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Juvenile Idiopathic Arthritis Maria Espinosa, MD,* Beth S. Gottlieb, MD, MS* Author Disclosure Drs Espinosa and Gottlieb have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device. Educational Gap Juvenile idiopathic arthritis affects around 294,000 children in the United States. In 2001, a new classification of the disorder and its subtypes was created. Current therapies, including the use of biologic medications, have improved the prognosis of this condition significantly. Objectives After completing this article, readers should be able to: 1. Understand the pathophysiology of juvenile idiopathic arthritis (JIA). 2. Recognize the clinical features of the different types of JIA. 3. Be aware of the complications of JIA. 4. Know the treatment of JIA. Introduction Juvenile idiopathic arthritis (JIA) is a broad term used to describe several different forms of chronic arthritis in children. All forms are characterized by joint pain and inammation. The older term, juvenile rheumatoid arthritis, has been replaced by JIA to distinguish child- hood arthritis from adult-onset rheumatoid arthritis and to emphasize the fact that arthritis in childhood is a distinct disease. JIA also includes more subtypes of arthritis than did ju- venile rheumatoid arthritis. JIA is the most common rheumatologic disease in children and is one of the more frequent chronic diseases of childhood. The etiology is not completely understood but is known to be multifactorial, with both genetic and environmental factors playing key roles. Without appro- priate and early aggressive treatment, JIA may result in signicant morbidity, such as leg-length discrepancy, joint contractures, permanent joint destruction, or blindness from chronic uveitis. Definition Arthritis is dened as joint effusion alone or the presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased warmth in one or more joints. JIA is broadly dened as arthritis of one or more joints occurring for at least 6 weeks in a child younger than 16 years of age. JIA is a diagnosis of exclusion. A number of conditions, such as infections, malignancy, trauma, reactive arthritis, and con- nective tissue diseases such as systemic lupus erythematosus (SLE), must be excluded before a diagnosis of JIA can be made (1) (Table 1). JIA is subdivided into seven distinct subtypes in the clas- sication scheme established by the International League of Associations for Rheumatology in 2001 (Table 2). The sub- types differ according to the number of joints involved, pat- tern of specic serologic markers, and systemic manifestations present during the rst 6 months of disease. These categories were established to reect similarities and differences among the different subtypes so as to facilitate communication among physicians worldwide, to facilitate research, and to aid in understanding prognosis and therapy. (2) Abbreviations ANA: antinuclear antibody ARF: acute rheumatic fever AS: ankylosing spondylitis IBD: inammatory bowel disease IL: interleukin IV: intravenous JIA: juvenile idiopathic arthritis MAS: macrophage activation syndrome NSAID: nonsteroidal anti-inammatory drug RF: rheumatoid factor SLE: systemic lupus erythematosus TNF: tumor necrosis factor *The Steven and Alexandra Cohen Children’s Medical Center of New York, North Shore Long Island Jewish Health System, New Hyde Park, NY. Article collagen vascular disorders Pediatrics in Review Vol.33 No.7 July 2012 303 at Chulalongkorn University on January 8, 2015 Downloaded from
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Juvenile Idiopathic ArthritisMariaEspinosa, MD,*Beth S. Gottlieb, MD, MS*AuthorDisclosureDrsEspinosaandGottliebhavedisclosednonancialrelationshipsrelevanttothisarticle. Thiscommentarydoesnotcontain a discussion ofanunapproved/investigativeuseofa commercial product/device.EducationalGapJuvenile idiopathic arthritis affects around 294,000 children in the United States. In 2001,a new classication of the disorder and its subtypes was created. Current therapies, includingthe use of biologic medications, have improved the prognosis of this condition signicantly.Objectives Aftercompletingthisarticle, readersshouldbeableto:1. Understandthepathophysiologyofjuvenileidiopathicarthritis(JIA).2. RecognizetheclinicalfeaturesofthedifferenttypesofJIA.3. BeawareofthecomplicationsofJIA.4. KnowthetreatmentofJIA.IntroductionJuvenile