Somatic Mutations in Rheumatology: The Paradigm of Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome is a recently recognized adult-onset autoinflammatory disease caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 ( UBA1) gene on the X chromosome, primarily affecting older males. It presents with systemic inflammation, relapsing polychondritis, vasculitis, neutrophilic dermatoses, macrocytic anemia, and characteristic bone marrow vacuoles. The disorder is often resistant to standard immunosuppression and may co-occur with clonal hematopoiesis mutations like TET2 and DNMT3A . Management includes glucocorticoids, JAK inhibitors, interleukin-6 blockers, and hypomethylating agents, while hematopoietic stem cell transplantation is being explored as a potential cure. VEXAS underscores the significance of somatic mutations in adult inflammatory syndromes.