Berard, Roberta A.

Laxer, Ronald M.

English

Scholarship@Western

Western University Scholarship@Western Paediatrics Publications Paediatrics Department 12-1-2014 Early aggressive therapy for patients with juvenile idiopathic arthritis: Are we there yet? Roberta A. Berard London Health Sciences Centre, roberta.berard@lhsc.on.ca Ronald M. Laxer University of Toronto Follow this and additional works at: https://ir.lib.uwo.ca/paedpub Citation of this paper: Berard, Roberta A. and Laxer, Ronald M., "Early aggressive therapy for patients with juvenile idiopathic arthritis: Are we there yet?" (2014). Paediatrics Publications. 798. https://ir.lib.uwo.ca/paedpub/798 2343Berard and Laxer: EditorialPersonal non-commercial use only. The Journal of Rheumatology Copyright © 2014. All rights reserved.EditorialEarly Aggressive Therapy forPatients with Juvenile IdiopathicArthritis: Are We There Yet?This is an extremely exciting time in the field of pediatricrheumatology. Advances in understanding the pathogenesisof juvenile idiopathic arthritis (JIA) have led to novel treat-ments with resultant marked improvements in patientoutcomes, as is eloquently summarized in a review byLovell and colleagues1.Critical to the study of these new therapies has been thedevelopment of standardized outcome measures. These arenot only relevant to research studies but also assist inmaking treatment decisions in clinical practice. Thedefinition of improvement by the American College ofRheumatology (ACR) core set response criteria2 and morerecently, criteria of inactive disease and remission, both onand off medication, have been developed and adopted by theACR3 (Table 1). Application of these standardized outcomemeasures has greatly facilitated the reporting and general-izing of study results, as well as allowed comparison ofresults between trials. Earlier studies, in the “prebiologics era,” used differingmeasures for reporting remission and classifying patients;and the length of followup varied. As a result, it wasextremely difficult to compare results between studies. ACanadian multicenter retrospective cohort study reportedthat 10 years following diagnosis of juvenile rheumatoidarthritis4, the probability of remission (defined as 2 yearswithout taking medication) was 37% in patients withsystemic disease, 47% in oligoarthritis, 23% in rheumatoidfactor (RF)-negative polyarthritis, and 6% in RF-positivepolyarthritis5. This is in contrast to a multicenter retro-spective cohort study (Italy and the United States) in which,after a median of 7.7 years post-JIA diagnosis (similarcategories considered as above), 40% of patients were inremission (defined as 6 months without taking medication).However, at 2 years without medications (the more rigidcriteria defined by Oen, et al5), only 28% of patients were inremission6. Overall, in cohort studies reported in the pre-biologic era, patients had poor outcomes with little chanceof remission, particularly patients with more severepolyarthritis.Outcome studies reported more recently in the biologicsera, using the ACR definitions for clinical inactive disease(CID) and clinical remission while not taking medication(CR), report significantly better outcomes. Ringold, et al7reported a retrospective polyarticular JIA cohort study(28% RF-positive, 104 children) of patients followed for amedian of 27.4 months (range 6–77). Eighty percent ofpatients achieved CID at a median time of 7.6 months afterinitiation of treatment; 37% received anti-tumor necrosisfactor (TNF) therapy, 11.5% within their first 6 months ofcare. Forty-seven percent achieved clinical remission whiletaking medication, none achieved CR, and 20% neverachieved CID. The investigators of the ReACCh-Out study(Canadian Research in Arthritis in Canadian Childrenemphasizing Outcomes) report on the prospective inceptioncohort of newly diagnosed patients (< 6 mos) with allsubtypes of JIA. Of the data from 1104 patients, the proba-bilities of attaining an active joint count of 0 exceeded 70%within 2 years in all JIA categories, except for RF-positivepolyarthritis (48%). The probability of attaining CR(completely without medications for 12 months and noactive disease) within 5 years was 46–57% across JIAcategories except for patients with polyarthritis (0%RF-positive, 14% RF-negative). The probability of startinganti-TNF was 11.1% in the RF-positive polyarthritispatients within the first 6 months of care8. There is no debate regarding the efficacy of anti-TNF-αtherapy for patients with polyarticular JIA. A recent reviewreports increasing use over the last decade9. The