juvenile idiopathic arthritis: diagnosis and management · juvenile idiopathic arthritis: diagnosis...

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ABSTRACT• Objective:To provide an overview of diagnosis and

managementofjuvenileidiopathicarthritis(JIA).• Methods: Reviewoftheliterature.• Results: JIA is themostcommon rheumatologicdis-

ease in children.There are 7 categories of JIA.Thediagnosisismadebasedonphysicalexamandisoneofexclusion. JIA isassociatedwithuveitis; therefore,routine eye exams are indicated. Treatment optionshave exploded with the advent of biologics; choicedepends on severity, number of joints affected, andlevel of disability.Thegoal of treatment is topreventlong-termdisability,preservenormalgrowth,and im-provejointfunction.Thesoonerthatreferraltothepe-diatricrheumatologistismadeinachildwithsuspectedJIA the less likely thechildwillexperience long-termmorbidity.

• Conclusion: Theprimarycareproviderplaysafunda-mental role in the recognition, referral, and co-managementofachildwithJIA,especiallysincetime-ly and appropriate treatment can prevent long-termdisabilitythatmayotherwisebeincurredfromdelayeddiagnosisorreferralorundertreateddisease.

Juvenile idiopathic arthritis (JIA), previously termed juvenile rheumatoid arthritis (JRA), is defined as arthritis that is present for at least 6 weeks and begins

before age 16 years [1]. Arthritis, by definition, is intra-articular swelling, or decreased range of motion in a joint associated with redness, warmth, and pain [2].

JIA affects over 300,000 children in the United States and it is the most common rheumatologic disease in chil-dren, affecting up to 1 in 1000 children worldwide [3]. JIA is not a single disease; it is considered a heterogeneous group of autoimmune disorders affecting the joints and is categorized according to the number of joints affected, distribution of affected joints, and clinical presentation [4]. There are 7 categories of JIA as identified in the International League of Associations for Rheumatology

(ILAR). This classification system was developed in 1993 for research purposes to create homogenous groups of patients with the goal of developing common ter-minology, allowing better understanding of the etiol-ogy, pathogenesis, and treatment of JIA. It has evolved for clinical diagnostic purposes (Table 1) [5] and was updated in 2001 to make the classification easier to apply for clinical and research purposes [6]. It is considered a work in progress, acknowledging changes based on new insights and discoveries. Although the classification allows for greater understanding of each category, the underlying pathogenesis of each entity remains unknown [7].

The 7 categories of JIA (Table 1) aid in determining prognosis and response to treatment [8]. These catego-ries are: (1) oligoarticular, (2) rheumatoid factor negative polyarticular, (3) rheumatoid factor positive polyarticular, (4) psoriatic, (5) enthesitis-related arthritis, (6) undifferen-tiated, and (7) systemic [5]. Chronic arthritis in children is different from adult rheumatoid arthritis from a clinical, genetic, and pathophysiologic perspective. The one excep-tion is juvenile rheumatoid factor positive arthritis [4], which is analogous to rheumatoid arthritis in adults but begins in children under age 16 years [4–9].

The diagnosis of JIA is a clinical one and is not based on laboratory studies. Nonetheless, laboratory results can aid in excluding other diagnoses, help categorize the arthritis, and guide therapy.

CASE STUDY 1Initial Presentation

A 2-year-old female presents to her primary care physician for a limp.

HistoryMom reports that the child started walking at 10 months of age, but about 3 months ago she started favoring her

Juvenile Idiopathic Arthritis: Diagnosis and ManagementCase Studies and Commentary, Elisa Wershba, MD, and C. Egla Rabinovich, MD, MPH

From the Duke University Medical Center, Durham, NC.

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326 JCOM July 2013 Vol. 20, No. 7 www.jcomjournal.com

JUVENILE IDIOPATHIC ARTHRITIS

left leg, and mom recalls that the left knee felt warm. There is no history of trauma, recent illness or bug bites, and patient does not complain of pain. Over the past month she does not seem interested in playing or run-ning. She used to jump out of bed upon awakening, but lately is asking to be carried in the morning and when she does walk mom notes a limp lasting for an hour.

Patient’s past medical history is unremarkable. Her vaccines are up to date; there has been no travel outside of the country and no identified exposure to tuberculo-sis. Patient attends day care. Family history is significant

for a grandmother with hypothyroidism and a grand-father with adult-onset diabetes. Mom, dad, and patient’s 7-year-old sibling are healthy.

Review of systems is otherwise unremarkable with no history of rashes, systemic fevers, weight loss, decreased appetite, abdominal pain, nausea, vomiting or diarrhea. Patient is referred to a pediatric rheumatologist.

