VEXAS Syndrome: A Comprehensive Review of Pathogenesis, Clinical Manifestations, and Therapeutic Strategies

Abstract

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is a recently characterized, adult-onset systemic hematoinflammatory disease driven by acquired somatic mutations in the UBA1 gene.¹ This genetic aberration disrupts the cellular ubiquitylation cascade, precipitating profound innate immune hyperactivation and subsequent multiorgan inflammation.²

VEXAS syndrome demonstrates a highly heterogeneous clinical phenotype, predominantly presenting with recurrent fever, treatment-refractory neutrophilic dermatosis, relapsing polychondritis, pulmonary infiltrates, and systemic vasculitis.³ Concurrently, patients exhibit progressive hematologic anomalies, including macrocytic anemia, thrombocytopenia, characteristic myeloid and erythroid cytoplasmic vacuolization, and a substantial predisposition to myelodysplastic syndrome (MDS).⁴

Diagnosis relies on the identification of pathogenic UBA1 variants, optimized by targeted next-generation sequencing (NGS), integrated with comprehensive bone marrow evaluations.⁵ Due to its complex pathophysiology, disease management requires a multidisciplinary strategy.

Current therapeutic paradigms focus on eradicating UBA1-mutated clones utilizing hypomethylating agents (e.g., azacitidine) or allogeneic hematopoietic stem cell transplantation (AHSCT), alongside suppressing the autoinflammatory cascade via high-dose glucocorticoids and targeted biologicals, particularly Janus kinase (JAK) inhibitors.⁶ Considering the elevated mortality risk associated with VEXAS syndrome, early recognition, precise genetic screening, and individualized targeted therapies are imperative to optimize clinical outcomes and patient survival.⁷