Cycling Janus kinase inhibitors versus switching to biological disease-modifying anti-rheumatic drugs in rheumatoid arthritis with inadequate Janus kinase inhibitor response: a systematic review and meta-analysis

Objective: Current guidelines recommend switching to a biologic disease-modifying anti-rheumatic drug (bDMARD) after Janus kinase inhibitor (JAKi) failure in rheumatoid arthritis, assuming a mechanistic switch is required.However, real-world evidence on JAKi cycling remains inconsistent.We compared drug retention and efficacy between JAKi cycling and bDMARD switching, and explored subgroups that may benefit from each approach.Methods: We performed a systematic review and meta-analysis of observational cohorts and clinical trials, including data from the JAK-pot, FIRST, and ANSWER registries.The primary outcome was drug discontinuation hazard ratio (HR).Secondary outcomes included remission and changes in disease activity (CDAI/DAS28).Analyses were stratified by failure reason (primary non-response vs. secondary failure), JAKi generation, and subsequent bDMARD class (tumor necrosis factor inhibitor [TNFi] vs. non-TNFi).The review was registered in PROSPERO (CRD420261295330).Results: Five studies (4,373 treatment courses) were included.Cycling to a second JAKi showed significantly better retention than switching to a bDMARD (pooled HR 0.77, 95% confidence interval [CI] 0.64~0.92).The benefit was greatest in secondary failure (HR 0.70, 95% CI 0.55~0.88).Switching from a first-generation pan-JAKi to a second-generation selective JAK1 inhibitor had the lowest discontinuation risk (HR 0.53, 95% CI 0.28~0.95).However, switching to TNFis or non-TNFi biologics resulted in inferior retention rates compared to JAKi cycling.Conclusion: After initial JAKi failure, evidence from this meta-analysis suggests an association with better drug retention when cycling to a second JAKi compared to switching to a bDMARD, particularly in patients with secondary failure.