Physical Examination On examination by the pediatric rheumatologist, the child’s weight is 15 kg. Her blood pressure, respiratory

Table 1.ILARCriteria—AllCategoriesApplytoChildren<Age16YearsatTimeofDiagnosis

Oligoarticular Arthritisin4orfewerjointsduringthefirst6months

1)Persistent:nevermorethan4joints

2)Extended:Morethan4jointsaffectedafterthefirst6months

Polyarticular: rheumatoid factor negative 5ormorejointsduringthefirst6months;RFnegative

Polyarticular: rheumatoid factor positive 5ormorejointsduringthefirst6months;RFpositivein2ormorebloodtestsatleast3monthsapart

Psoriatic arthritis Arthritis+psoriasisORarthritis+2ofthefollowing:†

•Nailpitsoronycholysis

•Dactylitis

•Psoriasisinafirstdegreerelative

Exclusion:RF+,family-historyofHLAB27+infirst-degreerelative,orarthritisinamale>6yrwhoisHLAB27+

Enthesitis-related arthritis (ERA)(enthesitisreferstoinflammationoftheentheses,wheretendonattachestobone)

Alsoreferredtoasjuvenileankylosingspondylitisorspondyloarthropathy

Includesinflammatoryboweldisease(IBD)arthritis[4]

InflammationoftheenthesesandarthritisORarthritisorenthesitiswithatleast2ofthefollowing:

•Sacroiliacjointtenderness

•PresenceofHLAB27gene

•Familyhistoryinatleast1first-orsecond-degreerelativewithHLAB27-associateddisease

•Anterioruveitisassociatedwithredness,pain,orphotophobia

•Arthritisonsetinaboy>6yr

Undifferentiated Arthritis>6weeksthatdoesnotfulfillanyoftheabovecriteriaorfulfillsmorethan1criteria

Systemic Arthritisinanynumberofjoints+feverofatleast2weeks’durationthatoccursdailyforatleast3daysplus1ormoreoffollowing:

•Evanescentrash

•Generalizedlymphadenopathy

•Enlargedliverorspleen

•Serositis

Systemicsymptomscanprecedearthritisbyweekstomonthsandmaybeaslongas10years,butarthritismustbepresentbeforediagnosiscanbemade[8]

Datafromreference1andreference4.

*PercentageRF+inJIA=3%basedonEuropeanpopulation;serumAbtest.

†Skindiseaseoftenlagsbehindarthritisinabouthalfthecasesofpsoriaticarthritisinchildren,sometimesbymorethanadecade(NigrovicPA,SundelRP,PettyRE.Juvenilepsoriaticarthritis.In:CassidyJT,PettyRE,LaxerRM,LindsleyCB,editors.Textbookofpediatricrheu-matology.Vol6.6thed.Philadelphia:Saunders;2011:287).

*


rate, and pulse are normal. The child is initially appre-hensive, but begins to participate when examiner uses toys to grab her attention. The physician uses patient’s stuffed animal to track her neck range of motion by hold-ing it above the head, behind her, and at her feet. Patient follows the object without limited range of motion or discomfort of her neck. Upper extremity exam reveals that when she reaches for the animal with her left arm, she does not fully extend at the left elbow. The examiner feels fullness and warmth at the left elbow and there is tenderness noted with passive flexion and extension. Lower extremity exam reveals an effusion in the left knee and a mild leg length discrepancy with the left leg 1 cm longer than the right. Left knee flexion and extension is limited by 5 degrees. Ankles are asymmetric on inspec-tion, with left ankle fullness to palpation and decreased range of passive motion. The remainder of the lower extremity exam is normal.

CASE STUDY 2Initial Presentation

A 12-year-old female with no significant past medical history started developing left ankle

swelling and limp 6 months prior to evaluation. Parents initially took her to an urgent care facility where radio-graphs were reportedly consistent with a Salter-Harris type 1 fracture (directly across the growth plate, often with normal x-rays) [10]. She was placed in a splint for 6 weeks, but when the splint was removed her ankle was stiff and swollen. Shortly after that, her parents noted her neck appeared stiff. She then developed pain and swelling of the right ankle and when the left ankle was not improving parents took her to the family physician. At that time there was no history of preceding illness. Labs included a complete blood cell count (CBC) and differential with a white blood cell count of 10,000, hemoglobin 10.6 g/dL, and platelets of 504,000. The erythrocyte sedimentation rate (ESR) was 47 mm at 1 hour (normal, 0–13 mm) and the C-reactive protein was normal. Antinuclear antibody (ANA) and rheuma-toid factor were negative. Complete metabolic panel was unremarkable. Parvovirus C19 and Epstein-Barr virus titers were negative. Repeat ankle x-rays showed no frac-tures. She was started on ibuprofen for a few weeks with minimal to no improvement and was eventually referred to a pediatric rheumatologist.

On evaluation at the pediatric rheumatologist’s, the child denies any problems writing or using her hands

or any problems chewing. She has pain and stiffness of both ankles in the morning lasting 30 minutes. Patient and parents deny any rashes, fevers or fatigue but note decreased physical activity. Otherwise she has been eating well and is average height for her age.

Physical ExaminationNeck range of motion revealed decreased extension, flexion, and rotation. She was noted to have swelling in multiple proximal interphalangeal joints (PIP), especially the bilateral 2nd and 3rd PIPs. She had tenderness on the 3rd metacarpophalangeal joint (MCP), swelling in the right wrist with limited extension to 45 degrees, and swelling in the right elbow with a 15- to 20-degree restriction of extension. The left wrist, left elbow, and both shoulders were normal. Lower extremity exam revealed a small right knee effusion and both ankles were noted to have swelling with limited range of motion. Examination of the hips demonstrated full range of motion with passive internal and external rota-tion. There was tenderness to palpation of all bilateral metatarsals.

