VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe, treatment-refractory, monogenic, multiorgan, autoinflammatory condition with vasculitic and hematological complications.
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Epidemiology
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 presentation
Clinical manifestations may be broadly divided into inflammatory and hematological:
- inflammatory
- non-specific and constitutional manifestations 1-3
- fever
- weight loss
- polyarthritis and polyarthralgia
- alveolitis
- specific syndromic manifestations 1-3,5,6
- non-specific and constitutional manifestations 1-3
- hematological 1-3,7
- cytopenias: anemia (characteristically macrocytic), thrombocytopenia
- venous thromboembolism
- lymphadenopathy
- myelodysplastic syndrome
- multiple myeloma and monoclonal gammopathy of uncertain significance
- hemophagocytic lymphohistiocytosis (rare)
Pathology
Genetics
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 5. UBA1 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.
Microscopic appearance
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.
Treatment and prognosis
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.
History and etymology
VEXAS syndrome was first described in a seminal case series in 2020 1.