VEXAS syndrome.

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a disorder discovered in 2020 that bridges haematology, immunology and genetics. VEXAS syndrome arises from somatic mutations in UBA1, which encodes an E1 ubiquitin-activating enzyme, acquired in haematopoietic stem cells. These mutations disrupt ubiquitin-dependent protein homeostasis, triggering proteotoxic and inflammatory stress that drives systemic inflammation, cytopenias and clonal haematopoiesis. Clinically, VEXAS syndrome presents predominantly in older men with glucocorticoid-dependent inflammation, neutrophilic dermatoses, chondritis and myelodysplastic features. Diagnosis relies on characteristic clinical features and confirmation of UBA1 mutations. Prognosis is dismal in many patients, and treatment remains largely empirical. Glucocorticoids and cytokine blockade are used to provide transient control over inflammation, and hypomethylating agents aim to eradicate the mutant clone and induce disease remission. Allogeneic stem cell transplantation offers a potential cure. VEXAS syndrome exemplifies a new paradigm linking somatic genetics, inflammation and clonal haematopoiesis, reshaping our understanding of adult-onset inflammatory disease.