• Whatisthedifferentialdiagnosis?

The clinical history and physical examination in both children is suggestive of JIA. The swelling, warmth, and decreased range of motion of joints on examination are diagnostic of arthritis. The absence of erythema and severe pain is less suggestive of septic arthritis. The his-tory of morning stiffness is supportive of inflammatory arthritis. The unremarkable history for fever, weight loss, fatigue, paleness and other systemic symptoms help rule out other diagnoses that must be on the differential (Table 2) when working up a child for JIA but do not negate the importance of performing a complete workup. Nonetheless, presence of systemic symptoms mandates a workup for a malignancy, infection, inflammatory bowel disease or other autoimmune process and is necessary prior to initiating treatment for JIA. The initial CBC and differential, vital signs, and history can aid in determin-ing the direction of the further workup.

There are clues from the history that help with the diagnosis. Pain that awakens a child from sleep is atypical for JIA but is more classic in children with malignancy. Leukemia, neuroblastoma (especially in children less

CASE-BASED REVIEW



than 5 years), or lymphoma must be considered in any child presenting with musculoskeletal complaints that disrupts sleep. Abnormally low cell counts in 2 or more cell lines are especially concerning for a malignancy, so obtaining a CBC with differential is important in all children presenting with arthritis [11]. Presence of

gastrointestinal symptoms may point to an underly-ing bowel disease with musculoskeletal manifestations. Many infections, especially with parvovirus, Bartonella, EBV, varicella, and Streptococcus (post-streptococcal arthritis) can cause a reactive transient arthritis. There-fore, history should include the approximate date of the onset of arthritis along with associated symptoms such as prior infections.

Once malignancy, infection, and other autoimmune diseases have been ruled out, the clinician can pro-ceed with the treatment of JIA. As mentioned above, making the diagnosis of juvenile arthritis mandates that arthritis is present at least 6 weeks in a child less than age 16 years. The specific category of JIA is as-signed by the pediatric rheumatologist after 6 months (Table 1).

JIA is a clinical diagnosis without diagnostic labora-tory studies. Rheumatoid factor seropositivity in a child is present in less than 10% of children with JIA [4]. Although not diagnostic, the ANA is used to determine a child’s risk for development of uveitis (Table 3). There is suggestion that ANA positivity in patients with JIA represents a homogenous group of patients characterized by female predominance, earlier onset of JIA, asymmet-ric arthritis, and high risk for uveitis [12]. The highest prevalence of ANA positivity in children with JIA is found in those with oligoarticular disease and uveitis. It is important to understand that healthy children can have a persistent positive ANA without diagnostic sig-nificance [4]. The presence of the HLA-B27 gene in the serum, enthesitis on exam and sacroiliac joint ten-derness (Table 1) is more indicative of enthesitis related arthritis [4].

The approach to systemic JIA (sJIA) is different and although outside the scope of this article, is characterized by arthritis, daily or twice daily spiking fever, and a charac-teristic salmon-colored transient rash. Children with sJIA usually appear much sicker on presentation than children with JIA without systemic symptoms; the disease may be marked by the extra-articular manifestations more than the arthritis. For example, lab findings that may indicate systemic JIA include elevated levels of ferritin, D-dimer, C-reactive protein, erythrocyte sedimentation rate, and elevated liver enzymes (AST and ALT). Additionally, these children may have moderate to significant anemia depend-ing on the severity of the disease. However, because the presentation of sJIA may mimic the presentation of leu-kemia, it is imperative to rule out a malignancy prior to

Table 2.DifferentialDiagnosisofJIA

Infection-related

ViralsynovitisincludingparvovirusandEBV

Lymedisease

Tuberculosis

Bartonella

Post-streptococcalarthritis

Reactivearthritis

Varicella

Septicarthritis(Streptococcus,Staphylococcus,Gonococcus, Chlamydia, andKingella kingae)

Malignancy

Leukemia/lymphoma*

Neuroblastoma

Bonetumor

Hematologic

Sicklecelldisease

Hemophilia

Mechanical

Trauma

Benignnocturnalidiopathiclegpain(growingpains)

Osgood-Schlatterdisease

Avascularnecrosis

Slippedcapitalfemoralepiphysis(kneepainreferredfromhip)

Chondromalaciapatellae

Hypermobilitysyndrome

Genetic/metabolic/storagedisease

Gaucher’sdisease

Mucopolysaccharidoses

Otherconnectivetissuedisorders

Systemiclupuserythematosus

Mixedconnectivetissuedisease

Vasculitis

Sarcoidosis

HenochSchönleinpurpura

Polyarteritisnodosa

Datafromreference1andreference13.