idiopathic arthritis (JIA) is a broad term used to describe several different forms ofchronic arthritis in children. All forms are characterized by joint pain and inammation.The older term, juvenile rheumatoid arthritis, has been replaced by JIA to distinguish child-hood arthritis from adult-onset rheumatoid arthritis and to emphasize the fact that arthritisin childhood is a distinct disease. JIA also includes more subtypes of arthritis than did ju-venile rheumatoid arthritis.JIA is the most common rheumatologic disease in children and is one of the more frequentchronic diseases of childhood. The etiology is not completely understood but is known to bemultifactorial, with both genetic and environmental factors playing key roles. Without appro-priate and early aggressive treatment, JIAmay result in signicant morbidity, such as leg-lengthdiscrepancy, joint contractures, permanent joint destruction, or blindness fromchronic uveitis.DenitionArthritis is dened as joint effusion alone or the presence of two or more of the followingsigns: limitation of range of motion, tenderness or pain on motion, and increased warmth inone or more joints. JIA is broadly dened as arthritis of one or more joints occurring for atleast 6 weeks in a child younger than 16 years of age. JIA isa diagnosis of exclusion. A number of conditions, such asinfections, malignancy, trauma, reactive arthritis, and con-nective tissue diseases such as systemic lupus erythematosus(SLE),mustbeexcludedbeforeadiagnosisofJIAcanbemade (1) (Table 1).JIA is subdivided into seven distinct subtypes in the clas-sication scheme established by the International League ofAssociations for Rheumatology in 2001 (Table 2). The sub-types differ according to the number of joints involved, pat-tern of specic serologic markers, and systemic manifestationspresent during therst 6 months of disease. These categorieswere established to reect similarities and differences amongthedifferent subtypes soas tofacilitatecommunicationamongphysicians worldwide, tofacilitateresearch, andtoaid in understanding prognosis and therapy. (2)AbbreviationsANA: antinuclear antibodyARF: acute rheumatic feverAS: ankylosing spondylitisIBD: inammatory bowel diseaseIL: interleukinIV: intravenousJIA: juvenile idiopathic arthritisMAS: macrophage activation syndromeNSAID: nonsteroidal anti-inammatory drugRF: rheumatoid factorSLE: systemic lupus erythematosusTNF: tumor necrosis factor*TheStevenandAlexandraCohenChildrensMedicalCenterofNewYork, NorthShoreLongIslandJewishHealthSystem, NewHydePark, NY.Article collagenvasculardisordersPediatricsinReviewVol.33No.7July2012 303 at Chulalongkorn University on January 8, 2015 Downloaded from EpidemiologyIt has been estimated that JIA affects w294,000 childrenbetween the ages of 0 and 17 years in the United States.Theincidenceandprevalenceof JIAvaryworldwide.Thisdifferencelikelyreectsspecicgenetic(eg, HLAantigen alleles) and environmental factors in a given geo-graphic area. The incidence rate has been estimated as 4to 14 cases per 100,000 children per year, and the prev-alence rates have been reported as 1.6 to 86.0 cases per100,000 children. JIA tends to occur more frequently inchildren of European ancestry, with the lowest incidencerates reported among Japanese and Filipino children.In white populations with European ancestries, oligo-articular JIA is the most common subtype. In children ofAfrican American descent, however, JIA tends to occurat an older age and is associated with a higher rate ofrheumatoid factor (RF)-positive polyarticular JIA anda lower risk of uveitis.Different subtypes of JIA vary with respect to age andgenderdistributions(Table2). OligoarticularJIA, forexample, occurs more frequently in girls, with a peak in-cidence in children between 2 and 4 years of age. Poly-articular JIA also occurs more frequently in girls and hasa biphasic age of onset; therst peak is from 1 to 4 yearsof age and the second peak occurs at 6 to 12 years of age.