Patients taking Janus kinase (JAK) inhibitors for immune-mediated inflammatory diseases (IMIDs) face no greater risk of serious infections, malignant neoplasm or major cardiovascular adverse events (MACE) compared to those using tumor necrosis factor (TNF) antagonists, according to a new systematic review and meta-analysis. The findings have been published in JAMA Network Open. JAK inhibitors served as an important treatment option, offering rapid and targeted immunomodulation in IMIDs. However, regulatory agencies modified the label for JAK inhibitors based on the ORAL Surveillance trial. The trial focused on older high risk patients with rheumatoid arthritis, limiting the applicability of the trial findings to broader population. Given the lack of generalizability of the trial, the researchers conducted a systematic review and meta-analysis of head to head comparative effectiveness studies of JAK inhibitors and TNF antagonist for serious infections, malignant neoplasms, major adverse cardiovascular events (MACE) and venous thromboembolism (VTE) to provide a comprehensive safety assessment across IMIDs. For the study, researchers searched the Ovid Medline, Ovid EMBASE and Web of Science databases from inception to June, 2025. The study included head-to-head comparative studies of adults (>18 years) with IMIDs (rheumatoid arthritis, inflammatory bowel disease, psoriasis or psoriatic arthritis, and spondyloarthropathy) treated with either JAK inhibitors or TNF antagonists. Only studies with sample sizes of>500 were included. Randomized clinical trials and comparative observational studies were considered. The review followed PRISMA guidelines. The primary outcome was risk of serious infections (requiring hospitalization, intravenous antibiotics, or therapy cessation or causing death), malignant neoplasms (excluding non-melanoma skin cancer), MACE (myocardial infarction, stroke or cardiovascular mortality), and Venous thromboembolism (pulmonary embolism or deep venous thrombosis). 42 head to head comparative effectiveness studies (41 published and 1 unpublished), including 813881 patients (128705 treated with JAK inhibitors compared with 685176 treated with TNF antagonists) were involved in the review following a detailed literature review. The key findings from the study include: This comprehensive study provides a strong evidence thatJAK inhibitors do not pose a significantly higher riskofserious infections, malignant neoplasms, orMACEcompared to TNF antagonists in the treatment of immune-mediated inflammatory diseases (IMIDs). However, amodestly increased risk of venous thromboembolism (VTE)was observed with JAK inhibitors, particularly in patients withrheumatoid arthritis. These findings suggest that while JAK inhibitors remain a valuable treatment option offering rapid immunomodulation,careful patient selection and VTE risk assessmentare warranted, especially in higher-risk subgroups. The findings also call for revisiting the strict regulatory guidelines for the use of these agents. Reference:Solitano V, Ahuja D, Lee HH, Gaikwad R, Yeh KH, Facciorusso A, Singh AG, Ma C, Ananthakrishnan AN, Yuan Y, Singh N, Jairath V, Singh S. Comparative Safety of JAK Inhibitors vs TNF Antagonists in Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2025 Sep 2;8(9):e2531204. doi: 10.1001/jamanetworkopen.2025.31204. PMID: 40928778; PMCID: PMC12423869.