*Must evaluate for malignancy with CBC/diff and consider bonemarrowbiopsy,especiallypriortotheinitiationofcorticosteroids.


initiation of treatment for systemic JIA. Therefore, a bone marrow biopsy is often essential prior to making the diag-nosis of systemic JIA. Systemic JIA, similar to the other categories of JIA, is a diagnosis of exclusion despite the numerous abnormal laboratory findings that are helpful in the diagnosis, since none of the laboratory findings are specific to systemic JIA.

• Whatareindicationsforreferral?

Once a diagnosis of JIA is suspected or established, referral to a pediatric rheumatologist is appropriate. Referral to a pediatric ophthalmologist to evaluate for uveitis should also be made and can often happen prior to the initial rheumatology appointment, especially if there is a long wait to see the rheumatologist. For chil-dren presenting to their primary provider with arthritis for less than 6 weeks, other diagnoses such as viral synovitis, post-infectious arthritis, trauma, malignancy, and septic joint should be considered prior to referral. It may be helpful to obtain an initial CBC with differen-tial, lactate dehydrogenase, and uric acid to evaluate for malignancy. Obtaining a radiograph of an affected joint to evaluate for trauma, fracture, or malignancy is also indicated prior to a diagnosis of JIA. It is often helpful to work with the specialist to initiate the workup prior to the initial evaluation. While the patient awaits the pediatric rheumatology appointment, a therapeutic dose of an NSAID can be initiated and will not hinder the initial evaluation and may provide useful information in terms of response and need for initiation of second-line therapy. On the other hand, initiation of a corticosteroid can hinder the validity of the exam or partially treat a malignancy and is usually contraindicated until a firm diagnosis is established.

• What is the approach to management andtreatment?

Evaluation and management should be tailored to the individual patient based on age, comorbidities, sever-ity, and level of disability. The pediatric rheumatologist considers the presence of contractures, functional status, number of joints involved, and evidence of joint erosion or destruction on radiographic studies when deciding on a treatment plan. Patients with rheumatoid factor positiv-ity, arthritis of the hip or cervical spine, wrists and small joints of the hands, and those with positive anticitrulli-nated protein antibodies are at highest risk for long-term disability and/or joint destruction [13]. A recent mul-ticenter, randomized double-blind placebo-controlled trial of 85 children diagnosed with polyarticular JIA for less than 1 year demonstrated that the sooner treatment for polyarticular JIA is initiated, the more likely it is for clinical remission to occur by the sixth month of treat-ment [14].

Patient and parent education includes an overview of JIA, a description of the variability of symptoms and edu-cation that pain may not be a good indicator of disease activity in children. Patient information also includes an explanation of the benefits, risks, and side effects of medi-cations. Physical therapy and/or occupational therapy are often essential in treatment and improvement of outcome [4], especially in patients who have joint contractures. If there is a leg length discrepancy on exam, then evaluation by a physical therapist for a shoe lift is suggested to help prevent permanent gait irregularity.

The goal of therapy is to treat active disease, pre-vent long-term disability, improve joint function, and preserve normal growth [3]. With the advancement of disease-modifying antirheumatic drugs (DMARDs) in-

CASE-BASED REVIEW

Table 3.RecommendationsfromtheAmericanAcademyofPediatricsforEyeExamsinPatientswithOligoarticular,Polyarticular,andSystemicJIA

JIA Category < 7 years ≥ 7 years

ANA+polyarticularoroligoarticular Every3-4monthsx4years,thenevery6monthsfor3years,thenyearly

Every6monthsx4years,thenyearly

ANA–polyarticularoroligoarticular Every6monthsx4years,thenyearly Every6monthsx4years,thenyearly

SystemicJIA(ANA+/–) Yearly Yearly

Adaptedfromreference1.



cluding biologics, the long-term prognosis of juvenile arthritis is much better than previous treatment allowed (Table 4).

NSAIDSNSAIDs are recommended as initial treatment for patients with low disease activity and those without joint contrac-tures. The American College of Rheumatology guidelines

for treatment of JIA (2010) suggest that if patients have persistent active arthritis for greater than 2 months, then monotherapy with an NSAID is inadequate and more aggressive therapy is needed to prevent long-term joint and tissue damage [15]. Prior to initiating treatment with an NSAID it is recommended that the provider obtain a serum creatinine, urinalysis, complete blood cell count and liver enzymes [16]. See Table 5 for dosing.

Table 4.Non-NSAIDAgentsUsedtoTreatJIA*

Agent

Pharmacotherapy

Indication for Use/ FDA-Approved Use

Major Side Effects/Toxicity†

Comments/Monitoring Parameters

Non-DMARDs

Glucocorticoids SupplementaltherapyformoresevereJIAeffect-ingqualityoflifeusuallyinitiatedwhileawaitingeffectsofDMARDsorbiologics

Cushingsyndrome,growthsuppression,AVN,osteoporosis,immunosuppression,behavioraleffects,hy-pertension,glucoseintolerance,lymphopenia,neutrophilia,myopathy,cataracts,glaucoma

Acuteadrenalinsufficiencywithrapidwithdrawal

Considercalciumandvita-minDsupplementationforbonehealth

Intra-articularcorticosteroids

LackofresponsetoNSAID,jointdeformity,growthdisturbanceordiscrepancy,temporizingmeasurewhileawaitingresponsetosystemicmedication

