Comparative safety of JAK inhibitors versus TNF inhibitors in psoriatic arthritis: a real-world propensity score-matched cohort study

Background: Janus kinase inhibitors (JAKi) and tumor necrosis factor inhibitors (TNFi) demonstrate therapeutic efficacy in psoriatic arthritis (PsA), yet comparative real-world safety data remain limited. This study quantified adverse outcome risks between JAKi and TNFi in PsA patients. Methods: Retrospective cohort study utilized the TriNetX Global Collaborative Network electronic health records. Adults aged 18–99 years with PsA initiating JAKi or TNFi without prior exposure to the alternative class were identified. Cohorts underwent rigorous 1:1 propensity score matching on 42 baseline covariates, including inflammatory markers and indication-bias proxies. Incident adverse outcomes at 1–1825 days after treatment initiation were assessed using Kaplan–Meier analysis and absolute risk calculations. Results: Post-matching analysis included 2723 patients per cohort. Over a 5-year follow-up, JAKi initiation was associated with increased all-cause mortality 96 vs. 63 events; hazard ratio (HR) 2.012, 95% confidence interval 1.462–2.771, P = 0.048, herpes zoster (HR 1.888, P < 0.001), pneumonia (HR 1.380, P = 0.011), and sepsis (HR 1.421, P = 0.045). TNFi use demonstrated an increased risk of skin and soft tissue infections compared with JAKi (189 vs. 147 events; risk difference −0.017, P = 0.016). Rigorous adjustment eliminated a previously suspected signal for osteomyelitis. No significant differences were observed for major adverse cardiovascular events or venous thromboembolism. Conclusions: JAKi and TNFi exhibit distinct safety profiles in PsA. JAKi were associated with higher risks of mortality and severe or viral infections, whereas TNFi carried a higher skin and soft tissue infection risk. These findings emphasize the need for rigorous methodological adjustment in observational data and support individualized shared decision-making.