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VEXAS Syndrome
VEXAS = Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic
A severe adult-onset autoinflammatory disorder caused by acquired (somatic) mutations in the UBA1 gene in hematopoietic stem cells.
First described in 2020 by researchers at the National Institutes of Health.
1. Cause & Pathophysiology
- Somatic mutation in UBA1 (ubiquitin-activating enzyme E1)
- Mutation occurs in bone marrow stem cells (not inherited)
- X-linked → predominantly affects men
- Leads to:
- Dysregulated innate immunity
- Excess inflammatory cytokine production
- Bone marrow dysfunction
- Cytoplasmic vacuoles in myeloid precursors
2. Who Gets It?
- Typically men >50 years
- Rare in women (usually with X monosomy or mosaicism)
- Often previously diagnosed with:
- Relapsing polychondritis
- Vasculitis
- Myelodysplastic syndrome (MDS)
3. Clinical Features
Systemic
- Recurrent fevers
- Weight loss
- Severe fatigue
Skin
- Neutrophilic dermatoses
- Vasculitic rashes
Cartilage
- Ear/nasal chondritis (mimics relapsing polychondritis)
Pulmonary
- Infiltrates
- Pleural effusions
Hematologic
- Macrocytic anaemia
- Thrombocytopenia
- Myelodysplastic syndrome
- High CRP/ESR
Thrombosis
- Increased risk of venous thromboembolism
4. When to Suspect VEXAS
Consider in an older male with:
- Steroid-dependent systemic inflammation
- Macrocytic anaemia
- Elevated inflammatory markers
- Relapsing chondritis or unexplained vasculitis
- Bone marrow showing vacuoles in myeloid/erythroid precursors
5. Diagnosis
Step 1 – Lab Clues
- Persistent CRP elevation
- Macrocytosis (↑ MCV)
- Cytopenias
Step 2 – Bone Marrow
- Cytoplasmic vacuoles in myeloid precursors
Step 3 – Confirmatory Test
- Genetic testing showing somatic UBA1 mutation
Diagnosis is molecular.
6. Treatment
No standardized cure; management is evolving.
1️⃣ Corticosteroids
- Often highly responsive
- Many become steroid-dependent
2️⃣ Steroid-Sparing Agents
- Limited efficacy:
- Methotrexate
- Azathioprine
- Mycophenolate
3️⃣ Biologics
- IL-6 inhibitors (e.g., Tocilizumab)
- JAK inhibitors (e.g., Ruxolitinib)
- Increasing evidence of benefit
4️⃣ Hematologic Management
- Treat MDS if present
- Transfusions as needed
5️⃣ Allogeneic Stem Cell Transplant
- Potentially curative
- Consider in severe disease
- High-risk procedure
7. Prognosis
- Chronic, relapsing course
- Significant morbidity
- Mortality often related to:
- Infection
- Thromboembolism
- Progressive bone marrow failure
8. Key Clinical Pearls
- Think VEXAS in older men with unexplained inflammatory disease + macrocytosis
- Steroid dependence is a major clue
- It bridges rheumatology + hematology
- Increasingly recognized as underdiagnosed
If you’d like, I can also provide:
- A diagnostic algorithm
- A comparison table: VEXAS vs relapsing polychondritis vs MDS
- Exam-style revision notes
- A hematology board-level summary
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