(1)(3)PathogenesisThe cause of JIA is not well understood, but is believed tobe inuenced by both genetic and environmental factors.Twin and family studies strongly support a genetic basisof JIA; concordanceratesinmonozygotictwinsrangebetween25%and40%, andsiblings of thoseaffectedbyJIAhaveaprevalenceofJIAthatis15-to30-foldhigher than the general population.Strong evidence has been reported for the role of HLAclass I and II alleles in the pathogenesis of different JIAsubtypes. HLA-B27 has been associated with the devel-opment of inammation of the axial skeleton with hip in-volvement, andoftenis positiveinpatients whohaveenthesitis-relatedarthritis. HLA-A2is associatedwithearly-onset JIA. The class II antigens (HLA-DRB1*08,11, and 13 and DPB1*02) are associated with oligoar-ticular JIA. HLA-DRB1*08 is also associated with RF-negative poly JIA.Clinical features of systemic-onset JIA mostly resembleautoinammatory syndromes, such as familial Mediterra-nean fever, and there is a lack of an association betweensystemic-onset JIA and HLA genes. As a result, many con-clude that systemic-onset JIA should be considered a sep-arate entity, distinct from the other JIA subtypes. (4)Cell-mediatedandhumoral immunityplayaroleinthepathogenesisofJIA.Tcellsreleaseproinamma-tory cytokines, such as tumor necrosis factora (TNF-a),interleukin-6 (IL-6), and IL-1, which are found in high lev-els in patients who have polyarticular JIA and systemic-onset JIA. Evidence for the role of T cells in JIA comesfromstudies that showoligoclonal expansion of T cells anda high percentage of activated T cells in the synovium ofpatients who have JIA.Table 1. DifferentialDiagnosisofArthritisReactive PoststreptococcalRheumaticfeverSerumsicknessReitersyndromeInammatory JuvenileidiopathicarthritisInammatoryboweldiseaseSarcoidosisInfection SepticjointPostinfectious:toxicsynovitisViral(eg, Epstein-Barrvirus,parvovirus)LymediseaseOsteomyelitisSacroilitis, bacterialDiscitisSystemic SystemiclupuserythematosusHenoch-SchonleinpurpuraSerumsicknessDermatomyositisMixedconnectivetissuediseaseProgressivesystemicsclerosisPeriodicfeversyndromesPsoriasisKawasakidiseaseBehcetdiseaseMalignancy LeukemiaNeuroblastomaMalignantbonetumors(eg,osteosarcoma, Ewingsarcoma, rhabdosarcoma)Benignbonetumors OsteoidosteomaOsteoblastomaImmunodeciency CommonvariableimmunodeciencyTraumaAdapted from Weiss JE, Illowite NT. Juvenile idiopathic arthritis.Rheum Dis Clin N Am. 2007;33:441470.collagenvasculardisorders juvenileidiopathicarthritis304PediatricsinReviewVol.33No.7July2012 at Chulalongkorn University on January 8, 2015 Downloaded from Table2.InternationalLeagueofAssociationsforRheumatologyClassicationofJuvenileIdiopathicArthritisCategoryDenitionFrequency(%ofallJIA)AgeofOnsetSexRatioSusceptibilityAllelesSystemiconsetjuvenileidiopathicarthritis(JIA)Arthritisinoneormorejointswithorprecededbyfeverofatleast2weeksdurationthatisdocumentedasdaily(quotidian)foratleast3daysandaccompaniedbyoneormoreofthefollowing:(1)rash(evanescent),(2)lymphadenopathy,(3)hepatomegalyorsplenomegaly,(4)serositis4%17%ChildhoodF[MHLA-DRB1*11OligoJIAArthritisaffectingonetofourjointsduringtherst6monthsofdisease27%56%Earlychildhood;peakat24yearsF>>>MHLA-DRB1*08HLA-DRB1*11HLA-DQA1*04HLA-DQA1*05PersistentAffectsnomorethanfourjointsthroughoutthediseasecourseHLA-DQB1*04HLA-A2(earlyonset)ExtendedAffectsmorethanfourjointsaftertherst6monthsofdiseasePolyarthritis(RF-negative)Arthritisaffectsveormorejointsintherst6monthsofdisease.TestsforRFarenegative11%28%Biphasicdistribution;earlypeakat24yearsandlaterpeakat612yearsF>>MHLA-DRB1*0801Polyarthritis(RF-positive)Arthritisaffectsveormorejointsintherst6monthsofdisease.TestsforRFarepositiveonatleasttwooccasionsthatare3monthsapart2%7%LatechildhoodoradolescenceF>>MHLAB1*04HLA-DR4PsoriaticarthritisArthritisandpsoriasis,orarthritisandatleasttwoofthefollowing:(1)dactylitis,(2)nailpitting,(3)familyhistoryofpsoriasisinarst-degreerelative2%11%Biphasicdistribution;earlypeakat24yearsandlaterpeakat911yearsF>MHLA-B27IL23R(newassociation)Enthesitis-relatedarthritisArthritisorenthesitiswithatleasttwoofthefollowing:(1)sacroiliactendernessorlumbosacralpain,(2)presenceofHLA-B27antigen,(3)onsetofarthritisinamale>6yearsold,(4)acuteanterioruveitis,(5)familyhistoryinarst-degreerelativeofHLA-B27associateddisease3%11%LatechildhoodoradolescenceM>>FHLA-B27ERAP1(newassociation)UndifferentiatedarthritisArthritisthatfulllscriteriainnocategoryorintwoormoreoftheabovecategories11%21%AdaptedfromRavelliA,MartiniA.Juvenileidiopathicarthritis.Lancet.2007;369:767768.HinksA,MartinP,FlynnE,etal.SubtypespecicgeneticassociationsforJIA:ERAP1withtheenthesitisrelatedarthritissubtypeandIL23Rwithjuvenilepsoriaticarthritis.ArthritisResTher.2011;13:R12.HLAhumanlymphocyteantigen;JIAjuvenileidiopathicarthritis;RFrheumatoidfactor.collagenvasculardisorders