Background/Purpose: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined disease cause by myeloid-restricted somatic mutations in blood. Missense mutations at codon 41 of UBA1 comprise almost all cases of VEXAS and lead to amino acid substitutions of a methionine for either a threonine, valine, or leucine. Reduced translation of the UBA1b isoform and loss of cellular ubiquitylation contribute to severe inflammation. Median survival and predictors of mortality in VEXAS have not been defined and may be essential to guide management.

Methods: Patients referred to two centers for possible VEXAS were included if Sanger sequencing confirmed disease-associated variants in UBA1. Kaplan-Meier was used to estimate median survival. Difference in survival was compared by genotype using the logrank test. Cox proportional hazard regression was used to identify associations between clinical features of disease (age at disease onset, thromboembolic disease, pulmonary infiltrates), transfusion dependance, genotype, and mortality. In vitro expression systems were used to study associations between genetic variants and UBA1b isoform expression.

Results: 73 patients with genetically-confirmed VEXAS syndrome were included. Median age at disease onset was 66 years (range 40-85). All patients were male and white. All patients were treated with glucocorticoids.

Prior to genetic testing, the most common clinically assigned diagnosis was relapsing polychondritis (53%), myelodysplastic syndrome (35%), or Sweet syndrome (20%). The most common variants at methionine 41 were threonine (p.Met41Thr) = 42, valine (p.Met41Val) = 16, and leucine (p.Met41Leu) = 11. Four patients had variants outside of codon 41 and were excluded from further analysis.

The overall mortality was 27%. Median survival from symptom onset was 10 years (Figure 1A). Death was more common in patients with the valine variant (50%) compared to patients with leucine (18%) or threonine (22%). Median survival of patients with the valine variant was 9 years and was significantly shorter compared to patients with other variants (p< 0.01, Figure 1B). In multivariable Cox regression, there were two independent predictors of mortality; patients with the valine variant and patients who became transfusion dependent had 3.84x (95% CI 1.50-9.81, p=0.01) and 3.48x (95%CI 1.28-9.49, p< 0.005) increased risk of death respectively. No other clinical features were associated with mortality. Translation of the UBA1b isoform was reduced in p.Met41Val compared to p.Met41Leu or p.Met41Thr.

Conclusion: A relationship between genotype, bone marrow failure, and survival is seen in patients with the VEXAS syndrome. While mortality rate is high in VEXAS, patients who become transfusion dependent and have a valine amino acid substitution at codon 41 have the highest risk for death. In vitro expression systems provide a mechanistic basis for the genotype specific mortality. Given the high mortality rate and lack of effective medical treatments, patients with VEXAS should be considered for bone marrow transplantation, with particular focus on patients with risk factors for increased mortality.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genotype-and-transfusion-dependence-predicts-mortality-in-vexas-syndrome-a-newly-described-disease-with-overlap-inflammatory-and-hematologic-features/