Article title: Mapping the infectious burden in VEXAS syndrome:a systematic review and rationale for prevention
First author: Valentine Ribier
Journal: Lancet Rheumatology
Link to the article: https://doi.org/10.1016/S2665-9913(25)00225-5
Author of the abstract: Rim BOURGUIBA
Introduction:
VEXAS syndrome is an autoinflammatory disease associated with somatic mutations in the X‑linked UBA1 gene. Patients present with systemic inflammatory manifestations and an increased susceptibility to infections. In the French cohort, more than 50% of mortality was attributed to infections. Several factors have been identified as contributors to infection risk in these patients: long‑term corticosteroid therapy, combination and prolonged use of immunosuppressive treatments such as JAK inhibitors, and a likely functional immune deficiency of myeloid cells related to the disease itself. Multiple publications have reported opportunistic and invasive infections in VEXAS even in the absence of immunosuppressive or immunomodulatory therapy. Few recommendations existed regarding infection prophylaxis in VEXAS. The objectives of this review were: 1) to characterize the spectrum of infections in VEXAS, 2) to identify a high‑risk subgroup for infections, and 3) to propose a preventive strategy to reduce infection‑related complications.
Methods:
This systematic review followed PRISMA guidelines. The literature search included publications from October 2020 to October 31, 2024 without language restrictions on PubMed. The authors included case reports and case series. Eligibility criteria were the presence of infection, its frequency, and its nature among patients with VEXAS syndrome. Infection was confirmed when a pathogen was identified. A severe infection was defined as one requiring hospitalization with intravenous antibiotic therapy or resulting in death.
Results:
The authors identified 506 potentially eligible studies; after exclusions, 57 studies were retained, encompassing 813 patients.
Infection frequency was high: 37–60% of patients experienced at least one infection, with 12–15% dying from infections in large cohorts. Severe infections accounted for up to 60% of cases. The most frequent infection sites were respiratory (28–59%), skin and soft tissue (10–49%), and bloodstream (bacteremia 8–13%), with genitourinary and gastrointestinal infections less common. Main pathogens included bacteria (Gram‑negative bacilli and Gram‑positive cocci), and opportunistic infections such as Legionella, atypical mycobacteria, Pneumocystis jirovecii, VZV, CMV, HSV, Aspergillus, and Nocardia. (Figure 1)
Factors associated with infections included exposure to immunosuppressive treatments: azacitidine was associated with 44–62% infections, including deaths; IL‑6 inhibitors with 29–47%; and JAK inhibitors with 18–37%. IL‑1 inhibitors were associated with a lower rate (3%). Chronic corticosteroid therapy was associated with mycobacterial infections or pneumocystosis.
The authors proposed the following prevention strategy:
Targeted anti‑infective prophylaxis, for example co‑trimoxazole to prevent Pneumocystis jirovecii pneumonia and valaciclovir to prevent VZV reactivation.
Systematic vaccinations, including influenza, pneumococcus, VZV, and SARS‑CoV‑2, despite a potential for reduced vaccine responses.
Comprehensive infectious disease screening before initiating immunosuppression, including serologies (HIV, HBV, HCV, TB) and chest CT.
Conclusion:
VEXAS syndrome is associated with a major predisposition to infections, resulting from both an intrinsic immune deficit linked to UBA1 mutation and the effects of immunosuppressive treatments. Infections are a leading cause of morbidity and mortality, particularly affecting the respiratory tract and skin. Prevention should be a central pillar of care, based on vaccination, targeted anti‑infective prophylaxis, and risk assessment prior to any immunosuppression. These data support an integrated, multidisciplinary, and proactive approach to improve survival and quality of life for people living with VEXAS.
Figure 1: Distribution of infection sites and pathogens across studies