juvenileidiopathicarthritisPediatricsinReviewVol.33No.7July2012 305 at Chulalongkorn University on January 8, 2015 Downloaded from Recently, inamedjoints inpatients whohaveJIAhave been shown to have high levels of IL-17producingT cells; IL-17 induces the production of other interleu-kinsandmatrixmetalloproteinasesthatareall involvedinjointdamage.TheroleofhumoralimmunityinJIApathogenesis is supported by the increased level of auto-antibodies, suchas antinuclear antibodies (ANAs)andimmunoglobulins, by complement activation, and by thepresence of circulating immune complexes. (5)Other possible factors that have been implicated in thepathogenesis of JIA include immunologic dysregulation,psychological stress, trauma, hormonal abnormalities, andinfectious triggers.ClinicalFeaturesJIA is divided into seven subtypes dened by clinical fea-tures during the rst 6 months of disease. The InternationalLeague of Associations for Rheumatology classication ofJIA includes the following subtypes: (1) Systemic-onsetarthritis, (2) oligoarticular arthritis,(3) polyarticular RF-positivearthritis, (4) polyarticular RF-negativearthritis,(5) psoriaticarthritis,(6) Enthesitis-relatedarthritis,and(7) undifferentiatedarthritis, or other.Eachsubtypevaries withrespect to clinical presentation,pathogenesis,treatment outcomes, and prognosis. All subtypes of JIA,however, sharecommonsymptoms, suchasmorningstiffness or gelling phenomenon (stiffness after a jointremainsinonepositionforaprolongedperiod)thatimproves throughout the day, limp, swollen joints, limita-tion of activities because of pain, and periods characterizedby disease remission interspersed with diseaseares.ThereisnodiagnostictestforJIA; therefore, othercauses of arthritis must be excluded carefully before thediagnosis is made.Systemic-OnsetJIASystemic-onset JIA is distinct compared with the othersubtypes in that it is characterized by the presence ofhigh-spiking fevers of at least 2 weeks duration in ad-ditiontoarthritis. Thediseaseaffects10%to15%ofchildrenwhohaveJIA, andtendstoaffectboysandgirls equally, with a peak age of onset between 1and5years.Earlyinthediseasecourse,patientscanpresent withfatigueandanemia.ThefeverinsystemicJIAischaracterizedbytemperatures >39Cthatoccurdaily or twice daily, with a rapid return to baseline or belowbaseline (quotidian pattern). Fever spikes usually occur inthelateafternoonorevening. Childrenoftenappearillduring febrile periods and look well when the feversubsides.The rash in systemic JIA is described typically as an ev-anescent, salmon-colored macular rash that accompaniesfebrile periods (Fig 1). The rash generally is nonpruriticand occurs most commonly on the trunk and proximalextremities, includingtheaxillaandinguinal areas. (2)Otherextra-articularmanifestationsthatcanbe seeninsystemic JIA include hepatosplenomegaly, lymphade-nopathy, pulmonary disease, such as interstitialbrosis,and serositis, such as pericarditis. The febrile period andother systemic features may precede the onset of arthritisby weeks to months. A denite diagnosis of JIA, however,cannot be made until arthritis is detected on physical ex-amination. (6)Laboratory abnormalities typically observedinsys-temic JIA include anemia, leukocytosis, thrombocytosis,elevated liver enzymes, and acute-phase reactants, such aserythrocytesedimentationrate, C-reactiveprotein, andferritin. ANA titer is usually negative and is not helpfulin making the diagnosis.Complications of systemic JIA include infection fromimmunosuppressive therapy, growth disturbances, os-teoporosis, cardiac disease, amyloidosis (rare in NorthAmerica compared with other parts of the world), andmacrophage-activation syndrome (MAS) (Table 3). MASoccurs in about 5% to 8% of children who have systemicJIA and is characterized by persistent fever, pancytope-nia, hepatosplenomegaly, liver dysfunction, coagulopathy,andneurologicsymptoms. BonemarrowexaminationFigure 1. Salmon-colored rash in systemic juvenileidiopathicarthritis. (Courtesy of Charles H. Spencer [].)collagenvasculardisorders juvenileidiopathicarthritis306PediatricsinReviewVol.33No.7July2012 at Chulalongkorn University on January 8, 2015 Downloaded from in patients who have MAS reveals phagocytosis of hema-topoietic cells by macrophages. (2) Triggers of MAS in-clude viral infections and certain changes in medications.Laboratory abnormalitiesincludepancytopenia,pro-longation of the prothrombin time and