401. Genotype, Transfusion Dependence and Ear Chondritis Predicts Mortality in VEXAS Syndrome
Creators: name: Ferrada1, Marcela
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined disease cause by myeloid-restricted somatic mutations in blood<em>. </em>Missense mutations at codon 41 of <em>UBA1 </em>comprise almost all cases of VEXAS and lead to amino acid substitutions of a methionine for either a threonine, valine, or leucine. Median survival and predictors of mortality in VEXAS have not been defined and may be essential to guide management. <strong>Methods:</strong> Patients were included if Sanger sequencing confirmed variants at p.Met41 in <em>UBA1</em>. 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 transfusion dependance, genotype, and mortality. In vitro expression systems were used to study associations between genetic variants and UBA1b isoform expression. <strong>Results</strong>: 83 patients were included. Median age at disease onset was 66 years (range 41-80). All patients were male and white. The most common clinically assigned diagnosis was relapsing polychondritis (52%), myelodysplastic syndrome (31%), or Sweet syndrome (22%). The overall mortality was 25%. 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 (13%) or threonine (18%) and also had a median survival that was significantly shorter compared to patients with other variants (p&lt; 0.01, Figure 1B). In multivariable Cox regression, there were three independent predictors of mortality; patients with the valine variant and patients who became transfusion dependent had 2.56x (95% CI 1.01-6.47, p=0.01) and 4.47x (95%CI 1.79-11.1, p&lt; 0.01) increased risk of death respectively whereas patients with ear chondritis were less likely to die (HR=0.32, 95% CI 0.12-0.90; p=0.03). Translation of the UBA1b isoform was reduced in p.Met41Val compared to p.Met41Leu or p.Met41Thr. <strong>Conclusion:</strong> A relationship between genotype, bone marrow failure, and survival is seen in patients with the VEXAS syndrome. Patients who become transfusion dependent and have a valine amino acid substitution at codon 41 have the highest risk for death. The only clinical symptom associated with mortality was ear chondritis. 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. <strong>Disclosure: </strong>None related to this body of work. Preliminary data presented here: https://acrabstracts.org/abstract/genotype-and-transfusion-dependence-predicts-mortality-in-vexas-syndrome-a-newly-described-disease-with-overlap-inflammatory-and-hematologic-features/