Wladimir Mauhin

La maladie de Fabry (MF) est une maladie lysosomale liée à l’X, due à des mutations du gène GLA codant pour l’alpha-galactosidase A, caractérisée par une accumulation en glycosphingolipides. L’enzymothérapie substitutive (ES) par agalsidase alfa ou beta, a une efficacité inégale selon les patients. Ce travail a exploré les mécanismes inflammatoires impliqués dans la réponse à l’ES et dans la physiopathologie propre de la MF. Après élaboration d’un test ELISA permettant le dépistage concomitant des anticorps (Ac) anti-agalsidase alfa et beta, on observait un risque accru de développer ces Ac chez les patients de phénotype classique, sans retentissement clinique évident mais associé à des taux de lysoGb3 plasmatiques plus élevés suggérant un pronostic péjoratif. Ces Ac, notamment les IgG4, avaient un pouvoir inhibiteur enzymatique dose-dépendant. Alors que la réactivité croisée entre les deux ES était totale et que le risque de développer des Ac n’était pas lié à l’ES reçue, l’analyse des leucocytes circulants a mis en évidence une élévation du pourcentage de cellules NK chez les patients traités par agalsidase beta suggérant son immunogénicité accrue. Indépendamment du traitement, on observait des perturbations des lymphocytes T CD4 et CD8 CCR7- ayant un profil atypique immature CD27+ et CD57-. L’expression du CCR7 était inversement corrélée aux concentrations de lysoGb3 et de sphingosine-1-phosphate (S1P) dans les lymphocytes T CD4+. Enfin, on observait une augmentation du S1P chez les patients non-classiques. Notre travail fournit des outils indispensables au développement de thérapies géniques et ouvre des pistes de recherche sur la maturation lymphocytaire T et la S1P.

Objectives: Anti‐MDA5 dermatomyositis (anti‐MDA5 DM) is the most severe subtype of dermatomyositis, due to its pulmonary involvement. Current treatment involves corticosteroids and immunosuppressants, but variability in responses exists. This study aims to evaluate the efficacy and safety of Janus kinase (JAK)– and calcineurin–inhibitor combination (JAK–CNI) in anti‐MDA5 DM patients. Methods: A nested case–control study was conducted within a retrospective cohort of 234 anti‐MDA5 DM patients. Patients receiving JAK–CNI were matched 1:2 with comparators. All‐cause mortality or transplant within a year was compared using Cox proportional hazards models. Infectious and noninfectious side effects were also assessed. Results: Twenty‐seven patients receiving JAK–CNI were compared to 52 matched controls. Almost all these patients had pulmonary involvement. Thirty‐nine (49%) died or were transplanted during follow‐up. No significant improvement in survival or transplant‐free survival was observed with JAK–CNI compared with comparators (hazard ratios 1.02, 95% confidence intervals [0.48–2.16]). Results were consistent regardless of intensive care unit (ICU) admission status and when analyses were restricted to patients with rapidly progressive interstitial lung disease. A trend toward a beneficial effect of the JAK–CNI combination was observed in non‐ICU patients. Infectious complications were frequent ( n = 49, 62%), with no excess risk in patients receiving JAK–CNI. Conclusion: JAK–CNI showed a similar outcome to other immunosuppressive combinations. However, as the study included the most severe cases, the potential benefit of early JAK–CNI introduction in less severe forms cannot be dismissed, as suggested by the nonsignificant trend in non‐ICU patients. Future studies are needed to clarify the optimal timing and patient selection for JAK–CNI therapy in anti‐MDA5 DM.

The average length of stay (ALOS) has increased in our Internal Medicine Department since 2020 and we decided to investigate its origin. We analysed retrospective data from hospital stays between 2018 and 2024. In 2024, we also prospectively studied the hospital stays with delayed discharge defined by prolonged stays for no medical reason. Between 2020 and 2024, ALOS increased from 6.5days to 9.3days. Performance index based on ALOS, that allows a stratification of ALOS on patient severity, also increased linearly by 2.6 points per year (R²=0.84). We observed a constant reduction in the access to rehabilitative care departments (-30%). In 2024, 11.0% (96/869) of discharges were considered delayed, cumulating 1261days of stay with no medical reason (15.7% of the activity). Among the causes of hospitalisation, the fall was associated with the highest cumulative delay of discharge (402days for 26stays), the psychiatric disorders were associated with the highest delay per stay (199days for 7stays). Delayed discharges were mainly due to delays to access to rehabilitative departments (55stays; 760days). Improving the ALOS cannot be achieved without a global reflexion including strong social services supported by the hospital management and public policies decisions.

