Among patients with vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, residual UBA1b translation appears to have a marked effect on disease prognosis and overall clinical outcomes, according to research published in Blood. Transfusion dependence, furthermore, appears to be a predictor of worse overall survival in this patient population.
The hematological manifestations in adults with VEXAS syndrome may appear, without molecular considerations, to be unconnected. Yet recent research suggests that these symptoms are linked with somatic mutations in UBA1 hematologic progenitor cells; most of these mutations are in p.Met41, the translation initiation codon for UBA1b.
Although previous research has suggested that bone marrow transplantation may be effective for treating patients with VEXAS syndrome, many patients are ineligible for this intervention. For this study, researchers aimed to determine whether any patient or disease characteristics predict outcomes in VEXAS syndrome to help further personalize treatment for this patient population.
Overall, 83 patients with VEXAS syndrome with UBA1 mutations at p.Met41 were included. These included 15 patients with the Leu mutation variant, 18 patients with the Val variant, and 50 patients with the Thr variant. In the overall cohort, the median age of disease onset was 66 years, 83% of patients were White, and 97% and 83% of patients presented with macrocytic anemia and thrombocytopenia, respectively.
Multivariate analysis showed that undifferentiated inflammatory syndrome was most common among patients with the Val variant; this variant was also linked with poorer survival (hazard ratio [HR], 2.56; 95% CI, 1.01-6.47) and reduced UBA1b translation, compared with the other evaluated variants.
Ear chondritis was linked with improved overall survival in the general cohort (HR, 0.32; 95% CI, 0.12-0.90), whereas transfusion dependence was linked with worse survival (HR, 4.47; 95% CI, 1.79-11.18).
The authors also presented a case study showing that 2 novel UBA1 mutations were linked with significant reduction in UBA1b translation and UBA1b level rescue, respectively.
“VEXAS syndrome connects a set of patients with seemingly unrelated clinical diagnoses,” the authors wrote in their report. “In addition to the diagnostic value of molecular genetics, this study establishes a prognostic role for molecular genotyping as a biomarker of disease severity in VEXAS syndrome.”
Ferrada MA, Savic S, Cardona DO, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood. 2022;140(13):1496-1506. doi:10.1182/blood.2022016985