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.

Genetic and clinical features of Familial Mediterranean Fever in a cohort of patients with kidney failure

First author: Ahmed Sheyyab

Journal: Journal of Nephrology

Link to the article: doi.org/10.1007/s40620-025-02272-y

Author of the abstract: Rim BOURGUIBA

Introduction

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide. In its classic form, it is mainly associated with mutations in exon 10 of the MEFV gene. AA amyloidosis is the most severe complication of FMF.

The aim of this study was to compare the frequency of MEFV variants in hemodialysis patients versus healthy controls in a Mediterranean country, Jordan.

Methods

This was a cross‑sectional study including 78 patients with end‑stage kidney disease on hemodialysis and 201 healthy controls in Jordan. All patients underwent Sanger sequencing for the main MEFV variants. The following variants were tested: p.E148Q, p.P369S, p.F479L, p.M680I (G/C), p.M680I (G/A), p.I692del, p.M694V, p.M694I, p.K695R, p.V726A, p.A744S, and p.R761H.

Patients carrying a variant were then clinically assessed according to the Tel‑Hashomer criteria. Five underwent rectal biopsy to detect amyloidosis.

Results

Among dialysis patients, 16% had at least one MEFV variant versus 12.9% in the control group (not significant). The two most frequent mutations in the hemodialysis group were M694V (p = 0.035) and V726A (p = 0.009). The variants detected in both groups are summarized in Table 1. In the control group without renal failure, 22 individuals were heterozygous for the E148Q variant. Three patients met diagnostic criteria for FMF, and one case of AA amyloidosis was confirmed by biopsy.

Conclusion

FMF is the most common autoinflammatory disease in Mediterranean countries, yet it remains underdiagnosed even in high‑risk populations. This diagnostic delay leads to complications, notably AA amyloidosis. This study shows that 4% of hemodialysis patients were diagnosed with FMF. It also confirms the non‑pathogenic nature of the E148Q variant, which was detected in 22 healthy, asymptomatic individuals.

Overall, these findings underscore the importance of testing for MEFV mutations in patients with AA amyloidosis in countries where FMF is highly prevalent, in order to offer appropriate treatment to prevent AA amyloidosis and progression to renal failure.

Genetic and clinical features of familial Mediterranean fever in a cohort of patients with.

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VEXAS syndrome: a Spanish national research project to better understand this rare disease.

Article title : VEXAS syndrome through a rheumatologist's lens: insights from a Spanish national cohortservices de rhumatologie espagnols

First author: García-Escudero P

First author: Rheumatology

Lien vers l'article: https://pubmed.ncbi.nlm.nih.gov/39937690/

Auteur du résumé: Philippe Mertz

Introduction

VEXAS syndrome (Vacuoles, E1 enzyme, X‑linked, Autoinflammatory, Somatic) is a recently described, severe autoinflammatory disease associated with somatic variants in the UBA1 gene. It primarily affects men over 50 and combines systemic inflammatory manifestations with hematologic abnormalities. The aim of this study was to describe the clinical and genetic features of VEXAS seen in patients followed in Spanish rheumatology departments and to analyze genotype–phenotype correlations.

Methods

This was a multicenter retrospective study conducted in 126 Spanish hospitals, including 39 patients diagnosed between December 2020 and January 2024. Clinical, laboratory, and genetic data were collected and analyzed.

Key results

All patients were men, with a mean age of 73 years (range 40–92) at diagnosis. Initial working diagnoses included seronegative polyarthritis (9/39), relapsing polychondritis (6/39), Sweet’s syndrome (4/39), polymyalgia rheumatica (4/39), systemic lupus, and medium‑vessel vasculitis (3/39 each). The most frequent clinical features were skin involvement (87%), followed by polyarthritis (82%) and fever (79%). Renal involvement affected 20% of patients, a higher rate than previously reported cohorts, and polyarthritis also appeared more frequent than in earlier series.

Genetically, notable correlations emerged. The UBA1 M41V variant was significantly associated with renal involvement, whereas M41T correlated with thrombocytopenia and an increased rate of thromboembolic events. The study also identified a potentially pathogenic novel UBA1 variant (c.209T>A; p.L70H).

Regarding treatment, all patients received corticosteroids, with better responses observed after diagnostic confirmation and dose adjustments. Interleukin‑6 inhibitors and JAK inhibitors, notably ruxolitinib, showed the highest response rates, reaching 75% and 76% respectively. In contrast, anti‑TNF agents and hypomethylating agents were largely ineffective.

Conclusion

This study confirms that VEXAS remains under‑recognized in rheumatology, particularly among older men presenting with polyarthritis, unexplained cytopenias, or steroid dependence. It also underscores that genotype influences clinical expression, with certain variants associated with more severe disease or specific complications such as renal or thromboembolic involvement. Finally, the results support JAK and IL‑6 inhibitors as key therapeutic strategies in this condition.

In clinical practice, these findings support considering VEXAS promptly in any man over 50 with seronegative polyarthritis and atypical systemic features, cytopenias, or steroid dependence, to avoid diagnostic delay and better tailor therapy.

Le syndrome VEXAS une recherche nationale espagnole pour mieux comprendre cette maladie r.

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