VEXAS Syndrome: A Clinical Case Series from Calgary

Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was first described in November 2020.[1] It is typically an adult-onset, treatment-refractory autoinflammatory disorder caused by somatic mutations in the UBA1 gene.[1] Canadian data remain limited.[2] We describe a case series of 5 patients with VEXAS syndrome from Calgary, 2 of whom underwent allogenic hematopoietic stem cell transplant (alloHSCT) with excellent response.

Case Report This case series features 5 male patients (Table 1). The median age at disease onset was 65 (range 50-77) years. The median delay in diagnosis was 18 (range 1-46) months. The median disease duration was 44 (range 20-79) months. All patients had somatic UBA1 variants: p.Met41Val (n=2), p.Met41Thr, p.Met41Leu, and 1 uncharacterized p.? variant (Table 1). All patients reported constitutional symptoms. Initial working diagnoses included unspecified inflammatory condition, adult-onset Still’s disease, relapsing polychondritis (n=2), and atypical polyarteritis nodosa vs undifferentiated connective tissue disease (Table 1). Elevated inflammatory markers were observed in all patients (CRP frequently >100 mg/L). Vacuoles were confirmed on bone marrow biopsy in 4 patients. Three patients presented with, and 1 later developed, macrocytic anemia, whereas 1 patient had intermittent normocytic anemia. Thrombocytopenia and lymphopenia were each observed in 3 patients. Two patients developed myelodysplastic syndrome following diagnosis of VEXAS. Patients trialed several different therapies including hydroxychloroquine, methotrexate, azathioprine, mycophenolate, rituximab, anakinra, tocilizumab, tofacitinib, ruxolitinib, colchicine and dapsone with limited or no sustained benefit. Corticosteroids were required at moderate-to-high doses in most patients. At present, patient A is maintained on prednisone 35 mg daily. Patient B is taking prednisone 15 mg daily and ruxolitinib 20 mg twice daily. Patient C underwent alloHSCT in April 2025 with resolution of symptoms and discontinuation of prior medications (prednisone and ruxolitinib). Repeat bone marrow biopsy showed <0.5% UBA1. Patient D continues with prednisone 5-6 mg daily and azacitidine. Patient E underwent alloHSCT in August 2023. He developed chronic graft-versus-host disease requiring treatment with prednisone 7 mg daily and belumosudil. There was no evidence of UBA1 mutation on repeat bone marrow biopsy.

Conclusion In conclusion, this case series highlights the multisystem nature of VEXAS syndrome and the substantial diagnostic delay often encountered in clinical practice. We recommend considering VEXAS syndrome in patients with treatment-resistant autoinflammatory syndrome and cytopenias, especially macrocytic anemia. While conventional immunosuppressive medications have provided limited benefit, allogeneic hematopoietic stem cell transplant may be promising for select patients.

References [1.] Beck D. N Engl J Med 2020;383:2628-38. [2.] Williams S. J Rheumatol 2024;51:734-7.