteria for definiteantiphospholipid syndrome: report of an inter-nationalworkshop.Arthritis Rheum.1999;42(7):1309-1311.

23. Ravelli A,MartiniA.Antiphospholipid syn-drome.Pediatr ClinNorth Am. 2005;52(2):469-491.

24. LimW,CrowtherMA,Eikelboom JW.Manage-ment of antiphospholipid antibody syndrome: asystematic review. JAMA. 2006;295(9):1050-1057.

25. NeimanAR,LeeLA,WestonWL,Buyon JP.Cutaneousmanifestations of neonatal lupuswithout heart block: characteristics ofmothersand children enrolled in a national registry.JPediatr. 2000:137(5):674-680.

26. SilvermanED,LaxerRM.Neonatal lupuserythematosus.RheumDisClinNorth Am.1997;23(3):599-618.

27. Buyon JP, ClanceyRM.Neonatal lupus: reviewof proposed pathogenesis and clinical data fromtheUS-basedResearchRegistry forNeonatalLupus.Autoimmunity. 2003;36(1):41-50.

28. ChalomEC,Ross J,AthreyaBH. Syndromesand arthritis.RheumDisClinNorth Am.1997;23(3):709-727.

29. Padeh S. Periodic fever syndromes.Pediatr ClinNorth Am. 2005;52(2):577-609.

30. Zulian F. Scleroderma in children.Pediatr ClinNorth Am. 2005;52:521-545, vii.

31. Zulian F,AthreyaBH,LaxerR,NelsonAM,Feitosa deOliveira SK, PunaroMG, et al.Juvenile localized scleroderma: clinical and epi-demiological features in 750 children.An inter-national study.Rheumatology (Oxford).2006;45(5):614-20.

32. PetersonLS,NelsonAM,SuWP.Classificationofmorphea (localized scleroderma).MayoClinProc. 1995;70(11):1068-1076.

33. UzielY, FeldmanBM,KrafchikBR,YeungRS,LaxerRM.Methotrexate and corticosteroidtherapy for pediatric localized scleroderma.JPediatr. 2000;136(1):91-95.

Additional Reading

Cassidy JT, PettyRE, LaxerRM,LindsleyCB, eds.Textbook of Pediatric Rheumatology. 5th ed.Elsevier/Saunders; 2005.


12. Questions

1. Characteristic features of PFAPAinclude all ofthe following EXCEPT:

A. Aphthous stomatitis

B. Fever

C. Pharyngitis

D. Arthralgia

E. Generalized adenopathy

2. The chance of recurrence in a sibling of a patientwith congenital heart block is:

A. 5%

B. 10%

C. 15%

D. 20%

E. 25%

3. Match the doses (mg/kg) with the appropriatemedications for pediatric use:

1. Naproxen A. 5-7

2. Cyclosporine B. 0.4

3. Hydroxychloroquine C. 1-2

4. Etanercept D. 10-20

5. Indomethacin E. 3-5

4. A7-year-old girl is seen with coupe de sabrelesions on the right side of the face. In the inves-tigations of this child, which of the followingstatements is TRUE?:

A. ANAis always positive

B.MRI is a required study

C. Eye examination is optional

D. Anti Scl 70 will be present

E. Anti ssDNAis prognostic

5. You are consulted to see an 11-month-old with 4days of high fever and regional lymphadenopa-thy. The child is irritable and you suspectKawasaki syndrome, but the patient does notfulfill criteria. In this case, a useful test to helpdecide appropriate treatment is:

A. Angiogram

B. CT of the sinuses

C. Abdominal sonogram

D. Blood culture

E. Liver function test

6. A5-year-old girl is in the hospital with a firmdiagnosis of Henoch-Schönlein purpura. Thedoctors in the emergency department admittedher for intense abdominal pain. She looks dis-tressed but nontoxic. Abdominal examination isdifficult, but the pain localizes consistently tothe right lower quadrant. She vomited twice andis now receiving nothing bymouth. There wasno blood in the vomitus, and there was a normalstool (heme negative) an hour ago. There is pal-pable purpura and limb edema, and the urine testresults have been normal. Your next step is:


A. Prescribe narcotic therapy for pain control

B. Obtain barium enema

C. Recommend exploratory abdominal surgery

D. Continue observing for a few hours with thepatient on intravenous fluids

E. Obtain abdominal angiogram

7. You are consulted by a physician who has beentreating a 5-year-old girl for facial and knuckleatopic dermatitis with topical corticosteroids.She is now complaining of pain in her legs andarms. You find on examination a typical der-matomyositis rash and some proximal muscleweakness on pelvic extensors and neck flexors.Your recommendations for the next step in man-agement could include any of the followingEXCEPT to:

A. Obtain muscle enzymes

B. Obtain anMRI of the lower limbs with T2-weighted fat suppressed images

C. Obtain an EMG followed bymuscle biopsy ifthe electric study results are abnormal

D. Have a full evaluation of muscle power by aphysical therapist

E. Perform a careful examination of the nail beds

8. Your orthopedic consultant asked you to see a13-year-old boy with the third episode ofAchilles tendonitis. You confirm the history andfind in addition that the child has right knee syn-ovitis and a thickened Achilles insertion site.There is family history of acute anterior uveitis.You tell your colleague that you suspect aspondyloarthropathy. He questions your diagno-sis as he shows you anMRI of the pelvis withnormal sacroiliac joints.Which of the followingstatements is correct?

A.MRI is an insensitive technique todemonstrate sacroiliitis.

B. Aknee aspiration for cell count and culture isnecessary before any diagnosis is considered.

C. Your orthopaedic consultant is right.

D. Sacroiliac involvement is unusual at the onsetof pediatric spondyloarthropathies.

E. Lower extremity large joint asymmetricalarthritis is an exceptional finding inspondyloarthropathies.

Answers

1. E.

2. D.

3. 1. = D.; 2. = E.; 3. = A.; 4. = B.; 5 = C.

4. B.

5. C.

6. D.

7. C.

8. D.


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