Peripheral blood UBA1 variant burden predicts poor outcomes in VEXAS syndrome: a nationwide prospective study

Vacuole, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome (VS) is a severe autoinflammatory disease caused by acquired pathogenic UBA1 variants and is associated with high mortality. This study aimed to identify predictors of poor outcomes in VEXAS syndrome.

We conducted a nationwide prospective registry in Japan, in which all suspected cases underwent next-generation sequencing to detect pathogenic UBA1 variants and estimate the variant allele frequency (VAF) at baseline. Disease activity (VEXAS Current Activity Form [VEXASCAF]), serum C-reactive protein (CRP) level, prednisolone (PSL) dose, adverse events (AEs), mortality, and transfusion dependency were evaluated every 3 months for 1 year.

Among the screened patients, we included 60 patients with pathogenic UBA1 variants (all males; median age, 74 years) and 45 male patients with VS-like syndrome of similar age but without UBA1 variants served as controls. During a median follow-up of 343 days, the VEXASCAF and CRP levels decreased, whereas the PSL dose did not significantly change. Grade ≥3 AEs occurred in 50% of patients within 1 year. In the multivariable Cox regression analysis, a higher baseline VAF and higher PSL dose independently predicted poor prognosis, defined as death or transfusion dependence. The association between a higher VAF and poor outcomes was confirmed in 34 independent patients with VS. After adjusting for disease onset, patients carrying the UBA1 p.Met41Leu variant showed better survival. A similarly poor prognosis was observed in VEXAS-like patients.

Baseline pathogenic UBA1 VAF serves as a potent prognostic biomarker for poor outcomes in VS and highlights its potential role in risk stratification.