BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is the most prevalent pediatric rheumatologic illness. Forty percent of children with JIA have polyarthritis (poly-JIA), which is associated with persistently active disease characterized by synovitis, joint damage, decreased physical functional ability, and a progressive decrease in quality of life. Recent studies in adult rheumatoid arthritis suggest there exists a "window of opportunity" very early in the disease course during which aggressive therapeutic approaches result in profound alteration of disease progression. This clinical trial seeks to determine if aggressive treatment initiated within 6 months of the onset of poly-JIA is capable of inducing a state of inactive disease (ID) within 6 months of initiation and later clinical remission on medication (CRM). METHODOLOGY: This proposal is a randomized, multi-center, prospective clinical trial up to 1 year in duration. A placebo-controlled double-blind phase of up to 6 months represents the pivotal portion of the trial. 86 children aged 2-17 years with poly-JIA of recent onset will be randomized to 1 of 2 aggressive treatment regimens: Arm A = Methotrexate (MTX;0.5 mg/kg/wk;max 40 mg/wk SQ) + dummy etanercept SQ weekly + dummy daily oral prednisone;Arm B = MTX (as in Arm A) + etanercept (0.8 mg/kg/wk SQ, max 50 mg/wk) + prednisone (0.5 mg/kg/d;max dose of 60 mg/d tapered to zero by 17 weeks). Subjects who achieve ID by or at the 6 month visit will continue treatment for an additional 6 months to determine if CRM is achieved. Those patients who do not achieve an ACR Pediatric 70 response by 4 months, or ID by 6 months will be offered open label Treatment Arm B. The primary analyses will compare the proportions of subjects in each treatment arm that achieve ID by 6 months and the safety profiles of the treatment groups. Secondary analyses will determine time to achieve ID, the proportion of subjects that attain CRM and the effect of CRM on physical functional ability and health related quality of life. MRI with IV gadolinium will be performed at baseline and at 6 months on 1 knee of 30 subjects (15 each from Arm A and B) to observe biologic correlates of active and inactive disease. SIGNIFICANCE: If a therapeutic strategy for poly-JRA can be identified that increases the likelihood of disease quiescence early in the disease course, much of the associated morbidity, decreased quality of life, and health care costs associated with this illness likely can be avoided.