ObjectiveOral Janus kinase inhibitors (JAKi) represent an effective strategy for rheumatoid arthritis (RA) treatment. A recent study on patients with a pre-existing risk supported that tofacitinib is associated with higher incidence of cardiovascular and neoplastic events compared to Tumor Necrosis Factor α inhibitors. Given the apparent discrepancy between these data and real-life experience we aimed to investigate the safety and efficacy of the available JAKi in a multicenter cohort.MethodsWe retrospectively evaluated patients with RA who ever received one JAKi (tofacitinib, baricitinib, upadactinib, filgotinib) from four tertiary care centers in Milan, Italy. Outcomes related to JAKi safety were recorded, particularly as major cardiovascular events as well as adverse events of special interest (AESI) which included serious infections, opportunistic infections, venous thrombo-embolism, herpes zoster infections, liver injury, malignancies, and deaths while retention rates were also calculated. Further analyses included patients fulfilling the risk factors suggested to influence tofacitinib safety.ResultsSix hundred-eighty-five patients were included and received baricitinib (48%), tofacitinib (31%), upadacitinib (14%), or filgotinib (7%), in 47% as first-line innovative treatment prior to a biologic. Out of a total of 1137 patient-years of observation, we recorded 1 stroke, 123 (18%) AESI, including 3 deaths, all due to severe infections. Among patients with a higher cardiovascular risk, we observed a higher frequency of adverse events of special interest (23%).ConclusionOur real-life data confirm that JAKi are effective and carry a low risk of AESI, especially in patients that do not display cardiovascular risk factors at baseline. Our study could not identify differences between molecules and different profiles should be defined in larger prospective cohorts.