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1 The ratioale for early aggressive treatmet i juveile idiopathic arthritis Evaluatio of: Wallace CA, Giaii EH, Spaldig SJ et al. Trial of early aggressive therapy i polyarticular juveile idiopathic arthritis. Arthritis Rheum. 64, (2012). The last two decades have brought dramatic chages to the therapy of childre ad adolescets with rheumatic diseases. A greater uderstadig of the uderlyig disease mechaisms ad the itroductio of biologic agets have resulted i uprecedeted treatmet outcomes ad markedly improved quality of life (QoL). Historically, treatmet of juveile idiopathic arthritis with NSAIDs, corticosteroids ad traditioal disease-modifyig atirheumatic drugs was frequetly limited by iadequate efficacy ad sigificat toxicity. Despite the recetly published ACR treatmet guidelies, which provide directios for cliicias o whe ad how to effectively maage these aggressive diseases, there still remai some delays i the adaptatio of these recommedatios owig to fear of a overly aggressive treatmet approach ad ofte overstated reports about the toxicity ad maligacy risks of biologics. Cosequetly, the precise timig ad method of implemetig the most effective therapy remais icosistet ad ucertai. This review attempts to give some isight ito the ratioale for early aggressive therapy i patiets with juveile idiopathic arthritis. Keywords: biologics early aggressive treatmet juveile idiopathic arthritis outcomes remissio therapy treatmet Katherie Marza*1 & Adreas Reiff1 Childre s Hospital Los Ageles, Keck School of Medicie of Uiversity of Souther Califoria, CA, USA Tel.: Fax: kmarza@chla.usc.edu 1 Treatmet data from adult rheumatoid arthritis (RA) suggest that early aggressive treatmet withi a widow of opportuity is associated with the highest likelihood of achievig remissio ad avoidig log-term joit damage [1]. A similar view has recetly bee proposed i pediatric rheumatology, suggestig that early aggressive therapy could lead to better disease cotrol ad iductio of remissio [2 4]. This is of particular sigificace i juveile idiopathic arthritis (JIA), where early joit damage ca lead to lifelog disability. Earlier studies i JIA have idicated a possible beefit of early aggressive treatmet. Two retrospective studies i methotrexate-treated JIA patiets demostrated that a ACR cliical respose score for pediatrics (ACR Pedi) 70 treatmet respose at 6 moths ad achievig remissio withi the first 5 years after disease oset was associated with less cumulative damage ad improved radiographic ad fuctioal log-term outcomes [4,5]. However, it was ot util recetly that two studies i JIA specifically focused o early aggressive therapy icludig biologics, suggestig that this approach would be more advatageous tha the traditioal therapeutic pyramid approach. The first study by Tyjälä et al., ACUTE-JIA [6], examied early aggressive therapy with three treatmet arms: TNF (methotrexate ad ifliximab), COMBO (methotrexate, sulfasalazie ad hydroxychloroquie) ad MTX (methotrexate mootherapy). I this 54-week multiceter, radomized, ope-label cliical trial, 60 disease-modifyig atirheumatic drug-aive, maily seroegative, polyarticular JIA patiets with a disease duratio of 6 moths (mea: 1.9 moths) were evely radomized ito oe of the three treatmet arms. A total of 37% of the patiets were ati-uclear atibody-positive ad 2% were rheumatoid factor (RF)-positive. The mea physicia s global assessmet was 5.5 (0 10 visual aalog scale). The primary ed poit was a ACR Pedi 75 at 54 weeks. The secodary outcomes icluded cliically iactive disease (CID) ad duratio of iactive disease. A ACR Pedi 75 at 54 weeks was achieved by 100, 65 ad 50% of the TNF, COMBO ad MTX mootherapy arms, respectively (p < ). At 6 moths, CID was achieved by 60% i the TNF arm, 30% i the COMBO arm ad 5% i the MTX mootherapy arm. I the secod study by Wallace et al., TREAT [7], the goal was to determie whether early aggressive treatmet i RF-positive or RF-egative polyarticular JIA (poly-jia) could iduce CID withi 6 moths. The study s secodary ed poit was a ACR Pedi 70 at 4 moths. This two-phase (a pivotal ad exploratory phase), multiceter, prospective, double-blid, radomized, placebo-cotrolled /IJR Future Medicie Ltd It. J. Cli. Rheumatol. (2012) 7(6), part of ISSN

