juvenile idiopathic arthritis changing times, changing...

Juvenile Idiopathic Arthritis ndash Changing TimesChanging Terms Changing Treatments

Susan Shenoi MBBS MS

Department of Pediatrics Division of Rheumatology University of Washington School of Medicine amp Seattle Childrenrsquos Hospital Seattle WA

Education Gap

The management of juvenile idiopathic arthritis (JIA) has changed

radically over the last few decades This article provides an update on

identification of JIA complications of the condition and common

management strategies to help practitioners treat affected children in

conjunction with other specialists as part of a multidisciplinary team

Objectives After completing this article readers should be able to

1 Recognize the clinical findings associatedwith the various categories of

juvenile idiopathic arthritis (JIA)

2 Recognize the laboratory findings associated with the different

categories of JIA and its complications

3 Formulate a differential diagnosis for children with joint pain

4 Recognize the long-term complications associated with JIA

5 Plan the appropriate management of JIA while recognizing adverse

effects of some therapies

INTRODUCTION

Arthritis is a common cause of disability in childhood In children the condi-

tion previously was known as juvenile chronic arthritis or juvenile rheumatoid

arthritis Currently the preferred name for childhood arthritis is juvenile idio-

pathic arthritis (JIA) because this term denotes the idiopathic or unknown cause

of the condition The exact incidence and prevalence of JIA is unknown and

likely varies across the world The estimated incidence and prevalence of JIA

in the United States is approximately 14 per 100000 children (95 confidence

interval 10ndash18) and 113 per 100000 (95 confidence interval 55ndash155) respec-

tively (1) JIA is believed to have a multifactorial etiology with both genetic and

nongenetic (ie environmental) contributing causes Due to the paucity of practicing

pediatric rheumatologists pediatricians or family practice physicians often are

ldquoon the front linerdquo for initial identification and treatment of JIA This article

focuses on key points for diagnosis and initial evaluation of JIA and provides an

overview of treatment

AUTHOR DISCLOSURE Dr Shenoi hasdisclosed that she has been a speaker forNovartis This commentary does contain adiscussion of an unapprovedinvestigativeuse of a commercial productdevice

ABBREVIATIONS

ALT alanine aminotransferase

ANA antinuclear antibody

AST aspartate aminotransferase

CARRA Childhood Arthritis and

Rheumatology Research Alliance

CBC complete blood cell

CRP C-reactive protein

DMARD disease-modifying antirheumatic

drug

ERA enthesitis-related arthritis

ESR erythrocyte sedimentation rate

FDA Food and Drug Administration

HLA human leukocyte antigen

IAS intraarticular corticosteroid

injection

IL interleukin

ILAR International League of

Associations for Rheumatology

IV intravenous

JIA juvenile idiopathic arthritis

MAS macrophage activation syndrome

NSAID nonsteroidal anti-inflammatory

drug

PVNS pigmented villonodular synovitis

RF rheumatoid factor

SJIA systemic juvenile idiopathic

arthritis

TMJ temporomandibular joint

TNF tumor necrosis factor

Vol 38 No 5 MAY 2017 221

CLASSIFICATION AND CATEGORIES OF JIA

According to the International League of Associations for

Rheumatology criteria (ILAR) JIA is defined as chronic

arthritis (Dagger6 weeks duration) with no known cause occur-

ring in children before the 16th birthday (2) The 6-week

minimum duration to define chronicity and onset before

the 16th birthday to define ldquojuvenilerdquo are based on expert

opinion rather than derived from data The ILAR classifi-

cation categorizes JIA into 7 mutually exclusive categories

based on the number of joints involved extra-articular fea-

tures and serology identified in the first 6 months of dis-

ease presentation (Table 1) This categorization attempts

to cluster similar JIA presentations into distinct categories

to improve research into etiology disease course long-

term outcomes response to treatment and development of

future therapies This classification system will likely evolve

and be refined over the next few decades as knowledge of

this disease increases

TABLE 1 Categories of Juvenile Idiopathic Arthritis (2)

ILAR CATEGORYPREVIOUSNOMENCLATURE ILAR DEFINITION EXCLUSION ADULT EQUIVALENT

Systemic-onsetJIA

Systemic-onset juvenilerheumatoid arthritis

Arthritis and fever (Dagger2 weeks documentedquotidian 3thorn days)

1 2 3 4 Adult Still disease

Plus 1 or morebull Evanescent erythematous rashbull Generalized lymphadenopathybull Hepatosplenomegalybull Serositis

PolyarticularRF-negative

Arthritis Dagger5 joints during the first 6 monthsof disease and RF-negative

1 2 3 4 5

PolyarticularRF-positive

Arthritis Dagger5 joints during the first 6 months of diseaseand RF-positive 2 at least 3 months apart

1 2 3 5 Rheumatoid arthritis(RF-positive)

Oligoarthritis Pauciarticular juvenilerheumatoid arthritis

Arthritis pound4 joints during the first 6 months of disease2 subtypes are identified

1 2 3 4 5

bull Persistent OJIA affecting no more than 4 jointsbull Extended OJIA affecting a total of gt4 joints afterthe first 6 months of disease

ERA Seronegative enthesitisand arthritis syndrome

Spondyloarthropathy

Arthritis and enthesitis 1 4 5 Ankylosing spondylitis(if bilateral sacroiliitis)or

Arthritis or enthesitisPlus 2 ofbull Sacroiliac joint tenderness or inflammatorylumbosacral pain

bull HLA-B27thornbull Onset of arthritis in a male older than age 6 yearsbull Acute anterior uveitisbull History of ankylosing spondylitis ERA sacroiliitiswith inflammatory bowel disease reactivearthritis or acute anterior uveitis in first-degreerelative

Psoriatic arthritis Arthritis and psoriasis or Arthritis plus 2 of 2 3 4 5 Psoriatic arthritisbull Dactylitisbull Nail pitting or onycholysisbull Psoriasis in a first-degree relative

Undifferentiatedarthritis

Arthritis that fulfills criteria forbull No categoryorbull Two or more categories