optimaltiming of introduction and withdrawal of these medicationsis not known. Unique in its design, the Trial of EarlyAggressive Therapy (TREAT) in JIA studied the effect ofearly introduction of etanercept (ETN) plus prednisolone(PSL) and methotrexate (MTX) compared to MTX alone onthe attainment of CID at 6 months10. Eighty-five patientsSee Extension trial of early aggressive therapy in JIA, page 2459 www.jrheum.orgDownloaded on August 8, 2022 from 2344 The Journal of Rheumatology 2014; 41:12; doi:10.3899/jrheum.141051Personal non-commercial use only. The Journal of Rheumatology Copyright © 2014. All rights reserved.with polyarticular JIA < 12 months’ duration were studied inthis prospective, randomized, double-blind, placebo-control-led trial. Patients received either MTX 0.5 mg/kg/week (maxi-mum 40 mg) subcutaneously (SC), ETN 0.8 mg/kg/week(maximum 50 mg) SC, and PSL 0.5 mg/kg/day (maximum60 mg) orally and tapered to 0 mg by 17 weeks (arm 1); orMTX (same dosage as arm 1), ETN placebo, and PSLplacebo (arm 2). The study design limited the time for thepatient taking placebo; if subjects failed to meet an inter-mediate endpoint of 70% improvement according to ACRPediatric criteria at 4 months, they entered the open-labelETN/MTX/PSL arm. By 6 months, CID had been achievedin 17 of 42 patients (40%)  in arm 1 and 10 of 43 patients(23%)  in arm 2 (chi-squared = 2.91, p = 0.088). After 12 months, clinical remission while takingmedication (CRM) was achieved in 9 patients in arm 1 and3 patients in arm 2 (p = 0.053). The trial failed to meet itsprimary endpoint (attainment of CID at 6 mos); the authorsnote this was potentially explained by the overly ambitiousgoal of 60% CID in the MTX/ETN/PSL arm as well ashigher (potentially more effective) doses of MTX used.Importantly, CID was induced in 32% of patients by 6months and in 66% by 12 months in this severely affectedgroup of patients. The TREAT study participants were themost severely affected patients with polyarthritis, comparedto the patients reported by Ringold, et al7 and Guzman, etal8, and this difference explains the lower proportion ofTREAT patients attaining CID and CRM. In this issue of The Journal, Wallace, et al report on anopen-label extension phase of the TREAT trial11. Data from76% (48/63) of eligible patients were reported, with a meanobservation period of 39 months (range 24–54): Fiftypercent of patients spent more than half their followup inCID; 88% of patients achieved CID at one or more studyvisits, 54% achieved CRM, but 12% never achieved CID.Forty-three of 48 patients in the extension study werereceiving MTX and ETN and only 5 were taking MTXalone. Interestingly, baseline active joint counts andduration of symptoms prior to treatment did not correlatewith proportion of time in CID. This is in contrast to theoriginal 6-month trial that reported an OR for achieving CIDof 1.324 for each month earlier that a patient was treated10.One of the main concerns with the TREAT trial design isthe use of prednisone (0.5 mg/kg/day to a maximum of 60mg/day) with ETN and MTX. The study did not address thepotential effect on outcomes of early prednisone use(tapered off by 4 mos). A provocative editorial in TheJournal earlier this year argued that even short-term use ofsteroids in pediatric patients is unacceptable and can haveside effects such as infection and affect self-image, growth,metabolism, and bone structure12. Despite the growing body of literature on longterm safetyin the use of biologics, the risks of potential seriouslongterm side effects (e.g., malignancy) are relativelyunknown13,14,15,16,17, and certainly in the short term, seriousinfections are possible18.The TREAT extension study reported intermediate 2-yearoutcomes on a severely affected group of patients withaggressively treated polyarticular JIA with superioroutcomes. Early aggressive therapy was similarly evaluated innewly diagnosed patients with polyarticular JIA in theACUTE-JIA trial reported by Tynjala, et al19. This was a54-week open-label trial of 60 patients randomized to 1 of 3treatment arms: infliximab plus MTX (TNF); MTX,sulfasalazine, and hydroxychloroquine (COMBO), or MTX(MTX) alone. The primary endpoint was 75% improvementaccording to the ACR Pediatric criteria, achieved in 100%receiving TNF, 65% in the COMBO group (95% CITable 1. ACR definitions of clinical inactive disease and clinical remission for JIA. From: Wallace, et al.Arthritis Care Res 2011;63:929-363; with permission.Definition of “clinical inactive disease (CID)” for JIA (all 6 conditions must be met)• No joints with active