BACKGROUND: A novel autoinflammatory syndrome was described recently in male patients who harboured somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenias, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis and vasculitis, abbreviated as VEXAS.
OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients that had been previously registered with unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease.
METHODS: A systematic re-analysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in the Netherlands was performed. When no sequencing data was available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.
RESULTS: A total of 12 male patients were identified that carried mutations in UBA1. These patients presented with adult-onset (mean age 67 years, range 47-79) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory with a high mortality rate of 50%.
CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation, characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures, and provide better prognostic information and more suitable treatment options, including stem cell transplantation.