VEXAS

VEXAS syndrome is a rare, adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene on the X chromosome. The acronym VEXAS stands for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. The condition predominantly affects men and is not inherited; mutations arise in hematopoietic cells during life.

Most cases harbor somatic variants at methionine-41 (M41) of UBA1 in a mosaic pattern, impairing ubiquitin activation and triggering downstream inflammatory cascades. The result is systemic inflammation with widespread organ involvement.

Clinical features include fevers, weight loss, cytopenias (anemia and thrombocytopenia), and elevated inflammatory markers. Organ involvement commonly includes relapsing polychondritis-like ear cartilage inflammation, neutrophilic skin lesions, interstitial lung disease, vasculitis, and thromboembolic events. Bone marrow shows characteristic vacuolization of myeloid precursors.

Diagnosis relies on clinical suspicion in older men with inflammatory syndrome and cytopenias, confirmed by sequencing peripheral blood or bone marrow for UBA1 somatic mutations and by detecting marrow vacuolization.

Treatment is not standardized. Corticosteroids are often required, with steroid-sparing agents such as methotrexate or azathioprine; IL-1 blockade and, in some cases, JAK inhibitors may help. Hematopoietic stem cell transplantation has been used in selected severe cases. Prognosis varies with the extent of organ involvement and infection risk.