VEXAS syndrome through a rheumatologist's lens: insights from a Spanish national cohort

Summarized by: le Pr Sophie Georgin-Lavialle

Reference: Garcia-Escudero P, VEXAS syndrome through a rheumatologist’s lens: insights from a Spanish national cohort, Rheumatology, 2025, 00, 1-9

PubMed link: https://pubmed.ncbi.nlm.nih.gov/39937690/

Summary:

VEXAS syndrome is a rare, acquired autoinflammatory disease first described in 2020, associated with somatic mutations in the UBA1 gene. This article presents a Spanish multicenter case series of 39 Caucasian male patients followed in rheumatology, with a mean age at diagnosis of 73 years and an average age at symptom onset of 67. Prior diagnoses included seronegative polyarthritis (n=9), relapsing polychondritis (n=6), Sweet syndrome (n=4), polymyalgia rheumatica (n=4), systemic lupus erythematosus (n=3), and medium-vessel vasculitis (n=3). The most frequent clinical features, in decreasing order, were skin lesions (87%)—mainly neutrophilic dermatosis—polyarthritis (82%), fever (79%), chondritis (51.3%), ophthalmologic involvement (48.7%) mainly periorbital edema, pulmonary involvement (38%), deep vein thrombosis (30.8%), and renal involvement (20%).

From a hematological perspective, 92% of patients had macrocytic anemia, and 46% had myelodysplastic syndrome. A monoclonal gammopathy was present in 25.6% of cases. Cytoplasmic vacuoles were found in 82% of patients.

The three main UBA1 mutations identified were M41T (36%), M41V (15.7%), and M41L (47%). A genotype-phenotype correlation was observed: M41V was associated with renal involvement, and M41T with deep vein thrombosis and thrombocytopenia. A novel mutation (c.209T>A; p.L70H) in exon 4 was also reported.

Most patients presented with macrocytic anemia (92%), sometimes associated with myelodysplasia (46%) or monoclonal gammopathy (26%). Bone marrow examination showed vacuoles in 72% of cases.

All patients received corticosteroids, with significant improvement after diagnosis, likely due to increased doses. IL-6 inhibitors (75%) and JAK inhibitors (77%)—especially ruxolitinib (90%)—showed good efficacy. TNF inhibitors were ineffective.

Eight patients (20.5%) died during follow-up, with 5 deaths directly attributed to VEXAS syndrome.

This study highlights the crucial role of rheumatologists in identifying VEXAS syndrome, particularly in men over 50 with atypical inflammatory presentations, macrocytic anemia, and corticosteroid dependence. The described genotype-phenotype correlations may be validated in larger cohorts and could help refine diagnostic strategies and guide treatment choices.

The role of 18FDG-PET imaging in VEXAS syndrome: a multicentric case series and a systematic review of the literature

Summarized by: Sophie GEORGIN LAVIALLE

Reference: Bixio R, The role of 18FDG–PET imaging in VEXAS syndrome: a multicentric case series and a systematic review of the literature, Internal and Emergency Medicine, 2024 Nov;19(8):2331-2345.

PubMed link: https://pubmed.ncbi.nlm.nih.gov/39251478/

Summary:

Introduction:

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene. Patients typically present with systemic symptoms (fever, weight loss, skin rashes, lung involvement, chondritis, vasculitis, etc.), macrocytic anemia, and often a myelodysplastic syndrome. Given the clinical heterogeneity and lack of established diagnostic criteria, 18F-fluorodeoxyglucose PET (18FDG–PET) imaging may help with diagnosis and disease monitoring.

Patients and Methods:

This article reports a multicenter Italian case series of 8 patients, combined with a systematic review of the literature, totaling 35 cases.

Results:

All patients were male, with a median age of 70 years. The most common mutations were Met41Thr, Met41Val, and Met41Leu. The main indication for PET imaging was to investigate inflammatory foci or rule out malignancy.

PET scan analysis showed a high prevalence of bone marrow hypermetabolism (77%), followed by lymph nodes (35%), lungs (29%), spleen, large vessels, and cartilage (23% and 20% respectively). In six cases, PET imaging performed before diagnosis already showed increased bone marrow uptake. In some patients, follow-up PET scans after treatment (glucocorticoids or JAK inhibitors) revealed a reduction or even disappearance of hypermetabolic foci.

The authors also provide a summary diagram of the main lesions (see next page).

Conclusion:

Although no specific uptake pattern was identified, bone marrow hypermetabolism may precede clinical manifestations, suggesting a potential role for PET imaging in the early diagnosis and monitoring of VEXAS syndrome. Additionally, PET scans can assist in excluding differential diagnoses, especially malignancies and infections.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX

First author: Hadjadj et al.

Link to article: DOI: 10.1136/ard-2024-225640

Summary:

Study Objective:

To assess the efficacy and safety of targeted therapies in VEXAS syndrome, an adult-onset autoinflammatory disease associated with somatic mutations in the UBA1 gene.

Methodology:

A multicenter retrospective study including 110 patients who received at least one targeted therapy. Complete response (CR) and partial response (PR) were defined based on specific clinical and biological criteria.

Results:

A total of 110 patients received 194 targeted therapies: 78 (40%) JAK inhibitors (JAKi), 51 (26%) IL-6 inhibitors, 33 (17%) IL-1 inhibitors, 20 (10%) TNFα blockers, and 12 (6%) other targeted therapies.

At 3 months, the overall response rate (CR and PR) was 24% with JAKi, 32% with IL-6 inhibitors, 9% with IL-1 inhibitors, and 0% with TNFα blockers or other targeted therapies.

At 6 months, the overall response rate was 30% with JAKi and 26% with IL-6 inhibitors.

Treatment-free survival was significantly longer with JAKi compared to other targeted therapies.

Among patients who discontinued treatment, reasons included primary failure, secondary failure, serious adverse events, or death, with varying rates depending on the therapy.

Conclusions:

JAK and IL-6 inhibitors show clinical benefits, while other therapies demonstrate lower efficacy. These findings require confirmation in prospective trials.