Summary of AHRQ’s Comparative Effectiveness Review of Disease-Modifying Antirheumatic Drugs for Children with Juvenile Idiopathic Arthritis

Abstract

JIA is a chronic inflammatory disease affecting approximately 300,000 children and adolescents in the United States.1 Initially manifesting with inflammation, swelling, pain, and stiffness of the joints, the disease as no apparent or known cause. JIA is a clinical diagnosis based on several actors including the number of affected joints and the involvement of other tissues (e.g., the skin and lymphoid tissues), and JIA has 7 categories: systemic-onset arthritis, oligoarthritis, rheumatoid-factor positive polyarthritis, rheumatoid-factor negative polyarthritis, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis.2 Complete remission and resolution of disease activity are the ultimate treatment goals; however, there is no present cure. Inhibition of inflammation, prevention of joint damage, and promotion of a high level of functioning are the immediate goals of treatment. Even with treatment, patients with JIA continue to experience disease activity, joint destruction, suboptimal function, and impaired quality of life, all of which extend into adulthood.3 JIA can be severely debilitating and places a heavy physical and psychological burden on children and families affected by the disease. Methotrexate is a nonbiologic DMARD with an unknown mechanism of action. Methotrexate has been used for so long in the treatment of JIA that it is frequently considered a part of conventional treatment; the evidence shows that methotrexate is superior to conventional treatment with NSAIDsand/or intra-articular corticosteroids. The introduction of newer biologic DMARDs has spawned optimism that treatment will increasingly lead to improved outcomes for JIA, but the evidence is insufficient to support superiority over methotrexate. There is moderate evidence to support the claim that continued treatment from 4 months to 2 years with a biologic DMARD in children who have responded to a biologic DMARD decreases the risk of a flare. However, the safety of biologic DMARDs for long-term use has not been determined and may be associated with the developmentof cancer. The association between tumor necrosis factor (TNF) alpha inhibitors and potential increased risk of lymphoma caused the U.S. Food and Drug Administration (FDA) to place boxed warning labels on biologic DMARDs including etancercept, infliximab, and adalimumab. The effectiveness of the DMARDs appears to vary among categories of JIA and the treatment history of individual patients. Except for methotrexate, there is insufficient evidence to support selection of a specific drug or drug class over another in the treatment of JIA. The AHRQ review examines the scientific literature on DMARDs used in children with JIA in an effort to synthesize what is known about the subject, and the comprehensive review identifies important research gaps in the literature that need to be addressed. Only 8 studies (in 9 publications) were rated "good quality" by the AHRQ investigators.

Retrospective data collection of psoriasis treatment with fumaric acid esters in children and adolescents in Germany (KIDS FUTURE study)

“…Thus, the prescribing doctor is in a legal gray area, especially because there is only very limited safety data for long‐term treatment of psoriasis in this age group . With respect to children and adolescents, experience with conventional systemic therapeutic agents also used in the treatment of psoriasis comes from other approved indications such as juvenile arthritis and Crohn's disease, as well as following organ transplants . Thus, according to a German consensus recommendation, children and adolescents with psoriasis requiring systemic therapy should initially be treated with methotrexate and cyclosporine, or alternatively fumaric acid esters (FAEs) and retinoids .…”

Systemic-Onset Juvenile Idiopathic Arthritis

“…Methotrexate has been a mainstay of therapy with adequate effi cacy for many children [ 19 ]. It has been the most commonly used secondline agent for children with JIA of all subtypes for many years but has been less effective in SoJIA than in other subtypes.…”

Advances from clinical trials in juvenile idiopathic arthritis

“…The patient populations in randomized clinical trials are often much more homogeneous than standard clinical populations and these trials seldomly compare active treatments with each other (especially in patients with JIA) because of the numbers of patients needed to do so. A 2012 formal literature review 46 focused on the comparative effectiveness of biologic agents and traditional DMARDs; the authors concluded that the publications on JIA studies are robust and reliable enough to show that the biologic agents tested in randomized trials decreased the rate of flares, and that methotrexate was superior to other conventional non biologic therapies. 46 However, the published literature was insufficient to address the effects of the treatments on radiologic progression or health status, the comparative rates and types of adverse events, and the precise determination of the risk:benefit ratio for each therapy.…”

“…A 2012 formal literature review 46 focused on the comparative effectiveness of biologic agents and traditional DMARDs; the authors concluded that the publications on JIA studies are robust and reliable enough to show that the biologic agents tested in randomized trials decreased the rate of flares, and that methotrexate was superior to other conventional non biologic therapies. 46 However, the published literature was insufficient to address the effects of the treatments on radiologic progression or health status, the comparative rates and types of adverse events, and the precise determination of the risk:benefit ratio for each therapy. 46 This formal review of the literature was demanding but highlights areas to address in future studies.…”

“…46 However, the published literature was insufficient to address the effects of the treatments on radiologic progression or health status, the comparative rates and types of adverse events, and the precise determination of the risk:benefit ratio for each therapy. 46 This formal review of the literature was demanding but highlights areas to address in future studies. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) has since developed standardized treatment plans for new-onset systemic JIA 47 and poly articular JIA (unpublished).…”