VEXAS syndrome

Last revised by Daniel J Bell on 07 Aug 2022

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe, treatment-refractory, monogenic, multiorgan, autoinflammatory condition with vasculitic and hematological complications.

VEXAS syndrome is likely to be rare, but also likely to be underdiagnosed. It is almost exclusively seen in males 1-3, although cases have been described in females with monosomy X (Turner syndrome) 4. It tends to manifest in middle-aged adults 1-3.

Clinical manifestations may be broadly divided into inflammatory and hematological:

VEXAS syndrome is caused by somatic (acquired) mutations, typically missense mutations, to the UBA1 gene in hematopoietic progenitor cells of the erythroid and myeloid lineages 1-3. The UBA1 gene is encoded on the X chromosome and escapes X inactivation in females, which is why it is almost exclusively seen in males 1-3, and only seen in females in the context of monosomy X 5UBA1 encodes for the E1 enzyme, a ubiquitin activating enzyme, which when defective in hematopoietic progenitor cells leads to activation of the innate immune system, and thus, autoinflammatory clinical manifestations 1-3.

A characteristic hematopathological feature of VEXAS syndrome is the presence of abnormal cytoplasmic vacuoles in erythroid and myeloid precursor cells in the bone marrow 1-3. Importantly, lymphoid precursors are not implicated 1,2.

No disease-modifying treatment is available (as of August 2022) 2. High-dose corticosteroids are the current mainstay of treatment for inflammatory manifestations, with inflammatory manifestations tending to be highly refractory to steroid-sparing immunosuppressive therapies, such as disease-modifying antirheumatic drugs (DMARDs) 1,2. Hematological manifestations are also likely to be refractory to standard treatments, such as azacitidine for myelodysplastic syndrome 2,8.

VEXAS syndrome was first described in a seminal case series in 2020 1.

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