VEXAS syndrome and immune-mediated rheumatic diseases: overlaps in clinical features and mechanisms

Vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic (VEXAS) syndrome is a newly identified disorder caused by an acquired monogenic somatic UBA1 gene mutation, affecting nuclear and cytoplasmic ubiquitination. This mutation triggers immune dysregulation, leading to diverse clinical and pathological features resembling inflammatory rheumatic diseases. Blood abnormalities stem from myeloid precursor dysfunction, presenting as elevated concentrations of inflammatory markers and cytokines, leukopenia, and macrocytosis. These abnormalities can lead to inflammatory arthritis, vasculitis, polychondritis, thrombosis, and connective tissue disease-like syndromes. This Review explores the clinical and mechanistic links between VEXAS syndrome and rheumatic diseases, offering guidance on current best management strategies. Although rare, VEXAS syndrome has high morbidity and mortality, providing valuable insights into how genetic mutations drive immune system activation and rheumatic disease development.