Time course of the placebo response and associated factors in clinical trials of biologic agents for ankylosing spondylitis

Aims To characterize the time course and influencing factors of placebo response in randomized trials of biologic and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) for ankylosing spondylitis (AS).Patients and Methods We systematically searched major electronic databases (up to June 14, 2024) for randomized double-blind placebo-controlled trials of biologics or Janus kinase inhibitors in AS. Model-based meta-analysis with nonlinear mixed-effects modeling was conducted to pool placebo-arm ASAS20 (≥20% improvement by Assessment of SpondyloArthritis International Society criteria) and ASAS40 (≥40% improvement) response trajectories, using an exponential rise-to-maximum model with covariate screening and model validation.Results Thirty-eight trial arms from 36 trials (3046 placebo-treated participants) were included. The estimated maximum response (Pmax) was 31.1% for ASAS20 (90% of Pmax reached at 6.5 weeks) and 18.6% for ASAS40 (90% of Pmax reached at 17.0 weeks). ASAS20 Pmax increased by 2.7% per publication year. Smaller trials, no background therapy, lower male proportion, and lower baseline HLA-B27 positivity were associated with higher placebo response.Conclusions The AS placebo response, particularly for ASAS20, shows a significant upward secular trend. This model provides a quantitative benchmark for trial design, anomalous placebo responses identification, and interpreting efficacy in trials lacking a concurrent placebo arm.