VEXAS syndrome: from a vascular perspective

In this issue of Blood, Kusne et al¹ described the incidence of venous and arterial thrombosis in a large cohort of patients with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, and its association with clinical and survival outcomes.

VEXAS syndrome is a recently described autoinflammatory disease characterized by somatic mutation of UBA1, a gene on the X chromosome that encodes the E1 enzyme that initiates protein ubiquitination in the cell cytoplasm.² Patients present with a wide range of systemic manifestations, including recurrent fever, chondritis, skin lesions, and/or joint involvement. They also present with hematologic abnormalities, such as macrocytic anemia, myelodysplasia, or plasma cell dyscrasias.³ Moreover, a significant proportion of patients with VEXAS syndrome experience venous thrombosis events. For example, in the case series of Georgin-Lavialle et al, 35% of patients had an unprovoked venous thrombosis.³ Data on arterial involvement are scarce and suggest a lower prevalence than venous thrombosis, ranging from 1% to 10%.^3,4 However, no study has yet specifically addressed the question of the incidence of thrombosis within a meaningfully large cohort.

With this context, Kusne et al provide valuable insight into thrombosis in VEXAS syndrome in a large cohort of 119 patients. Consistent with existing studies, venous thrombotic events occurred more frequently (n = 49 [41%]) than arterial thrombosis (n = 15 [13%]). The study reports a 40% cumulative incidence of venous thromboembolism at 5 years. Among the 49 patients with venous thromboembolism, 35% had a pulmonary embolism, and 65% of venous thrombotic events were unprovoked. The pathogenesis of venous thrombosis in VEXAS syndrome remains unclear, although several mechanisms have been proposed, including systemic inflammation, vessel wall inflammation, endothelial dysfunction, coagulation cascade activation, and the presence of anti-phospholipid antibodies.^4,5 These mechanisms might combine to form the classic Virchow triad of thrombosis: altered blood flow, hypercoagulability, and vessel wall injury.

First, inflammation is a well-known risk factor for venous thromboembolism, especially in several inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis, with an increased risk during acute flares. In VEXAS syndrome, UBA1 gene mutations lead to impaired ubiquitination, activating the innate immune system and releasing proinflammatory cytokines, such as tumor necrosis factor-α, interferon gamma, interleukin-6, and interleukin-8.² In this cohort, most patients who experienced venous thrombosis were not on corticosteroids or immunosuppressive treatment at the time of the event, and most of thrombosis occurred early in the disease course, suggesting that uncontrolled disease might contribute to thrombosis risk. Second, a previous study reported that vasculitis in 2 patients with VEXAS syndrome might contribute to thrombosis pathogenesis due to vein vessel wall inflammation, as described in Behçet disease.⁶ Finally, the authors reported an increased factor VIII (FVIII) activity in their cohort and a high incidence of lupus anticoagulant (LA), in line with existing literature. However, patients who did not experience thrombosis also had increased FVIII activity, and the presence of LA did not correlate with thrombosis. Consequently, interpreting these findings as indicative of a thrombotic risk or hypercoagulability state is difficult, as they could be false positives due to concomitant inflammation. Further studies will be required to investigate a patient’s hypercoagulability and to determine whether the increased venous thrombosis rate observed is only due to the inflammatory process or whether specific mechanisms are intrinsic to VEXAS syndrome.

Interestingly, 41% of patients experiencing venous thrombosis had recurrent venous thrombosis, and 20% had venous thrombosis while on therapeutic anticoagulation. Although venous thrombosis was not associated with poorer overall survival in this cohort, venous thromboembolism is reported as 1 of the leading causes of disability-adjusted life years lost in hospitalized patients and should be prevented.⁷ This underscores the need for better thrombosis risk stratification among patients with VEXAS syndrome and further studies investigating anticoagulant strategies in terms of dosages and duration, especially as patients with VEXAS syndrome are typically older individuals with cytopenia, therefore presenting a high bleeding risk.

Regarding arterial events, the authors report an 11% cumulative incidence at 5 years from symptom onset. Among the 15 patients with arterial thrombosis, myocardial infarction, stroke, and acute or chronic lower limb ischemia were observed. Those results are complex to interpret given the older population with VEXAS syndrome with frequent cardiovascular risk factors. Almost half of these patients had arterial hypertension or hyperlipidemia, and nearly a quarter had diabetes or were smokers, factors likely contributing to significant atherosclerosis. Further studies are needed to assess whether arterial events are more frequent among patients with VEXAS syndrome than among similar cardiovascular high-risk patients. Still, there are many reasons why this patient population would have an increased risk for arterial event incidence, such as vascular wall inflammation, as seen in giant cell arteritis, accelerated atherosclerosis, as observed with other autoimmune diseases, or secondary to the effect of glucocorticoid exposure or Janus kinase inhibitors.⁸ Additionally, patients with VEXAS syndrome have had a high frequency of typical clonal hematopoiesis mutations, particularly DNMT3A and TET2,⁹ known to be associated with coronary heart disease and accelerated atherosclerosis.¹⁰ Confirming the increased risk of arterial events in VEXAS syndrome and identifying responsible mechanisms are essential for implementing cardiovascular preventive measures and evaluating the benefit-risk balance of immunosuppressive treatments known for adverse cardiovascular effects.

The authors' findings both confirm and expand on the existing literature on thrombosis incidence among patients with VEXAS syndrome, offering fresh insights into the vascular nature of VEXAS syndrome. Further investigations are required to better understand the mechanisms involved in the pathogenesis of venous thrombosis and the anticoagulation strategies to be employed, and to determine whether patients with VEXAS syndrome face an increased arterial risk beyond that attributable to age-adjusted atherosclerosis.

Conflict-of-interest disclosure: The author declares no competing financial interests.