2 Marza & Reiff trial compared two treatmet arms; arm oe icluded treatmet with MTX (0.5 mg/kg/week subcutaeous, 40 mg maximum) i combiatio with etaercept 0.8 mg/kg/week (50 mg maximum), ad predisoloe 0.5 mg/kg/day (60 mg maximum) that was tapered off by 17 weeks. Arm two icluded the same dose of MTX but etaercept ad predisoloe placebo. The pivotal phase evaluated achievemet of a ACR Pedi 70 at 4 moths ad CID at 6 moths. The exploratory phase cotiued up to 12 moths ad icluded patiets placed o ope-label (methotrexate, etaercept ad predisoloe taper) treatmet. Eighty five childre aged 2 16 years with a disease duratio of less tha 12 moths were erolled. A total of 68% were ati-uclear atibody positive ad 36% were RF positive. Although ot statistically sigificat, 17 out of 42 (40%) patiets i arm oe ad te out of 43 (23%) i arm two achieved CID by 6 moths, (c2 = 2.91; p = 0.088). After 12 moths, ie patiets i arm oe, but oly three i arm two achieved cliical remissio (p = ). No sigificat differeces i adverse evets were oted betwee the two treatmet groups. Nevertheless, the study did ot meet its primary ed poit of early aggressive therapy achievig CID withi 6 moths. Discussio Does TREAT, therefore, ivalidate the cocept of early aggressive therapy or the beefit of early use of biologics? I order to address this questio, we first have to examie the ratioale for a early aggressive treatmet approach. Studies i adult rheumatoid arthritis (RA) have demostrated improved cliical outcomes icludig decreased or o radiographic progressio with early implemetatio of aggressive treatmet withi a early widow of opportuity that defies the logterm outcome [1,3,8]. This also appears to be the case i juveile arthritis. While the outcome of JIA caot be predicted by baselie features ad log-term radiographic studies are lackig, it has bee well established that juveile arthritis ca persist ito adulthood, causig disability, pai ad physical dysfuctio [9,10]. There is still a commo miscoceptio that childre with JIA outgrow their disease. While curret maagemet with disease-modifyig atirheumatic drugs ad biologics results i sigificat improvemet of cliical symptoms, may patiets with JIA retai some degree of persistet disease activity ad i reality, log-term remissio is ifrequet, with remissio rates (defied as drug-free 592 It. J. Cli. Rheumatol. (2012) 7(6) ad asymptomatic for 2 years) varyig greatly amog disease subtypes [11 17]. I their retrospective aalysis of 392 patiets with juveile arthritis ( 8 years of age), Oe et al. oted that the probabilities of remissio was 6, 23, 47 ad 37% for RF-positive polyarticular, RF-egative polyarticular, oligoarticular ad systemic-oset juveile arthritis (JA), respectively, 10 years after disease oset. Relapse rates varied from 30 to 100% at 15 years [11]. I additio, Wallace et al. oted that oly 6% of JIA patiets were able to sustai cliical remissio off medicatios at 5 years [18]. A review of seve epidemiologic studies demostrated the impact of JA ito adulthood. Of the 983 patiets who had bee followed for a mea of 20.5 years (mea age of 30 years), 47% were foud to still have active arthritis, 46% had difficulties with daily activities ad 22% had arthritis-related surgery [9]. I aother study, severe fuctioal limitatios were observed i up to oe-third of 246 adults with log-stadig JIA [10]. Childre with JIA experiece impairmet i health-related quality of life compared to their healthy peers, as measured by decremets i the domais of physical ad psychosocial wellbeig [19]. Chroic arthritis also egatively impacts