VEXAS syndrome

VEXAS syndrome is an adult-onset autoinflammatory disease affecting males, caused by a somatic mutation of the UBA1 gene in hematopoietic progenitor cells.[1][2][3][4][5] The name derives from Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic.[6]

The disease arises in late adulthood (typically after the age of 50) and causes both autoinflammatory and hematologic symptoms.[7] Fever and skin conditions—particularly rashes resembling those seen in Sweet syndrome—are common signs. Other autoinflammatory conditions that can occur in individuals with VEXAS syndrome include periorbital angioedema, uveitis and scleritis, relapsing polychondritis, and polyarteritis nodosa. Inflammation may also affect the lungs.[7][8] Hematologic issues include macrocytic anemia, a low platelet count, and a predisposition towards developing hematologic malignancies, especially myelodysplastic syndrome. On bone marrow examination, people with the disease exhibit abnormal vacuoles in precursor cells of the myeloid and erythroid lineages.[7]

VEXAS syndrome becomes more severe over time and carries a high mortality rate. Symptoms can be managed with high-dose corticosteroid therapy, but this can cause serious adverse effects, and symptoms typically recur after the dosage is lowered. A variety of alternative treatments are under investigation.[7][8]

The syndrome was first reported in a paper in The New England Journal of Medicine in October 2020, by Beck et al, who write: "Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes."[9] An editorial in the same issue describes the work as a "fascinating discovery" which "is of immediate importance to rheumatologists and has far-reaching consequences of general clinical interest. It builds on previous findings suggesting that postzygotic somatic mutation may be a more frequent cause of human disease than previously recognized".[10]