Decoding VEXAS syndrome: emerging insights into pathogenesis and clinical management

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly discovered, adult-onset, hemato-inflammatory disease driven by clonal dominance of pro-inflammatory hematopoietic cells bearing a somatic mutation in the UBA1 gene. This review aims to integrate and discuss the most recent insights into the evolving understanding of VEXAS pathogenesis and clinical management.

An interplay between inflammation and clonal dominance of UBA1 mutant hematopoietic clones underlies the pathogenesis of VEXAS syndrome. Mutant cells both generate and sustain a toxic inflammatory milieu that impairs wild-type hematopoiesis. Despite exhibiting dysfunctional differentiation, VEXAS cells activate pro-survival pathways that support their persistence and progressive dominance.Recent international guidelines offer evidence-based recommendations to optimize therapy and manage both inflammatory and hematologic features of the disease.

This review dissects the key molecular mechanisms driving inflammation and clonal survival in UBA1 mutant cells, and outlines current therapeutic strategies proposed to counteract VEXAS progression and improve patient outcomes. The recent findings presented here, along with the deeper understanding that will be built upon them, not only advance the knowledge of the disease pathobiology, but also pave the way for more precise, mechanism-driven treatment approaches aimed at intercepting disease progression and improving long-term outcomes.