Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients with VEXAS Syndrome.

OBJECTIVE Somatic mutations in ubiquitin activating enzyme 1 (UBA1) cause a newly defined syndrome known as VEXAS. More than fifty percent of patients currently identified with VEXAS meet diagnostic criteria for relapsing polychondritis (RP). Clinical features that characterize VEXAS within a cohort of RP have not been defined. METHODS Exome and targeted sequencing of the UBA1 gene was performed in a prospective observational cohort of patients with RP. Clinical and immunological characteristics of patients with RP were compared based on presence or absence of UBA1 mutations. Random forest was used to derive a clinical algorithm to identify patients with UBA1 mutations. RESULTS Seven out of 92 patients with RP (7.6%) had UBA1 mutations (VEXAS-RP). Patients with VEXAS-RP were male, ≥ 45 years at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than RP (27% vs 2%, p=0.01). Elevated acute phase reactants and hematologic abnormalities (e.g. macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, MCV>100fL, and platelet count<200k/uL classified between VEXAS-RP and RP with 100% sensitivity and 96% specificity. CONCLUSION Mutations in UBA1 are causal for disease in a subset of patients with RP. These patients are defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.