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SynopsisVEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe and progressive adult-onset systemic inflammatory condition with hematologic, rheumatologic, pulmonologic, and dermatologic manifestations that was first described in 2020. The vast majority of reported patients are men and develop clinical disease in the fifth decade or later.
VEXAS syndrome is caused by a somatic mutation in UBA1 on the X chromosome. This mutation affects hematopoietic progenitor cells, decreasing cell ubiquitylation and increasing activated innate immune pathways in cells of myeloid lineage, with subsequent upregulation of proinflammatory markers that drives systemic inflammation.
Inflammatory manifestations of VEXAS syndrome include chondritis, vasculitis, and neutrophilic dermatosis. Many reported patients carry diagnoses of relapsing polychondritis, giant cell arteritis, Sweet syndrome, and polyarteritis nodosa. Erythema nodosum is a further reported finding. Other autoimmune and inflammatory diseases that have been reported include rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and Kikuchi-Fujimoto disease. Hematologic manifestations include thrombocytopenia, macrocytic anemia, thromboembolism, bone marrow failure, and an increased risk of hematologic malignancies, such as myelodysplastic syndrome (MDS), monoclonal gammopathy of unknown significance (MGUS), and multiple myeloma. Ocular manifestations (eg, uveitis and scleritis), periorbital edema, and lymphadenopathy have also been reported. Fever and pulmonary involvement (including neutrophilic alveolitis most commonly and pleural effusions) are further common findings with pulmonary disease developing later in the disease course.
The prognosis is poor, often with severe and progressive clinical presentations, but there is early data to suggest that phenotype-genotype correlations exist and that some cohorts have a milder disease course.
D89.89 – Other specified disorders involving the immune mechanism, not elsewhere classified
M94.1 – Relapsing polychondritis
724834006 – Neutrophilic dermatosis
782964007 – Genetic disease
Differential Diagnosis & PitfallsThe differential diagnosis includes each of the conditions seen in VEXAS syndrome, when occurring in isolation, and their differential diagnoses.
Differential diagnosis of vacuoles in bone marrow myeloid / erythroid precursors:
- Alcohol intoxication
- Copper deficiency
- Zinc toxicity
- Myeloid neoplasms