The future of pediatric rheumatology: Many questions remain

Abstract

In a report published elsewhere in this issue of Arthritis & Rheumatism, Ruperto et al describe a randomized, placebo-controlled trial of infliximab plus methotrexate (MTX) for the treatment of polyarticularcourse juvenile rheumatoid arthritis (JRA) (1). The trial resulted from the combined effort of 39 authors from 30 institutions in 13 countries, working together in an excellent example of multi-institutional, international collaboration. This study would be hailed as a hallmark of what pediatric rheumatologists can accomplish, except that the results failed to reach statistical significance. Infliximab plus MTX is effective therapy for RA (2), and the majority of pediatric rheumatologists believe it is effective for polyarticular-course JRA as well. What, then, should we conclude from the lack of statistical significance of the primary end point result in this study? Should it be concluded that the combination of infliximab and MTX is ineffective for treatment of polyarticular JRA? JRA is clearly not the same disease as adult RA, and the findings of this randomized, placebo-controlled trial (1) do not support an evidencebased conclusion that the combined use of infliximab and MTX is beneficial in JRA. An alternative explanation for the negative results might be a questionable study design, the small number of subjects (despite the large number of authors and institutions), or simply the random nature of Type II statistical error. The difficulty of organizing large, randomized, placebo-controlled trials and recruiting a sufficient number of subjects is well recognized. It is a problem for studies of adults with rheumatic disease and is compounded manyfold for studies of children with rheumatic disease, because of the smaller numbers of affected children and the concerns of physicians, parents, and institutions that children receive optimal care at all times, leading to unwillingness to commit patients to participation in trials in which they might receive placebo. If the study by Ruperto et al had been performed in adults, it could have been repeated with appropriate modification of the study design or increase in the number of subjects; many studies of the combined use of MTX and infliximab in adults with RA have been reported in the literature (3–5). However, because of the small numbers of available patients, this cannot be done easily for a study of a pediatric rheumatic disease. The resources of the pediatric rheumatology community are clearly limited. Should these resources be used in attempts to replicate the findings in studies of adult patients, or would they be better utilized in other investigations? A strong argument for the former is that the rheumatic diseases of childhood are not identical to those of adults. However, there are currently no examples of therapies that have proven successful in adults with RA that have not been efficacious in JRA patients as well. Not all drugs that are safely used in adults can be safely used in children, and every new therapy for rheumatic diseases must be carefully reevaluated before it is broadly applied to pediatric patients. The Food and Drug Administration has a responsibility to assure the safety of these regimens before sanctioning their use in children. Such studies can be accomplished with far fewer resources than are necessary for randomized, placebo-controlled trials of efficacy. Unless one is prepared to argue that the failure of Ruperto and colleagues’ study to prove the efficacy of combined inflixThomas J. A. Lehman, MD: Hospital for Special Surgery and Weill Medical Center of Cornell University, New York, New York. Address correspondence and reprint requests to Thomas J. A. Lehman, MD, Chief, Division of Pediatric Rheumatology, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021. E-mail: goldscout@aol.com. Submitted for publication March 13, 2007; accepted in revised form May 16, 2007. Arthritis & Rheumatism