Cardiovascular and Thromboembolic Risk of Janus Kinase Inhibitors Compared to Other Disease-Modifying Drugs in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

<b>Background/Objectives</b>: Janus Kinase inhibitors (JAKi) are an effective treatment option for rheumatoid arthritis (RA); however, emerging concerns regarding cardiovascular and thromboembolic risk have prompted further investigation. We conducted a systematic review and meta-analysis to compare the risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) in patients receiving JAKi versus other disease-modifying anti-rheumatic drugs (DMARDs). <b>Methods:</b> Following PRISMA 2020 guidelines and a preregistered protocol, we systematically searched PubMed, Embase, and the Cochrane Library. Observational studies and randomized controlled trials (RCTs) reporting MACE or VTE among adults with RA treated with JAKi or comparator DMARDs were included. Hazard ratios (HRs) from observational studies and odds ratios (ORs) from RCTs were pooled using fixed- or random-effects models depending on heterogeneity. A sensitivity analysis was conducted for participants aged ≥ 65 years. <b>Results:</b> Twenty-five observational studies and eight RCTs were included. Across observational studies, the pooled HRs for MACE showed no significant difference between JAKi and other DMARDs, HR = 0.98, 95% CI = 0.85-1.13. This finding remained consistent in individuals aged ≥ 65 years. No increase in MACE risk was observed across RCTs, OR = 1.27, 95% CI = 0.89-1.81. In contrast, JAKi use was associated with a significantly higher risk of VTE in the observational studies (HR = 1.32, 95% CI = 1.08-1.61) but not in the RCTs (OR = 1.69, 95% CI = 0.94-3.02). <b>Conclusions:</b> JAKi use does not appear to increase the risk of MACE compared to DMARDs, including in older adults, but may be associated with a higher risk of VTE. These findings highlight the importance of a personalized approach when considering JAKi therapy, incorporating structured cardiovascular and thrombotic risk assessment, patient preferences, and mitigation of modifiable risk factors.