VEXAS Syndrome Treatment Approach
Immediate Diagnostic Confirmation
VEXAS syndrome requires genetic confirmation via UBA1 mutation testing, specifically targeting the p.Met41 variant on the X chromosome, with next-generation sequencing of the entire gene being the preferred method and turnaround time typically under 12 weeks 1, 2.
- Characteristic cytoplasmic vacuoles in myeloid and erythroid precursors on bone marrow examination are present in the vast majority of cases and serve as a key diagnostic marker 3, 2.
- C-reactive protein (CRP) is selected by over half of clinicians as the most useful marker for monitoring disease relapse 1.
- Evaluate for concomitant myelodysplastic syndrome (MDS), as VEXAS patients have increased risk of myelodysplastic and plasma cell neoplasms 4, 2.
First-Line Treatment Algorithm
Initial Corticosteroid Therapy
Start with corticosteroids at 1 mg/kg daily, which is the most common initial dosing used by nearly 65% of clinicians managing VEXAS syndrome 1.
- Corticosteroids remain first-line therapy but are rarely sufficient as monotherapy 5, 6.
- Traditional immunosuppressants and TNF inhibitors are generally ineffective and should be avoided 3.
Upfront Addition of Immunomodulatory Therapy
More than half of clinicians add systemic immunomodulatory treatment upfront rather than waiting for corticosteroid failure 1.
The two most effective steroid-sparing agents are JAK inhibitors and IL-6 targeted monoclonal antibodies (such as tocilizumab), each selected by approximately 32% of clinicians as first-choice treatments 1, 5.
- IL-1 inhibitors (such as canakinumab) demonstrate promising steroid-sparing efficacy in selected patients 5.
- Both IL-1 and IL-6 pathway inhibitors allow for reduction of corticosteroid doses while achieving clinical stabilization 5.
Disease-Specific Considerations
VEXAS with Concomitant MDS
Azacitidine should be used in patients with concomitant myelodysplastic syndrome, with nearly 70% of clinicians reserving this agent specifically for this indication 1.
- Azacitidine and decitabine have shown promise in reducing disease burden beyond their use in isolated MDS 3.
- The clinical dyad of VEXAS/MDS generally belongs to lower-risk IPSS-R/M categories, but the morbidity associated with VEXAS may prioritize transplant consideration even in lower-risk disease given the recalcitrant hyperinflammatory picture 4.
Definitive Curative Treatment
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment, though only 29.6% of centers report successful completion of this procedure, reflecting its significant risks 1, 3.
- Patients with VEXAS and known germ line predisposition should be preferentially managed within clinical programs or research protocols in partnership with experts in the field 4.
- For VEXAS/MDS patients, transplant indication may come from evaluation of severity of cytopenias, transfusion burden, and failure of immunosuppressive treatment 4.
Monitoring and Follow-Up
Regular clinic review at intervals under 7 weeks is typical practice for the majority (59.5%) of clinicians managing VEXAS syndrome 1.
- Monitor CRP as the preferred marker of disease relapse 1.
- Assess for cytopenias, particularly macrocytic anemia, which is a hallmark feature 3, 2.
- Evaluate for multisystem inflammatory manifestations including chondritis, neutrophilic dermatoses, vasculitis, and pulmonary inflammation 6, 2.
Multidisciplinary Care Structure
Both hematologists and rheumatologists serve as the main care providers (each representing 32.4% of managing clinicians), identifying the need for a multidisciplinary approach 1.
- Management requires coordination between hematology, rheumatology, and other specialties with expertise in autoinflammatory disorders 1, 3.
- Centralize care at centers with experience managing VEXAS syndrome whenever feasible 1.
Critical Pitfalls to Avoid
- Do not rely on traditional immunosuppressants or TNF inhibitors, as they are generally ineffective 3.
- Do not delay genetic testing when clinical suspicion is high, as diagnostic delay is common due to overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still's disease, and myelodysplastic syndromes 3, 6, 2.
- Do not use azacitidine in patients without concomitant MDS, as this is not the standard indication 1.
- Do not overlook the need for bone marrow examination to identify characteristic vacuoles in myeloid and erythroid precursors 3, 2.
Treatment Heterogeneity and Unmet Needs
Treatment modalities remain heterogeneous globally, with several unmet needs including lack of longitudinal follow-up data, absence of on-label drugs, and financial toxicity concerns 1.