Case Presentation: Our patient is a 73-year-old male with past medical history including monoclonal gammopathy of undetermined significance (MGUS), inflammatory symmetric arthritis, relapsing chondritis, bilateral episcleritis/scleritis, sinusitis, bilateral deep vein thromboses and recurrent pleural effusions. This was refractory to methotrexate, infliximab, rituximab, tofacitinib, and abatacept. He had not tolerated cyclophosphamide, tocilizumab, or sarilumab due to severe neutropenia. He was on chronic high dose prednisone and rivaroxaban. In the setting of multiple therapies resulting in inadequate control, a bone marrow biopsy (BMx) was done for further evaluation. This showed clonal cytopenias of uncertain significance and vacuolization. Genetic testing revealed a UBA1, DNMT3A and TET2 mutation diagnostic of VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome. He was started on ruxolitinib, but a few months later developed macrocytic anemia. A repeat BMx showed MDS and a bone marrow transplant (BMT) was planned. Two days prior to the BMT, he presented to our hospital with severe bilateral lower extremity weakness and febrile neutropenia. After an extensive unrevealing workup, he was transferred to his transplant center where a BMT was done. Two years later, he is doing well off steroids and immunosuppressants.

Discussion: VEXAS syndrome is an acquired monogenic autoinflammatory disease caused by somatic mutations of the UBA1 gene in blood cell precursors. This causes an overactive myeloid compartment with excessive pro-inflammatory cytokine signaling and systemic inflammation. The mortality rate is 12-40%. [1,2,3,4]This syndrome confers several challenges. Firstly, VEXAS can mimic systemic rheumatologic disorders and coexist with hematological disorders. Our patient had MGUS, inflammatory symmetric arthritis, relapsing chondritis, bilateral episcleritis/scleritis and sinusitis which are commonly seen in patients with VEXAS. [5] Second, coordination of multidisciplinary care can be time consuming and delay diagnosis. Our patient waited 18 months between rheumatology recommending a BMx and hematology reviewing the results. The characteristic features are often missed on the initial biopsy read and specific evaluation needs to be requested. [6]Third, there are no clear guidelines to inform patient care. Inflammatory manifestations typically improve on high dose of steroids. Other agents including calcineurin inhibitors, synthetic immunosuppressants biologics and hypomethylating agents have variable rates of response. Our patient’s inflammation was refractory to several medications. BMT, as undertaken our patient, is the only curative option. [7,8,9] Finally, the available treatment carries significant toxicity. [9] Our patient developed osteopenia with steroid use and severe neutropenia when cyclophosphamide, tocilizumab, and sarilumab were tried. Following his BMT, he developed BK virus cystitis and an Achromobacter bacteremia with an epidural abscess requiring surgical wash out.

Conclusions: The diagnosis of VEXAS syndrome requires a high degree of suspicion and should be considered in males over 50 years old with systemic inflammation involving multiple organs and cytopenias. [8] Hospitalists are likely to encounter these patients at some point during their clinical course and have the inpatient resources to initiate appropriate work up and coordinate multidisciplinary care which may expedite diagnosis and management.