Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS

Abstract

Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS‐RP). Patients with VEXAS‐RP were all male, were on average ≥45 years of age 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 in RP (23% versus 4%; P = 0.029). 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, a mean corpuscular volume >100 fl, and a platelet count <200 ×103/μl differentiated VEXAS‐RP from RP with 100% sensitivity and 96% specificity. Conclusion Mutations in UBA1 were causal for disease in a subset of patients with RP. This subset of patients was 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.

Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS

“…Although the clinical symptoms and distribution of organ involvement broadly resembled the findings of previous studies, 7,8,10 several observations are complementary. First, patient B presented without episodic fever but did have progressive renal insufficiency with marked proteinuria and dysmorphic erythrocyturia.…”

“…7 Most recently, others have identified novel somatic variants in UBA1. [8][9][10] In this study, we characterize a small cohort of patients with VEXAS syndrome. We discuss novel clinical observations and strategies to improve diagnosis and treatment of VEXAS.…”

USAID Associated with Myeloid Neoplasm and VEXAS Syndrome: Two Differential Diagnoses of Suspected Adult Onset Still’s Disease in Elderly Patients

“…A third of our patients screened for UBA1 were positive for this mutation (including one woman). As a cohort of comparison, in relapsing chondritis, a frequently associated clinical picture usually described with VEXAS, only 7.6% had UBA1 mutations [ 25 ]. USAID appeared as a new pattern of VEXAS.…”

Atypical extensive lupus tumidus‐like eruption as an early presentation of VEXAS syndrome

“…Cutaneous involvement typically included neutrophilic skin infiltration or vasculitis in the first descriptions. [1][2][3][4][5] We report here two cases in which symptoms were limited to skin, without fever or systemic involvement. In both cases, the diagnosis of Sweet's syndrome was clinically considered, but clinicopathologic correlation was suggestive of widespread refractory lupus tumidus, with atypias: need of steroid therapy because of extension and severity of skin involvement (though systemic steroids are not a usual treatment option in cutaneous lupus), presence of histiocytes and few neutrophils in the dermal infiltrates in one of our patients.…”