VEXAS syndrome, immunodeficiency, and risk of infection

Background: VEXAS syndrome is a recently described X-linked somatic autoinflammatory syndrome which manifests with exaggerated hyperinflammation, an MDS-like syndrome, and probable immunodeficiency. Objective: The objective of this study is to describe the clinical presentation and outcomes of patients with VEXAS syndrome with a focus on immunodeficiency and infectious complications. Methods: We performed a retrospective case analysis of consecutive VEXAS patients seen in our center and a literature review surrounding immunodeficiency and infectious complications. Results: We identified five patients who were diagnosed with VEXAS syndrome between 2021 and 2023. All patients had autoinflammatory syndromes, UBA1 mutations, and characteristic vacuolization on bone marrow biopsy, while none met the criteria for MDS. Infectious complications were identified in all patients at the time of diagnosis. At presentation, patient 1 had Klebsiella pneumoniae bacteremia, patient 2 had disseminated nocardiosis, patient 3 had community acquired pneumonia (CAP), patient 4 had disseminated histoplasmosis, and patient 5 had CAP complicated by cavitary pulmonary lesions. Lymphocyte subset measurements revealed a reduced frequency of circulating effector T and B lymphocytes. All patients received corticosteroids and tocilizumab once infection was treated. Conclusion: We identified a trend of severe infections in five consecutive patients associated with peripheral B and T cell depletion. UBA1-mutations may directly contribute to infection risk through monocyte dysfunction and lymphocyte depletion. Future research should aim to establish the utility of infection prophylaxis.