ERAfrac14enthesitis-related arthritis ILARfrac14International League of Associations for Rheumatology HLAfrac14human leukocyte antigen JIAfrac14juvenile idiopathicarthritis OJIAfrac14oligoarticular juvenile idiopathic arthritis RFfrac14rheumatoid factorExclusion definitions 1 Psoriasis in patient or first-degree relative 2 HLA-B27thornmale older than age 6 years 3 Ankylosing spondylitis ERA sacroiliitis withinflammatory bowel disease Reiter syndrome or acute anterior uveitis in a first-degree relative 4 RF-positive in 2 assessments 3 months apart 5 Systemic-onset JIA in patientReproduced with permission from inPracticecom Essentials of Juvenile Idiopathic Arthritis for the Adult RheumatologistInternist

222 Pediatrics in Review

KEY CLINICAL PRESENTING FEATURES

JIA is diagnosed clinically because no laboratory results can

uniquely distinguish JIA from other diseases A thorough

history and physical examination are the key elements to

making the diagnosis Important features of the history that

are suggestive of JIA include presence of morning stiffness

achiness for at least 15 minutes (in toddlers this is often

described as a grumpy or limping child in the mornings

or after naps) improvement in stiffnesspain with activity

or as the day progresses presence of gelling (joint stiff-

ness after prolonged periods of inactivity) and swelling or

decreased range of motion of the joints Often pain is not

the primary symptom of JIA and occasionally arthritis or

synovitis can be painless During a clinic visit several clues

can be inferred by observing how a child positions and

uses extremities gets on or off the examination table and

walksruns in the hallway All jointsmust be examined for the

presence of arthritis (ie swelling warmth restricted range

of motion or tenderness with range of motion) Other ex-

amination clues that may signify chronic arthritis (usually

seen several months later) include the presence of muscle

weakness or atrophy (due to disuse) bony overgrowth

(commonly seen at the affected knee) leg length discrep-

ancy (the affected leg may be longer due to overgrowth)

and micro- or retrognathia (due to temporomandibular

joint [TMJ] arthritis) Although TMJ disease may present

as jaw pain or difficulty chewing it is often asymptomatic

Jaw involvement can be evaluated by measuring the inter-

incisormouth opening (normal Dagger4 cm) or assessing for devi-

ation of the jaw to the affected side with mouth opening

Enthesitis is inflammation of the entheses which are

the sites at which tendons or ligaments insert onto bone

Enthesitis can occur in several categories of JIA and should

be assessed for during the physical examination Common

locations include the Achilles tendons around the knees

(at the 2 6 and 10 orsquoclock positions) (Fig 1) greater

trochanter metatarsal heads and planter fascia insertion

on the feet The presence of psoriasis nail pits and ony-

cholysis may favor a diagnosis of psoriatic arthritis

Uveitis (inflammation of the eyes)may be associated with

several categories of JIA Presence of synechiae (abnormal

distorted pupillary shape due to presence of uveitis) signi-

fies long-standing uveitis requiring immediate evaluation

by an ophthalmologist (which should include a slit lamp ex-

amination) and treatment Because ocular inflammation in

JIA is often asymptomatic children with JIA must be re-

gularly screened for uveitis by an ophthalmologist based

on the current American Academy of Pediatrics guidelines

(Table 2) (3)

Systemic JIA (SJIA) is a unique form of JIA with a

clinical presentation that is remarkably distinct from the

other JIA categories The typical SJIA presentation is daily

(or quotidian) intermittent fever with temperatures as high

as 1022 to 104degF (39-40degC) with or without classic evanes-

cent (transient) salmon-pink macular rash Other features

of SJIA include lymphadenopathy hepatosplenomegaly

and serositis (such as pericarditis pleuritis or peritonitis)

A subset of SJIA patients can present with or later develop

macrophage activation syndrome (MAS) MAS is a life-

threatening complication characterized by persistent fe-

vers fixed rash cytopenias elevated liver enzymes elevated

D-dimers low fibrinogen and dropping erythrocyte sedi-

mentation rate (ESR) elevated triglycerides and coagulop-

athy Affected patients may develop abnormal bleeding and

cardiac liver or renal failure

Oligoarticular JIAOligoarticular JIA is the most common category of JIA and

by definition involves fewer than 5 joints The disease in

some affected children progresses after the first 6 months to

involve additional joints and then is classified as ldquoextended

oligoarticular JIArdquo The typical phenotype of oligoarticular

JIA is a well-appearing 2- to 4-year-old girl presenting with

morning limp and swelling of 1 of the lower extremity

joints most commonly the knees Laboratory evaluation

often yields normal results including complete blood cell

(CBC) count with differential count ESR and C-reactive

protein (CRP) Up to 70 of these children may have a

positive antinuclear antibody (ANA) and need to be screened

Figure 1 Knee in juvenile arthritis patient showing active arthritis of leftknee (red arrow) and the positions for checking enthesitis (2 6 and 10orsquoclock black arrows)