arthritis• No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributed to JIA• No active uveitis• ESR or CRP level (or both if tested) within normal limits for the laboratory where tested, or, if elevated,not attributed to JIA• Physician’s global assessment of disease activity score as lowest possible on whichever scale is used• Duration of morning stiffness < 15 minDefinition of “clinical remission on medication (CRM)”• Satisfaction of the definition of clinical inactive disease for at least 6 continuous months while on therapy for JIADefinition of “clinical remission off medication (CR)”• Satisfaction of the definition of clinical inactive disease for at least 12 continuous months while off all therapy for JIA ACR: American College of Rheumatology; JIA: juvenile rheumatoid arthritis; ESR: erythrocyte sedimentationrate; CRP: C-reactive protein.  www.jrheum.orgDownloaded on August 8, 2022 from 2345Berard and Laxer: EditorialPersonal non-commercial use only. The Journal of Rheumatology Copyright © 2014. All rights reserved.44–86%), and 50% taking MTX (95% CI 28–72%), p <0.0001. CID according to the Wallace criteria3 (applied in aposthoc analysis) was achieved in 13 patients (68%)receiving TNF (95% CI 47–89%); 7 (35%) in the COMBOgroup (95% CI 6–44%); and 5 (20%) taking MTX (95% CI3–39%); p = 0.001. Similarly to the TREAT extension trial,patients taking TNF spent a mean of 25 weeks (46%; 95%CI 17–33) in CID, significantly longer than those in theCOMBO group (11 weeks; 95% CI 5–17), or those takingMTX (5 weeks; 95% CI 1–9); p = 0.003. Now that anti-TNF agents have been shown to beeffective in JIA, investigators are turning to the question ofhow long patients must be maintained on this treatment.Considerations include the potential for short-term andlongterm side effects from anti-TNF agents, and in manyparts of the world, the difficulty accessing these drugs.Ideally, results from translational research will guide thesafe and rational use of these biologics, with definedrecommendations on the duration of treatment once apatient has achieved CRM. A recent exploratory study byRingold, et al to identify biomarkers of disease activitymay help to answer this question. In their study of 31patients with polyarticular course JIA, serum amyloid A,C-reactive protein, interleukin 6, and matrix metallopro-teinase 3 were elevated in the active disease group ascompared to the children with CID and controls20.Similarly, using pretreatment blood samples from theTREAT trial, a panel of immunologic assays (immunesignatures including phenotypical and functional data)could predict CID vs no CID after 6 months of theMTX/ETN/PSL aggressive treatment arm with 90% sensi-tivity and specificity21. Despite the superior outcomes reported, early universalintroduction of anti-TNF agents for all patients withpolyarticular JIA is not currently feasible; nor has therebeen, in our opinion, sufficient longterm data to support thesafety profile of this approach. Access to these therapies isan issue; and their cost is considerable. Certainly, in theCanadian landscape, with both private and publicly fundedinsurers, the use of biologic agents is not yet a first-linetreatment. In addition, there is a marked variability in accessto biologics between provinces22. The priority for investigators is to identify patients mostin need of anti-TNF therapy (based on their genetic,immunologic, and/or biomarker susceptibility) in whomearly introduction will result in an alteration of the longtermprognosis in terms of sustained CRM. In addition, studies ofthe potential of biologic agents to modify radiographicevidence of disease progression are lacking. The very earlyintroduction of biologic therapies should be targeted topatients at highest risk of poor functional or radiographicoutcome to mitigate risk of potential adverse effects andlimit cost. Careful clinical observation, and data collectionand analysis, will be critical to understanding which patientsshould receive early biologic treatment, as well as how earlytreatment should be started.ROBERTA A. BERARD, MD, MSc, FRCPC,Pediatric Rheumatologist, Children’s Hospital, London Health Sciences Centre;Assistant Professor of Pediatrics, Western University;RONALD M. LAXER, MD, FRCPC,Professor of Pediatrics and Medicine, University of Toronto,Staff Rheumatologist, The Hospital for Sick Children,Toronto, Ontario, Canada.Address reprint requests to Dr. Laxer; E-mail: ronald.laxer@sickkids.caREFERENCES1. Lovell DJ, Ruperto N, Giannini EH, Martini A. Advances fromclinical trials in juvenile idiopathic arthritis. Nat Rev Rheumatol2013;9:557-63.2. