VEXAS syndrome through a rheumatologist’s lens: insights from a Spanish national cohort

Abstract Objectives To describe the clinical spectrum of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome in patients managed by rheumatology units and analyse genotype–phenotype correlations. Methods A multicentre, cross-sectional, retrospective study was conducted across 126 Spanish hospitals. Patients with VEXAS syndrome diagnosed between December 2020 and January 2024 were included. Demographic data, clinical manifestations, laboratory findings, genetic analyses, treatments and outcomes were collected from medical records. Results Thirty-nine male patients were included (mean age at diagnosis: 72.78 years). Common manifestations were cutaneous lesions (87.18%), polyarthritis (82.05%) and fever (79.49%). Renal involvement was observed in 20.51% of patients. Genetic testing confirmed ubiquitin-like modifier-activating enzyme 1 mutations in all cases: 18 M41L, 14 M41T, 6 M41V and 1 novel mutation of unknown significance at site c.209T>A. The M41V mutation was significantly associated with renal involvement, while M41T was linked to deep vein thrombosis and thrombocytopaenia. Glucocorticoids were used in all patients, with improved response rates post-diagnosis (55.26% vs 97.14%) probably influenced by an increase in administered doses. IL-6 inhibitors and JAK inhibitors showed promising response rates (75% and 76.92%, respectively). Conclusions This study provides insights into the clinical spectrum of VEXAS syndrome in rheumatology settings, highlighting a higher prevalence of joint symptoms and renal involvement than previously reported. Genotype–phenotype correlations were observed, with M41V significantly associated with renal involvement and M41T linked to deep vein thrombosis and thrombocytopaenia. A new, presumably causative variant of VEXAS syndrome at site c.209T>A was described. These findings contribute to the growing understanding of VEXAS syndrome and may inform future diagnostic and treatment strategies.