Vol 38 No 5 MAY 2017 223

frequently (every 3 months) for uveitis The long-term prog-

nosis is usually good if they do not develop extended disease

Polyarticular JIABy ILAR definition children who have polyarticular JIA have

more than 4 joints involved in the first 6 months of disease

onset Depending on the presence or absence of rheumatoid

factor (RF) the disease is classified further as RF-positive or

-negative Because RF is transiently positive in other con-

ditions such as infections its positivity should be confir-

med by repeating RF evaluation 3 months later There are

typically 2 peaks of presentation ages 1 to 3 years and dur-

ing adolescence Fig 2 shows a teenage girl with polyarti-

cular JIA and arthritis of several proximal interphalangeal

joints bilaterally and flexion contractures with boutonniere

deformity (proximal interphalangeal joint flexion and distal

interphalangeal joint hyperextension) of bilateral fifth fingers

Systemic JIAChildren who have SJIA must undergo complete infec-

tious and malignancy evaluation for their fevers including

cultures serology imaging andor bone marrow examination

before being diagnosed with SJIA Occult MAS can occur in

up to one-third of children and must be recognized and

treated promptly Clinicians should not be reassured by a

decreasing ESR in an ill-looking patient because this may

signify MAS MAS is considered a secondary form of he-

mophagocytic lymphohistiocytosis and is a life-threatening

condition that involves rapid expansion of macrophages

and T cells leading to massive overproduction of cytokines

Among the JIA categories this complication appears to be

unique to SJIA Features of MAS include persistent fevers

bleeding diathesis central nervous system involvement with

drowsiness or seizures fixed rashes decreasing white blood

cell and platelet counts decreasing fibrinogen elevated

D-dimer elevated triglycerides and abnormal liver function

tests (aspartate aminotransferase [AST] alanine aminotransfer-

ase [ALT]) Hyperferritinemia (ferritin levels are often gt5000

ngmL [11235 pmolLngmL]) and hemophagocytosis

(often seen in bone marrow or other tissues such as lymph

node or spleen) are hallmarks of MAS

Psoriatic JIAChildren may present with classic psoriasis nail changes

suggestive of psoriasis or family history of psoriasis in a

first-degree relative in addition to arthritis Affected chil-

dren often present with ldquosausage digitsrdquo or dactylitis

Enthesitis-related ArthritisEnthesitis-related arthritis (ERA) is more common in boys

and usually presents with enthesitis and arthritis Axial

involvement of the spine or sacroiliac joints with back pain

is common This is the only category of JIA that can present

with an ldquoacute painful red eyerdquo rather than asymptomatic

uveitis Some children may have the acute iritis months to

years before joint symptoms develop

TABLE 2 Initial Screening Frequency Recommendations for PatientsWithout Known Iridocyclitis (3)

DISEASE FEATURES ONSET AGE YOUNGER THAN 7 YEARS ONSET AGE 7 YEARS OR OLDER

ANA-positive (OJIA and PJIA) Every 3-4 months Every 6 months

ANA-negative (OJIA and PJIA) Every 6 months

SJIA and ERA Every 12 months

ANAfrac14antinuclear antibody ERAfrac14enthesitis-related arthritis OJIAfrac14oligoarticular juvenile idiopathic arthritis PJIAfrac14polyarticular juvenile idiopathicarthritis SJIAfrac14systemic juvenile idiopathic arthritisOnce uveitis is detected the treating ophthalmologist determines the frequency of screening to ensure the inflammation is responding appropriately tothe therapy Patients with JIA onset of agelt7 years who reach age 7 years or those with JIA onset of age Dagger7 years who are 4 years into their diagnosis areconsidered to be at lower risk for uveitis and can transition to annual ophthalmologic examinations going forwardReproduced with permission from inPracticecom Essentials of Juvenile Idiopathic Arthritis for the Adult RheumatologistInternist

Figure 2 Arthritis of several proximal interphalangeal joints bilaterallyand flexion contractures with boutonniere deformity of bilateral fifthfingers in a child who has polyarticular juvenile idiopathic arthritis


Undifferentiated ArthritisThis category includes children who meet criteria for 2 or

more categories or those who do not meet criteria for any

category Examples include a child who has involvement of

only 2 joints but is RF-positive on 2 separate tests or a child

with arthritis in 3 joints whose mother has psoriasis

LABORATORY EVALUATION

JIA is a clinical diagnosis Although no laboratory tests are

diagnostic of JIA such evaluations are helpful for exclud-

ing other diagnoses For example in an acutely (hours to

days) swollen painful joint synovial fluid analysis may be

important to rule out septic arthritis (50000-300000 cells

with gt 75 neutrophils low glucose and positive culture

or Gram stain) Indolent infections such as Lyme disease

or tuberculosis should be screened for on history and ap-

propriate testing may include screening enzyme-linked im-

munosorbent assay with confirmatory Western blot for

suspected Lyme disease or purified protein derivative

interferon-g release assay gold for tuberculosis

Clinicians should consider and excludemalignancy especially

in the presence of bone pain pain out of proportion to exami-

nation findings pain that wakes the child from sleep and pres-

ence of cytopenias or elevated markers of cell turnover (such

as lactate dehydrogenase and uric acid) Both generalized

malignancies (such as leukemia lymphoma or neuroblas-

toma) and localized tumors (such as pigmented villonodular

synovitis [PVNS] or Ewing sarcoma) can mimic JIA

Normal values for inflammation markers (ESR or CRP)

should not deter a diagnosis of JIA because these may be

normal in localized disease such as oligoarticular JIA Most

polyarticular JIA and SJIA (except when in MAS) presents

with elevated values of inflammatory markers (ESR CRP)

andor elevated platelet counts

The ANA is not useful for diagnosis of JIA because

40 to 50 of JIA can be ANA-negative In addition its util-

ity is limited by frequent low titer positivity (up to 1160) in

healthy children without rheumatic disease (4) The primary

utility of ANA testing in children with JIA is to stratify the risk

of uveitis Childrenwith JIAwho areANA-positive are at higher

risk for uveitis and need to be screenedmore frequently by the

ophthalmologist The immunofluorescent testing method is

considered the gold standard for ANA testing

Because only 10 of children with JIA are RF-positive

this test cannot be relied upon to make the diagnosis Human

leukocyte antigen (HLA) B27 testing for the ERA category is

limited by its lack of sensitivity and specificity Children can

have ERA in the absence of HLAB27 positivity and not all

HLAB27-positive children meet criteria for ERA

IMAGING EVALUATION

Imaging is increasingly used in the diagnosis and manage-

ment of JIA Point-of-care ultrasonography and magnetic

resonance imaging (with intravenous [IV] gadolinium con-

trast) can identify active synovitis particularly in clinically

difficult-to-examine joints such as the hips shoulders or

TMJ Imaging is also useful for early identification of joint

damage such as joint space narrowing (indicative of carti-

lage damage) or erosions (bone damage) (Fig 3) Imaging

modalities are limited by their inability to differentiate the

underlying cause of arthritis such as infectious malignant

or inflammatory Therefore the onus of determining the

correct diagnosis rests with the treating physician

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of JIA is broad because arthritis

arthralgias can occur in several conditions including

1) Infections bacterial viral fungal

2) Postinfectious conditions poststreptococcal arthritis

rheumatic fever reactive arthritis (Salmonella sp Shigella

sp Campylobacter sp Clostridium difficile Chlamydia

trachomatis Mycoplasma genitalium Yersinia sp)