emotioal, social ad school fuctioig [11,12,19,20]. Adult patiets who had childhood-oset arthritis have bee show to have high rates of axiety ad depressive illess [10], ad have a higher mortality rate compared with the geeral populatio [21]. Furthermore, some studies have reported radiographic chages i up to 88% of childre with JIA at the time of diagosis that progressed with disease activity over time. While osteopeia was the most commo fidig, joit space arrowig ad erosios were also observed [22,23]. Other studies usig MRI demostrated irregular syovial thickeig ad low-itesity syovial tissue, ot oly i recet-oset JIA, but also i joits prior to the oset of cliical symptoms [24,25]. I additio, localized growth disturbaces have bee reported i 10 48% of childre withi the first 2 3 years after diagosis [16,22]. Lastly, severity ad duratio of disease impact boe mieral desity ad boe mieral cotet, which is frequetly decreased i JIA [26,27]. As it takes a average of 13 moths for a JIA patiet to achieve remissio [18], earlier ad more aggressive treatmet strategies for the developmet of a healthy musculoskeletal system i childre eed to be pursued. The itroductio of the ACR Pedi 30 criteria i 1997 helped further this goal as it stadardized the assessmet of cliical respose ad improvemet i juveile arthritis

3 Early aggressive treatmet i juveile idiopathic arthritis trials [8]. Followig the developmet of the ACR Pedi criteria, published studies have primarily utilized this validated outcome measure as the bechmark to establish the efficacy of therapies i JA. Furthermore, it has allowed the compariso of treatmet therapies across studies. A ACR Pedi 30 respose is defied as a improvemet of at least 30% i a miimum of three variables with o worseig by more tha 30% i more tha oe variable: Physicia global assessmet of disease activity; Paret/patiet assessmet of overall wellbeig; Fuctioal ability (disability idex of the Childre s Health Assessmet Questioaire); Number of joits with active arthritis; Number of joits with limited rage of motio; CRP or erythrocyte sedimetatio rate. However, achievig oly a 30% improvemet from baselie should o loger be acceptable as a desirable therapeutic goal. ACR Pedi 50, 70, 90 ad 100 resposes implyig 50, 70, 90 ad 100% improvemet, respectively, are more meaigful parameters to evaluate true improvemet ad should become the actual bechmark of a successful cliical outcome. The itroductio of biologics has trasformed the ladscape of cliical trials such that it is o loger uusual for substatial umbers of patiets to achieve ACR Pedi 70, 90 ad 100 resposes [28 34]. While the TREAT study did ot meet its primary ed poit ad o statistical differece i CID betwee the two study arms could be established, there was strog evidece to support a ratioale for early aggressive therapy ad the role of early iitiatio of biologic therapy. Shorter disease duratio at baselie ad achievig a ACR Pedi 70 at 4 moths were sigificat predictors of CID at 6 moths. For each moth earlier that a patiet was treated, their chace of achievig CID was icreased by a factor of I additio, at 4 moths a ACR Pedi 70 was achieved by 71% of patiets i arm oe ad oly 44% of patiets i arm two (c² = 6.46; p = 0.011). Moreover, whe oe takes ito accout the umber of patiets i each arm who wet o to receive ope-label medicatio (MTX, etaercept ad predisoloe taper); the role of early combiatio therapy appears to be eve more substatial. Te patiets i arm oe ad 21 patiets i arm two who failed to achieve a ACR Pedi 70 at 4 moths, as well as 11 patiets i arm oe ad eight patiets i arm two that failed to achieve CID at 6 moths were cotiued o ope-label therapy util the completio of the exploratory phase. With this i mid, the role of a biologic i early aggressive therapy appears critical. At 12 moths a substatially greater proportio (59%) of patiets who bega i arm oe ad had cotiued to receive the combiatio therapy were i CID compared