Iatrogenicsepticarthritis,atrophicskinchangeatinjectionsiteespeciallyinsmallerjoints,somesystemiceffects(depend-ingondose,#ofjointsinjected)

Usedmostofteninoligoar-ticulardisease

Youngkidsareoftensedatedforthisprocedure

DMARDs

Methotrexate(MTX)

Folicacidanalogue;competitiveinhibitorofDHFR;slowacting

Anti-inflammatoryandimmunomodulatoryagent

FDAapprovedinpolyJIAforchildren≥2yr

Abdominaldiscomfort,nausea,stomatitis/oralulcers,transienttransami-nitis,macrocyticanemia,leukopenia,spontaneousabortion

CBC/diff,LFTsevery4-12weeks;folatesupplementa-tionminimizestoxicity

OralandSCform;oralformhasvariableabsorption

Photosensitivitycanoccur

Sulfasalazine Analogueof5-aminosali-cylicacid

Anti-inflammatoryand/orimmunomodulatory

FDAapprovedinpolyJIAforchildren≥4yr

Intolerance,headache,toxicreactions,rashes,Steven’sJohnsonsyn-drome,agranulocytosis,aplasticanemia,neutro-penia,thrombocytopenia,anorexia,nausea,vomit-ing,dyspepsia,hepatitis

CBC/diff,LFTs,serumCr/BUN,UA,especiallydur-inginitiationoftherapyandwhiletitratinguptogoaldose

Photosensitivitycanoccur

Leflunomide‡ Inhibitsdenovopyrimi-dinesynthesis

Immunomodulatory

Teratogenic,longhalf-life,sideeffectsdoserelated,headache,dizziness,anemia,elevatedLFTs,abdominalpain,dyspep-sia,nausea,vomiting,diarrhea,anorexia,rash,alopecia

ConsiderinpatientswhodonottolerateMTX

RoutinemonitoringofCBC/diff,liverenzymes,electro-lytesandpregnancytestiffemaleofchildbearingpotential


CASE-BASED REVIEW

Table 4. (cont’d)

Agent

Pharmacotherapy




Biologics§

Anti-TNF Agents Potential side effects for all anti-TNF agents:IncreasedriskofinfectionandreactivationofTB;livevaccinescontraindicated;injectionsitereactions;opticneuritis,demyelinatingevents,lupus-likesyndrome,autoantibodyformation,psoriaformrash/psoriasis

Maybeadministeredwithorwithoutmethotrexate

CBC/diff,AST,ALTalbuminevery3-6months

Etanercept InhibitsTNF-α;fullyhumanAb

Indicatedonceinad-equateresponsetoMTX;responseusuallydra-maticafter3-4injections;FDAapprovedinpolyJIAforchildren≥ 2yr

Well-tolerated WeeklySCinjections;improvementinphysicalfunction,qualityoflife,andslowingofradiographicprogression

Adalimumab RecombinanthumanIgG1mAbthatinhibitsTNF-α

FDAapprovedforpolyJIAinchildren≥4yr

Injectionsitepainmorecommonthanwithotherbiologics

EveryotherweekSCinjections;injectionsitereactionsmorecommonthanwithetanercept;effectiveinuveitis

Infliximab‡ ChimericIgG1anti-TNF-αAbconsistingofmouseAbandhumanAb

Oftenusedinthetreat-mentofuveitis

Infusionreactionsmorelikelytooccuron2ndor3rdinfusionsandrangefrommildallergicreactiontoanaphylaxis,serumsickness-likereaction;nausea,vomiting,diar-rhea,dyspepsia

AdministeredIVevery4-8weeks

AST,ALT,hepatitisBserol-ogy

Golimumab‡ RecombinanthumanIgGmAbtoTNF-α

FDAapprovedforadultsin2009formoderatetosevereRA,activepsoriat-icarthritisandankylosingspondylitis

Elevatedliverenzymes,parasthesias,neutro-penia,pancytopenia,aplasticanemia

SCinjectionsmonthly,AST,ALT,hepatitisBserology,ongoingpediatrictrials

Anti-IL-1 Agents

Rilonacept‡ BlocksIL-1 PreliminarydatashowsimprovementinchildrenwithsJIA

Upperrespiratoryinfec-tion,abdominalpain,nausea,vomiting,diarrhea,headache,dizziness,angioedema,hypercholesterolemia,hypertriglyceridemia

WeeklySCinjections;lipidmonitoring2-3monthsafterinitiation

Anakinra‡ IL-1receptorantagonist DramaticresponseinsJIA

FDAapprovedforuseincryopyrin-associatedperiodicfeversyndromeinchildren

Injectionsitereactions;pneumoniaandcellulitismorecommoncomparedtoplacebo,antibodyformation,neutropenia,headache,nausea,diar-rhea

DailySCinjections;oktousewithMTX.MonthlyCBC/diff×3monthsthen4×/yr.