3) Malignancies leukemia lymphoma neuroblastoma

PVNS

4) Other inflammatory diseases systemic lupus erythem-

atosus juvenile dermatomyositis scleroderma Kawasaki

diseaseHenoch-Schoumlnlein purpura vasculitis sarcoidosis

5) Gastrointestinal conditions inflammatory bowel disease

celiac disease

6) Endocrine conditions thyroid disease

7) Hematologic diseases sickle cell hemophilia thalassemia

8) Heritable diseases mucopolysaccharidosis Fabry dis-

ease Marfan syndrome Ehlers-Danlos syndrome

9) Immunodeficiency syndromes combined variable

immunodeficiency DiGeorge syndrome autoimmune

lymphoproliferative syndrome and

10) Miscellaneous toxic synovitis of hip serum sickness

hypertrophic osteoarthropathy Before diagnosing a

child with JIA it is crucial to rule out infectionmalignancy

and other causes of arthritisarthralgia Other conditions to

consider that present with joint pain (usually without joint

swelling) include mechanical conditions such as hyper-

mobility trauma benign nocturnal limb pains of childhood

(growing pains) avascular necrosis conditions (Perthes

Sever disease) or slipped capital femoral epiphysis

SJIA fever must be differentiated from infectious or ma-

lignant fevers as well as other conditions such as Kawa-

saki disease or periodic fever syndromes (eg familial

Vol 38 No 5 MAY 2017 225

Mediterranean fever PFAPA [periodic fever aphthous

ulcers pharyngitis adenitis] TRAPS [tumor necrosis factor

[TNF]-associated periodic syndrome] cryopyrinopathies

(familial cold autoinflammatory syndrome Muckle-Wells

syndrome) or hyperimmunoglobulin D syndrome

LONG-TERM COMPLICATIONS OF JIA

JointsUntreated inflammatory arthritis can lead to early (months)

or longer-term destruction of the joint including cartilage

loss (manifesting as joint space narrowing) and bony erosions

Among the other complications are osteopeniaosteoporosis

epiphyseal overgrowth premature fusion of growth plates

(leading to brachydactyly) subluxedunstable joints (seen com-

monly at wrists or atlantoaxial joints) or eventual fusion

ankyloses of joints Bilateral TMJ involvement can quickly

result in destruction of the growth center for the mandible

with subsequent micrognathia and retrognathia

EyesComplications of uveitis include posterior synechiae pre-

senting as fixed irregular pupillarymargin (due to adhesions

between the iris and lens) glaucoma (related to topical cor-

ticosteroid medication or due to inadequate drainage from

circumferential synechiae) band keratopathy cataracts (due

to inflammation or topical corticosteroids) and eventual

blindness Thus it is important to ensure slit lamp oph-

thalmologic evaluations at diagnosis and regular intervals

thereafter (3)

MANAGEMENT OF JIA

Over the last few decades there has been a major paradigm

shift in treatment strategies for JIA Rather than the previously

recommended step-up approach current recommenda-

tions suggest rapid and aggressive therapy to control in-

flammation followed by a gradual taper of medications

once complete remission has been established The avail-

ability of biologic and targeted therapies for JIA has re-

volutionized its treatmentGoals of therapy include pain relief

maintenance of function and range of motion of joints

achievement of remission (either on or off medications)

andminimization of adverse effects of medications The Child-

hood Arthritis and Rheumatology Research Alliance

(CARRA) has published consensus treatment plans for

polyarticular JIA and SJIA These are not meant to be guide-

lines but rather outline the most common treatment strate-

gies currently used by pediatric rheumatologists The goal of

establishing these treatment plans is to collect data to enable

comparative effectiveness studies and identify superior treat-

ment strategies through evidence The American College

of Rheumatology has published evidence-based recommen-

dations for JIA treatment

Oligoarticular JIAInitial treatment of oligoarticular disease may include anti-

inflammatory doses of nonsteroidal anti-inflammatory drugs

(NSAIDs) such as ibuprofen 10 mgkg per dose 3 times a day

to a maximum of 3200 mgday or naproxen 10 mgkg per

dose twice a day to a maximum of 1000 mgday or intra-

articular corticosteroid injection (IAS) (triamcinolone hex-

acetonide is superior to triamcinolone acetonide because of

Figure 3 Radiograph of foot showing first metatarsal head erosion in aboy with enthesitis-related arthritis


its longer-lasting effect in the joint) IAS can be performed

under anesthesia (conscious sedation nitrous oxide or gen-

eral anesthesia) for younger children or in the outpatient

clinic setting under local anesthesia (lidocaine or J-tip) for

the cooperative older child Increasingly pediatric rheu-

matologists are favoring use of ultrasonography to ensure

appropriate needle placement for IAS Failure to achieve

inactive disease frequent need for joint injections (Dagger3 in a

year) or extension of disease to involve additional joints

warrants systemic therapy with disease-modifying anti-

rheumatic drugs (DMARDs) such as methotrexate or bio-

logics such as TNF inhibitors

Polyarticular JIATreatment of this condition usually involves rapid initia-

tion of methotrexate with or without a biologic agent and

with or without a brief course of oral prednisone andor IAS

Methotrexate is used at 03 to 1 mgkg per dose once weekly

(maximum dose 25 mgweek) either orally or subcutane-

ously The subcutaneous route is preferred due to supe-

rior bioavailability Because methotrexate can take up to 3

months to achieve full effect some clinicians use cortico-

steroids as a bridge while the methotrexate is building up to

full effect (prednisone 01 to 1 mgkg per day maximum 60

mgday) with subsequent taper for rapid symptom control

Common adverse effects of methotrexate are nausea eme-

sis oral ulcers decreased appetite (addition of daily oral folic

acid at 1 mgday may alleviate some of the gastrointestinal

adverse effects) and elevated liver enzymes (usually tran-

sient) Unfortunately similar adverse effects can be seen

with NSAIDs so determining causality if these problems

occur may be challenging Adolescent girls should be

counseled about the teratogenic effects of methotrexate and

may need a referral for birth control Laboratory tests that

should be monitored after 1 month on therapy and subse-

quently every 3 months include CBC count with differential

count AST ALT blood urea nitrogen and creatinine With

the advent of several biologic medications (that are either

approved by the Food and Drug Administration [FDA] or

used off-label) previously used DMARDs such as hydroxy-

chloroquine leflunomide sulfasalazine and azathioprine

have fallen out of favor and are not commonly used

Recent trials demonstrate that aggressive initial therapy

improves outcomes in polyarticular JIA The Trial of Early

Aggressive Therapy (TREAT) study randomized patients

with severe polyarticular JIA (lt1 year duration) to receive

methotrexate thorn placebo or methotrexate thorn etanercept thornprednisolone (5) For each month earlier that a patient was

