721 - Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis

Sunday, November 6, 2011: 12:00 PM
W375d (McCormick Place West)
Carol Wallace1, Edward H. Giannini2, Steven J. Spalding3, Philip Hashkes4, Kathleen M. O'Neil5, Andrew S. Zeft3, Ilona S. Szer6, Sarah Ringold7, Hermine Brunner8, Laura E. Schanberg9, Robert P. Sundel10, Diana Milojevic11, Marilynn G. Punaro12, Peter Chira13, Beth S. Gottlieb14, Gloria Higgins15, Norman T. Ilowite16, Yukiko Kimura17, Anne Johnson18, Stephanie Hamilton1, Bin Huang8 and Daniel J. Lovell8, 1Childrens Hosp & Regional Med, Seattle, WA, 2PRCSG-Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 3Cleveland Clinic, Cleveland, OH, 4Shaare Zedek Medical Center, Tel Aviv, Israel, 5Okla Univ Health Science Ctr, Oklahoma City, OK, 6Rady Childrens Hosp San Diego, San Diego, CA, 7Children's Hosp Regional Med, Seattle, WA, 8Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 9Duke University Medical Center, Durham, NC, 10Childrens Hosp Medical Center, Boston, MA, 11UCSF, San Francisco, CA, 12Texas Scottish Rite Hospital, Dallas, TX, 13Stanford University, Palo Alto, CA, 14Schneider Children's Hospital, New Hyde Park, NY, 15PRCSG, Columbus, OH, 16Children's Hospital Montefiore, Bronx, NY, 17Hackensack Univ Medical Ctr, Hackensack, NJ, 18Cincinnati Child Hosp Med Ctr, Cincinnati, OH
Presentation Number: 721

Background/Purpose: 

Early aggressive therapy produces superior outcomes in adults with RA, but evidence for a similar benefit has not been demonstrated in children with JIA.

Method: 

The objectives of this study (abbrev TREAT) were to determine if aggressive treatment initiated early in the course of RF (+) or (-) polyarticular JIA (poly JIA) can induce clinical inactive disease (CID) within 6 mos (primary endpoint) and clinical remission on medication (CRM: CID for 6 continuous mos on medication; exploratory endpoint) within 1 yr of starting therapy.  Other endpoints were changes in the ACR pediatric core variables.

TREAT was designed as a multi-center, prospective, double blind, randomized, placebo controlled trial in children aged 2-16 yrs with onset of poly JIA <12 mos in duration.  Subjects 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 (ETN) 0.8 mg/kg/wk (50 mg max), plus prednisolone (pred) 0.5 mg/kg/d (60 mg max) tapered to 0 by 17 wks or; (Arm 2) MTX (same dose as Arm 1) plus ETN placebo, plus pred placebo, then followed on protocol for up to 12 mos.  After 4 mos on therapy subjects who failed to achieve at least an ACR Pediatric 70 received open label ETN, MTX, and pred in the same doses as Arm 1.  At 6 mos, subjects who did not achieve CID received open label medication.  Efficacy analyses focused on the intent-to-treat approach.  Safety data were recorded for all subjects.

Result: 

15 centers enrolled 85 subjects (64 [75%] female; median age 11.1 yrs; disease duration 4.1 mos).  69% were ANA+ and 36% were RF(+).  Median values at baseline of ACR pediatric core variables were: physician’s global assessment of disease activity 7.5; parent global assessment of well-being 5.5; ESR 33; number of joints with arthritis 19; number of joints with limited motion 11.5, C-HAQ 1.1.

At 4 mos, 30 of 42 (71%) subjects in Arm 1 and 19 of 43 (44%) in Arm 2 achieved an ACR Pediatric 70 (X2 = 6.5; p=0.011).  At 6 mos, 17 of 42 (40%) of subjects in Arm 1 achieved CID, compared to 10 of 43 (23%) in Arm 2 (X2 = 2.91; p = 0.088).  Logistic regression showed the only variable predictive of CID at 6 mos was disease duration at baseline.  The odds of CID increased by 1.324 times for each month earlier treatment was started after onset of symptoms (p=0.011).  Although all 6 ACR pediatric core variables showed highly significant improvement by 6 mos in both Arms (all p values <0.001), 5 showed statistically greater improvement in Arm 1 vs. Arm 2.  By 12 mos, 12 (14%) subjects achieved CRM; 9 (21%) had remained in Arm 1, and 3 (6%) had remained in Arm 2 throughout the study (p=0.053). 

      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 subjects achieving an ACR Pediatric 70 at 4 mos, CID at 6 mos, and CRM within 12 mos of treatment initiation.


Keywords: juvenile idiopathic arthritis (JIA)

Disclosure: C. Wallace, Amgen, 2, Pfizer Inc, 2, Bristol myers Squibb, 5 ; E. H. Giannini, None; S. J. Spalding, None; P. Hashkes, None; K. M. O'Neil, None; A. S. Zeft, None; I. S. Szer, None; S. Ringold, None; H. Brunner, None; L. E. Schanberg, Pfizer Inc, 2 ; R. P. Sundel, None; D. Milojevic, None; M. G. Punaro, None; P. Chira, None; B. S. Gottlieb, None; G. Higgins, None; N. T. Ilowite, Abbott Immunology Pharmaceuticals, 8, Genentech and Biogen IDEC Inc., 8, Regeneron, 2, Novartis Pharmaceutical Corporation, 5, Centocor, Inc., 5 ; Y. Kimura, Genentech and Biogen IDEC Inc., 5 ; A. Johnson, None; S. Hamilton, None; B. Huang, None; D. J. Lovell, Abbott Immunology Pharmaceuticals, 5, Bristol-Myers Squibb, 5, Centocor, Inc., 5, Hoffmann-La Roche, Inc., 5, UBC, 5 .