Canakinumab SelectiveblockofIL-1β FDAapprovedforsJIAinchildren≥2yr

Injectionsitereactions,hypersensitivityreactions,

diarrhea,nausea,ab-dominalpain,headache,neutropenia,leukopenia

SCinjectionsq8weeks



CorticosteroidsIntra-articular corticosteroid injections are often useful when there are a small number of joints inflamed or as a bridge therapy waiting for long-term drug therapy to be-come efficacious. Intra-articular corticosteroid injections are especially an effective therapy in patients with oligo-articular JIA, especially if a DMARD is not indicated; treatment with intra-articular corticosteroid injections often results in correction of joint contractures and de-formities [15,17]. Intra-articular corticosteroid injections

or low-dose prednisone may also be used to treat poly-articular arthritis while awaiting efficacy of a DMARD.

DMARDsMethotrexate is the most commonly used DMARD in JIA, especially in the polyarticular JIA type [18] and has been used in the treatment of JIA for over 20 years [15]. The exact mechanism of action remains uncertain, but methotrexate is thought to inhibit de novo synthesis of purine and pyrimidine [18]. Common side effects of

Table 4. (cont’d)

Agent

Pharmacotherapy




Other

Abatacept PreventsT-cellactivation FDAapprovedforuseinpolyarticularJIAinchil-dren≥6yr

Welltolerated

Infusionreactionshavebeenreported;headache,dizziness,nausea,diar-rhea,abdominalpain

IVinfusionsq2weeks×3dosesthenq4weeks.Givenwithorw/oMTX.CBC/diff,AST,ALT,albuminq4–12weeks;Holdifsus-pectedbacterialinfectionorvaricella

Rituximab‡ Chimericmonoclonalmouse-humanAb;targetsBcells

UseinRF+JIAafterfail-ingmultipleotheragents

Flushinganditchingonfirstdosebutcanbeeliminatedwithpretreat-mentofBenadryl,Tylenolandcorticosteroids.In-creaseinviralinfectionss/ptreatment.RareandunknownassociationofPML.Myalgia/arthralgias/pinfusion,headache,dizziness,peripheralneuropathy

CheckBcellspriorandw/in1monthsofinitialdose.

Quantitativeimmunoglobu-linsq3months

CBC/diff,serumelectro-lytes;serumCr/BUN

Tocilizumab InhibitortoIL-6receptor FDAapprovedforchil-dren>2yrwithsJIAandpolyarticularJIA;efficacyinpatientsrefractorytoTNFinhibitors

Infusionreactions,mildincreaseinASTandALT,neutropenia,throm-bocytopenia,headachehypercholesterolemia,demyelinatingevents,antibodyformation

IVinfusionsq2weeks;canbegivenw/MTX

CBC/diff,ALT,AST,serumlipidprofile

Datafromreferences21,22,26,and27.AVN=avascularnecrosis;DHFR=dihydrofolatereductase;PML=progressivemultifocalleuko-encephalopathy;SC=subcutaneous;sJIA=systemicJIA.

*SeeTable5forNSAIDs.

†Multiplesideeffectshavebeenreportedforvariousagentsandnotalllistedinthistable.Themorefrequentlyreportedormorecommonadverseeventsarementioned.

‡NotFDA-approvedforuseinJIA,butusedoff-labelbyrheumatologists.

§Increasedriskof infections,especiallyTB, fungal infections,andhistoplasmosis;Anti-TNFtreatmentshouldbeheldforserious infec-tionsbutnotnecessaryinupperrespiratoryinfections.Holdatleast1weekbeforeandaftersurgery.FDAwarningofriskformalignancy,particularlylymphomahasbeenplacedonthiscategoryofdrugs.ThestrengthofthisassociationisdifficulttoquantifybecauseofthepossibleincreasedriskofmalignancyinpersonswithJIAandbecausemanycasesoflymphomaoccurredinpatientsreceivinginfliximabforCrohn’sdiseaseorulcerativecolitiswhowerealsoreceivingazathioprineormercaptopurine[21].


methotrexate include nausea, oral ulcers, transient eleva-tion in liver enzymes and macrocytic anemia [15]. Folic acid supplementation has been shown to decrease these side effects without decreasing efficacy. Measurement of liver enzymes and complete blood cell counts are recom-mended every month when initiating treatment and every 3 to 4 months after that to evaluate for toxicity [15]. Mild abnormalities can often be reversed through hold-ing treatment until resolution of transaminitis (elevated liver enzymes) or hematologic toxicity such as macrocytic anemia [19]. Although there is concern by parents and care providers of increased risk of infection with the use

of methotrexate, a randomized placebo-controlled trial of methotrexate use in JIA did not show increased fre-quency of infection with methotrexate [19].

Treatment with biologics has become recommended treatment in children with JIA who do not respond to methotrexate [20]. Therapy with biologic DMARDs is classified based on which pro-inflammatory cytokine, cellular or receptor protein is targeted for blockade. Cur-rent biologics include the anti-tumor necrosis factor alpha (anti-TNFα) agents such as etanercept, adalimumab, and infliximab. TNFα is an inflammatory cytokine which has been identified in joint fluid in children with JIA [3].

