Increase in Placebo Response From 1999 to 2018 in Rheumatoid Arthritis

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Researchers assessed the change in placebo responses over time in rheumatoid arthritis randomized placebo-controlled trials for drug licensing authorization.

An increase in placebo response across rheumatoid arthritis (RA) clinical trials in the last 2 decades demands heightened awareness from investigators, particularly when evaluating novel agents against established therapies, according to study results published in Journal of Rheumatology.

Investigators of the study sought to determine whether placebo response has been increasing across randomized placebo-controlled trials (RCTs) in RA that are used for drug licensing authorization. They searched the Cochrane Controlled Trials Register databases to identify all biologic and targeted synthetic disease-modifying antirheumatic drugs currently licensed for treatment.

A total of 1828 clinical trials were identified, of which 32 met the inclusion criteria. Overall, 15 RCTs evaluated the use of antitumor necrosis factor therapy (adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab) and the remaining trials evaluated tocilizumab, abatacept, rituximab, and Janus kinase inhibitors. The studies were published between 1999 and 2018; median time to primary outcome was 24 weeks (range, 8-52 weeks), with a shortened placebo duration over the last 20 years (β, -0.44 [95% CI, -0.87 to -0.004]; P =.048).

Across the placebo arms, the median number of patients was 128 (interquartile range [IQR], 66-212), with a mean age of 53±2 years; 79% of patients were women. No significant trends in the age or sex of patients in the placebo arm were noted (P =.56 and P =.39, respectively) during the study period. Mean disease duration was 8.7±2 years, except for the 2 studies that recruited patients with early RA.

Researchers did not note any significant trends in conventional synthetic disease-modifying antirheumatic drugs exposure. They observed that recent studies were more likely to include a larger percentage of patients with previous exposure to biologics. Before 2008, the average percentage exposure was less than 1% compared with 4% from 2008 onward. Significant trends were noted in terms of baseline disease activity over time, with reduction in tender joint counts (median, 28 [IQR, 24-30]; P =.02), swollen joint counts (median, 17 [IQR, 15-21]; P =.003), and Disease Activity Score in 28 Joints-Erythrocyte Sedimentation Rate (mean, 6.47±0.31; P =.001).

Across placebo arms, the median percentage of patients who achieved American College of Rheumatology 20% Response (ACR20) was 31% (IQR, 25%-39%); median ACR50 response was 10% (IQR, 8%-16%), and ACR70 response was 3% (IQR, 2%-5%). Based on placebo arm size, there was a statistically significant increase in placebo ACR50 and ACR70 responses between 1999 and 2018 (β, 0.39 and 0.17; P =.03 and P =.02, respectively). Excluding 1 trial with an outlier, ACR70 response did not alter research findings, although ACR20 trends did become statistically significant (β, 0.70, P =.04).

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After adjustment for age, sex, disease duration, baseline tender and swollen joint count, C-reactive protein, and time to primary outcome, changes in the ACR50 and ACR70 responses remained significant.

“It is essential that we improve our understanding of the mechanisms behind this phenomenon,” the researchers concluded. “A rising placebo response has important implications when comparing the efficacy of treatments across clinical trials, including in network [meta-]analyses.”


Bechman K, Yates M, Norton S, Cope AP, Galloway JB. Placebo response in rheumatoid arthritis clinical trials. J Rheumatol. 2020;47(1):28-34.