Monitoring the long‐term safety of therapies for children with juvenile idiopathic arthritis: Time for a consolidated patient registry

Introduction Juvenile idiopathic arthritis (JIA; formerly juvenile rheumatoid arthritis) is a chronic rheumatic disease characterized by persistent joint inflammation and an onset prior to age 16 years. The JIA phenotype consists of 7 categories: oligoarticular (up to 4 affected joints), polyarticular (more than 4 joints) rheumatoid factor (RF) positive, polyarticular RF negative, systemic, enthesitis-related arthritis, psoriatic, and undifferentiated. JIA is an uncommon disease with an estimated incidence of 1.3 to 22.6 new cases per 100,000 person-years (1–7). Treatment for JIA includes simple analgesics and nonsteroidal antiinflammatory drugs to reduce pain and inflammation, and intraarticular and oral corticosteroids, traditional disease-modifying antirheumatic drugs (DMARDs), and biologic agents, such as tumor necrosis factor antagonists, to prevent joint destruction. The goal of therapy for JIA is clinical remission (i.e., the absence of the signs and symptoms over time). Although many children do achieve remission while receiving medication, the majority experiences disease reoccurrence within 2–3 years of discontinuing drug therapy (8). Therefore, most children with JIA are typically treated with one or more medications over the long term. However, there are critical gaps in medical knowledge on the effectiveness and safety of existing JIA drug regimens used over an extended period of time, the long-term impact of such medications on children’s growth and development, and which drug or drug combinations are most efficacious for which particular categories of JIA. In addition, certain key questions have not been addressed, including the use of medications in the outpatient setting, optimal dosing regimens, and toxicity rates compared with background rates of adverse events in children with JIA. Longitudinal data for many patients with JIA are urgently needed to guide clinicians in the optimal selection of JIA medications and the management of their risks and toxicities to improve the overall quality of care of children with JIA. At present, the long-term safety of traditional DMARDs and biologic agents used in the treatment of JIA is monitored in two ways: through passive adverse event surveillance systems (e.g., the US Federal Adverse Event Reporting System), and via product-specific observational registry studies conducted by pharmaceutical industry sponsors to fulfill mandatory Food and Drug Administration (FDA) postmarketing commitments. Both approaches, however, have significant limitations. Passive adverse event surveillance systems are known to substantially underestimate the true incidence rate of adverse event occurrence, are subject to reporting bias, and often do not provide reliable denominator data (9). Similarly, for an uncommon condition such as JIA, single-drug registries have inherent limitations of scale, thus making it difficult to identify rarer safety signals. Existing product-based registries result in competing and duplicative efforts by multiple biopharmaceutical companies to collect similar information on a small patient population. Furthermore, current registries typically have restrictive enrollment criteria and limited sample sizes, and are usually not designed to capture data on background rates of diseaserelated adverse events and medication switching. In contrast, a consolidated registry with broad sponsorship by industry, federal agencies, research networks, and patient advocacy groups would offer a unique alternative approach to monitoring the long-term safety of pediatric rheumatology treatments, one that does not have the shortcomings of either of the two foregoing options. The topic of a consolidated registry was addressed in a public workshop sponsored by the FDA on May 12–13, 2009, in BeDr. Wallace’s work was supported by grants from Amgen, Centocor, and Pfizer. Meredith Y. Smith, PhD, MPA: Abbott Laboratories, Abbott Park, Illinois; Rachel E. Sobel, DrPH: Pfizer, New York, New York; Carol A. Wallace, MD: University of Washington and Seattle Children’s Hospital, Seattle. Dr. Smith owns stock and/or holds stock options in Abbott Laboratories. Dr. Sobel owns stock and/or holds stock options in Pfizer. Address correspondence to Carol A. Wallace, MD, University of Washington School of Medicine, Division of Rheumatology–Pediatrics, Seattle Children’s Hospital, 4800 Sand Point Way NE R-5420, Seattle, WA 98104. E-mail: cwallace@ u.washington.edu. Submitted for publication October 12, 2009; accepted in revised form February 4, 2010. Arthritis Care & Research Vol. 62, No. 6, June 2010, pp 800–804 DOI 10.1002/acr.20128 © 2010, American College of Rheumatology