Case Presentation: A 70-year old-man with a history of HLA-B27-associated anterior uveitis, spondyloarthropathy, and drug- induced leukocytoclastic vasculitis on chronic prednisone and mycophenolate, presented with 3-weeks of worsening fatigue and weakness. At admission, he was afebrile, tachycardic, and had a diffuse rash. On day 2, he began spiking fevers. Labs were notable for WBC count of 7.9uL, Hgb 6.7g/dL, and platelets 48uL. Inflammatory markers revealed a ferritin of 42,807 ng/ml, CRP 12.9mg/dL, and ESR 28mm/hr. Creatinine and liver enzymes were abnormally elevated as well. Extensive infectious and rheumatologic workup were unrevealing, but his inflammatory markers and cytopenias worsened. He underwent bone marrow biopsy as his hemophagocytic lymphohistiocytosis (HLH) H-score was 161, indicating 41-50% probability of having the syndrome. Empiric treatment for HLH was started with high-dose IV steroids and anakinra, an IL-1 receptor antagonist. Soluble IL-2 returned elevated at 11,191.6 pg/ml. Bone marrow biopsy revealed hemophagocytic cells and dyserythropoiesis due to vacuole irregularities and slight left shift in myeloids concerning for HLH and an evolving myeloid neoplasm. His clinical course deteriorated when attempts were made to taper HLH treatment. Previously ordered UBA1 genetic testing showed a pathologic mutation consistent with Vacuoles, E1, X-linked, autoimmunity, somatic (VEXAS) syndrome. The patient continued to decline, and he transitioned to comfort measures.
Discussion: VEXAS syndrome is a novel, autoimmune disease with overlapping inflammatory and hematologic features first discovered in 2020. It consists of rheumatologic and hematologic abnormalities secondary to an acquired X-linked mutation in the UBA1 gene (1). VEXAS primarily affects men, middle-aged or older, presenting with recurrent fevers and evidence of inflammation most commonly involving the skin, joints, and lungs (2). A number of autoimmune disorders have been associated with VEXAS including spondylarthritis, relapsing polychondritis, and vasculitides among others (3). The most frequent hematologic manifestations include macrocytic anemia, myelodysplastic syndrome (MDS), and bone marrow vacuolization affecting myeloid precursor cells (2). Some studies suggest the prevalence of VEXAS is approximately 1 in 13,591 adults, which is higher than previously thought (4). Currently, there is no established treatment for VEXAS and mortality from the disease remains high because of its widespread involvement. Therapeutic regimens have all included glucocorticoids, but a number of immunotherapies such as tocilizumab and janus kinase inhibitors have been proposed as well (3). Additionally, some cases have been treated with bone marrow transplants with mixed outcomes (5).
Conclusions: VEXAS syndrome is a newly discovered, auto-inflammatory condition with progressive hematologic and rheumatologic manifestations. Patients can present with a variety of non-specific complaints across multiple organ systems. Clinicians should consider VEXAS syndrome in the differential diagnosis when patients present with treatment refractory autoimmune conditions that co-occur with hematologic abnormalities, especially MDS. In the absence of successful, standardized therapies, it is critical to identify more patients with this disease in order to conduct further research regarding its pathophysiology and potential treatments.
