Placebo and nocebo responses in randomized controlled trials of non-tumor necrosis factor biologics and Janus kinase inhibitors in patients with active rheumatoid arthritis showing insufficient response to tumor necrosis factor inhibitors: A meta-analysis

Objective This study evaluated the frequency and magnitude of placebo and nocebo responses in placebo-controlled RCTs of non-tumor necrosis factor (TNF) biologics and Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) patients with insufficient response to TNF inhibitors. Methods A meta-analysis on rates of placebo response, adverse effects (AEs), severe AEs (SAEs), and withdrawal due to AEs in placebo-controlled RCTs of non-TNF biologics and JAK inhibitors in patients with RA and an insufficient response to TNF inhibitors was conducted. Results In 9 RCTs containing 3442 patients the pooled incidence of ACR20 response rate in placebo-treated patients was 22.1 (95% CI 16.4-29.1%) and 27.9% (95% CI 24.5-31.6%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong negative correlation was observed between ACR20 response and AE rates in the placebo arm, indicating that the greater the placebo response, the weaker the nocebo response (r = -0.762, P = 0.017). Strong positive correlation was observed between ACR20 response in the placebo and active comparator arms, indicating that the greater the placebo response, the greater the treatment response (r = 0.737, P = 0.003). The pooled estimate in placebo-treated patients with >= 1 AE was 71.8 (95% CI 57.4-82.7%) and 58.7% (95% CI 52.8-64.3%) in RCTs of non-TNF and JAK inhibitors, respectively. The pooled estimate in placebo-treated patients withdrawing due to an AE was 3.8 (95% CI 2.7-5.3%) and 4.0% (95% CI 2.7-6.0%) in RCTs of non-TNF and JAK inhibitors, respectively. Strong positive correlation was observed between AE rates in the placebo and active arms, indicating that the greater the nocebo response, the stronger the AE rate in the active arm (r = 0.855, P = 0.003). Conclusion There were higher placebo and less nocebo effects of JAK vs. non-TNF inhibitors in RA patients with an insufficient response to TNF inhibitors, and the greater the placebo response, the weaker the nocebo response and the greater the efficacy.