VEXAS Syndrome: A Comprehensive Overview
VEXAS syndrome is a recently discovered adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene on the X chromosome, characterized by systemic inflammation, hematological abnormalities, and multi-organ involvement that primarily affects males over 50 years of age. 1
Genetic and Molecular Basis
VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome results from:
- Somatic mutations in the UBA1 gene (X-linked gene) primarily affecting methionine-41 (p.Met41) 2
- Disruption of the ubiquitin-proteasome system, leading to dysregulated protein degradation 1
- Activation of innate immune pathways causing systemic inflammation 2
- Predominantly affects males due to X-linked inheritance pattern 3
Clinical Manifestations
Inflammatory Manifestations
- Persistent fever (often treatment-refractory)
- Neutrophilic dermatosis and skin lesions
- Auricular and nasal chondritis (resembling relapsing polychondritis)
- Pulmonary infiltrates and inflammation
- Ocular inflammation
- Arthritis and joint pain
- Venous thrombosis 1, 3
Hematological Abnormalities
- Macrocytic anemia (often severe and transfusion-dependent)
- Thrombocytopenia
- Characteristic vacuoles in myeloid and erythroid precursor cells (diagnostic hallmark)
- Bone marrow dysplasia (often resembling myelodysplastic syndrome) 1, 3
Diagnostic Approach
The diagnosis of VEXAS syndrome should be considered in:
- Males over 50 years of age
- Unexplained systemic inflammatory conditions
- Treatment-refractory inflammatory symptoms
- Concurrent hematological abnormalities 4
Key Diagnostic Tests
- Genetic testing: Identification of UBA1 gene mutation (essential for definitive diagnosis)
- Bone marrow examination: Presence of characteristic vacuoles in myeloid and erythroid precursors
- Blood tests:
- Complete blood count: Macrocytic anemia, thrombocytopenia
- Inflammatory markers: Elevated ESR, CRP
- Comprehensive metabolic panel 2
Treatment Approaches
Treatment of VEXAS syndrome focuses on two main strategies:
1. Controlling Inflammatory Symptoms
- Corticosteroids: First-line therapy but often requires high doses with limited long-term efficacy
- JAK inhibitors: Emerging treatment option showing promise
- IL-6 blockade: Tocilizumab may be effective in some cases 3
2. Targeting the UBA1-Mutated Hematopoietic Population
- Azacitidine: May target the mutated clone
- Allogeneic hematopoietic stem cell transplantation (AHSCT): Potentially curative but carries significant risks 3
Supportive Care
- Red blood cell and platelet transfusions
- Erythropoiesis-stimulating agents
- Thromboprophylaxis
- Antimicrobial prophylaxis 1
Prognosis and Complications
VEXAS syndrome is associated with:
- High morbidity and mortality
- Reduced life expectancy
- Potential for multi-organ failure
- Thrombotic complications
- Infections due to immunosuppression 5
Clinical Pearls
- VEXAS syndrome may mimic other rheumatologic conditions such as relapsing polychondritis, vasculitis, and adult-onset Still's disease
- The combination of treatment-refractory inflammatory symptoms and hematological abnormalities should raise suspicion for VEXAS syndrome
- Early diagnosis is crucial as the condition carries significant mortality risk
- Multidisciplinary management involving rheumatology, hematology, and other specialists is essential 4
Ongoing Research
- International registries (such as the AutoInflammatory Disease Alliance registry) are being developed to better understand the disease course and optimal management 4
- Consensus diagnostic criteria are needed to better define VEXAS and related disorders 5
- Prospective studies are required to determine optimal treatment strategies based on disease severity and prognosis 5
VEXAS syndrome represents a new paradigm in understanding adult-onset monogenic autoinflammatory diseases and highlights the importance of considering genetic testing in adults with unexplained inflammatory conditions, especially when accompanied by hematological abnormalities.