to those i arm two (16%) who remaied o MTX mootherapy. Additioally, at 12 moths, 65% of patiets i arm oe had achieved a ACR Pedi 70, while oly approximately 20% of the patiets i arm two were able to achieve this outcome. Moreover, whe oe icludes all patiets who received opelabel treatmet i the 12-moth assessmet, this proportio icreased to early 85% ad approximately 70% for arm oe ad two, respectively. This differece ot oly emphasizes the critical role of biologics, but also the importace of early combiatio therapy i early aggressive therapy. The results of the ACUTE-JIA trial where treatmet was started after a eve shorter disease duratio support this cocept, with 60% of patiets achievig CID at 6 moths ad 100% of patiets achievig a ACR Pedi 75 at 54 weeks, respectively, i the TNF treatmet arm. Eve though ACUTE-JIA ad TREAT were similar i their goal to address the role of early aggressive treatmet i JIA, they differed i their patiet populatios, study desig, study drugs ad ed poits (Table 1). The ACUTE-JIA trial had a slightly shorter average disease duratio (1.9 vs 5 moths) prior to start of treatmet ad less RF-positive patiets tha the TREAT study (2 vs 36%), which may have cotributed to the seemigly better treatmet respose. Both studies had treatmet arms with a ati-tnf aget; however, ifliximab was utilized i ACUTE-JIA ad etaercept i TREAT. Oe could argue that the itraveous admiistratio of the ifliximab was a more aggressive therapy although the dose used was oly 3 5 mg/kg. I additio, the primary ad secodary outcomes were ot idetical. Patiets i TREAT who did ot achieve a ACR Pedi 70 at 4 moths were placed o ope-label treatmet ad were ot icluded i the ed poit aalysis of each arm. Despite these differeces, the results of both ivestigatios provide additioal evidece for the beefit of early aggressive therapy. With the availability of ew outcome data, JIA, similar to other childhood rheumatic diseases, ca o loger be cosidered a beig disease. Early, aggressive pharmacologic itervetio is a critical compoet of optimal disease 593

4 Marza & Reiff Table 1. Summary of the ACUTE-JIA ad TREAT trials. Study characteristics ACUTE-JIA TREAT Number of patiets Diagosis JIA (poly-rf positive ad RF egative, ERA ad PsA) JIA (poly-rf positive ad RF egative) RF-positive patiets 2% 36% Age (mea) 9.5 years 10.5 years Disease duratio >6 weeks, but <6 moths <12 moths Average disease duratio (moths) Treatmet arms 3 2 TNF: INF + MTX Arm oe: ETN + MTX + CS # COMBO: MTX, SSZ ad HCQ Arm two: MTX + ETN placebo + CS placebo MTX Previous DMARD DMARD aive +/- previous DMARD Legth of study 54 weeks 52 weeks Primary ed poit ACR Pedi 75 at 54 weeks CID at 6 moths Secodary ed poit CID at 54 weeks ad duratio of iactive disease ACR Pedi 70 at 4 moths CID at 6 moths 60% TNF 40% arm oe 30% COMBO 23% arm two 5% MTX Medicatio adjustmets Dosage chages allowed No dosage chages allowed INF dosig: 3 5 mg/kg at 0, 2 ad 6 weeks the every 6 weeks. MTX dosig ACUTE: 15 mg/m2, maximum dose 25 mg/week. ETN dosig: 0.8 mg/kg/week subcutaeously. MTX dosig TREAT: 0.5 mg/kg, maximum dose 40 mg/week. # CS dosig: 0.5 mg/kg, maximum dose 60 mg/day. SSZ dosig: 40 mg/kg, maximum dose 2 g/day. HCQ dosig: 5 mg/kg/day, maximum dose 300 mg/day. ACR Pedi: ACR cliical respose score for pediatrics; CID: Cliically iactive disease; COMBO: Methotrexate, sulfasalazie ad hydroxychloroquie; CS: Predisoloe; DMARD: Disease-modifyig atirheumatic drug; ERA: Ethesitis-related arthritis; ETN: Etaercept; HCQ: Hydroxychloroquie; INF: Ifliximab; JIA: Juveile idiopathic arthritis; MTX: Methotrexate; PsA: Psoriatic arthritis; RF: Rheumatoid factor; SSZ: Sulfasalazie; TNF: Methotrexate ad ifliximab. maagemet i order to prevet further disease progressio, restore orga fuctio, ad promote ormal growth ad developmet. The adaptatio of a comprehesive maagemet approach with early aggressive treatmet i cojuctio with physical ad occupatioal therapy ad psychosocial