Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: A comprehensive review of cases across different ethnicities

First author: Yixiang Yves-Jean Zhu

Journal: European Journal of Internal Medicine

Reference: https://doi.org/10.1016/j.ejim.2025.05.023

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a rare autoinflammatory disease associated with somatic pathogenic variants in the UBA1 gene. First described in 2020, it has since been reported in many countries, but its distribution across the world remained unclear. We conducted a literature review between October 2020 and April 2025, identifying more than 670 cases across 32 countries and 4 continents. Among patients with documented origins, several ethnic groups were represented, including Caucasian, East and South Asian, Middle Eastern, and South American. These findings confirm that VEXAS syndrome diverse ethnic backgrounds and has a broad worldwide distribution. It is therefore crucial to consider VEXAS in patients with compatible symptoms, regardless of their country or ancestry, to avoid diagnostic delays.

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VEXAS syndrome: what can we learn from France's experience with azacitidine?

Article title: Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from FRENVEX

First author: Vincent Jachiet

Journal: Blood

Link to the article: https://pubmed.ncbi.nlm.nih.gov/40373272/

Author of the abstract: Philippe Mertz

Three key points to remember:

1. Azacitidine is an effective treatment option for VEXAS syndrome even without associated myelodysplasia, with simultaneous effects on inflammation, cytopenias, and the UBA1 clone.

2. The response is often delayed and requires prolonged exposure (≥6 cycles) before evaluation. Adverse effects, particularly infectious ones, occur mainly in the first 3 cycles of treatment. Discontinuation of AZA leads to relapse in the majority of cases, suggesting a suspensive rather than curative effect.

3. Molecular monitoring (UBA1 VAF) allows for objective assessment of clonal response and could become a biomarker for monitoring this disease.

   
   

VEXAS syndrome is an acquired monogenic autoinflammatory disease associated with somatic mutations in the UBA1 gene. Patients present with a wide spectrum of severe inflammatory manifestations and cytopenias, which may be associated with myelodysplastic syndrome (MDS). Treatment is mainly based on corticosteroids, with frequent corticosteroid dependence despite associated sparing therapy with targeted therapies (anti-IL-6, anti-JAK, etc.) that have inconsistent efficacy. Azacitidine (AZA), a hypomethylating agent used in MDS, has shown potential in VEXAS, but published data remain limited.

This is a retrospective multicenter study conducted in France by the FRENVEX group, including 88 patients with genetically confirmed VEXAS who received at least one cycle of AZA between 2009 and 2024.

In this study, inflammatory response was defined as both clinical and biological improvement in systemic manifestations, including reduction in inflammatory symptoms and sustained decrease in biological markers such as CRP. The hematologic response followed the 2018 International Working Group criteria for MDS and corresponded to a significant improvement in cytopenias, including an increase in hemoglobin, platelets, or neutrophils, or a reduction in transfusion requirements. Finally, the molecular response was established on the basis of at least a 25% reduction in the mutational burden (VAF) of the UBA1 variant, assessed by targeted sequencing during treatment. Treatment side effects were described according to the Common Terminology Criteria for Adverse Events (version 5.0).

Inflammatory, hematological, and molecular responses were evaluated, as well as tolerance, regardless of the presence of associated MDS (present in 80%).

The main results of this study show:

• A partial or complete inflammatory response observed in 61% of patients (41% at 6 months, 54% at 12 months). The median response time was sometimes delayed (>6 cycles).

• A hematological response with improvement in hemoglobin in 65% and platelet count in 77%, with clinical benefit in terms of cytopenias and transfusion requirements.

• A molecular response with at least a 25% reduction in UBA1 mutation burden was observed in 65% of patients, correlating with the clinical response.

• Severe adverse events (grade III and IV) occurred in 60% of patients, mainly infections (34%) and cytopenias (36%), occurring predominantly in the first 3 cycles.

• 75% of patients relapse after stopping AZA (median duration of treatment-free period of 3.1 years), but resumption of treatment is effective in 80% of cases.

