VEXAS Syndrome: Genetics, Gender Differences, Clinical Insights, Diagnostic Pitfalls, and Emerging Therapies

Abstract

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still's disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease.

Keywords: VEXAS syndrome; X-linked pathology; clinical features; hematological and inflammatory manifestations; lyonization affects; therapeutic approaches.

Figure 1

This figure illustrates how UBA1 mutations disrupt immune homeostasis by altering ubiquitin activation in hematopoietic stem cells. This dysfunction leads to clonal expansion and the development of pathological features such as macrocytic anemia, cytoplasmic vacuoles, and systemic inflammation. At the molecular level, aberrant activation of key signaling pathways—namely NF-κB, JAK-STAT, and mTOR—drives chronic inflammation through excessive cytokine production, prolonged inflammatory signaling, and metabolic dysregulation. These processes collectively result in steroid-dependent inflammation, neutrophilic dermatoses, and multi-organ involvement, contributing to resistance to conventional immunosuppressive therapies. This visual representation provides a comprehensive overview of the pathophysiological mechanisms underlying VEXAS syndrome, offering insights into its impact on immune homeostasis and hematopoiesis.

Figure 2

Proposed diagnostic workflow for VEXAS syndrome. The process is structured in two main phases. The first step involves clinical suspicion based on characteristic signs and symptoms (e.g., persistent fever, chondritis, cytopenia, macrocytic anemia, and characteristic vacuoles in myeloid precursor cells in bone marrow aspirate). The second step includes blood collection, genetic analysis, and the study of UBA1 gene variants, which confirms the diagnosis. The “+” and “−” signs indicate the relative frequency of mutations (literature data) in male and female patients. This pathway helps guide the diagnostic evaluation, especially in adult patients with systemic inflammation and hematologic abnormalities.

Figure 3

Comparing clinical features between males and females.