support will probably improve the log-term outcome ad quality of life of our patiets with juveile arthritis. Fiacial & competig iterests disclosure The authors have o relevat affiliatios or fiacial ivolvemet with ay orgaizatio or etity with a fiacial iterest i or fiacial coflict with the subject matter or materials discussed i the mauscript. This icludes employmet, cosultacies, hooraria, stock owership or optios, expert testimoy, grats or patets received or pe dig, or royalties. No writig assistace was utilized i the productio of this mauscript. Executive summary Over the last two decades, tremedous advacemets have bee made i the uderstadig of the pathogeesis ad treatmet of juveile idiopathic arthritis. Due to the log-term cosequeces of ucotrolled disease, aggressive treatmet, particularly i the early phase, is critical. With the itroductio of biologics, this goal is ow achievable ad treatmet outcomes have sigificatly improved. The curret treatmet goal is ow remissio ad o loger just disease cotrol. Ofte overstated reports of toxicity ad risks of maligacy may cotribute to the hesitatio i adoptig early aggressive therapy. There are ow data to show that early aggressive therapy with biologics is efficacious ad critical. Early aggressive itervetio is critical for juveile idiopathic arthritis patiets to have optimal outcomes. 594 It. J. Cli. Rheumatol. (2012) 7(6)

5 Early aggressive treatmet i juveile idiopathic arthritis Refereces 11 Papers of special ote have bee highlighted as: of iterest of cosiderable iterest 1 2 O Dell JR. Treatig rheumatoid arthritis early: a widow of opportuity. Arthritis Rheum. 46, (2002). Albers HM, Wessels JAM, Va der Straate RJHM et al. Time to treatmet a importat factor for the respose to methotrexate i juveile idiopathic arthritis. Arthritis Rheum. 61, (2009). 3 Woo P. Theoretical ad practical basis for early aggressive therapy i paediatric autoimmue disorders. Curr. Opi. Rheumatol. 21, (2009). 4 Bartoli M, Tarò M, Magi-Mazoi S et al. The magitude of early respose to methotrexate predicts log-term outcomes of patiets with juveile idiopathic arthritis. A. Rheum. Dis. 7, (2008) Tyjälä P, Vähäsalo P, Tarkiaie M et al. Aggressive combiatio drug therapy i very early polyarticular juveile idiopathic arthritis (ACUTE-JIA): a multicetre radomized ope-label cliical trial. A. Rheum. Dis. 70, (2011). Oe K, Malleso PN, Cabral DA, Roseberg AM, Petty RE, Cheag M. Disease course ad outcome of juveile rheumatoid arthritis i a multiceter cohort. J. Rheumatol. 29(9), (2002). Kirkhus E, Flato B, Riise O et al. Differeces i MRI fidigs betwee subgroups of recet-oset childhood arthritis. Pediatr. Radiol. 41, (2011). 25 Garder-Medwi JM, Killee OG, Ryder CA et al. Magetic resoace imagig idetifies features i cliically uaffected kees predictig extesio of arthritis i childre with mooarthritis. J. Rheumatol. 33, (2006). 26 Lie G, Flato B, Hauge M et al. Frequecy of osteopeia i adolescets with earl-oset juveile idiopathic arthritis. A log-term outcome study of oe hudred five patiets. Arthritis Rheum. 48, (2003). Describes remissio rates of subtypes of JIA. 13 Leviso JE, Wallace CA. Dismatlig the pyramid. J. Rheumatol. 19(Suppl. 330), 6 10 (1992). 14 Mide K. Adult outcomes of patiets with juveile idiopathic arthritis. Horm. Res. 72(Suppl. 1), 2 25 (2009). 15 Flato B, Hoffma-Vold AM, Reiff A et al. Log-term outcome ad progostic factors i Ethesitis related arthritis: a case cotrol study. Arthritis Rheum. 54, (2006). 27 Mide K, Niewerth M, Listig J et al. Log-term outcome i patiets with juveile idiopathic arthritis. Arthritis Rheum. 46, (2002). Burham JM, Shults J, Duber SE et al. Boe desity, structure, ad stregth i juveile idiopathic arthritis: Importace of disease severity ad muscle deficits. Arthritis Rheum. 58, (2008). 28 Lovell DJ, Giaii EH, Reiff A et al. Etaercept i childre with polyarticular juveile rheumatoid arthritis. N. Egl. J. Med. 342, (2000) Wallace CA, Giaii EH, Spaldig SJ et al. Trial of early aggressive therapy i polyarticular juveile idiopathic arthritis. Arthritis Rheum. 