Somatic UBA1 Mutations Causal for VEXAS in Patients With Relapsing Polychondritis

Somatic mutations in the gene encoding for ubiquitin activating enzyme 1 (UBA1) are causal for a recently discovered syndrome that has been identified in a subset of patients with relapsing polychondritis (RP), according to study findings presented at the European Alliance of Associations for Rheumatology (EULAR) 2021 Virtual Congress.¹

In a previous study assessing gene function in adult-onset inflammatory syndromes, a team of investigators “identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes.” They named this condition vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome; it was also found that more than half of patients with VEXAS meet the diagnostic criteria for RP.^1,2

Researchers conducted a prospective observational study in which they performed exome and targeted sequencing of UBA1 from patients with RP to determine the prevalence of VEXAS in this population.¹ Researchers also compared clinical, laboratory, and immunologic characteristics and performed genetic screening for VEXAS in patients with RP.

Of 98 patients included in the study, 85 had relapsing polychondritis, 13 of whom had UBA1 mutations (VEXAS-RP; 100% White). Patients with VEXAS-RP were men and were older at disease onset (P <.0001 for both). Fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates were common among patients with VEXAS-RP; however, airway chondritis, costochondritis, and tenosynovitis/arthralgias were more prevalent among patients with RP.

Compared with patients with RP, patients with VEXAS-RP had significantly more deaths (P =.029) and unprovoked deep vein thrombosis (P <.0001). Values for erythrocyte sedimentation rate, C-reactive protein, and mean corpuscular volume were significantly greater among patients with VEXAS-RP; however, absolute monocyte, lymphocyte, and platelet counts were significantly lower in this population.

Study authors noted that patients with VEXAS-RP were “defined by disease onset in the fifth decade of their life or later, male sex, ear/nose chondritis, and hematologic abnormalities.” Early identification is important in VEXAS given the associated high mortality rate,” they concluded.

References

1. Ferrada M, Sikora K, Lou Y, et al. Classification of patients with relapsing polychondritis based on somatic mutations in UBA1. Presented at: EULAR 2021 Virtual Congress; June 2-5, 2021. Abstract OP0090.
2. Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med. 2020;383:2628-2638. doi:10.1056/NEJMoa2026834