The effects of early aggressive therapy in JIA: results of the TREAT study

Abstract

Purpose: Early aggressive therapy has been shown to result in superior outcomes in adults with RA, but evidence for a similar benefit has not been demonstrated in children with JIA. The objective was to determine if aggressive treatment initiated within the first 12 mos after onset of extended oligoarticular (e-oligo), or RF + or (-) polyarticular JIA (poly JIA) can induce inactive disease (ID) within 6 mos (primary endpoint) and clinical remission on medication (CRM: ID for 6 continuous mos on medication; exploratory endpoint) within 1 yr of starting therapy. Methods: TREAT was designed as a multi-centered, prospective, double blind, randomized, placebo controlled clinical trial in children aged 2 to 16 yrs with e-oligo or poly JIA of (less-than or equal to) 12 mos duration. Participants were randomized 1:1 into 1 of 2 aggressive treatment arms: (Arm 1) MTX 0.5 mg/kg/wk SQ (40 mg max), plus etanercept 0.8 mg/kg/wk (50 mg max), plus prednisone 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 wks or; (Arm 2) MTX (same dose as Arm 1) plus etanercept placebo, plus prednisolone placebo, then followed on protocol for up to 12 mos. After 4 mos on therapy participants who failed to achieve at least an ACR Pediatric 70 received open label etanercept, MTX, and prednisolone in the same doses as Arm 1. At 6 mos the participants who achieved ACR Pediatric 70 but failed to achieve ID received open label medication as in Arm 1. Efficacy analyses focused on the intent-to-treat approach. Safety data were recorded for all participants who received at least one dose of medication. Results: 15 centers enrolled 85 participants (64 [75%] female) with a median age of 11.1 yrs and disease duration of 4.1 mos. 70% were ANA+, 33% RF+, and 33% anti-CCP+. At baseline the median physician's global assessment of disease activity and parent global assessment of overall well-being were 7 and 5 respectively. There were no significant inter-Arm differences in any of these variables. At baseline, Arm 2 had a statistically higher mean ESR (45 vs. 29 mm/hr) and active joint count (25.5 vs. 18.9) compared to Arm 1. By 4 mos, 30 of 42 (71%) participants in Arm 1 and 19 of 43 (44%) in Arm 2 achieved an ACR Pediatric 70 (X2 = 6.5; p < .001), 5 of 6 core set variables showed statistically greater improvement in Arm 1 vs. Arm 2. By 12 mos, 12 (14%) participants achieved CRM; 9 (21%) had remained in Arm 1, and 3 (6%) had remained in Arm 2 throughout the study (p = 0.0534). There were no significant inter-arm differences in the incidence of Grade 3 or higher adverse events, including infections requiring systemic therapy. There were 3 SAEs: pneumonia (Arm 1), psychosis (open label), and bacteremia with septic arthritis (open label). All resolved without sequelae. Conclusion: Although this trial did not reach its primary endpoint, early aggressive therapy in this cohort of children with severe JIA and a high rate of RF positivity resulted in substantial proportions of participants achieving an ACR Pediatric 70 by 4 mos, ID by 6 mos, and CRM within 12 mos of treatment initiation.