VEXAS Syndrome
VEXAS syndrome is a rare disease that causes late onset recurrent episodes of inflammation and hematologic abnormalities in men over the age of 50. Clinical manifestations of VEXAS syndrome are variable and include skin lesions, recurrent fever, weight loss, inflammatory arthritis, orchitis, hepatosplenomegaly, orbital inflammation, uveitis, scleritis, episcleritis, and sensorineural hearing loss. Approximately 40% to 60% of patients develop thromboembolism, and up to 77% have pulmonary infiltrates on computed tomography scans. Patients diagnosed with VEXAS syndrome have a 5-year survival of approximately 63%.
Patients with VEXAS syndrome have frequently been misdiagnosed with Sweet syndrome, giant cell arteritis, polyarteritis nodosa, relapsing polychondritis, myelodysplastic syndromes, and multiple myeloma.
VEXAS syndrome is caused by a UBA1 gene variant in hematopoietic progenitor cells. UBA1 gene variants reduce function of the UBA1 enzyme. This enzyme facilitates protein ubiquitination, which is a posttranslational modification that is essential for cell signaling and protein degradation. UBA1 gene variants are somatic gene variants that are X-linked. VEXAS syndrome has been reported only in men, or in women with monosomy of the X chromosome (Turner syndrome). Because it is caused by a somatic gene variant, VEXAS syndrome is not inherited.
VEXAS syndrome was first described in 2020 and its prevalence is uncertain. One study performed exome sequencing on DNA extracted from peripheral blood and found that 1 in 4269 men older than 50 years had a UBA1 variant associated with VEXAS syndrome. However, not all patients with a UBA1 variant develop symptoms of VEXAS syndrome.
Laboratory abnormalities include elevated inflammatory markers such as C-reactive protein and the erythrocyte sedimentation rate. Hematologic findings include macrocytic anemia, lymphopenia, and thrombocytopenia. Bone marrow biopsy demonstrates cytoplasmic vacuoles in more than 10% of myeloid and erythroid precursor cells. The definitive diagnosis of VEXAS syndrome requires detection of UBA1 gene variants by DNA sequencing. DNA can be extracted from peripheral blood, bone marrow, or formalin-fixed paraffin-embedded tissue.
References
Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383(27):2628-2638. doi:10.1056/NEJMoa2026834.
Kucharz EJ. VEXAS syndrome: a newly discovered systemic rheumatic disorder. Reumatologia. 2023;61(2):123-129. doi:10.5114/reum/163090.
Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA. 2023;329(4):318-324. doi:10.1001/jama.2022.24836.
Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood. 2021;137(26):3591-3594. doi:10.1182/blood.2021011455.
Tiwari V, Miller AT. Fever, Rash, and Shortness of Breath in a 69-Year-Old. JAMA. 2024;331(8):698–699. doi:10.1001/jama.2023.25521.