treated the odds of achieving inactive disease by 6 months

of treatment increased by 132 (P frac14 01) Tynjaumllauml et al (6)

compared the efficacy of infliximab thorn methotrexate versus

methotrexate alone versus methotrexate thorn sulfasalazine thornhydroxychloroquine (combination triple therapy) in very

early polyarticular JIA and showed significantly better

response rates at 12 months for those receiving infliximab

and methotrexate (100 response versus 50 response for

methotrexate only versus 65 response for combination

triple therapy) Table 3 lists the common biologic agents

currently in use Common adverse effects of the biologic

agents include increased risk for infection (especially oppor-

tunistic infections screen for tuberculosis before use)

elevated liver enzymes local injection site reactions or

infusion reactions cytopenias (neutropenia with tocilizu-

mab rituximab) and hypogammaglobulinemia (seen with

rituximab) Currently biologic agents carry a warning label

for the potential of lymphoproliferative malignancies with

use Several recent studies have indicated that an in-

creased risk of malignancy might be due to JIA itself rather

than therapy (including biologics) as is being found in

adults with rheumatoid arthritis (7) Careful monitoring and

caution with use are advised It is important to avoid

live vaccines while a patient is receiving methotrexate or bio-

logic therapy

ERAPsoriatic JIATreatment of these diseases is similar to that for polyartic-

ular JIA Axial involvement in ERA is more likely to respond

to anti-TNF inhibitors although specific studies on this

topic in pediatric patients are lacking

Systemic JIABecause the clinical presentation of SJIA is extremely vari-

able treatment depends on the severity of involvement

About 33 of SJIA-related MAS requires intensive care

unit-level care and carries an 8 mortality risk (8) Mild

disease may be treated with NSAIDs corticosteroids meth-

otrexate (better for arthritis than for the systemic features of

the disease such as rash and fever) or biologic agents (anti-

interleukin [IL]1 and anti-IL6 agents are preferred) MAS

should be treated aggressively with IV pulse methylpred-

nisolone (usually 30 mgkg per day to a maximum of

1000 mgday for 1-3 consecutive days) high-dose anakinra

(2-10 mgkg per day either once or several times daily

subcutaneous or IV) andor cyclosporine (3-5 mgkg

per day) Anti-IL1 and anti-IL6 therapies have drastically

changed the management and outcomes for SJIA and have

been demonstrated to be extremely effective in SJIAmanage-

ment in randomized controlled trials There are no trials

directly comparing IL1 to IL6 therapy for SJIA

Vol 38 No 5 MAY 2017 227

TABLE 3 Biologic Therapies for JIA

BIOLOGIC AGENTBRAND NAME ROUTEDOSE FDA-APPROVED INDICATIONS

OFF-LABELUSES MECHANISM OF ACTION

Etanercept SC Moderately to severely active PJIAin patients age Dagger2 years

Inhibits the action of TNF bybinding to TNF-a andpreventing its interactionwith the receptor

EnbrelAmgen ThousandOaks CA

Once weekly 08 mgkg perdose (maximum dose50 mg)

AdalimumabHumiraAbbVie Inc NorthChicago IL

SC Moderately to severely activePJIA in children age Dagger4 years

Anterior uveitis Recombinant humanmonoclonal antibodyagainst TNF-a

For patients ages 4-17 yearsNoninfectious intermediate

posterior and panuveitisWeight 15-30 kg 20 mg every

other weekWeight Dagger30 kg40 mg every other weekWeight lt15 kg limited data

InfliximabRemicadeJanssenBiotech Titusville NJ

IV infusionAuthor-recommended dose

6-15mgkg per dose IV at 0 26 weeks then every 4-8 weeks

Children ages Dagger6 years withpediatric Crohn disease orpediatric ulcerative colitis

Adults with AS and PsA

JIA (incombinationwithmethotrexate)

Chimeric monoclonalantibody against TNF-a

Uveitis

CertolizumabCimziaUCB Inc Smyrna GA

SCRA 400 mgdose at 0 2 4

weeks then 200 mg every2 weeks

Moderately to severely activeCrohn disease in adults withinadequate response toconventional therapy

JIA in olderchildren

Recombinant humanizedpegylated monoclonalantibody against TNF-athe pegylated structureallows for longer durationof action

Alternative dosing400 mgdose at 0 2 4 weeks

then 400 mg every 4 weeks

Moderately to severely active RAin adults

Golimumab SC Active AS PsA in adults JIA in olderchildren

Recombinant humanmonoclonal antibodyagainst TNF-a

SimponiJanssen Biotech IncTitusville NJ

RA PsA AS 50 mg oncemonth Moderately to severely active RAin adults (in combination withmethotrexate)

Moderately to severely activeulcerative colitis in adults withcorticosteroid dependence orwho are refractoryintolerantto oral aminosalicylates oralcorticosteroids azathioprineor 6-mercaptopurine

Tocilizumab IV infusion Age Dagger2 years SJIA or PJIA(monotherapy or incombination withmethotrexate)

Uveitis Humanized monoclonalantibody against IL-6receptor

ActemraGenentech USAInc SouthSan Francisco CA

SJIA Older than 2 years withactive disease

Weight lt30 kg 12 mgkg perdose every 2 wks

Weight Dagger30 kg 8 mgkg perdose every 2 weeks(maximum 800 mg)

