VEXAS syndrome

VEXAS syndrome is an adult-onset autoinflammatory disease with prominent haematological involvement and substantial morbidity. Onset is typically after the fifth decade, with the great majority of affected individuals being men in their sixties to seventies at presentation. The clinical picture combines features across multiple organ systems: cutaneous lesions (neutrophilic dermatosis, cutaneous vasculitis), recurrent high-grade fever, pulmonary infiltrates, cartilaginous inflammation (auricular, or nasal chondritis), medium-vessel vasculitis, ocular inflammation, venous thromboembolism, and constitutional symptoms. Cutaneous involvement and recurrent fever are the most frequent presenting features. A progressive haematological component is consistent, including macrocytic anaemia and persistent lymphopenia; concurrent myelodysplastic syndrome is reported in roughly half of patients in large referral cohorts. Inter-individual variability of organ involvement is substantial, and isolated chondritis, neutrophilic dermatosis, or cytopenia frequently precedes recognition of the systemic process. Morbidity and mortality are considerable, driven by infectious complications, MDS progression, and cardiovascular events.

Initially considered an ultra-rare disease, VEXAS syndrome is likely underdiagnosed and underrecognized. A general-population prevalence has not yet been established. In a study involving 163,096 unselected participants, the estimated prevalence is approximately 1/ 4,000 in men aged over 50 with a combination of inflammatory and hematologic manifestations.

VEXAS arises from acquired somatic pathogenic UBA1 variants in haematopoietic stem cells. UBA1 (Xp11.23) encodes the principal ubiquitin-activating enzyme; the gene is not affected in the germline, so the mutations occur in adult life and are not inherited. Most affected individuals carry a missense variant at codon 41; rarer non-codon-41 splice-site and missense variants (e.g. c.118-1G>C, p.Ser56Phe) act through the same mechanism. These variants prevent translation of the cytoplasmic UBA1b isoform, impairing cytoplasmic ubiquitin activation and triggering chronic activation of innate-immune and proinflammatory cytokine pathways together with characteristic myeloid-precursor vacuolation.