The placebo response in clinical trials for rheumatoid arthritis appears to have grown over the last two decades with patients exhibiting significant improvements in pain scores with placebo treatment.
A review of 32 clinical trials of common rheumatoid arthritis treatments found statistically significant increases in placebo responses for ACR50 and ACR70.
“There has been a rise in the placebo response in RA clinical trials over the last two decades. Shifting rheumatoid arthritis phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon,” researchers wrote this month in The Journal Rheumatology.
The report, which was led by Katie Bechman, King’s College London, is based on a review of a database search for research clinical trials of biologics or synthetic disease-modifying antirheumatic drugs (DMARD) for rheumatoid arthritis (RA). The review did not include patients who had not taken conventional synthetic DMARDs or did not receive background csDMARD therapy.
The final analysis included 32 clinical trials conducted between 1999 and 2018. It included 15 trials on anti–tumor necrosis factor therapies; four for tocilizumab, two for abatacept, two for rituximab and nine studies on Janus kinase inhibitors. There were no significant trends in age or sex of patients in the placebo arm. The study found that disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline, all significantly declined over time. The increases in placebo remained significant after controlling for potential confounders.
“Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit,” authors wrote.
Other researchers have examined this phenomenon, including N. Abdullah of the University of Nottingham, United Kingdom, who in 2015 conducted a systematic review and meta-analysis of 165 research clinical trials for NSAIDS, DMARDS, biologics and complementary and alternative medicines.
The review included 17,894 patients. Researchers found that placebo treatment was effective in relieving pain. For example, the placebo effect size of NSAID treatment was 0.30; 0.34 for biologics; 0.24 for DMARDS; and 0.27 for complimentary and alternative medicines. Placebo was also significantly effective in improving tender joint counts, swollen joint counts and function.
The placebo effect was not shown to be consistent in either study as effects were different with different treatments, different study designs and patient characteristics. Nonetheless, it appears to have a tangible effect on patient outcomes.
“Placebo is effective in pain reduction in RA and also improves other outcomes. This contextual effect accounts for up to 40-60% of the therapeutic benefit observed in research clinical trials of treatments in people with RA,” N. Abdullah wrote.