PJIA Older than 2 years withactive disease

Weight lt30 kg 10 mgkg perdose every 4 weeks

Weight Dagger30 kg 8 mgkg perdose every 4 weeks

Abatacept IV infusion Age Dagger6 years moderately toseverely active PJIA(monotherapy or withmethotrexate)

CTLA4-IgFCg costimulationblocker binding to CD80CD86 on antigen-presenting cells andpreventing interactionwith CD28 resulting indampened T-cell activity

OrenciaBristol-MyersSquibb CompanyNew York NY

JIA Age Dagger6 yearsWeightlt75 kg 10mgkg at 0 2

4 weeks and every 4 weeksWeight 75-100 kg 750 mgdose

at 0 2 4 weeks and every4 weeks

Weightgt100 kg 1000mgdose at0 2 4 weeks and every 4 weeks

Continued


UveitisCollaboration between pediatric rheumatology and ophthal-

mology for management of this condition is imperative Slit

lamp examination to determine extent and severity of in-

volvement is required at regular intervals (3) Most ophthal-

mologists treat mild disease with topical corticosteroids

and mydriatic agents Lack of response to this initial therapy

necessitates the use of systemicmedications includingmeth-

otrexate adalimumab infliximab tocilizumab cyclosporine

or mycophenolate mofetil

Other Considerations for ManagementThe presence of active disease should not be tolerated

Treatment should aim to achieve inactive disease defined

TABLE 3 (Continued)



Rituximab IV infusion Adults withmoderately to severelyactive RA who have inadequateresponse to 1 or more TNFinhibitors (use in combinationwith methotrexate)

Refractory PJIA Chimeric cytolyticmonoclonal antibody toCD20 (on pre-B andmature B cells)

RituxanGenentech USAInc SouthSan Francisco CA

Refractory PJIA 375 mgm2 IVweekly 4 weeks repeatedcourse every 6 months or 750mg m2 IV on days 1 and 14

SJIAUveitis

SJIA uveitis 375-500 mgm2 IVweeks 0 and 2 (withmethotrexate)

Subsequent courses can beadministered every 24 weeks(based on clinicalexamination findings)

AnakinraKineretSobi IncWaltham MA

SC1-4 mgkg SC daily (maximum

100 mgday) best studied at1 mgkg per day (Note canbe used as IV or IV continuousinfusion off-label 1-10 mgkgover 4 hours has been used insevere MAS with SJIA)

Moderately to severely activeDMARD-refractory RA

NOMID

SJIASJIA with MAS

Fully human recombinantIL-1RA (receptor antagonist)

Competes with IL-1 forbinding of the receptorso that it is unavailable tobind with IL-1

CanakinumabIlarisNovartisPharmaceuticalsCorp EastHanover NJ

Active SJIA Age Dagger2 years 4 mgkgper dose (maximum dose 300mg) for patients with weightDagger75 kg repeat dose for diseaserelapse approximately every4 weeks

Cryopyrin-associated periodicsyndromes (including familialcold autoinflammatorysyndrome Muckle-Wellssyndrome) for patients ageDagger4 years

Fully human anti-IL-1bmonoclonal antibody

Cryopyrin-associated periodicsyndromes Weight 15-40 kg2 mgkg per dose (canincrease to 3 mgkg ifunresponsive)

Weight gt40 kg 150 mgdoseSC dose every 8 weeks

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome(TRAPS)

Hyperimmunoglobulin DSyndrome (HIDS)MevalonateKinase Deficiency (MKD)

Familial Mediterranean Fever(FMF)

SJIA Dagger2 years

Rilonacept SC Cryoprin-associated periodicsyndromes for patients ageDagger12 years

SJIA IL-1 trap agent acts as asoluble decoy receptorand consequently blocksIL-1 signaling

ArcalystRegeneronTarrytown NY

Loading dose 44 mgkg(maximum 320 mg) in 1-2 SCinjections (same day differentsites) maximum volume2 mLinjection maintenancedosing 22 mgkg per dose(maximum 160 mg) weekly

Age Dagger4 years44 mgkgper week

ASfrac14ankylosing spondylitis DMARDfrac14disease-modifying antirheumatic drug FDAfrac14US Food and Drug Administration ILfrac14interleukin IVfrac14intravenousMASfrac14macrophage activation syndrome NOMIDfrac14neonatal-onset multisystem inflammatory disease PJIAfrac14polyarticular juvenile idiopathic arthritisPsAfrac14psoriatic arthritis RAfrac14rheumatoid arthritis SCfrac14subcutaneous SJIAfrac14systemic juvenile idiopathic arthritis TNFfrac14tumor necrosis factor Reproducedwith permission from inPracticecom Essentials of Juvenile Idiopathic Arthritis for the Adult RheumatologistInternist

Vol 38 No 5 MAY 2017 229

as absence of arthritis rash serositis splenomegaly lymph-

adenopathy due to JIA and uveitis as well as 15 minday

or less of morning stiffness normal ESR and CRP and

physician global assessment of disease activity as zero (best

score on scale used) Clinical remission either on or off

medications is the ultimate goal of therapy and is defined

as inactive disease for 6 months while receiving therapy

and inactive disease for 12 months after discontinuation of

therapy respectively (9) How when and whether medica-

tions should be tapereddiscontinued after a child achieves

inactive diseaseremission is currently controversial and

there are no data to guide physicians on these important deci-

sions Most treating physicians continue medications in inac-

tive diseaseremission for several months or years before

considering taper or withdrawal Data are emerging that pa-

tients with some categories of JIA may need to continue low-

dose therapy over the long term to prevent return of disease

Multidisciplinary team treatment is important to achieve

the best possible outcomes for every child This includes

family-centered care involving the pediatric rheumatologist

and other specialties includingbull occupational and physical therapy to maintainimprove

