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.

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.

Download • 997KB

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

Download PDF • 1.70MB