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my aap grand rounds newsletter resources 
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AAP Grand Rounds 20:54-55 (2008) Another Biologic Agent for the Treatment of Juvenile ArthritisSource: Lovell DJ, Ruperto N, Goodman S, et al. Adalimumab with or without methotrexate in juvenile rheumatoid arthritis. New Engl J Med. 2008;359(8);810–820; doi:10.1056/NEJMoa0706290.
The Pediatric Rheumatology Collaborative Study Group conducted a randomized controlled trial to evaluate the safety and efficacy of adalimumab, a monoclonal antibody against tumor necrosis factor (TNF), for polyarticular-course juvenile rheumatoid arthritis (JRA). Patients were eligible if they were between 4–17 years of age and had at least five swollen joints that had not responded to nonsteroidal anti-inflammatory agents (NSAIDs). The American College of Rheumatology Pediatric 30% (ACR Pedi 30) was used to assess response to therapy. The ACR Pedi scale is a measure of clinical improvement for juvenile arthritis consisting of six core criteria. An ACR Pedi 30 means that there was a 30% or greater improvement in at least three criteria, with no more than a 30% worsening in one criterion. The study consisted of three phases: a 16-week open-label lead-in phase; a 32-week double-blind treatment phase; and an open-label extension phase for up to two years. In the initial open-label phase, all patients received adalimumab (24 mg/m2 up to 40 mg) subcutaneously every other week. All patients who achieved an ACR Pedi 30 at 16 weeks were randomized to either adalimumab or placebo injections every other week for 32 weeks. In the open-label lead-in phase, 85 patients receiving methotrexate and 86 patients not receiving methotrexate were enrolled. Of these, 133 who responded well to adalimumab with an ACR Pedi 30 or better entered the double-blind phase. Study participants in both the open-label and double-blind phases of the study were predominantly female (approximately 75%) and Caucasian (95%), with a mean age of approximately 11 years. During the double-blind phase of the study (weeks 16–48) among patients not receiving methotrexate, disease flares occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=.02). At the end of the double-blind period, among those receiving methotrexate, more patients treated with adalimumab than placebo achieved an ACR Pedi 30, 50, 70, or 90 response. In the open-label extension, response rates were sustained after 104 weeks of treatment. Fourteen patients had serious adverse events (SAE) that may have been related to the study drug, including seven serious infections. Anti-adalimumab antibodies developed in 16% although no SAEs were associated with this. The authors conclude that adalimumab is effective for the treatment of polyarticular JRA.
Dr. Li has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. TNF has been found in inflammatory joints, and adalimumab has been shown to be efficacious for treating adult rheumatoid arthritis (RA) patients.1,2 The majority of JRA patients have a different disease than adult RA, so it is important to evaluate adalimumab in children to determine its efficacy and safety. This is an important study because the authors assess the safety and efficacy of adalimumab as a treatment for polyarticular JRA using the "gold standard" of a randomized, placebo-controlled clinical trial. They report substantial and sustained benefit, with many patients even achieving an ACR Pedi 90 or 100 response rate, a level at or close to remission. This is a very impressive finding considering the severity of the patients enrolled into the study; this level of response was extremely rare prior to the use of biologics and methotrexate. Encouragingly, most adverse events were considered mild to moderate, and no unusual SAEs developed. This study highlights some of the difficulties with conducting such trials. JRA is an uncommon disease and 31 sites were involved in recruiting the 171 patients enrolled in the study. Although the primary endpoint was reached, the study was not sufficiently powered to evaluate the efficacy of treatment with adalimumab alone versus adalimumab plus methotrexate. JRA can be slow to show improvement or worsening, so longer times are required for monitoring treatment response; the double-blind phase of the study was eight months, and the entire study took 26 months to complete not including the open-label extension phase which still continues. Such trials require dedicated patients and families in addition to the clinicians. Although placebo-controlled trials are ideal in terms of allowing better assessment of the efficacy of the study drug, such trials must also be ethical. Because of advances in the field, most rheumatologists would not be willing to participate in a trial that involves treating these patients with only placebo versus study drug because of the potential for serious morbidity from untreated JRA and the availability of effective medicines. Newer study designs are therefore required that can balance ethical concerns with sufficient scientific rigor. This study’s design was generated in consultation with the FDA. A nice addition to this study was the inclusion of a long open-label extension phase that enables better assessment of potential adverse events, as well as of efficacy. This is an exciting time in pediatric rheumatology because of the number and variety of treatments becoming available, and the increased interest in studying these medications in our patients.
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