What is the treatment for VEXAS (VEXAS syndrome) syndrome in a patient presenting with recurrent fever, elevated Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), episcleritis, and macrocytic anemia?

Treatment of VEXAS Syndrome

For VEXAS syndrome presenting with recurrent fever, elevated inflammatory markers, episcleritis, and macrocytic anemia, initiate corticosteroids immediately for symptom control while simultaneously starting either a JAK inhibitor (ruxolitinib) or IL-6 blockade (tocilizumab or siltuximab) as disease-modifying therapy. 1, 2

Immediate Therapeutic Approach

First-Line Corticosteroid Therapy

• Start prednisone 0.5-1 mg/kg/day (typically 40-60 mg daily) to rapidly control systemic inflammation, fever, and inflammatory manifestations 1, 2
• Corticosteroids provide rapid symptom relief but are insufficient as monotherapy and require concurrent disease-modifying agents 1
• The goal is to taper corticosteroids as quickly as possible once disease-modifying therapy takes effect 1

Disease-Modifying Therapy: Two Primary Options

Option 1: JAK Inhibitor (Preferred for most patients)

• Ruxolitinib has demonstrated favorable mid-term responses in VEXAS syndrome 2
• This approach targets both the inflammatory cascade and the underlying clonal hematopoietic expansion 1, 2
• JAK inhibition addresses the pathophysiology more comprehensively than pure anti-inflammatory approaches 1

Option 2: IL-6 Blockade

• Tocilizumab (anti-IL-6 receptor antibody) has shown efficacy in controlling inflammatory symptoms 3, 4, 1
• Siltuximab (anti-IL-6 antibody) has been successfully used with sustained benefit for over one year without relapse 3
• IL-6 blockade is particularly rational given the prominent inflammatory cytokine profile in VEXAS 3

Addressing Specific Clinical Manifestations

Ocular Involvement (Episcleritis)

• Topical corticosteroids with cycloplegic agents for local control 5
• Ophthalmology consultation is essential even for mild presentations 5
• Systemic therapy (as outlined above) will address the underlying autoinflammatory process driving the episcleritis 5

Hematologic Management

• Red blood cell transfusions for symptomatic macrocytic anemia 1
• Erythropoiesis-stimulating agents may be considered for anemia management 1
• Monitor for thrombocytopenia and provide platelet transfusions if needed 1
• Thromboprophylaxis should be implemented given the high risk of venous thromboembolism in VEXAS 1, 2

Advanced Therapeutic Considerations

Azacitidine

• Consider azacitidine (hypomethylating agent) for patients with concurrent myelodysplastic features or those refractory to JAK inhibitors and IL-6 blockade 1, 2
• This targets the UBA1-mutated hematopoietic clone directly 1

Allogeneic Hematopoietic Stem Cell Transplantation

• This is the only curative option for VEXAS syndrome 2
• Should be strongly considered for younger, fit patients with poor prognostic factors or symptoms recalcitrant to medical therapy 2
• Transplantation eliminates the UBA1-mutated hematopoietic stem cell population 2

Critical Monitoring and Supportive Care

Infection Prophylaxis

• Anti-infectious prophylaxis is essential given the combination of immunosuppression from disease and treatment 1
• Monitor closely for infectious complications, which represent a major cause of morbidity and mortality 4

Monitoring for Life-Threatening Complications

• Screen actively for macrophage activation syndrome (MAS), which can occur at any point and requires high-dose corticosteroids, anakinra, ciclosporin, and/or IFN-γ inhibitors 5
• Monitor for CNS vasculitis (rare but severe complication) with neurological examination and brain MRI if symptoms develop 4
• Assess for pulmonary involvement, cardiac manifestations, and venous thrombosis regularly 1, 2

Common Pitfalls to Avoid

• Do not rely on corticosteroids alone—they provide only temporary symptom control and patients will become steroid-dependent without disease-modifying therapy 1
• Do not delay JAK inhibitor or IL-6 blockade initiation—early aggressive therapy improves outcomes 1, 2
• Do not overlook hematologic complications—macrocytic anemia, thrombocytopenia, and thrombotic risk require active management 1, 2
• Do not miss the window for transplant evaluation—younger patients should be referred early to transplant centers before accumulating excessive organ damage 2

Treatment Algorithm Summary

1. Day 1: Start prednisone 40-60 mg daily + initiate ruxolitinib or tocilizumab/siltuximab simultaneously 1, 2
2. Week 1-4: Assess response with fever resolution, normalization of CRP/ESR, improvement in clinical symptoms 5
3. Month 1-3: Begin corticosteroid taper if disease-modifying therapy is effective 1
4. Month 3-6: If inadequate response, consider switching between JAK inhibitor and IL-6 blockade, or adding azacitidine 1, 2
5. Ongoing: Evaluate for transplant candidacy in appropriate patients; maintain supportive care including transfusions, thromboprophylaxis, and infection monitoring 1, 2