AB0199 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
Authors: Y. H. Lee, G. G. Song
Journal: Annals of the Rheumatic Diseases (2021)

Background: Placebo and nocebo responses have important consequences for the development of pharmaceutical drugs and the design of randomized controlled trials (RCTs). They can lead to the incorrect measurement of treatment-related efficacy and adverse effects (AEs). Objectives: The goal of this study was to evaluate 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 patients with rheumatoid arthritis (RA) showing an insufficient response to TNF inhibitors. Methods: We performed a meta-analysis on the rates of placebo response, AEs, severe AEs (SAEs), and withdrawal owing to AEs in placebo-controlled randomized clinical trials (RCTs) of non-TNF biologics and JAK inhibitors in patients with RA showing an insufficient response to TNF inhibitors. Results: Nine RCTs contained a total of 3,442 patients (1,840 experimental subjects and 1,602 controls). The pooled incidence of an 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 inhibitors and JAK inhibitors, respectively. A strong negative correlation was observed between drug efficacies (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). A strong positive correlation was observed between drug efficacies (ACR20 response) in the placebo and active comparator, 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 at least one AE was 71.8% (95% CI 57.4–82.7%) and 58.7% (95% CI 52.8–64.3%) in RCTs of non-TNF inhibitors and JAK inhibitors, respectively. The pooled estimate in placebo-treated patients who withdrew from treatment owing 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 inhibitors and JAK inhibitors, respectively. A 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: The frequency of the placebo and nocebo responses was 22.1% vs. 27.9% and 71.8% vs. 58.7% in placebo-controlled RCTs of non-TNF inhibitors and JAK inhibitors for RA, respectively, and the greater the placebo response, the weaker the nocebo response and the greater the efficacy. References: [1]Mitsikostas DD, Chalarakis NG, Mantonakis LI, Delicha EM, Sfikakis PP. Nocebo in fibromyalgia: meta-analysis of placebo-controlled clinical trials and implications for practice. Eur J Neurol 2012;19:672-80. [2]Kravvariti E, Kitas GD, Mitsikostas DD, Sfikakis PP. Nocebos in rheumatology: emerging concepts and their implications for clinical practice. Nat Rev Rheumatol 2018;14:727-40. [3]Colloca L, Barsky AJ. Placebo and Nocebo Effects. N Engl J Med 2020;382:554-61. Disclosure of Interests: None declared