VEXAS syndrome and cancer: Insights about a possible “Tip of the Iceberg”. Ambidirectional data from the international AIDA network registries

Background VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an acquired autoinflammatory disorder characterized by severe chronic inflammation and an increased occurrence of hematologic neoplasms. Although chronic inflammation is a well-established risk factor for cancer, the specific contribution of UBA1 gene mutations to tumorigenesis remains unclear. Therefore, this study aimed to evaluate the overall cancer risk in patients with VEXAS syndrome, including both hematologic and non-hematologic neoplasms. Methods The relative risk (RR) of cancer was compared between VEXAS patients and a control cohort comprising individuals with Still's disease, Beh & ccedil;et's disease, and Schnitzler's syndrome. Logistic regression analysis was performed to identify variables potentially associated with cancer development. Patient's data were drawn from the International AutoInflammatory Disease Alliance (AIDA) Network registries for VEXAS syndrome, Still's disease, Beh & ccedil;et's disease, and Schnitzler's syndrome. Results Ninety-six VEXAS patients and 2181 controls were enrolled. To minimize selection bias, only subjects aged >60 years were included, yielding 90 and 174 individuals in the exposed and control groups, respectively. The overall RR for cancer in VEXAS patients was 1.93 (95 % Confidence Interval [C.I.] 1.03-3.60, p = 0.036). Logistic regression analysis identified associations between cancer development and relapsing polychondritis (RR = 2.67, 95 %C.I. 1.22-10.64, p = 0.01), the p.Met41Thr mutation (RR = 3.33, 95 %C.I. 1.29-17.33, p = 0.02), elevated serum erythrocyte sedimentation rate (RR = 1.02, 95 %C.I. 1.01-1.05 p = 0.01), and lactate dehydrogenase (RR = 1.02, 95 %C.I. 1.01-1.07 p = 0.04) levels outside of flares. Conclusions VEXAS patients exhibit a significantly increased risk of both hematologic and non-hematologic malignancies compared with controls, particularly among those with RP, p.Met41Thr mutation, and persistent systemic inflammation.