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, MartiniA. Preliminary definition of improvement in juvenile arthritis.Arthritis Rheum 1997;40:1202-9.3. Wallace CA, Giannini EH, Huang B, Itert L, Ruperto N; ChildhoodArthritis Rheumatology Research Alliance, et al. American Collegeof Rheumatology provisional criteria for defining clinical inactivedisease in select categories of juvenile idiopathic arthritis. ArthritisCare Res 2011;63:929-36.4. Brewer EJ, Bass J, Baum J, Cassidy J, Fink C, Jacobs J. Currentproposed revision of JRA criteria. Arthritis Rheum 1977;20Suppl:195-9.5. Oen K, Malleson PN, Cabral DA, Rosenberg AM, Petty RE,Cheang M. Disease course and outcome of juvenile rheumatoidarthritis in a multicenter cohort. J Rheumatol 2002;29:1989-99.6. Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH.Patterns of clinical remission in select categories of juvenileidiopathic arthritis. Arthritis Rheum 2005;52:3554-62.7. Ringold S, Seidel KD, Koepsell TD, Wallace CA. Inactive diseasein polyarticular juvenile idiopathic arthritis: current patterns andassociations. Rheumatology 2009;48:972-7.8. Guzman J, Oen K, Tucker LB, Huber AM, Shiff N, Boire G, et al.The outcomes of juvenile idiopathic arthritis in children managedwith contemporary treatments: results from the ReACCh-Outcohort. Ann Rheum Dis 2014 May 19 (E-pub ahead of print).9. Mannion ML, Xie F, Curtis JR, Beukelman T. Recent trends inmedication usage for the treatment of juvenile idiopathic arthritisand the influence of tumor necrosis factor inhibitors. J Rheumatol2014;41:2078-84.10. Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O’Neil KM,Zeft AS, et al. Trial of early aggressive therapy in polyarticularjuvenile idiopathic arthritis. Arthritis Rheum 2012;64:2012-21.11. Wallace CA, Ringold S, Bohnsack J, Spalding SJ, Brunner HI,Milojevic D, et al. Extension study of participants from the TRialof Early Aggressive Therapy in Juvenile Idiopathic Arthritis. J Rheumatol 2014;41:2459-65. 12. Lehman TJ. The TREAT study — trial or tribulation? J Rheumatol2014;41:1038-9.13. Hashkes PJ, Uziel Y, Laxer RM. The safety profile of biologictherapies for juvenile idiopathic arthritis. Nat Rev Rheumatol2010;6:561-71.14. Bernatsky S, Rosenberg AM, Oen KG, Duffy CM,  www.jrheum.orgDownloaded on August 8, 2022 from 2346 The Journal of Rheumatology 2014; 41:12; doi:10.3899/jrheum.141051Personal non-commercial use only. The Journal of Rheumatology Copyright © 2014. All rights reserved.Ramsey-Goldman R, Labrecque J, et al. Malignancies in juvenileidiopathic arthritis: a preliminary report. J Rheumatol 2011;38:760-3.15. Diak P, Siegel J, La Grenade L, Choi L, Lemery S, McMahon A.Tumor necrosis factor alpha blockers and malignancy in children:forty-eight cases reported to the Food and Drug Administration.Arthritis Rheum 2010;62:2517-24.16. Hasija RP, Silverman ED, Cho S, Fung L, Benseler SM, CameronB, et al. A170: Neoplasms in pediatric patients with rheumaticdiseases exposed to biologics — A quarternary centre’s experience[abstract]. Arthritis Rheumatol 2014;66 Suppl 3:S220.17. Ruperto N, Martini A. Juvenile idiopathic arthritis and malignancy.Rheumatology 2014;53:968-74.18. Beukelman T, Xie F, Baddley JW, Chen L, Delzell E, Grijalva CG,et al. Brief report: incidence of selected opportunistic infectionsamong children with juvenile idiopathic arthritis. Arthritis Rheum2013;65:1384-9.19. Tynjala P, Vahasalo P, Tarkiainen M, Kröger L, Aalto K, Malin M,et al. Aggressive combination drug therapy in very earlypolyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis2011;70:1605-12.20. Ringold S, Lu L, Wallace CA, Sasso EH, Eastman PS. Initialassessment of multi-biomarker disease activity assay in JIA[abstract]. Arthritis Rheumatol 2014;66 Suppl 3:S10.21. Rossetti M, Spreafico R, Zhang H, Moshref M, Singer NG, LovellDJ, et al. Predictive markers of therapeutical outcome and their rolein the ethiopathology of juvenile idiopathic arthritis [abstract].Arthritis Rheum 2012;64 Suppl 10:S1097.22. Leblanc CM, Lang B, Bencivenga A, Chetaille AL, Dancey P, DentP, et al. Access to biologic therapies in Canada for children withjuvenile idiopathic arthritis. J Rheumatol 2012;39:1875-9.J Rheumatol 2014;41:2343–6; doi:10.3899/jrheum.141051 www.jrheum.orgDownloaded on August 8, 2022 from 

Early aggressive therapy for patients with juvenile idiopathic arthritis: Are we there yet?

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Early aggressive therapy for patients with juvenile idiopathic arthritis: Are we there yet?

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