range of motion and strength

bull behavioral health for counseling and teaching coping

strategies to children and their families

bull social work to help liaise with schools for potential

accommodations or financial assistance

bull primary care physician for routine well-child visits

anticipatory guidance and immunizations

bull ophthalmologist for iritis screening and surgeons

orthopedic physicians for deformity corrections such

as micrognathia or leg length discrepancies

OUTCOMES IN JIA

Although long-term data are lacking at this time improved

recognition early identification and early aggressive treat-

ment of JIA should result in lower JIA-related morbidity

and mortality as has been well demonstrated in adults with

rheumatoid arthritis A Canadian cohort study (ReACCh-

Out) noted that children with JIA can achieve inactive

disease with the likelihood of achieving remission at about

50 in 5 years for all categories except polyarticular disease

(10)More studies to characterize long-term outcomes in this

era of biologics are needed CARRA has developed a North

American registry to specifically examine the long-term

outcomes and potential medication adverse effects of treat-

ment for children with JIA

ACKNOWLEDGMENTS

The author would like to thank Dr Carol Wallace and Dr

Alexandra Aminoff for reading the article and providing

comments

References and Suggested Readings for this article are at http

pedsinreviewaappublicationsorgcontent385221

Summarybull On the basis of expert opinion case reports or reasoning (level ofevidence D) juvenile idiopathic arthritis (JIA) is defined as chronicarthritis (Dagger6 weeks duration) without known cause occurring inchildren younger than age 16 years and consists of 7 mutuallyexclusive categories of arthritis (2)

bull JIA is a clinical diagnosis of exclusion laboratory test results areonly supportive and may yield normal results in some cases

bull Early identification and referral to a pediatric rheumatologistenables early aggressive management that is likely to result inimproved outcomes (5)(6)

bull Because uveitis is usually asymptomatic (except in enthesitis-related arthritis) regular ophthalmologic screenings with slitlamp evaluation are essential

bull Management includes anti-inflammatory therapies such asnonsteroidal anti-inflammatory drugs corticosteroidsmethotrexate and biologic agents and depends on the numberof joints involved and presence of systemic features The goal oftherapy is to achieve inactive disease and remission (on or offmedications)

bull On the basis of randomized controlled studies or supportiveobservational studies (level of evidence B) both methotrexateand biologic therapies are extremely effective for JIA and requireregular laboratory and clinical monitoring for safety

bull On the basis of randomized controlled studies or supportiveobservational studies as well as case reports or cohort studies(level of evidence B and C) anti-interleukin (IL)1 and anti-IL6therapies are the preferred biologics for systemic JIA It isimportant to suspect recognize and treat developingmacrophage activation syndrome rapidly and aggressively


PIR QuizThere are two ways to access the journal CME quizzes

1 Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue

2 To access all CME articles click ldquoJournal CMErdquo from Gatewayrsquos orange mainmenu or go directly to httpwwwaappublications

orgcontentjournal-cme

REQUIREMENTS Learnerscan take Pediatrics in Reviewquizzes and claim creditonline only at httppedsinrevieworg

To successfully complete2017 Pediatrics in Reviewarticles for AMA PRACategory 1 CreditTM learnersmustdemonstrate aminimumperformance level of 60 orhigher on this assessmentwhich measures achievementof the educational purposeandor objectives of thisactivity If you score less than60 on the assessment youwill be given additionalopportunities to answerquestions until an overall 60or greater score is achieved

This journal-based CMEactivity is available throughDec 31 2019 however creditwill be recorded in the year inwhich the learner completesthe quiz

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1 A 3-year-old child is evaluated for 7 weeks of morning stiffness and pain in her kneesthat improves as the day progresses The joint stiffness seems to worsen again if thechild tries to rest for prolonged periods The parents have also noted swelling inboth knees There has been no fever or rash On physical examination the child clearlyhas decreased range of motion in the knees bilaterally as well as swelling andwarmth of both joints Laboratory studies are ordered Which of the following is thesingle most helpful finding in establishing the diagnosis of juvenile idiopathic arthritis(JIA) in this child

A Cartilage biopsyB Characteristic clinical findingsC Elevated antinuclear antibodyD Elevated erythrocyte sedimentation rateE Elevated rheumatoid factor

2 A 3-year-old child has been diagnosed with oligoarticular JIA During the discussion aboutlong-term care and follow-up the family is told that frequent visits to an ophthalmologistare particularly important Which of the following is the most appropriate rationale for theimportance of the frequent visits to the ophthalmologist

A Children frequently complain of eye painB Children with JIA need frequent changes in their corrective lensesC Eye exercises can substantially decrease the rate of complicationsD Ocular inflammation in JIA is often asymptomaticE Children with JIA require vision correction early in their lives

3 A 14-year-old girl with systemic JIA who is takingmethotrexate presents to the emergencydepartment with the acute onset of fever bleeding from the gums seizures decreasedwhite blood cell and platelet counts elevated D-dimer and elevated aspartateaminotransferase and alanine aminotransferase Her erythrocyte sedimentation rate todayis lower than it was 2 weeks ago during a regular follow-up visit Which of the following isthe most likely diagnosis in this patient

A Autoimmune hemolysisB Macrophage activation syndromeC Methotrexate overdoseD Overwhelming sepsisE Secondary leukemia

4 A 3-year-old girl with oligoarticular JIA presents to the clinic with a limp on theright side associated with spiking fevers Her right knee and ankle appearnormal on physical examination with no redness warmth or swelling Youorder point-of-care right hip ultrasonography Which of the following is themost important information that this imaging study will provide you in thispatient

A Confirm the presence of late ischemic changes of the jointB Diagnose malignant bone tumors in deep-seated joint spacesC Distinguish between inflammatory and infectious arthritisD Evaluate the integrity of the lymphatic drainage of the affected limbE Identify active synovitis of the hip joint

Vol 38 No 5 MAY 2017 231

5 A 6-year-old child is recently diagnosed with severe polyarticular JIA The treatingrheumatologist discusses with the family the optimal treatment course The family isconcerned about the potential adverse effects of the medications used Which of thefollowing is the best early treatment regimen that is more likely to achieve the highest rateof remission in this patient

A High-dose nonsteroidal anti-inflammatory drugB Hydroxychloroquine and prednisolone combinationC Intravenous pulse methylprednisoloneD Intra-articular corticosteroid injections and nonsteroidal anti-inflammatory drug

combinationE Methotrexate and etanercept combination

Additional Resources for PediatriciansAAP Textbook of Pediatric Care 2nd Editionbull Chapter 324 Rheumatologic Diseases - httpspediatriccaresolutionsaaporgchapteraspxsectionIdfrac14124995829ampbookIdfrac141626ampresultClickfrac141139997278