Objective: Fabry disease is caused by enzymatic defects in alpha‐galactosidase A that leads to the accumulation of glycosphingolipids throughout the body, resulting in a multisystemic disorder. The most common neurological manifestations are neuropathic pain, autonomic nervous system dysfunction and strokes, but some rarer neurological manifestations exist. Among these, aseptic meningitis is a possible complication. Our objectives were to measure the prevalence of this complication in a cohort of patients with Fabry disease, and to describe its clinical features.Methods: We conducted a retrospective review of Fabry disease patients followed at our tertiary referral center between 1995 and September 2023 with at least one episode of meningitis, and performed a systematic review to identify similar published cases.Results: Four patients out of 107 (3.7%) had at least one episode of aseptic meningitis. Our systematic review identified 25 other observations. The median age of these 29 patients was 29.0 years, the median cerebrospinal fluid leukocyte count was 24 cells/mm3 with a predominance of lymphocytes in 64.7% of cases. In 82.8% of the patients, the diagnosis of Fabry disease was unknown before the meningitis. Large artery stenosis was present in 17.2% of patients and 57.1% of patients had a recent stroke concomitant with the meningitis. Several differential diagnoses were evoked, such as multiple sclerosis or central nervous system vasculitis.Interpretation: Our study suggests that Fabry disease should be considered as a cause of aseptic meningitis. The pathophysiological mechanisms underlying meningeal inflammation remain largely unknown but may reflect the dysregulation of pro‐inflammatory signaling pathways.

Fabry disease (FD) is an X‐linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti‐drug antibodies (ADA). Leucocytes from 41 male patients and 20 controls were analyzed with mass cytometry using both unsupervised and supervised algorithms. FD patients had an increased expression of CD27 and CD28 in memory CD45‐ and CD45 + CCR7‐CD4 T cells (respectively p < 0.014 and p < 0.02). Percentage of CD45RA‐CCR7‐CD27 + CD28+ cells in CD4 T cells was correlated with plasma lysoGb3 (r = 0.60; p = 0.0036) and phenotype (p < 0.003). The correlation between Gb3 and CD27 in CD4 T cells almost reached significance (r = 0.33; p = 0.058). There was no immune profile associated with the presence of ADA. Treatment with agalsidase beta was associated with an increased proportion of Natural Killer cells. These findings provide valuable insights for understanding FD, linking Gb3 accumulation to inflammation, and proposing new prognostic biomarkers.

Fabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6–227.9] vs. 169.4 ng/mL [121.1–203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lipid storage disorder caused by a deficiency in lysosomal enzyme acid sphingomyelinase which results in the accumulation of sphingomyelin, predominantly within cells of the reticuloendothelial system located in numerous organs, such as the liver, spleen, lungs, and central nervous system. Although all patients with ASMD share the same basic metabolic defect, a wide spectrum of clinical presentations and outcomes are observed, contributing to treatment challenges. While infantile neurovisceral ASMD (also known as Niemann–Pick disease type A) is rapidly progressive and fatal in early childhood, and the more slowly progressive chronic neurovisceral (type A/B) and chronic visceral (type B) forms have varying clinical phenotypes and life expectancy. The prognosis of visceral ASMD is mainly determined by the association of hepatosplenomegaly with secondary thrombocytopenia and lung disease. Early diagnosis and appropriate management are essential to reduce the risk of complications and mortality. The accessibility of the new enzyme replacement therapy olipudase alfa, a recombinant human ASM, has been expedited for clinical use based on positive clinical data in children and adult patients, such as improved respiratory status and reduced spleen volume. The aim of this article is to share the authors experience on monitoring ASMD patients and stratifying the severity of the disease to aid in care decisions.

Acid sphingomyelinase deficiency (ASMD) is an inherited lysosomal disease characterised by a diffuse accumulation of sphingomyelin that cannot be catabolised into ceramide and phosphocholine. We studied the incidence of cancer in ASMD patients. We retrospectively reviewed the medical records of the adult chronic visceral ASMD patients in our cohort. Thirty-one patients (12 females, 19 males) were included with a median age of 48.7 y. (IQ: 30.3–55.1). Five cancers were observed in 1 female (breast cancer) and 4 males (two lung cancers, one thyroid cancer and one bladder cancer), resulting in a prevalence of 16.1%. The existence of cancer was associated with a more severe ASMD characterised by a larger spleen (25 cm (22.5–25) vs. 18 cm (17–20); p = 0.042); lower diffusing capacity of the lung for carbon monoxide (DLCO; 29.5 % (17.8–43.0) vs. 58.5 % (49.8–69.5%); p = 0.01) and tobacco use (100% vs. 45%; p = 0.04). Three patients died, all from cancer (p = 0.002). The prevalence of cancer appeared to be strikingly elevated in our cohort of patients, without any specificity in the type of cancer. Systematic screening for cancer should be performed, and carcinogenic substances such as tobacco should be avoided in patients with ASMD.