partial thrombo-plastin time, and elevated levels of D-dimer, triglycerides,andferritin. Contrarytowhatwouldbeexpected, theerythrocyte sedimentation rate typically falls in MAS be-cause of the lowbrinogen levels resulting froma consump-tion coagulopathy and hepatic dysfunction. Because MAScarries a signicant mortality rate of approximately 20% to30%, early recognition and treatment of MAS with cortico-steroids or cyclosporine is important to prevent multisys-tem organ failure. (6)Diagnosis of systemicJIAinvolves theexclusionofother conditions, such as infections, malignancy, collagenvascular diseases, and acute rheumatic fever (ARF). Infec-tions tend to have less-predictable fever patterns than sys-temicJIA. Childrenwhohaveleukemiatendtohaveleukopenia, thrombocytopenia, and elevated lactic dehy-drogenase levels. In ARF, the fever tends to be persistent,the arthritis is migratory and asymmetric, cardiac involve-ment often is associated with endocarditis, and the rash(referred to as erythema marginatum) is associated withan expanding margin. Antistreptolysin O titers can be el-evated in any inammatory condition; however, the morespecic antibodies for streptococcal infection, suchasantideoxyribonucleaseb, antistreptokinsase, and antihy-aluronidase,wouldbeelevatedonlyinARF,indicatinga recent group A streptococcal infection.The prognosis of systemic JIA depends on the severityof the arthritis. Most systemic symptoms resolve overmonths to years, and mortality, which is 8yearsofage.Thistypeofarthritisischaracterized by the presence of enthesitis, or inamma-tion at the sites of tendon insertions onto bone. Most pa-tients aficted with this type of arthritis are HLA-B27positive. Patients typically complainof pain, stiffness,and loss of mobility of the lower back, and can presentwith arthritis in lower extremity joints. Unlike other JIAsubtypes, the sacroiliac joints can be involved at presen-tation. Children with this subtype may experience an-terior or acute iritis, which is characterized by injected,erythematous conjunctiva, photophobia, and pain. Manypatientswhohavethistypeof arthritishaveapositivefamilyhistoryof anHLA-B27relateddisease, suchasIBD, psoriasis, or ankylosing spondylitis (AS). (2)Patients whohaveenthesitis-relatedarthritis mayde-velop AS, reactive arthritis, or IBD-associated arthritis. Chil-dren who have AS typically present with limitation and painof thelumbarspineandmayhaveevidenceofsacroiliacjoint inammationonimaging. ASis most commoninboys, with a male-to-female ratio of 7:1, and 90%of patientsare found to be positive for HLA-B27. Reactive arthritis of-ten occurs after a genitourinary or gastrointestinal infectionand often is associated with conjunctivitis and urethritis. Pa-tients who have IBDmay present initially with an asymmet-ric arthritis involving joints of the lower extremities. Flaresof IBD also may be associated with episodic arthritis. (1)UndifferentiatedArthritisChildren diagnosed as having an undifferentiated arthritisgenerally do not meet inclusion criteria for any other cat-egory, or they may meet criteria for more than one. (2)Figure 3. Cataracts resulting from chronic uveitis in a patientwithjuvenileidiopathicarthritis.Figure 4. Proximal interphalangeal joint and metacarpal-phalangeal joint swelling (see thumbs) typical of polyarticularjuvenileidiopathicarthritis. (CourtesyofCharlesH. Spencer[].)Figure 5.Swellingofleftthirdproximalphalangealjointwithsausageappearanceofngerinapatientwithpsoriaticar-thritis. (Courtesy of Charles H. Spencer [].)collagenvasculardisorders juvenileidiopathicarthritisPediatricsinReviewVol.33No.7July2012 309 at Chulalongkorn University on January 8, 2015 Downloaded from ComplicationsOne of the more common and devastating complicationsassociated with JIA is iridocyclitis, a form of chronic an-terior uveitis. The condition occurs in approximately 15%to 20% of patients who have JIA and can lead to permanentblindness. (6) It is critical that children who have JIA bescreened routinely for iritis because the uveitis can be diag-nosed early in the course only with a slit lamp examinationby an ophthalmologist. The frequency of required exami-nationsisdeterminedbythechildsageandhisorherANA status. Children 20 mg/d) and in-cludeimmunosuppression,adrenalsuppression,increasedappetite and weight gain, acne, mood changes, osteoporo-sis and avascular necrosis, cataracts and increased intraocu-lar