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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Adult Familial Mediterranean Fever (FMF): is a single MEFV mutation sufficient to cause severe disease?

Article title: Clinical characteristics and outcomes of adult FMF patients: comparison between those with one versus two

pathogenic MEFV exon 10 mutations

First author: Anaël Dumont

Journal: Joint Bone Spine

Link to the article: doi.org/10.1016/j.jbspin.2025.105850

Author of the abstract: Rim BOURGUIBA

Introduction

Familial Mediterranean Fever (FMF) is an autoinflammatory disease caused by mutations in MEFV. While two pathogenic mutations typically lead to a classic and more severe phenotype, the clinical expression in patients with only one pathogenic mutation remains debated. This study compared adult FMF patients according to whether they carried one or two pathogenic MEFV mutations.

Methods

A French single‑center retrospective cohort included 581 adult FMF patients: 178 with a single pathogenic mutation and 403 with two pathogenic mutations. Diagnosis used Eurofever/PRINTO criteria, and all patients underwent MEFV sequencing. A focused analysis compared M694V/E148Q versus M694V/WT.

Results

Compared with biallelic patients, heterozygous patients were older at diagnosis and disease onset, had more personal and family history of recurrent aphthous stomatitis, and a higher BMI. No AA amyloidosis was observed in heterozygotes, and they required lower colchicine doses. These differences remained significant after adjustment for age at onset. No clinical difference was found between M694V/E148Q and M694V/WT.

Conclusion

Adult FMF patients with a single pathogenic MEFV mutation show distinct clinical features and outcomes compared with those carrying two mutations. Findings highlight FMF phenotypic heterogeneity and support tailoring management to the patient’s genetic profile.

FMF adulte : une seule mutation MEFV suffit‑elle à rendre la maladie sévère.

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Current landscape of monogenic autoinflammatory actinopathies: A literature review

First author : P. Mertz

Review: Autoimmunity Reviews

Link to article: https://doi.org/10.1016/j.autrev.2024.103715

Autoinflammatory diseases (AID) are conditions leading to a hyperactivation of innate immunity without any underlying infection, and may be poly- (e.g. Still's disease) or monogenic. The number of monogenic AID is continuously expanding, with the discovery of novel pathologies and pathophysiological mechanisms, facilitated in part by easier access to pangenomic sequencing. Actinopathies with autoinflammatory manifestations represent a newly emerging subgroup of AID, associated with defects in the regulation of actin cytoskeleton dynamics. These diseases typically manifest in the neonatal period and variably combine a primary immunodeficiency of varying severity, cytopenia (particularly thrombocytopenia), autoinflammatory manifestations primarily affecting the skin and digestive system, as well as atopic and autoimmune features.

Diagnosis should be considered primarily when encountering an early-onset autoinflammatory skin and digestive disorder, along with a primary immunodeficiency and either thrombocytopenia or a bleeding tendency. Some of these diseases exhibit specific features, such as a risk of macrophage activation syndrome (MAS) or a predisposition to atopy or lymphoproliferation. The complete pathophysiology of these diseases is not yet fully understood, and further studies are required to elucidate the underlying mechanisms, which could guide therapeutic choices. In most cases, the severity of the conditions necessitates allogeneic marrow transplantation as a treatment option.

In this review, we discuss these novel diseases, providing a practical approach based on the main associated biological abnormalities and specific clinical characteristics, with a special focus on the newly described actinopathies DOCK11 and ARPC5 deficiency. Nonetheless, genetic testing remains essential for definitive diagnosis, and various differential diagnoses must be considered.

Current landscape of monogenic autoinflammatory actinopathies.pdf

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