The response to TNF blockers depending on their comparator in rheumatoid arthritis clinical trials: the lessebo effect, a meta-analysis.

OBJECTIVE To compare the effect of the biological reference agents (infliximab, etanercept, adalimumab) in rheumatoid arthritis (RA) in pivotal superiority placebo-controlled trials (reference agent vs placebo) vs their effect in equivalence active comparator-controlled trials (reference agent vs biosimilar). METHODS The PubMed, EMBASE, Cochrane, databases were searched for randomized, double-blind, controlled trials up to March 2020 comparing a biological reference agent vs placebo or biosimilar. The study assessed the American College of Rheumatology (ACR) 20/50/70 responses of the reference agent in these groups (Reference-pbo and Reference-bs, respectively). The effect of the reference agent in both groups was estimated with 95% confidence intervals (95%CI), pooled using random-effects models and then compared using a meta-regression model. RESULTS We included 31 trials. The main characteristics of the population (disease duration and activity, % seropositivity and methotrexate dose) of the population in both groups were similar. The meta-analysis found a better ACR20 response to the biological originator in the Reference-bs group with a global rate of 70% (95%CI, 66-74) compared with 59% (95%CI, 55-62) in the reference-pbo group (p= 0.001). A significant difference was also found for ACR 50 [44% (95%CI, 39-50) vs 35% (95%CI, 31-39) respectively, p< 0.01]. CONCLUSION Effect of the reference biologic agent was better when compared with an active drug to a placebo. This could be linked to an increased placebo effect in active comparator-controlled studies or a nocebo effect in placebo-controlled studies. This effect can be called the Lessebo effect.