Intractable Rare Dis Res. 2026;15(2):166-172. (DOI: 10.5582/irdr.2026.01013)

A neurologist's guide to VEXAS syndrome: Differentiating somatic autoinflammation from autoimmune mimics

Mitsoudis N, Nikolakakis I, Apsemidou A, Bakirtzis C, Grigoriadis N

This review characterizes VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) as a prototype of adult-onset autoinflammation that challenges traditional autoimmune paradigms. Driven by constitutive activation of innate myeloid cells via Ubiquitin-Like Modifier Activating Enzyme 1 (UBA1) mutations, VEXAS affects the nervous system in approximately 6–10% of cases. We identify the peripheral nervous system as the primary target (70%), typically manifesting as refractory axonal polyneuropathy, while central involvement may present as neutrophilic meningoencephalitis. Crucially, we highlight the "hematologic paradox"—hyperinflammation co-occurring with macrocytic anemia rather than thrombocytosis—as the key biomarker distinguishing VEXAS from vasculitic mimics, necessitating early genetic sequencing for targeted clone suppression.

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