CASE-BASED REVIEW

Table 5.PediatricFDA-ApprovedNSAIDsandDosingCommonlyUsedinJIA

NSAID

Dose (PO)

Max Dose/Day

FDA-Approved Age Range for Use in JIA, yr

Comments†

Naproxen 10mg/kgBID 1000mg 2andolder MostfrequentlyusedinitialNSAID;over-allfavorableside-effectprofile;pseudo-porphyriainfair-skinnedchildren

Ibuprofen 30-50mg/kg/dayin3-4divideddoses

2400mg 12andolder Favorabletoxicityprofile

Indomethacin 1-2mg/kg/daydividedin3doses

200mg Onlyinpatients>14

UsefulinspondyloarthritisandfeverorpericarditisinsJIA.Headachecommonatinitiation;lessfavorabletoxicityprofile

Diclofenac 50-100mgBID;mayuseimmediatereleasetabs50mg3-4timesdailyor75mgtwicedaily

200mg N/A NotFDA-approvedforuseinJIAbutcommonlyusedinolderchildrenwithERA;similarpotencytoindomethacin;hepatotoxicityreported

Tolmetin 15-30mg/kg/daydividedin3-4doses

1800mg 2andolder Leastfavorabletoxicityprofile

Etodolac 20-30kg:400mgdaily

31-45kg:600mgdaily

46-60kg:800mgdaily

>60kg:1000mgdaily

1000mg 6andolder FirstapprovedNSAIDforJIA

Doserecommendationsinchildren≥6basedonweight

Meloxicam 0.125–0.25mg/kgdaily 15mg 2andolder Safetyandefficacydatasupport0.125mg/kg/dayupto7.5mg/daybutmaxdoseusedinolderchildrenis15mgdaily.Oncedailydosing.

Celecoxib(COX-2)

10-25kg:50mgBID

>25kg:100mgBID

10-25kg:100mg

>25kg:200mg

2andolder SelectiveinhibitionofCOX-2blockingprostaglandinsinvolvedininflammato-ryprocess.GIreactionsdooccurwithCOX-2inhibitorsbutatalowerratethanNSAIDsthatblockCOX1and2.

Datafromreferences21,26,and27.

*NotFDA-approvedforuseinJIA.

†AllNSAIDslistedareassociatedwithanincreasedriskofgastrointestinaladverseeventsincludingabdominalpain,dyspepsia,constipa-tion,diarrhea,ulcer,GIperforation,andanorexia.Theyarealsoassociatedwithanincreasedriskofplateletdysfunction,acuterenalinjury,pruritis,andanassociatedincreasedriskofthromboticeventsduetoCOX-1andCOX-2inhibition.CelecoxibistheonlyselectiveCOX-2NSAIDlistedhere[26].

*



Etanercept was the first of the TNFα antagonists to be approved for JIA in 1999 and is indicated for treatment of moderate to severe polyarticular JIA in children 2 years of age and older [3]. Other biologics include the IL-1 inhib-itors (anakinra, rilonacept, and canakinumab) (Table 4) which are most commonly used in the treatment of sJIA. Inhibitors of T-cell costimulation (abatacept), and an antibody targeting the IL-6 receptor (tocilizumab) are also FDA-approved for either first line or methotrexate resistant polyarticular and/or systemic arthritis [3].

Although there is no clear evidence to guide what to do with biologic medication in the presence of infection, common practice is to temporarily withhold therapy for significant infections with fever and at least 1 week before and 1 week after surgery. Immunizations with live vac-cines are contraindicated in patients with JIA receiving DMARDs [21]. Due to the increased risk of infection with biologic therapy, particularly tuberculosis (TB) and TB reactivation, a Mantoux purified protein derivative (PPD) must be performed and show no evidence of TB prior to initiating TNFα inhibitors [16] and repeated yearly. While rates of infections vary considerably be-tween studies, the approximate rate of serious infection, such as bacterial and varicella zoster, is 1 to 3 cases per 100 patient-years of treatment [22].

Treatment of systemic JIA can be more challenging. Approximately half of all patients with systemic JIA have an unremitting course of chronic arthritis and metho-trexate, and anti-TNFα inhibitors show limited efficacy. Two recent randomized, double-blind placebo-controlled trials showed the efficacy of canakinumab and tocilizum-ab (Table 4) in the treatment of systemic JIA [23,24]. Anakinra is also an accepted treatment [25].

Case1ManagementPatient 1 was diagnosed with oligoarticular arthritis based on clinical exam, which revealed

arthritis of the left elbow and the left knee with mild re-ducible flexion contractures. Radiographs demonstrated periarticular osteopenia and mild epiphyseal overgrowth. As her left leg was longer than her right, she was referred to a physical therapist who prescribed stretching exercises and a shoe lift for the right foot. She was started on naproxen 10 mg/kg per dose twice daily and had corti-costeroid injections of the left elbow and left knee under sedation which she tolerated well.

Patient’s laboratory studies revealed a positive ANA (1:320) and negative RF, normal CRP, ESR, CBC and

differential and comprehensive metabolic panel. She was referred to an ophthalmologist and was diagnosed with bilateral anterior uveitis. Despite treatment with topical corticosteroid eye drops she had active uveitis 3 months later, so weekly subcutaneous methotrexate was initiated by the pediatric rheumatologist in partnership with the ophthalmologist. Her naproxen was discontinued and her arthritis and uveitis remain under control on metho-trexate. She has liver enzyme monitoring every 2 to 3 months at the primary care provider’s office.

