Background: Janus kinase inhibitors (JAKi) are effective for treating rheumatoid arthritis (RA), but post-marketing safety concerns have triggered regulatory warnings and updated guidelines. The impact of these communications on real-world prescribing remains unclear.

Objectives: To assess the impact of major regulatory safety warnings on the initiation, discontinuation, and switching patterns of JAKi in RA patients, using data from 12 national registries.

Methods: This observational study analyzed 55,365 treatment courses (12559 JAKi and 42806 other bDMARDs) from 40,019 adult RA patients between 2015 and 2024. Segmented regression models examined trends around eight major regulatory events. Logistic generalized estimating equations (GEE), adjusted for demographic, disease, and treatment variables, were used. Sensitivity and subgroup analyses, including at-risk populations (age ≥65 with cardiovascular risk factors), were conducted.

Results: JAKi use rose from <1 % in 2015 to >20 % by 2024, with slowdowns after the 2019 FDA and 2022 EMA warnings. Initiation trends significantly slowed after the first FDA warning and the publication of increased risks for MACE and cancer in early 2021, primarily affecting tofacitinib. Discontinuations surged following the EMA's 2022 warning, again mainly affecting tofacitinib. Upadacitinib initiations also declined, and discontinuations increased after the publication of the ORAL Surveillance trial. Baricitinib use appeared to be less impacted by the safety signals, while filgotinib use steadily increased. Among the at-risk population, the rate of JAKi discontinuation significantly rose after the 2019 EMA warning.

Conclusions: Regulatory safety communications significantly influenced real-world JAKi prescribing patterns. Tofacitinib was most affected through both declines in initiation and increases in discontinuation.