This study supports the use of AZA as first-line treatment in patients with VEXAS syndrome and severe cytopenias, or as second-line treatment in cases of failure of anti-inflammatory biotherapies, even in the absence of associated MDS. Treatment-related adverse effects, particularly infections, appear to occur mainly during the first 3 cycles of treatment. Prospective studies are needed to confirm its positioning and optimize the therapeutic strategy.

VEXAS syndrome: a French study explores neurological damage

Article title: Neurological manifestations in patients with VEXAS syndrome

First author: Charlotte Bert-Marcaz

Journal: J Neurol

Link to the article: https://pubmed.ncbi.nlm.nih.gov/39891740/

Author of the abstract: Philippe Mertz

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease linked to somatic mutations in the *UBA1* gene. It mainly affects men over the age of 50 and is characterized by systemic inflammation, hematological abnormalities, and skin manifestations. However, its neurological involvement, both central and peripheral, remains poorly understood and is likely underdiagnosed.

This multicenter retrospective study analyzed the neurological manifestations of patients with VEXAS included in the French national registry between November 2020 and March 2023. Of the 291 patients in the registry, 17 (6%) had neurological involvement. Thirteen additional cases were identified through a national call for observations, bringing the total to 30 patients. All were men, with a median age at diagnosis of 70 years (IQR: 68–77). The most common *UBA1* variant was *p.Met41Thr* (63%).

Five patients (17%) presented with initial neurological manifestations (3 PNS, 2 CNS), but none had isolated neurological involvement at baseline. The median time between VEXAS diagnosis and the first neurological involvement was 32 months (IQR: 18–48) for PNS and 17 months (IQR: 2–31) for CNS.

PNS involvement affected 70% of patients and included polyneuropathies, cranial nerve involvement, and multiple mononeuropathies. CNS involvement (30% of cases) included encephalopathies, lacunar infarcts, PRES syndrome, and optic neuritis. No patients had concomitant involvement of both systems, although several developed different neurological manifestations during the course of the disease. Ocular involvement (scleritis, episcleritis, anterior uveitis, periorbital inflammation) was more common in the PNS group (p = 0.045).

Among the 15 patients who underwent lumbar puncture for CNS involvement, 6 (60%) had hyperproteinorachia (>0.45 g/L) and 1 (10%) had pleocytosis (>5/mm³). Brain MRI (15/15) showed leukopathy (81%), ischemic lesions (40%), vasogenic posterior edema (19%), or pachymeningitis (7%).

Among the 24 patients who underwent lumbar puncture in cases of PNS involvement, 8/9 (89%) had hyperproteinorachia and none had pleocytosis. All patients who underwent electromyography (17/17) had nerve conduction abnormalities.

Corticosteroid therapy led to an improvement in neurological symptoms in 68% of cases. Some conditions responded very well: cranial nerves (86%), non-length-dependent polyneuropathies (75%), optic perineuritis (100%), lacunar infarcts (100%), and encephalopathy (100%). In four cases, the condition resolved spontaneously (one cranial nerve disorder, one lacunar infarction, two PRES). Conversely, polyneuropathies were often resistant (56% stable, 33% worsened). Corticosteroid-sparing treatments (ruxolitinib, azacitidine, tocilizumab) were used. Mortality was 30% after a median follow-up of 4 years, mainly due to infectious and cardiovascular complications.

In conclusion, neurological involvement in VEXAS is rare (6% of the cohort) but probably underdiagnosed. It is the initial presentation in nearly 17% of cases and is always associated with other signs of VEXAS. PNS involvement is more common than CNS involvement. The good response to corticosteroids in the majority of cases suggests a direct link between these manifestations and VEXAS. Systematic screening could allow for earlier and more appropriate management.

*PNS: Peripheral nervous system

*CNS: Central nervous system

Neurological manifestations in patients with VEXAS syndrome.pdf

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