Canakinumab, rilonacept, and tocilizumab have been added to the list of medications recommended by the American College of Rheumatology for the treatment of systemic juvenile idiopathic arthritis, although no specific dosages or durations are listed. Secondary screening for tuberculosis in patients treated with biologics is also included in the updated guidelines.
Initially published in 2011, the American College of Rheumatology’s Guidelines for Systemic JIA were revised to include "data from randomized trials of new IL-1 [interleukin-1] inhibitors and IL-6 inhibitors," wrote lead coauthors Dr. Sarah Ringold and Dr. Pamela F. Weiss and their colleagues. "The overarching objective of this project was to update the 2011 ACR recommendations for the use of nonbiologic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs," they also wrote. Canakinumab, rilonacept, and tocilizumab are biologic DMARDs.
The recommendations are based on a systematic review of 1,226 clinical scenarios that were developed according to the RAND/University of California, Los Angeles (UCLA) appropriateness methodology. The authors include an international panel of JIA experts, an expert evidence-based medicine evaluator, and the parent of a child with systemic JIA. Biologic combination therapies were not considered due to safety concerns and a lack of data, the authors wrote. Appropriateness was defined according to whether the benefits exceeded the risks when rated on a scale from 1 to 9, with 1-3 considered "inappropriate," 4-6 "uncertain," and 7-9 "appropriate."
Evidence was then rated according to the Oxford Centre for Evidence-Based Medicine, as was the case for the original guidelines. The scale is from A through D, with A being the highest level of evidence, based on randomized controlled trials; B level is derived from nonrandomized studies; C-level evidence comes from uncontrolled trials; and D-level evidence is that based on expert opinion.
In all, the panel decided upon far more recommendations at the C and D levels, and advised caution when applying its A-level recommendations, such as the use of the IL-1 receptor antagonist anakinra after treatment with glucocorticoid (GC) monotherapy in children with active systemic features, because the study sample, while assigned randomly, numbered only 24 (Arthritis Rheum. 2013;65:2499-2512).
"The goal of this project was not to provide strict recommendations for therapy, but to provide a set of recommendations that physicians could apply to their patients. The timing of these recommendations is appropriate, as canakinumab and tocilizumab are recently FDA-approved and physicians are learning how to incorporate them into their practice. Given the nature of the field, we would not expect there to be significantly more data generated over the next year that would lead to different recommendations. As in the case of any recommendations, they will need reconsideration in the future as new therapies and new data become available," Dr. Ringold of Seattle Children’s Hospital wrote in an e-mail.
The panel evaluated scenarios delineated by three discrete phenotypes. The first was systemic JIA with active features and various degrees of synovitis. Instead of considering the combinations of symptoms such as fever and evanescent rash, panel members were asked to review the treatments in patients with a physician global assessment (MD global) of less than 5 joints and 5 or greater joints on a 10-point scale, and by active joint count (AJC) assessment of 0 joints, 1-4 joints, or more than 4 joints.
The second scenario included systemic JIA with active synovitis but not active systemic features. Treatments were rated for appropriateness based on the total number of active joints of 4 or less or 4 or greater. The third phenotype was systematic JIA with features of concern for macrophage activation syndrome (MAS). The update’s authors wrote that the requisite manifestations considered for MAS were "left intentionally broad given the lack of validated classification criteria for MAS." They also excluded children who were admitted to intensive care.
A fourth scenario was developed by the authors to address repeat tuberculosis (TB) screening across all JIA phenotypes where the patient was receiving biologic agents. In that case, evaluators were asked to consider the appropriateness of the various screening approaches.
Canakinumab, which targets interleukin-1 beta (IL-1B) and was approved for use in systemic JIA by the Food and Drug Administration (FDA) in May of this year, was recommended at level A for patients with continued disease activity after treatment with GC monotherapy, methotrexate, or leflunomide. Treatment with canakinumab following anakinra was rated level B, and the use of canakinumab after tocilizumab, irrespective of the MD global and AJC, was considered level C.
Canakinumab was also recommended for patients with an MD global of 5 or greater regardless of the AJC, and even if there was prior monotherapy with NSAIDs. The drug received a level B recommendation for an AJC assessment of more than 4 joints, but only after a trial of a DMARD plus anakinra or tocilizumab, or a DMARD plus a tumor necrosis factor–alpha inhibitor. A level C recommendation was assigned to canakinumab after abatacept for patients with an AJC assessment of more than 4 joints. The authors wrote that use of canakinumab was "uncertain, with the exception of patients with an MD global [less than] 5 who had received no prior therapy, GC monotherapy, or calcineurin monotherapy, in which case it was inappropriate (level D)."