Abstract
OBJECTIVE: To systematically characterize the complete phenotypic spectrum of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome through comprehensive analysis of all published cases since its discovery in 2020. METHODS: We conducted a systematic review following PRISMA guidelines across five databases. Studies reporting genetically confirmed VEXAS cases were included. To minimize duplicate counting while maximizing data utility, we applied stringent inclusion criteria. Prevalence estimates were calculated using Wilson score intervals. Results were discussed, with secondary analysis focusing on rare manifestations of the disease, and clinical recommendations as appropriate. RESULTS: Analysis of 720 patients from 33 case reports and 21 case series across 32 countries revealed cutaneous involvement as the predominant manifestation (81.8%, 95% CI: 78.8-84.5%), followed by constitutional symptoms (69.4%, 95% CI: 66.0-72.7%) and respiratory disease (61.3%, 95% CI: 57.6-64.7%). Joint involvement (47.3%, 95% CI: 43.5-51.2%), ocular disease (44.3%, 95% CI: 40.5-48.2%) and venous thromboembolism (41.8%, 95% CI: 38.3-45.4%) were also common. Myelodysplastic syndrome occurred in 35.8% (95% CI: 32.3-39.4%) of patients. Previously under-recognized manifestations included significant respiratory involvement and a broad spectrum of vascular complications. Rare but clinically significant features included cardiac involvement (7.6%), renal disease (7.0%) and CNS manifestations (7.8%). CONCLUSION: This systematic review provides the most comprehensive characterization of VEXAS syndrome to date, establishing robust prevalence estimates across all organ systems and identifying rare manifestations with important clinical implications. These findings will facilitate earlier diagnosis, inform monitoring strategies and guide future research priorities.