Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) encompasses a group of diseases of unknown etiology, defined by the International League of Associations for Rheumatology as having in common arthritis in one or more joints that persists for at least 6 weeks and beginning before 16 years of age with other conditions excluded (1). With a prevalence of approximately one per thousand children in the US, JIA is the most common pediatric rheumatic illness and cause of acquired childhood disability (2, 3). During the last 20 years the advent of a host of immune response modifiers (biologics) that directly inhibit the action of pro-inflammatory mediators has revolutionized the treatment and expected outcome of JIA (4-7) such that extended periods of clinically quiescent disease may now be induced. Newly published guidelines from the American College of Rheumatology (ACR) provide some guidance for the initiation and safety monitoring of drugs commonly used in JIA, including biologics (8). However, it remains unclear as to exactly when in the course of the disease and in what combination these treatments should be started to produce optimal outcomes. At present, it cannot be predicted with confidence which children with JIA have a less favorable outcome, although some risk factors have been identified (8-10). The polyarticular (both rheumatoid factor positive and negative) categories comprise approximately 30% of all patients with JIA, and the majority of these children remain on combinations of multiple medications for many years (11, 12); disease free periods off medication greater than 1 year are uncommon (13). Investigations in adult rheumatoid arthritis (RA) have demonstrated improved outcomes, including less radiographic progression of joint damage, when aggressive treatment is started early in the disease course (14-17). Thus, many rheumatologists now believe there is a “window of opportunity” early in the disease during which aggressive therapy has a profound long term effect (17-19). To date, there have not been any double-blind, randomized placebo controlled trials of biological agents in children with recent onset JIA in which the primary endpoint is clinical inactive disease (CID) (20). The trial described here was designed to determine if two aggressive treatment regimens started early in the course of polyarticular JIA results in CID within 6 months of initiation. An exploratory phase investigated the potential of the treatments to induce clinical remission on medication (CRM: 6 continuous months of CID while on treatment) within 12 months of initiation.