VEXAS Syndrome

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset autoinflammatory disease caused by somatic UBA1 mutations in haematopoietic cells.

• Predominantly men over 50 (X-linked, somatic mutation of UBA1 at methionine-41).

• Features: macrocytic anaemia, myelodysplasia, thrombocytopenia, vacuolated myeloid and erythroid precursors, venous thromboembolism.

• Prevalence about 1 in 4000 men over 50.

• Overlaps with relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis.

• Mortality high (about 40% at 5 years), from infection, myelodysplasia, thrombosis, steroid complications.

• Recurrent fever, neutrophilic dermatosis (Sweet-like, tender erythematous papules and plaques), chondritis (ear, nose), lung infiltrates, arthritis, orbital inflammation, vasculitis (cutaneous, medium vessel).

• Venous thromboembolism in a third.

• Fatigue, weight loss, cytopenias, steroid dependence.

• Macrocytic anaemia (MCV over 100), thrombocytopenia, lymphopenia, raised CRP/ESR, ferritin, hypergammaglobulinaemia.

• UBA1 sequencing on blood (somatic p.Met41 variants, allele fraction 20 to 90%) is diagnostic.

• Bone marrow: cytoplasmic vacuoles in myeloid and erythroid precursors, dysplasia, hypercellularity; cytogenetics (rule out MDS); skin biopsy (neutrophilic dermatosis, leukocytoclastic vasculitis).

• Chest CT for infiltrates, nasal/ear chondritis imaging, thrombosis imaging.

• Exclude relapsing polychondritis, Behçet, Still disease, MDS, infection.

• Glucocorticoids are required but high doses (prednisolone 20 to 40 mg or more) are needed to control disease; dependence and toxicity are common.

• Steroid-sparing therapy has limited efficacy: JAK inhibitor ruxolitinib 10 to 20 mg twice daily (most effective, monitor cytopenias and infections), tocilizumab 162 mg weekly or 8 mg/kg monthly, IL-1 blockade (anakinra 100 mg daily, canakinumab), methotrexate, mycophenolate, cyclosporin, azacitidine 75 mg/m2 for 7 days monthly in myelodysplasia with inflammation.

• Allogeneic haematopoietic stem cell transplant is potentially curative, for selected patients with refractory disease and high-risk features.

• Thromboprophylaxis or therapeutic anticoagulation for venous thromboembolism (apixaban 5 mg twice daily).

• Infection prophylaxis (co trimoxazole 960 mg three times weekly), antiviral prophylaxis, bone protection, transfusions.

• Monitor counts and inflammatory markers monthly; MDS surveillance.