Venous and arterial thrombosis in patients with VEXAS syndrome

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS syndrome. The risk factors and frequency of thrombosis in VEXAS syndrome are not well described, due to the disease's recent discovery and the paucity of large databases. We evaluated 119 patients with VEXAS syndrome for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two-thirds of VTEs were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism by univariate (odds ratio [OR]: 4.58, confidence interval [CI] 1.28-16.21, P = .02) and multivariate (OR: 16.94, CI 1.99-144.3, P = .01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival of the entire patient cohort at median follow-up time of 4.8 years was 88%, and there was no difference in survival between patients with or without thrombosis (P = .8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.

Graphical abstract

Figure 1.

Cumulative incidence of thrombosis in VEXAS syndrome. Fine-Gray competing risk regression models using death as a competing risk. (A) The cumulative incidence of VTE was 33% at median follow-up of 890 days, 17% by 1 year, and 40% by 5 years. (B) The cumulative incidence of arterial thrombosis was 9% at median follow-up of 890 days, 6% at 1 year, and 11% at 5 years. (C) The cumulative incidence of PE was 9.7% at median follow-up of 980 days, 4% by 1 year, and 13% by 5 years. (D) The cumulative incidence of DVT was 29% at median follow-up of 890 days, 16% by 1 year, and 35% by 5 years. (E) The cumulative incidence of VTE by UBA1 variant was 7% for M41L, 22% for M41V, and 18% for M41T at 1 year and 46% for M41L, 37% for M41V, and 41% for M41T. No patients with splice site variants had VTE.

Figure 2.

Predictors of VTE in VEXAS syndrome. Fine-Gray competing risk regression models using death as a competing risk: (A) VTE; (B) DVT; (C) PE. ∗P < .05. MSK, musculoskeletal; RP, relapsing polychondritis.

Figure 3.

OS of patients with VEXAS syndrome. (A) OS was not significantly different between those with or without thrombosis (P = .8). (B) Forest plot for survival. Using univariate Cox PH model, age at disease onset was significantly associated with survival (HR 1.07, P = .049) as were pulmonary manifestations or pulmonary effusions (HR 3.05, P < .0001). ∗P < .05. MSK, musculoskeletal; RP, relapsing polychondritis.

Figure 4.

Coagulation assay values for patients with VEXAS syndrome with and without thrombosis. There was no significant difference between those with thrombosis and those without in fibrinogen level (A), D-dimer (B), antithrombin III (C), protein C (D), VWF antigen (F), VWF activity (G), protein S (H), FVIII (I), FIX (J), FX (K), FXI (L), FII (M), FV (N), and FVII (O). However, plasminogen level (E) was significantly lower in those who had thrombosis (P = .034). ns, not significant.