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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


VEXAS syndrome: A comprehensive review of cases across different ethnicities

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: 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
Author of the abstract: Philippe Mertz

Efficacité et tolérance de l’azacitidine dans le syndrome VEXAS : données rétrospectives de la cohorte française FRENVEX

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 as a new differential diagnosis of late onset spondyloarthritis

Article title: Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé

First author: Jain H

Journal: MEDITERRANEAN JOURNAL OF RHEUMATOLOGY

Author of the abstract: Philippe Mertz


Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene, mainly observed in people over the age of 50. This gene encodes a key enzyme in the ubiquitination process, whose dysfunction leads to the activation of several inflammatory pathways. Signs suggestive of VEXAS syndrome include macrocytic anemia, neutrophilic dermatoses (such as Sweet's syndrome), pulmonary and ophthalmological involvement, thrombosis, and various rheumatological manifestations. The latter often present as arthralgia or mono-, oligo-, or polyarthritis.


Spondyloarthritis in older individuals is a rare condition that can be axial and/or peripheral, with an inflammatory component that is often more pronounced than in younger individuals. It requires the elimination of certain specific differential diagnoses, including microcrystalline rheumatism, rhizomelic pseudo-polyarthritis, giant cell arteritis, and paraneoplastic rheumatism.



The authors report the case of a 67-year-old man living in India with peripheral polyarthritis associated with chronic inflammatory low back pain. Skin lesions had also been observed for a month, and biopsy revealed neutrophilic dermatosis, which responded well to corticosteroid therapy. Rheumatological tests showed the presence of HLA B27, active bilateral sacroiliitis on MRI, synovitis of the wrists, and bilateral retrocalcaneal bursitis. Initial treatment with sulfasalazine and NSAIDs failed, and the introduction of methotrexate at 15 mg/week was also ineffective. Further investigations revealed macrocytic anemia (Hb = 8.3 g/dL, MCV = 106 fL) associated with a biological inflammatory syndrome (CRP = 38 mg/L). These abnormalities led to Sanger sequencing of the UBA1 gene, confirming the diagnosis of VEXAS syndrome due to the p.Met41Leu mutation. Corticosteroid therapy combined with sulfasalazine at 1 mg/day controlled the joint symptoms.


MRI of the sacroiliac joints in STIR sequence showing bilateral sacroiliitis characterised by increased signal intensity depicting bone marrow oedema in bilateral sacroiliac joints.

Two other cases of spondyloarthritis in older patients associated with VEXAS syndrome have been reported:

A 57-year-old man living in France, presenting with a similar clinical picture, including peripheral polyarthritis, bilateral sacroiliitis, HLA-B27 positivity, and biological inflammatory syndrome (2). When the first inflammatory symptoms appeared at the age of 57 in 2010, treatment with anti-TNF alpha initially provided good control of the symptoms. Subsequently, he developed acute anterior uveitis, chondritis of the ear and nose, chronic inflammatory bowel disease (IBD), and neutrophilic dermatosis. Several lines of treatment were attempted without lasting success, including methotrexate, azathioprine, cyclophosphamide, baricitinib, infliximab, tocilizumab, anakinra, and ustekinumab. Finally, a combination treatment of intravenous immunoglobulins (2 g/kg every 4 weeks) and secukinumab (300 mg every 4 weeks) proved effective. The diagnosis of VEXAS syndrome associated with the Met41Thr mutation was made retrospectively in 2020.


A 74-year-old Caucasian man with a recent history of venous thrombosis in the lower limbs presented with inflammatory low back pain with bilateral sacroiliitis on MRI, macrocytic anemia (Hb = 8.8 g/dL and MCV = 101 fL), but without significant biological inflammatory syndrome (3). He subsequently developed progressive anemia (Hb = 8.5 g/dL and MCV = 100 fL), purpura of the lower limbs, erythema nodosum, and chondritis of the ear. He was diagnosed with VEXAS syndrome associated with the Met41Thr mutation of the UBA1 gene. After several treatments failed, including tocilizumab complicated by abscessed diverticulitis, azacitidine at the standard dose of 75 mg/m²/day led to a significant reduction in corticosteroid therapy (from 40 mg/day to 5 mg/day) and clinical improvement of symptoms.


The manifestations of VEXAS syndrome are varied and still poorly defined. It appears to be one of the new differential diagnoses to consider in cases of spondyloarthritis in older patients, particularly those aged 50 and over, given the age of onset of VEXAS syndrome and especially in the presence of a biological inflammatory syndrome, hematological abnormalities with associated anemia, particularly macrocytic anemia, or other suggestive findings such as neutrophilic dermatosis. An atypical history or the appearance of new extra-rheumatological symptoms, such as venous thrombosis, inflammatory dermatoses (particularly neutrophilic), chondritis, or pulmonary involvement, should also point to this diagnosis. In addition, resistance to initial treatment with NSAIDs may be a warning sign, especially since the hematological abnormalities associated with VEXAS syndrome may appear secondarily.


REFERENCES

Jain H, Roy D, Mavidi S, Haldar S, Mondal S, Bhattacharya P, et al. Elderly Onset Spondyloarthropathy and VEXAS Syndrome: A Case Report. Mediterr J Rheumatol. 2024 Sep;35(3):490–3.

Magnol M, Couvaras L, Degboé Y, Delabesse E, Bulai-Livideanu C, Ruyssen-Witrand A, et al. VEXAS syndrome in a patient with previous spondyloarthritis with a favourable response to intravenous immunoglobulin and anti-IL17 therapy. Rheumatology (Oxford). 2021 Sep 1;60(9):e314–5.

Pereira da Costa R, Sapinho G, Bandeira M, Infante J, Marques T, Mimoso Santos C, et al. Case report: VEXAS syndrome: an atypical indolent presentation as sacroiliitis with molecular response to azacitidine. Front Immunol. 2024;15:1403808.



 
 
 
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