VEXAS Syndrome

VEXAS syndrome (VEXAS is the acronym for: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described monogenic, highly febrile, autoinflammatory disease of adulthood caused by somatic mutations in UBA1 in hematopoietic progenitor cells.

Patients develop diffuse inflammatory and hematologic symptoms and a high rate of thrombosis. Myeloid autoinflammation and progressive bone marrow failure lead to significant morbidity and mortality. VEXAS syndrome represents a prototype for a new class of diseases.

Patients must meet the following clinical criteria for a diagnosis of "VEXAS syndrome":

• An inflammatory syndrome (recurrent polychondritis -50% of patients), Sweet syndrome, polyarteritis nodosa or giant cell arteritis).
• or a haematological disease (myelodysplastic syndrome or multiple myeloma)
• or an inflammatory syndrome+haematological disease

Patients must meet the following clinical criteria for the diagnosis of "VEXAS syndrome":

• an inflammatory syndrome (recurrent polychondritis -50% of patients), Sweet syndrome, polyarteritis nodosa or giant cell arteritis)
• or a haematological disease (myelodysplastic syndrome or multiple myeloma)
• or an inflammatory syndrome+haematological disease

UBA1 mutations are found in more than half of hematopoietic stem cells, including peripheral blood myeloid cells, but not in lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and expression of a new, catalytically impaired isoform starting at p.Met67. This somatic mutation results in decreased ubiquitination. This defect also leads to dysregulated hemostasis and endothelial dysfunction (Oo TM et al. 2021), which explains the high thrombosis burden (Groarke EM et al. 2021).

In VEXAS, somatic mutations are detected affecting methionine-41 (p.Met41) in UBA1 (Ubiquitin Like Modifier Activating Enzyme 1, also referred to as E1). E1 is the major enzyme that initiates ubiquitination. The E1 encoding UBA1 gene is located on chromosome Xp11.3. The gene probably plays a role in DNA repair. It is part of a gene cluster on chromosome Xp11.23.

UBA1 mutations are found in more than half of hematopoietic stem cells, including myeloid cells of peripheral blood, but not in lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and expression of a new, catalytically impaired isoform starting at p.Met67. This somatic mutation results in decreased ubiquitination. This defect also leads to dysregulated hemostasis and endothelial dysfunction (Oo TM et al. 2021), which explains the high thrombosis burden (Groarke EM et al. 2021).

VEXAS patients develop an often fatal, refractory inflammatory syndrome in late adulthood with fever, cytopenias, characteristic vacuoles in myeloid and erythroid progenitor cells, dysplastic bone marrow, Sweet syndrome, neutophilic pneumonia, and (poly-) chondritis and vasculitis. Patients show a high rate of thrombosis.

The disorder is unique in that a genotype-driven approach has been used to identify a disorder that links apparently unrelated inflammatory syndromes in adulthood.