The work was based on data from 19 clinical trials involving more than a half-dozen biologics. It showed that while the benefit-risk balance of biologics was generally positive, the net benefit differed by JIA subtype and trial design. In addition, the findings highlighted the importance of assessing these therapies’ net benefit, regardless of the frequency of side effects reported in the trials.
The study, “The benefit–risk balance for biological agents in juvenile idiopathic arthritis: a meta-analysis of randomized clinical trials,” was published in the journal Rheumatology.
A type of disease-modifying antirheumatic drugs (DMARDs), biological therapies are a standard treatment option for people with JIA, particularly for those who are intolerant or do not respond to conventional (synthetic) DMARDs, such as methotrexate.
Most trials and meta-analyses — which perform a combined analysis of multiple other studies — evaluate a therapy’s effectiveness (benefit) and safety (risk) separately. As such, a treatment’s benefit-risk balance may not be straightforward to determine and is difficult to assess with current tools.
Now, researchers in France, along with a colleague in Paraguay, set out to evaluate the benefit-risk balance of biological therapies in people with JIA.
The team analyzed published studies through March 2019, comparing biologics — alone or in combination with conventional DMARDs — to a placebo or standard treatment in JIA patients younger than age 19.
From a total of 113 studies assessed for eligibility, 18 met the intended criteria and were included in the meta-analysis, covering 19 clinical trials and a total of 1,458 JIA patients with systemic, oligoarticular, polyarticular, and enthesitis-related JIA.
Among biologics, some trials evaluated TNF inhibitors — Enbrel (etanercept, by Amgen), Humira (adalimumab, by AbbVie), and infliximab (marketed as Remicade, among others) — which target an inflammation-causing substance called tumor necrosis factor or TNF. Others assessed treatments that block the inflammatory molecules interleukin 1, or IL-1 — Kineret (anakinra, by Sobi), Ilaris (canakinumab, by Novartis), and Arcalyst (rilonacept, by Regeneron Pharmaceuticals) — and IL-6, namely tocilizumab (marketed as Actemra by Genentech and as RoActemra in Europe by Roche). The effects of Orencia (abatacept, by Bristol-Myers Squibb), a suppressor of the activity of immune T-cells, also was analyzed
Trials evaluating IL-1 suppressors were conducted exclusively in sJIA patients. However, sJIA patients were mostly absent in studies investigating TNF inhibitors.
Of the clinical studies, 11 were parallel trials involving 754 patients, and eight were withdrawal trials that included 704 patients. Parallel trials assess a therapy’s effectiveness in achieving clinical remission while withdrawal trials evaluate the maintenance of remission and inactive disease in responders after switching or not to a placebo. Given the different study goals, the team analyzed the two groups of trials separately. They also divided JIA types into systemic and non-systemic.
The net benefit of each therapy was determined as the risk difference of effectiveness subtracted by the risk difference of safety. Effectiveness was assessed using the criteria from the American College of Rheumatology pediatric score 30%, or ACRPedi 30, which means a clinical improvement of at least 30% in three or more variables of JIA. Meanhwhile, safety was evaluated through the occurrence of serious adverse events.
The results showed that the net benefit differed among JIA subgroups and trial design.
In parallel trials, the net benefit ranged from 22.8% with Arcalyst to 70.3% with Ilaris in sJIA patients, and from 2.4% with Humira to 17.6% with Enbrel in those with non-systemic JIA. In withdrawal trials, the benefit ranged from 32.3% with Ilaris to 58.2% with tocilizumab in sJIA patients, and from 2.4% (Enbrel) to 36.7% (Orencia) in people with non-systemic JIA.
“The results suggest that a greater number of patients experienced therapeutic success without [serious adverse events] in the [systemic onset] JIA category compared with the BAs [biologic therapies] for non-systemic JIA categories,” the researchers wrote.
In addition, these findings indicated that the biologics’ safety was higher in withdrawal trials than in parallel ones.
“Despite their exploratory nature, our meta-analyses suggest that quantification of the benefit–risk balance of BAs is necessary regardless of the frequency of adverse events,” the team added.
However, the investigators added that not scoring serious adverse events, the short-term follow-up, and the relatively limited number of participants were limitations of their study. They noted that these factors may have affected the results.
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