pressures, cushingoid features, and diabetes. (2)Disease-modifyingantirheumaticdrugsareagentsthat slowtheradiologic progressionof diseaseandarerequiredbytwo-thirdsofchildren. Theseagentsinclude sulfasalazine, azathioprine, hydroxychloroquine,leunomide, cyclosporin, and methotrexate. Methotrex-ate, a folate antagonist, is the disease-modifying antirheu-matic drug most commonly prescribed in children whohavemoreaggressivearthritis.Methotrexateisgivenonceweeklyineithertheoral orsubcutaneousroute.The effects of this medication generally are seen within6 to 12 weeks. Adverse effects mainly include gastrointes-tinal manifestations, such as oral ulcers, abdominal pain,nausea, decreasedappetite, andhepaticdysfunction(ie, elevation of liver enzymes). Folic acid can be admin-istered to decrease these gastrointestinal side effects.Pulmonarytoxicityisaknownadverseeffectthatrarelyoccursinchildren.Thereisanincreasedriskofcollagenvasculardisorders juvenileidiopathicarthritis310PediatricsinReviewVol.33No.7July2012 at Chulalongkorn University on January 8, 2015 Downloaded from immunosuppression while on methotrexate and patientsshould not receive any live virus vaccines such as measles-mumps-rubella, varicella, and intranasal u vaccines. A childtakingmethotrexatewhodevelops a fever or is unwellshouldbeexaminedbythepediatricianandhavestudiessent (complete blood count, blood and urine cultures) toexclude an underlying bacterial infection. An increased riskof lymphoproliferative malignancies also is reported in chil-dren who take methotrexate, but this effect has not beenproven clearly. Blood counts and liver enzymes are moni-tored every 4 to 8 weeks while a child is taking metho-trexate. The treatment period is not dened clearly, butgenerally, a child is treated with methotrexate for at least1 year after achieving disease remission. Overall, methotrex-ate is a very safe and effective drug and is now considereda gold-standard therapy for children who have JIA. (2)(8)Use of biologic agents has improved the morbidity as-sociated with JIA signicantly. Biologic drugs are medi-cations, such as monoclonal antibodies, soluble cytokinereceptors, andreceptorantagonists, thattargetspecicproteins involved in the inammatory cascade. All biolog-ics are given through the IV or subcutaneous route. Allof these agents carry a risk of immunosuppression andcytopenias; therefore, a child taking a biologic agent mustbe followed closely with detailed physical examinationsand laboratory studies.As with methotrexate, a child taking a biologic who de-velops a fever or appears unwell even without a fever (bio-logics suchas anti-TNFs canblockthefebrileresponsedespite active infection) must be examined and have bloodwork to exclude a serious bacterial infection. Biologicsshould not be given while a child is acutely ill. Also, childrenon biologics should not be given live vaccines. Reactivationoftuberculosisisanotherpotential complication,andpa-tients are screened for tuberculosis before the start of ther-apy and then yearly while on these medications. (8)Elevated levels of TNF-a are found in patients who haveJIA.Etanercept,iniximab,andadalimumabarebiologicagents that block TNF-a. Etanercept is a soluble TNF re-ceptor that binds and inhibits TNF-a and was approved bythe FDA in 1999 for the treatment of JIA in children>2years of age. The drug has been shown to be highly effectivein patients who have extended oligoarthritis or polyarticularJIA who were not responsive to treatment with NSAIDs ormethotrexate. In additiontotheriskofimmunosuppres-sion, headache, upper respiratory tract infections, and injec-tion site reactions are other common adverse effects.Iniximab, a chimeric monoclonal antibody toTNF-athatis given through the IV route, has been shown to be ef-cacious in the treatment of JIA and uveitis. Adalimumab,a humanized monoclonal antibody to TNF, was thesecondbiologicagent tobeapprovedbytheFDAin2008formoderatetosevereJIAinchildren>4yearsof age. Unlike etanercept, which is given once weekly,adalimumab is given once every 2 weeks and has beenshown to be effective in patients who have polyarticular JIA.Elevated levels of IL-1 and IL-6 are found in the seraandsynovial uidofpatientswhohaveJIA.Theselevelsare particularly elevated in children who have systemic-onsetJIA. Recently, anakinra, an anti-IL-1 receptor antagonist,and tocilizumab, an anti-IL-6 monoclonal antibody, whichis