Point-of-Care Quick Referencebull Juvenile Idiopathic Arthritis - httpspediatriccaresolutionsaaporgContentaspxgbosidfrac14165535

Parent Resources from the AAP at HealthyChildrenorgbull Juvenile Idiopathic Arthritis httpswwwhealthychildrenorgEnglishhealth-issuesconditionsorthopedicPagesJuvenile-Idiopathic-Arthritisaspx

For a comprehensive library of AAP parent handouts please go to the Pediatric Patient Education site at httppatientedaaporg


CLASSIFICATION AND CATEGORIES OF JIA

According to the International League of Associations for

Rheumatology criteria (ILAR) JIA is defined as chronic

arthritis (Dagger6 weeks duration) with no known cause occur-

ring in children before the 16th birthday (2) The 6-week

minimum duration to define chronicity and onset before

the 16th birthday to define ldquojuvenilerdquo are based on expert

opinion rather than derived from data The ILAR classifi-

cation categorizes JIA into 7 mutually exclusive categories

based on the number of joints involved extra-articular fea-

tures and serology identified in the first 6 months of dis-

ease presentation (Table 1) This categorization attempts

to cluster similar JIA presentations into distinct categories

to improve research into etiology disease course long-

term outcomes response to treatment and development of

future therapies This classification system will likely evolve

and be refined over the next few decades as knowledge of

this disease increases

TABLE 1 Categories of Juvenile Idiopathic Arthritis (2)

ILAR CATEGORYPREVIOUSNOMENCLATURE ILAR DEFINITION EXCLUSION ADULT EQUIVALENT

Systemic-onsetJIA

Systemic-onset juvenilerheumatoid arthritis

Arthritis and fever (Dagger2 weeks documentedquotidian 3thorn days)

1 2 3 4 Adult Still disease

Plus 1 or morebull Evanescent erythematous rashbull Generalized lymphadenopathybull Hepatosplenomegalybull Serositis

PolyarticularRF-negative

Arthritis Dagger5 joints during the first 6 monthsof disease and RF-negative

1 2 3 4 5

PolyarticularRF-positive

Arthritis Dagger5 joints during the first 6 months of diseaseand RF-positive 2 at least 3 months apart

1 2 3 5 Rheumatoid arthritis(RF-positive)

Oligoarthritis Pauciarticular juvenilerheumatoid arthritis

Arthritis pound4 joints during the first 6 months of disease2 subtypes are identified

1 2 3 4 5

bull Persistent OJIA affecting no more than 4 jointsbull Extended OJIA affecting a total of gt4 joints afterthe first 6 months of disease

ERA Seronegative enthesitisand arthritis syndrome

Spondyloarthropathy

Arthritis and enthesitis 1 4 5 Ankylosing spondylitis(if bilateral sacroiliitis)or

Arthritis or enthesitisPlus 2 ofbull Sacroiliac joint tenderness or inflammatorylumbosacral pain

bull HLA-B27thornbull Onset of arthritis in a male older than age 6 yearsbull Acute anterior uveitisbull History of ankylosing spondylitis ERA sacroiliitiswith inflammatory bowel disease reactivearthritis or acute anterior uveitis in first-degreerelative

Psoriatic arthritis Arthritis and psoriasis or Arthritis plus 2 of 2 3 4 5 Psoriatic arthritisbull Dactylitisbull Nail pitting or onycholysisbull Psoriasis in a first-degree relative

Undifferentiatedarthritis

Arthritis that fulfills criteria forbull No categoryorbull Two or more categories

ERAfrac14enthesitis-related arthritis ILARfrac14International League of Associations for Rheumatology HLAfrac14human leukocyte antigen JIAfrac14juvenile idiopathicarthritis OJIAfrac14oligoarticular juvenile idiopathic arthritis RFfrac14rheumatoid factorExclusion definitions 1 Psoriasis in patient or first-degree relative 2 HLA-B27thornmale older than age 6 years 3 Ankylosing spondylitis ERA sacroiliitis withinflammatory bowel disease Reiter syndrome or acute anterior uveitis in a first-degree relative 4 RF-positive in 2 assessments 3 months apart 5 Systemic-onset JIA in patientReproduced with permission from inPracticecom Essentials of Juvenile Idiopathic Arthritis for the Adult RheumatologistInternist


















































(Table 2) (3)






























Vol 38 No 5 MAY 2017 223








































































































IMAGING EVALUATION






















PVNS





celiac disease




















Vol 38 No 5 MAY 2017 225

























thereafter (3)

MANAGEMENT OF JIA



































































































logic therapy























Vol 38 No 5 MAY 2017 227





















Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231

























































(Table 2) (3)






























Vol 38 No 5 MAY 2017 223








































































































IMAGING EVALUATION






















PVNS





celiac disease




















Vol 38 No 5 MAY 2017 225

























thereafter (3)

MANAGEMENT OF JIA



































































































logic therapy























Vol 38 No 5 MAY 2017 227





















Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231
















































































































IMAGING EVALUATION






















PVNS





celiac disease




















Vol 38 No 5 MAY 2017 225

























thereafter (3)

MANAGEMENT OF JIA



































































































logic therapy























Vol 38 No 5 MAY 2017 227





















Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231

































thereafter (3)

MANAGEMENT OF JIA



































































































logic therapy























Vol 38 No 5 MAY 2017 227





















Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231













































































logic therapy























Vol 38 No 5 MAY 2017 227





















Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231





























Uveitis































Continued













TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231




















TABLE 3 (Continued)







SJIAUveitis







NOMID

SJIASJIA with MAS












SJIA Dagger2 years







Vol 38 No 5 MAY 2017 229
































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231








































OUTCOMES IN JIA














ACKNOWLEDGMENTS



comments



























Vol 38 No 5 MAY 2017 231

























Vol 38 No 5 MAY 2017 231









juvenile idiopathic arthritis changing times, changing...

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