Real-World Safety of JAK Inhibitors in Skin Immune-Mediated Inflammatory Diseases: Boxed Warning Outcomes from a...

Janus kinase inhibitors (JAKis) have emerged as effective treatments for several skin immune-mediated inflammatory diseases (IMIDs). However, safety concerns have been raised due to boxed warnings from rheumatoid arthritis trials, and whether these risks apply to skin IMIDs remains uncertain. This multinational retrospective cohort study used the TriNetX database to compare the real-world safety of JAKis and conventional immunomodulators (cIMs) in patients aged 12 years or older with skin IMIDs (psoriatic disease, atopic dermatitis, or alopecia areata). Patients newly prescribed JAKis (tofacitinib, upadacitinib, deucravacitinib, baricitinib, abrocitinib, or ritlecitinib) were propensity score-matched (1:1) with those prescribed cIMs (methotrexate or cyclosporine) based on demographics, baseline skin IMIDs, and comorbidities, yielding 17,068 matched patients. Over 2 years, the JAKi cohort showed lower incidences of all-cause mortality (0.28% vs. 0.62%; P = 0.015) and major adverse cardiovascular events (MACE; 1.15% vs. 1.95%; P = 0.005) than the cIM cohort, corresponding to reduced risks (mortality: HR, 0.47; 95% CI, 0.25-0.88; MACE: HR, 0.63; 95% CI, 0.46-0.88). Risks of venous thromboembolism (HR, 0.80; 95% CI, 0.43-1.48) and malignancy (HR, 0.85; 95% CI, 0.63-1.16) were not increased. Subgroup analyses, including older adults and those with cardiometabolic risk factors, showed no signal of increased risk, with consistent findings across available agent-level and sensitivity analyses. These results suggest that, over 2 years, JAKis are not associated with increased risks of mortality, MACE, venous thromboembolism, or malignancy compared with conventional systemic agents in patients with skin IMIDs.