Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described adult-onset autoinflammatory disorder characterised by systemic inflammation and bone marrow dysfunction, causing severe disease and significant mortality. Though initially thought rare, recent population studies suggest a prevalence of approximately 1 in 4,000 men over 50 years old. Since its discovery in 2020, numerous case reports and series have documented diverse clinical manifestations, but a comprehensive analysis of the complete phenotypic spectrum has not been performed. Now, five years after its initial description, sufficient cases have accumulated for meaningful analysis — a crucial step toward establishing the diagnostic framework required for clinical trials and the development of targeted therapies.
Objectives: To systematically characterise the complete phenotypic spectrum of VEXAS 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 (PubMed, Embase, Web of Science, Scopus, Cochrane). The search strategy included comprehensive terms: VEXAS OR (SOMATIC AND UBA1) OR (VACUOLES AND E1 AND X-LINKED AND AUTOINFLAMMATORY AND SOMATIC). Studies were eligible if they included adult patients with genetically confirmed VEXAS syndrome and contained original clinical data. Initial screening identified 1,717 articles. After removing duplicates and applying eligibility criteria, 235 articles underwent full-text review. To minimise duplicate counting while maximising data utility, we applied a stringent inclusion criterion. We excluded case reports preceding larger case series (n=95), studies from same country/institute with larger available series (n=52), and other potential duplicates (n=33). We included two large French studies(n=116 and n=256) as they reported different clinical features and both were never used in the same calculation. The final analysis included 33 case reports and 21 case series, from 32 countries. Two independent reviewers extracted data using a standardised spreadsheet. For each clinical feature, proportions were calculated with corresponding 95% confidence intervals using Wilson score intervals. To prevent artificial deflation of prevalence estimates, studies with more than 20 patients were excluded from denominator calculations for specific features if those features were not explicitly assessed.
Results: Analysis of 720 patients across 32 countries revealed an almost exclusively male (98.6% (95% CI: 97.3%-99.3%) cohort, in keeping with the conditions X-linked nature. Cutaneous involvement was found to be 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. Of the specific cutaneous manifestations reported, neutrophilic dermatoses were most frequent (27.0%, 95% CI: 23.2-31.3%), followed by papules/plaques (20.8%, 95% CI: 16.3-26.1%) and vasculitic lesions (18.1%, 95% CI: 15.0-21.8%). Specifically reported respiratory involvement was mostly pulmonary infiltrates (46.2%, 95% CI: 41.7-50.8%) and dyspnoea (41.3%, 95% CI: 35.6-47.3%). Myelodysplastic syndrome occurred in 35.8% (95% CI: 32.3-39.4%) of patients, with notably low rates of progression to acute myeloid leukaemia (1.3%, 95% CI: 0.4-4.6%). Previously under-recognised 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 central nervous system manifestations (7.8%). Genetic analysis demonstrated that p.Met41Thr variant was most prevalent (49.3%, 95% CI: 45.1%-53.4%), followed by p.Met41Val (23.9%, 95% CI: 20.6%-27.6%) and p.Met41Leu (19.4%, 95% CI: 16.4%-22.9%).
Conclusion: This systematic review provides the most comprehensive characterisation of VEXAS syndrome to date, establishing robust prevalence estimates across all organ systems and identifying rare manifestations with important clinical implications. The findings demonstrate VEXAS as a complex multisystem disorder with a broader phenotypic spectrum than previously recognised, though with a cluster of features that increasingly characterise the disease. The high prevalence of specific manifestations should inform diagnostic strategies, particularly in older male patients presenting with characteristic features alongside cytopenias. Recognition of rare but serious complications affecting cardiac, neurological, ocular, and renal systems should guide development of risk-stratified monitoring protocols. These results will facilitate earlier diagnosis, inform monitoring strategies, and guide future research priorities. Large-scale prospective studies are now needed to validate these findings and establish standardised diagnostic criteria, utilising both clinical and genetic features, and evidence-based treatment algorithms for this increasingly recognised disorder.
REFERENCES: NIL.
Acknowledgements: NIL.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (