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.

Somatic mutations in VEXAS Syndrome and Erdheim-Chester disease: Inflammatory myeloid diseases.

Somatic mutations have been increasingly identified as etiologic for many hematologic and autoinflammatory disorders. VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome and Erdheim-Chester disease (ECD), a type of histiocytosis, can be classified as inflammatory myeloid diseases, characterized by systemic inflammation and multi-organ disease with predisposition to myeloid malignancies. VEXAS is a novel disease caused by UBA1 mutations that was first discovered using a genotype-driven approach (genotype was used to identify patients with undiagnosed inflammatory diseases). Since the initial description, many VEXAS cases have been reported and disease phenotype is expanding rapidly. In contrast, ECD was first characterized in the 1930s based on patients' phenotype, and only recently found to be caused by recurrent somatic mutations in the MAPK pathway (traditional phenotype-driven approach). The discovery of these mutations and development of target therapies have revolutionized the treatment of patients with histiocytosis, particularly ECD. Here we discuss the impact of causal and associated somatic mutations in VEXAS and ECD at both clinical and molecular levels.

The net benefit of thrombolysis in the management of intermediate risk pulmonary embolism: Systematic review and meta-analysis.

Background: Benefit of thrombolytic therapy in patients with massive pulmonary embolism (PE) is evident. However, evidence supporting benefit in clinical outcomes of this approach in intermediate risk PE is lacking. Objective: To determine the impact of thrombolysis on overall survival in intermediate risk PE patients. Methods: We searched in MEDLINE (OVID), EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL) from present day. We also searched in other databases and unpublished literature. We included clinical trials without language restrictions. The risk of bias was evaluated with the Cochrane Collaboration's tool. The primary outcome was overall survival. Secondary outcomes were adverse events, including major bleeding, and all-cause mortality. The measure of the effect was the risk ratio with a 95% confidence interval (CI). Results: We included 11 studies in the qualitative and quantitative analysis, with a total of 1855 patients. Risk of bias was variable among the study items. There were no results reported about overall survival in any of the studies. The risk ratio (RR) for all-cause mortality was 0.68 95% CI (0.40 to 1.16). The RR of overall bleeding, major bleeding and stroke were 2.72 95% CI (1.58 to 4.69), 2.17 95% CI (1.03 to 4.55), and 2.22 95% CI (0.17 to 28.73), respectively. Additionally, the RR for recurrent PE was 0.56 95% CI (0.23 to 1.37). Conclusions: In patients with intermediate risk PE, the risk of bleeding is higher when thrombolysis is used. There was no significant difference between thrombolysis and anticoagulation in recurrence of PE, stroke, and all-cause mortality.