Comprendre le syndrome VEXAS : Causes, symptômes et prise en charge

Une maladie auto-inflammatoire rare

Dans cet article, le Journal des Femmes Santé examine les causes, les symptômes et la gestion de cette maladie, avec des éclaircissements du Professeur Sophie Georgin-Lavialle, interniste à l'hôpital Tenon.

Le syndrome VEXAS est une maladie inflammatoire rare, décrite pour la première fois en 2020. Son nom est un acronyme qui signifie Vacuoles, enzyme E1 (UBA1), liée à l'X, auto-inflammatoire, somatique. Cette maladie est causée par une mutation acquise (somatique) du gène UBA1, situé sur le chromosome X. Cette mutation entraîne une inflammation chronique excessive dans tout le corps.

Qui est touché par le syndrome VEXAS ?

Cette maladie touche principalement les hommes de plus de 50 ans. Étant donné que les mutations ne sont pas présentes à la naissance, les symptômes apparaissent à l'âge adulte. Le plus jeune patient décrit avait 46 ans.

Symptômes courants

Les symptômes du syndrome VEXAS incluent :

• Anémie

• Fièvre persistante

• Fatigue sévère

• Douleurs dans les grandes articulations

• Lésions cutanées

• Perte de poids et perte d'appétit

• Inflammation du cartilage (oreilles, nez – chondrite)

• Possible atteinte pulmonaire

• Marqueurs inflammatoires fortement élevés (CRP)

  
  

Diagnostic et gestion

Le diagnostic repose sur le séquençage génétique. Cela a permis d'identifier de nombreux patients qui avaient été précédemment mal diagnostiqués avec d'autres maladies inflammatoires ou hématologiques.

Il n'existe pas de phase aiguë typique : l'inflammation est continue, parfois accompagnée de poussées.

Pourquoi certaines personnes développent-elles cette mutation ?

Le syndrome VEXAS reste mal compris, en particulier en ce qui concerne les raisons pour lesquelles certaines personnes développent cette mutation tandis que d'autres ne le font pas.

Conclusion

La recherche continue d'évoluer pour mieux comprendre cette maladie complexe. Il est essentiel de sensibiliser davantage à cette condition afin d'améliorer la prise en charge des patients. Pour en savoir plus sur le syndrome VEXAS, vous pouvez consulter cet article sur Journal des Femmes Santé.

Le Centre de Référence des Maladies Auto-Inflammatoires et de l’Amylose de Tenon (CEREMAIA-Tenon) s'engage à être le leader national dans la prise en charge experte, la recherche et l'éducation pour les maladies auto-inflammatoires rares et l'amylose. Cela vise à améliorer la vie des patients adultes.

CAPS: Improving Our Understanding of a Rare Inflammatory Disease Caused by a Partial NLRP3 Gene Mutation

Summary by: Dr Yixiang Yves-Jean Zhu

First author: Bonet N.

Journal: Journal of Clinical Immunology

Reference: J Clin Immunol. 2025 Sep 30;45(1):134. doi: 10.1007/s10875-025-01922-x

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/41026232/

Introduction:

Cryopyrin-associated periodic syndrome (CAPS) is a rare monogenic autoinflammatory disease associated with gain‑of‑function variants in the NLRP3 gene. These variants lead to constitutive activation of the corresponding inflammasome and excessive production of IL‑1β. The classic manifestations combine a urticaria‑like rash, arthralgia, recurrent fever, neurologic involvement, and sensorineural hearing loss, in a context of biological inflammation (elevated CRP). Within the clinical spectrum of CAPS, Neonatal Onset Multisystem Inflammatory Disease (NOMID) stands out because of its particular severity. Current treatment relies on IL‑1β‑blocking agents, and specific *NLRP3* inflammasome inhibitors such as MCC950 are under investigation. Transmission is usually autosomal dominant, but some cases result from post‑zygotic mutations leading to mosaicism, a phenomenon that remains poorly documented. This retrospective Spanish study reports the largest cohort to date of CAPS patients with NLRP3 mosaicism, providing clinical, genetic, and functional analyses of 17 patients.

Main results:

-Clinical characteristics: Seventeen individuals (7 men, 10 women) were included. Four had a NOMID phenotype, 14 had a CAPS phenotype other than NOMID, and one individual was asymptomatic. The mean age at onset was 26 years (range 0.1–76 years), with two patient subgroups: an early‑onset group (< 5 years) including 6 patients, and a late‑onset group (> 45 years) including 6 patients. The most frequent manifestations were a urticaria‑like rash (100%), arthralgia (87%), recurrent fever (75%), arthritis (68%), and headache (56%).

- Response to treatment: All symptomatic patients received an IL‑1 inhibitor: anakinra (14 patients) or canakinumab (2 patients). A complete response with CRP normalization and clinical improvement was observed in 94% of patients. One case with partial response to anakinra was successfully controlled after switching to canakinumab.

- Genetic and functional data: Sixteen different NLRP3 variants were identified, all located in exon 4, with allele frequencies ranging from 1.3% to 34.8%. In vitro studies confirmed hyperactivation of the inflammasome, which was sensitive to the specific NLRP3 inhibitor MCC950, except for the D303H variant, which was partially resistant.

- Clonal evolution: Longitudinal follow‑up showed stable allele frequency in 54% of cases, an increase in 23% (mainly in patients older than 50 years, suggesting possible clonal hematopoiesis carrying the pathogenic NLRP3 variant, and a decrease in 23%, which may reflect “fatigue” of the mutant clone.

- Distribution of mosaicism: In 64% of patients, mosaicism involved at least myeloid and lymphoid cells, while 36% had mosaicism restricted to myeloid cells. No major clinical differences were observed between these mosaic patterns.

Practical message:

This largest‑to‑date study of mosaic CAPS shows that:

- The clinical picture and treatment response are comparable to those of germline CAPS, and functional studies reveal a similar activation profile.

- Mosaicism may remain stable or fluctuate over time, and the usefulness of monitoring allele frequency for follow‑up remains to be determined.

- Mosaicism may be restricted to myeloid cells, suggesting a later‑acquired variant, without apparent impact on clinical features.

A diagnosis of CAPS should not be ruled out in patients with a compatible phenotype solely on the basis of negative family history. Screening for NLRP3 mosaicism is essential in any adult with a suggestive CAPS presentation, as these patients also show an excellent response to IL‑1 inhibitors. Because mosaicism is more sensitively detected by high‑throughput sequencing, this technique should be preferred when CAPS is suspected, with sufficient read depth to identify low‑frequency allele mosaicism.

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.

(VEXAS) syndrome: A comprehensive review of cases across different ethnicities.pdf

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