64, (2012). Oe K, Duffy CM, Tse SML et al. Early outcomes ad improvemet of patiets with juveile idiopathic arthritis erolled i a Caadia multiceter iceptio cohort. Arthritis Care Res. 62, (2010). Established the rarity of sustaied remissio i JIA. Gutierrez-Suarez R, Pistorio A, Cespedes Cruz A et al. Health-related quality of life of patiets with juveile idiopathic arthritis comig from 3 differet geographic areas. The PRINTO multiatioal quality of life cohort study. Rheumatology (Oxford) 46(2), (2007). Giaii EH, Ruperto N, Ravelli A, Lovell DJ, Felso DT, Martii A. Prelimiary defiitio of improvemet i juveile arthritis. Arthritis Rheum. 40, (1997). Deardo BA, Miller LC, Schaller JG, Tucker L. Youg childre with juveile rheumatoid arthritis are developmetally delayed i gross ad fie motor skills. Arthritis Rheum. 39(Suppl. 9), S1715 (1996). 21 Reiff AO. Juveile arthritis. I: Makig a Differece i Rheumatology: Early ad Aggressive Treatmet = Better Outcomes for Today s Patiets. Schiff MH (Ed.). The Veritas Istitute for Medical Educatio Ic., NJ, USA, (2004). Frech AR, Maso T, Nelso AM, O Fallo WM, Gabriel SE. Icreased mortality i adults with a history of juveile rheumatoid arthritis: a populatio-based study. Arthritis Rheum. 44(3), (2001). 22 Packham JC, Hall MA. Log-term follow-up of 246 adults with juveile idiopathic arthritis: fuctioal outcome. Rheumatology (Oxford). 41(12), (2002). Selvaag AM, Flato B, Dale K et al. Radiographic ad cliical outcome i early juveile rheumatoid arthritis ad juveile Spodyloarthropathy: a 3-year prospective study. J. Rheumatol. 33, (2006). 23 Maso T, Reed AM, Nelso AM et al. Frequecy of abormal had ad wrist radiographs at time of diagosis of Semial study demostratig substatial efficacy of biologic therapy i JIA. 29 Lovell DJ, Reiff A, Joes OY et al. Log-term safety ad efficacy of etaercept i childre with polyarticular-course juveile rheumatoid arthritis. Arthritis Rheum. 54(6), (2006). 30 Horeff G, Ebert A, Fitter S. Safety ad efficacy of oce weekly etaercept 0.8mg/kg i a multicetre, 12 week trial i active polyarticular course juveile idiopathic arthritis. Rheumatology 48, (2009). 31 Ruperto N, Lovell DJ, Quartier P et al. Abatacept i childre with juveile idiopathic arthritis: a radomised, double-blid, placebo-cotrolled withdrawal trial. Lacet 372, (2008). 32 Ruperto N, Lovell DJ, Quartier P et al. Log-term safety ad efficacy of abatacept i childre with juveile idiopathic arthritis. Arthritis Rheum. 62, (2010). 33 De Beedetti F, Bruer H, Alle R et al. Tocilizumab is efficacious i patiets with systemic juveile idiopathic arthritis across baselie demographics ad disease characteristics ad prior/baselie treatmets: 52 week data from a phase 3 cliical trial. Arthritis Rheum. 63(Suppl. 10), Abstract L111 (2011). 34 Yokota S, Imagawa T, Mori M et al. Efficacy ad safety of tocilizumab i patiets with systemic-oset juveile idiopathic arthritis: a radomized double-blid placebocotrolled withdrawal Phase III trial. Lacet 371, (2008). Wallace CA, Huag B, Badeira M et al. Patters of cliical remissio i select categories of juveile idiopathic arthritis. Arthritis Rheum. 52, (2005) Ilowite NT. Curret treatmet of juveile rheumatoid arthritis. Pediatrics 109(1), (2002). Role of early aggressive therapy i a ope-label study to achieve a ACR Pedi 75. Double-blid study to determie whether early aggressive therapy could iduce cliically iactive disease. polyarticular juveile rheumatoid arthritis. J. Rheumatol. 29, (2002). 12 Role of early respose to treatmet i log-term outcome of juveile idiopathic arthritis (JIA). Magai A, Pistori A, Magi-Mazoi S et al. Achievemet of a state of iactive disease at least oce i the first 5 years predicts better outcome of patiets with polyarticular juveile idiopathic arthritis. J. Rheumatol. 36, (2009). 595