nowapproved by the FDA, have demonstrated promisingresults in the treatment of patients who have systemic JIA.Abatacept, arecombinant fusionproteinthat down-regulatesT-cell stimulation, was approved by the FDA in 2008 formoderate to severe polyarticular JIA in children>6 yearsold. Other therapies, such as rituximab (an anti-CD20B-celldepleting monoclonal antibody) and rilonacept (anIL-1 blocking agent), are being studied for the treatmentof JIA. The duration of treatment with biologics is at leastfor 1 year after disease remission is achieved. (2)(7)(8)Treatment of uveitis depends largely on the ophthal-mologistsrecommendations. Typically, dilatingagentsand topical corticosteroids are usedrst. If inammationpersists or the patient is unable to taper off corticosteroidophthalmic drops, often methotrexate is started. Iniximaband adalimumab also have been found to be quite ben-ecial in the treatment of uveitis. (9)AutologousStemCellTransplantationPatients who have JIA that is refractory to the previouslydescribedmedicalinterventionsmayundergoautologousstem cell transplantation. Autologous stem cell transplan-tationinvolves usingimmunosuppressiontoremoveautoreactivelymphocytesfollowedbystemcelltrans-plantation. Thisprocedurewouldbeconsideredonlyfor a small subset of patients who have JIA that is re-fractory to all other treatments. (7)OtherConsiderationsOther treatment considerations must include physical ther-apyandoccupational therapytoimprovemobilityof af-fectedjoints andmaintainmusclestrength. Monitoringphysical andpsychological functioningmust beassessedroutinely,andcounselingorpsychotherapyofferedwhenneeded. Leg-lengthdiscrepancies mayrequiretreatmentif they become signicant and orthopedic referrals shouldbe made when appropriate.PrognosisApproximately 50% of children who have JIA continue tohave active disease into adulthood. In patients who havecollagenvasculardisorders juvenileidiopathicarthritisPediatricsinReviewVol.33No.7July2012 311 at Chulalongkorn University on January 8, 2015 Downloaded from active disease into adulthood, there can be signicant dis-ability, such as joint deformity, growth abnormalities, vi-sual disturbance caused by uveitis, functional limitationsbecauseof pain, andsoforth. Factorsaffectingdiseaseoutcomeincludedisease duration, presence of polyar-ticular disease, and use of systemic corticosteroid treat-ment. The mortality rate in JIA based on reports fromthe United States and Canada is 0.29 per 100 patients,andmostdeathsoccurinpatientswhohavesystemicJIA. (1)References1. WeissJE,IlowiteNT. Juvenileidiopathicarthritis.RheumDisClin North Am. 2007;33(3):441470, vi2. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):7677783. Rabinovich CE. Juvenile rheumatoid arthritis. Emedicine. Availableat: AccessedOctober 6, 20114. Woo P, Colbert RA. An overviewof genetics of paediatric rheumaticdiseases. Best Pract Res Clin Rheumatol. 2009;23(5):5895975. PrakkenBJ, Albani S. Usingbiologyof diseasetounderstandand guide therapy of JIA. Best Pract Res Clin Rheumatol. 2009;23(5):5996086. CassidyJT, PettyRE, Laxer RM, LindsleyCB. TextbookofPediatricRheumatology. 5thed. Philadelphia, PA: ElsevierInc.;20057. McCannLJ, WedderburnLR, HassanN. Juvenileidiopathicarthritis. Arch Dis Child Educ Pract Ed. 2006;91:ep29ep368. QuartierP.Currenttreatmentsforjuvenile idiopathicarthritis.Joint Bone Spine. 2010;77(6):5115169. Foeldvari I, NielsenS, Kmmerle-DeschnerJ, et al. Tumornecrosisfactor-alphablockerintreatmentofjuvenileidiopathicarthritis-associated uveitis refractory to second-line agents: results ofa multinational survey. J Rheumatol. 2007;34(5):11461150SummaryJuvenileidiopathicarthrithis(JIA)isthemostcommonrheumaticdiseaseofchildhood.JIA is a chronic disease that is associated with periodsofdiseasearesandperiodsofdiseaseinactivity.Early, aggressivetreatmentwithnonsteroidalanti-inammatorydrugs, intra-articularcorticosteroidinjections, or methotrexate, has signicantly improvedtheoutcomeofmostchildrenwhohaveJIA.Biologicshavebeenshowntobebothsafeandeffectiveforthetreatmentofmoreaggressiveformsofarthritisandforuveitis.Long-termsafetydataofbiologicsisstilluncertain.In the near future, it is hoped that genetic testing willallowearlierdiagnosisofJIAaswellashelppredictthediseasecourseofchildrenwhohaveJIA.GeneticPIRQuizThisquizisavailableonlineat NOTE:SinceJanuary2012,learners can take Pediatrics in Review quizzes and claim credit online only. No