Background: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a multisystemic autoinflammatory disease caused by somatic mutations in UBA1 (Ubiquitin-like modifier activating enzyme 1), affecting predominantly middle-aged male. Hematologic findings are common, including macrocytic anemia, myelodysplasia, vacuolization of in the bone marrow (BM) precursors.

Objectives: To describe a single center experience regarding treatment strategies and outcomes.

Methods: Retrospective review of demographic, clinical and laboratory features, treatment strategies, disease activity and outcome of patients with genetically confirmed VEXAS syndrome, followed at our tertiary university hospital center.

Results: Seven male patients were identified, median age at disease onset of 72 years (range 65-78), at last visit of 75 years (range 69-86), with median duration of disease of 6 years (range 1-7). UBA1 variant c.121A>C (p.Met41Leu) was identified in 4 (57%), c.121A>G p.(Met41Val) in 2 (29%) and c.122T>C(p.Met41Thr) in 1 (14%). The most common clinical inflammatory involvement was cutaneous (n=7, 100%), including Sweet-like lesions in 5 (71%). Constitutional involvement was present in all but one patient (n=6, 86%). Recurrent fever/low-grade fever was present in 5 (71%), as was chondritis. Ocular inflammation was present in 4 (57%). Hematologic manifestations were frequent, with macrocytic anemia present in all, often accompanied by leukopenia (n=4, 57%) and thrombocytopenia (n=4, 57%). Myelodysplastic syndrome (MDS) was identified in 6 (86%), multilineage MDS in 3 (43%). Most patients (n=4, 57%) scored for low-risk categories in the Revised International Prognostic Scoring System (IPSS-R) for MDS. Monoclonal gammopathy was identified in 4 (57%). Thrombotic manifestations were present in 3 (43%). Corticosteroid-dependent disease behaviour was seen in all patients, with a minimum dose for response of at least 10mg/day (prednisolone) during the course of disease. Failure to control disease activity or the need for high doses of corticosteroids led to add-on therapy with tocilizumab in 4 (57%) patients. Tocilizumab response failure was observed in 2 (50%), one of which was switched to ruxolitinib. One patient was treated with add-on methotrexate and another with corticosteroids plus imatinib (for t(9;22) positive refractory anemia with excess blasts (RAEB)). Three (43%) patients died during follow-up, one with leukemic transformation of RAEB (6 years after first symptoms – Met41Val), the other two with sepsis (1 – Met41Val, and 6 years – Met41Leu, after first symptoms). Transfusion dependency was observed in 4 patients (3 of which died). Clinical remission was never attained despite treatment in 3 (43%). For patients on active follow-up, disease activity at the last visit was classified as low in 2 patients (1 on corticosteroids monotherapy, 1 on corticosteroids plus tocilizumab), moderate in 1 patient (on corticosteroids plus tocilizumab) and high in 1 patient (on corticosteroids plus ruxolitinib).

Conclusion: VEXAS syndrome presents as both a diagnostic challenge in the older patient with inflammatory/hematologic manifestations, and a treatment challenge, in the absence of standard treatment guidelines, frequently evolving progressively with significant morbimortality. The risk for severe infection cannot be underestimated, related in part to the immunosuppressive therapies. Further data will be necessary to better define clinical subsets of patients, prognosis and treatment response.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: None declared.