Case2ManagementPatient 2 was initially placed in a splint for 6 weeks for a presumed Salter-Harris type 1 frac-

ture despite no obvious reports of trauma. This is not an uncommon occurrence as children with joint swelling are usually sent to an orthopedic physician prior to con-sideration of JIA in the differential diagnosis. Pediatric rheumatologists are typically less accessible than ortho-pedic physicians and there are several US states with only 1 board-certified pediatric rheumatologist and 8 states without any pediatric rheumatologist [28]. As expected, based on these statistics, the wait time to see a pediatric rheumatologist may be greater than 3 months in many states. Additionally, the American Academy of Pediatrics estimates that about 25% of children with a rheumatic disease live at least 80 miles from the nearest pediatric rheumatologist [28]. Therefore, communication between the pediatric rheumatologist and the primary care pro-vider is imperative for facilitation of routine laboratory monitoring and assistance in situations where a child may experience an acute flare and cannot commute to the pediatric rheumatologist’s office.

Once patient 2 was seen by the rheumatologist, she was diagnosed with polyarticular JIA, rheumatoid factor negative, based on clinical exam and laboratory tests. She had mild anemia and an elevated ESR but once infection and malignancy was ruled out she had intra-articular cor-ticosteroid injections of the right wrist, elbow, and knee and both ankles and was started on meloxicam and sub-cutaneous methotrexate. She had baseline radiographs of her cervical spine, hands and wrists, knees, feet and ankles which showed diffuse osteopenia and joint space narrowing of her carpals. The patient’s primary care provider had referred her to ophthalmology while she was awaiting her rheumatology appointment and she had a normal eye exam. At her 3-month follow-up with the pediatric rheumatologist, she had minor improvement in


her lower extremity arthritis but still had significant ar-thritis in her hands; etanercept was initiated with marked improvement 4 weeks later. She is currently doing well, her ESR is normal, and she is tolerating the etanercept, methotrexate, and folic acid. The meloxicam was dis-continued shortly after she responded to etanercept. She was recently discharged from occupational therapy after improvement in the range of motion of her fingers.

• WhatisthecourseandprognosisofJIA?

There is no cure for JIA, although treatment can induce remission and prevent joint destruction with resultant disability. The course and prognosis of JIA is unpre-dictable [4]. Multiple outcome studies have been con-ducted since the 1970s; however, the remission rates vary between studies, ranging from 15% to 70% [29]. Fur-thermore, heterogeneity in disease classification and patient selection in the various studies makes it difficult to interpret the outcomes. The remission rates do not include children lost to follow-up once they become adults or children who may not follow up because their disease is milder [29]. Nonetheless, delay in referral and initiation of appropriate therapy is associated with worse functional outcome [4]. The sooner that treatment is initiated, the more likely a child with JIA will achieve clinical remission. Therefore, the workup and initiation of treatment in a patient with JIA is time-sensitive and does require a sense of urgency by the care provider.

SummaryJIA is a diagnosis of exclusion based on physical exami-nation and by definition it occurs in children younger than 16 years of age. Children with JIA do not usually complain of joint pain [30], making the initial presenta-tion and diagnosis more difficult and contributing to delayed diagnosis. This often leads to increased contrac-tures and increased morbidity. The primary care provider is integral in suspecting JIA in children presenting with joint swelling, pain, warmth, or decreased range of mo-tion. When children have symptoms of arthritis that have persisted 6 weeks or longer, referral to the pediatric rheumatologist is warranted. The primary care provider is helpful in monitoring blood work and treating infectious complications in children with JIA while on systemic treatment.

Often, the only complaint from the parent or child may be a limp or morning stiffness that improves with physical activity. Laboratory and imaging studies are often nor-mal. If there is no history of trauma or clear radiographic evidence of a fracture JIA should be considered in the differential diagnosis of a child presenting with joint stiff-ness, swelling or limp. The ANA is useful in determining the frequency at which the patient requires screening for uveitis and there are suggestions that children with ANA positive JIA share similar clinical characteristics [12].

The PCP may choose to start an NSAID while the patient awaits initial evaluation by the rheumatologist, but initiation of a corticosteroid can mask signs and symptoms of an underlying malignancy or infection. Treatment varies and is based on symptoms, joint distri-bution and presence or absence of high risk factors for poor outcomes. The ultimate goal of therapy is to induce remission, allowing for improvement in the child’s qual-ity of life and to avoid consequences of long term dis-ability that may be incurred from a delay in diagnosis or under-treated disease. Collaboration between the pediat-ric rheumatologist, primary care provider and the patient and his or her family can improve the child’s quality of life and ultimate outcome.

Corresponding author: Elisa Wershba, MD, Duke Univer-sity Medical Center, Box 3212, Durham, NC 27710, [email protected].

Financial disclosures: Dr. Rabinovich reports that she has received research grants from Abbott, Janssen, and UCB.

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