paper answer form will be printedinthejournal.NewMinimumPerformanceLevelRequirementsPerthe2010revisionoftheAmericanMedical Association(AMA)PhysiciansRecognitionAward(PRA)andcreditsystem, aminimumperformancelevel mustbeestablishedonenduringmaterial andjournal-basedCMEactivities that are certied for AMA PRA Category 1 CreditTM. To successfully complete 2012 Pediatrics in ReviewarticlesforAMAPRACategory1CreditTM, learnersmustdemonstrateaminimumperformancelevelof60%orhigheronthisassessment, whichmeasuresachievementoftheeducational purposeand/orobjectivesofthisactivity.Startingwith2012PediatricsinReview, AMAPRACategory1CreditTMcanbeclaimedonlyif60%ormoreofthequestionsareansweredcorrectly.Ifyouscorelessthan60%ontheassessment, youwillbegivenadditionalopportunitiestoanswerquestionsuntilanoverall60%orgreaterscoreisachieved.analysis also may allow physicians to target therapiesmoreeffectively.Itishopedthatdevelopmentofmorespecictherapieswilldecreaseoverallimmunosuppressionandotherassociatedtoxicities.collagenvasculardisorders juvenileidiopathicarthritis312PediatricsinReviewVol.33No.7July2012 at Chulalongkorn University on January 8, 2015 Downloaded from 1. You are evaluating a 10-year-old girl for joint pain that has been present for w2 months. She has no fever butcomplains of pain and swelling in her hands and feet, which is worse in the morning. On physical examination,she has evidence of symmetric swelling of all proximal interphalangeal joints in her hands and feet and painover her temporomandibular joint. The remainder of the examination is normal. Which of the following is themostlikelydiagnosis?A. Enthesitis-relatedarthritisB. Oligoarticularjuvenileidiopathicarthritis(JIA)C. PolyarticularJIAD. PsoriaticarthritisE. Systemic-onsetJIA2. After determining the diagnosis in the patient mentioned above, you decide to initiate therapy for her arthritis.Whichofthefollowingmedicationsisthemostappropriaterstmedicationtobegin?A. CelecoxibB. IniximabC. MethotrexateD. NaproxenE. Prednisone3. WhichofthefollowingstatementsregardingJIAistrue?A. AfricanAmericanchildrenmoreoftenhavesystemic-onsetJIAthanothersubtypes.B. AssociationwithHLA-B27positivityistypicalinenthesitis-relatedarthritis.C. Oligoarthritisoccursmostcommonlyinadolescents.D. Polyarthritisoccursmostcommonlyinmalesubjects.E. Psoriaticarthritisisnotassociatedwithophthalmologicdisease.4. WhichofthefollowingpatientswhohaveJIAismostlikelytodevelopiritis?A. A15-year-oldboywhohasenthesitis-relatedarthritis, antinuclearantibody(ANA)-negativeB. A3-year-oldgirlwhohasoligoarticularsubtype, ANA-negativeC. A6-year-oldgirlwhohasoligoarticularsubtype, ANA-positiveD. A12-year-oldgirlwhohaspolyarticularsubtype, ANA-positiveE. A5-year-oldboywhohassystemiconsetsubtype, ANA-negative5. A 7-year-old girl has developed a limp and complains of painin her right knee,which is warm and swollen.Although she is afebrile in the ofce, her parents say she had a fever at home. You suspect oligoarticular JIAbuthaveconcernsaboutinfection.Whichofthefollowingtestswouldgiveyouadenitiveanswer?A. ANAB. ErythrocytesedimentationrateC. RheumatoidfactorD. SynovialuidanalysisE. Whitebloodcellcountcollagenvasculardisorders juvenileidiopathicarthritisPediatricsinReviewVol.33No.7July2012 313 at Chulalongkorn University on January 8, 2015 Downloaded from DOI: 10.1542/pir.33-7-3032012;33;303 Pediatrics in ReviewMaria Espinosa and Beth S. GottliebJuvenile Idiopathic ArthritisServicesUpdated Information & high resolution figures, can be found at: References article cites 7 articles, 2 of which you can access for free at: Subspecialty Collectionsular_-_other_multisystem_disorders_sub Vascular & Other Multisystem Disordersmusculoskeletal_disorders_sub Disordersfollowing collection(s): This article, along with others on similar topics, appears in thePermissions & Licensing its entirety can be found online at: Information about reproducing this article in parts (figures, tables) orReprints about ordering reprints can be found online: at Chulalongkorn University on January 8, 2015 Downloaded from DOI: 10.1542/pir.33-7-3032012;33;303 Pediatrics in ReviewMaria Espinosa and Beth S. GottliebJuvenile Idiopathic Arthritis on the World Wide Web at: The online version of this article, along with updated information and services, is Supplement at: Pediatrics. All rights reserved. Print ISSN: 0191-9601. 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