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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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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