A decade of biologic treatment observation in juvenile idiopathic arthritis: Lessons learned from the Dutch ABC Register

Since 1999, the treatment of juvenile idiopathic arthritis (JIA) has been extended with a new category of drugs: biologic agents (also known as biologicals or biologic disease modifying anti-rheumatic drugs). Biologic agents consist of natural proteins, like antibodies and cytokines, and have been developed to target one or more steps of the immune response. Elucidation of many of the cellular and molecular mechanisms of the immune system involved in inflammatory arthritis has resulted in an increasing development of different biologic agents and, in the future, this number will expand even further. Tumour necrosis factor (TNF) is a proinflammatory cytokine that plays a central role in the pathogenesis of juvenile idiopathic arthritis. In systemic disease, interleukin (IL)-1 (a proinflammatory cytokine synthesised by fibroblasts in the synovium and macrophages) and IL-6 (concentrations of which correlate with fever, disease activity, and platelet counts) are also thought to be important. If inhibition of these cytokines is not sufficient, other drugs that aim at T cell blockade and B cell depletion are available. Only etanercept (TNF-alpha receptor antagonist), adalimumab (anti-TNF-alpha antibody), abatacept (selective T-cell co-stimulation modulator) and tocilizumab (IL-6 receptor antibody) have been approved by the European Medicines Agency and the Food and Drug Administration for the treatment of JIA. Until now, also infliximab (anti-TNF-alpha antibody), anakinra (IL-1 receptor antagonist), canakinumab (anti-IL-1 antibody) and rilonacept (IL-1 receptor antagonist), though not approved, are available options or under investigation for the treatment of JIA. All of the above mentioned agents have been studied in randomized controlled clinical trials with inclusion of JIA patients.But after approval and sometimes off-label use in daily clinical practice, prospective observational studies are crucial to evaluate the longterm effectiveness and safety in a non-selected patient group. Furthermore, additional information with regard to the optimal use and the use in specific subgroups of patients is required. These studies are known as Phase IV post-marketing surveillance studies. Because of the long-term aspect and the requirements of studying a large population, such studies have for practical and financial reasons an observational character, as for example the Dutch national Arthritis and Biologics in Children (ABC) Register

Efficacy of biological agents in juvenile idiopathic arthritis: A systematic review using indirect comparisons

Objective Over the past decade, the availability of biological agents for the treatment of juvenile idiopathic arthritis ( JIA) has increased substantially. Because direct head-to-head trials comparing these agents are lacking, we indirectly compared their efficacy. Methods In a systematic review, all available efficacy data from randomised controlled trials performed in JIA with inclusion of biological agents were retrieved. Indirect between-drug comparisons (based on Bucher’s method) were conducted only if trials were comparable with regard to design and patients’ characteristics related to treatment outcome. Results We identified 11 randomised controlled trials. On the basis of the equality of the trials, six trials were grouped into two networks of evidence. Network 1 included withdrawal trials which evaluated etanercept, adalimumab and abatacept in polyarticular course JIA. Indirect comparisons identified no significant differences in short-term efficacy. Network 2 indirectly compared trials with a parallel study design investigating anakinra, tocilizumab and canakinumab in systemic JIA; no differences in comparative efficacy were identified. Although the two networks were constructed on the basis of comparability, small differences in trial design and case mix still existed. Conclusions Because of the small number of trials and the observed differences between trials, no definite conclusions could be drawn about the comparative effectiveness of the indirectly compared biological agents. Therefore, for now, the paediatric rheumatologist has to rely on observational data and safety, practical and financial arguments. Comparability of future trials needs to be improved, and head-to-head trials are required to decide on the best biological treatment for JIA