VEXAS syndrome in adults: A narrative review of genomic pathogenesis, multisystem phenotypes, diagnostic algorithms, and emerging therapeutic strategies.

AIM: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently defined adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. This narrative review synthesizes current insights into its epidemiology, pathogenesis, clinical spectrum, diagnostic strategies, and emerging therapeutic approaches, emphasizing data from the French and AIDA registries.

METHOD: We conducted a comprehensive literature search of PubMed, Scopus, and Web of Science databases up to 15 June 2025, using keywords including "VEXAS", "UBA1", "autoinflammatory syndromes", "myelodysplastic syndromes", and "JAK inhibitors". Studies reporting epidemiological data, clinical phenotypes, pathophysiological mechanisms, diagnostic pathways, or therapeutic outcomes were included. Case reports and non-English articles without abstracts were excluded.

DISCUSSION: Since its identification in 2020, more than 300 VEXAS cases have been reported, primarily affecting older males. The clinical phenotypes include relapsing polychondritis, cytopenias, neutrophilic dermatoses, and frequent overlap with myelodysplastic syndromes. Diagnosis is confirmed by detecting somatic mutation in UBA1, most commonly at codon 41. Treatment responses are heterogeneous: corticosteroids are often used initially,but longer-lasting benefits are observed with JAK inhibitors, hypomethylating agents, or hematopoietic stem-cell transplantation. However, therapeutic decision-making remains empirical mainly due to the lack of controlled trials.

CONCLUSION: VEXAS syndrome exemplifies the interface between clonal hematopoiesis and systemic inflammation. Early molecular diagnosis and genotype-informed treatment strategies are critical. Collaborative, prospective studies are urgently needed to refine diagnostic algorithms and optimize therapeutic outcomes.