Clinical and Pathological Features of VEXAS in Sweet Syndrome-Diagnosed Males

Summary: Background VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disorder first described in 2020. It results from a mutated gene, UBA1, which encodes a ubiquitin activating E1 enzyme on the X-chromosome. VEXAS often presents first with cutaneous manifestations – typically, neutrophilic dermatoses mimicking Sweet syndrome. As the constellation of VEXAS symptoms are now defined, we identified the presence of symptoms potentially indicative of VEXAS syndrome in a population previously diagnosed with Sweet syndrome. Methods In this single-center retrospective study, 35 male patients with Sweet syndrome diagnosed between January 1, 2008 and December 31, 2020 and bone marrow and skin biopsy reports were included for chart review. The study received approval from our institutional IRB Board (Protocol Number 832147). Results Most males were white (77%) and 50-69 years old (25%, Table 1.) 66% of patients were diagnosed with malignancy-associated Sweet syndrome, most commonly acute myeloid leukemia (49%) and myelodysplastic syndrome (31%) at the time of diagnosis. Etiology was indeterminate between malignancy or a drug for 29% of cancer patients. The most commonly mentioned drugs associated with Sweet syndrome were azacytidine (23%), G-CSF (17%), and topoisomerase inhibitors (17%). Most patients (63%) presented with diffuse cutaneous lesions (Table 2). Isolated lesions were typically located on the head and neck (46%) or upper extremities (54%). Skin biopsy reports mentioned vasculitis in 14% and subcutaneous nodules in 9% of males. Cell vacuolization, a hallmark of VEXAS, was mentioned in 31% of bone marrow and 6% of skin biopsy reports. 89% presented with systemic symptoms co-occurring with their initial cutaneous lesions, particularly fever. 83% of patients were anemic and 80% were thrombocytopenic. 29% had pulmonary infiltrates on chest imaging. 40% of patients relapsed or did not respond to initial treatment, typically comprised of topical or systemic corticosteroids. 83% of patients are deceased, 59% of which were presumed malignancy-related deaths. Conclusions 30-40% of males diagnosed with Sweet syndrome demonstrated clinical and pathological hallmarks of VEXAS, most notably vacuolization and relapse or nonresponse to typical Sweet syndrome treatments with poor prognosis. Though confirmatory UBA1 testing is not yet performed, males exhibiting the signs we described may be considered for UBA1 testing.