Endocannabinoid system modulation in peripheral blood mononuclear cells from dimethyl fumarate-treated multiple sclerosis patients.

Background: The endocannabinoid system (ECS) consists of lipid metabolites, their receptors and the enzymes implicated in their synthesis and degradation. The ECS exerts anti-inflammatory and neuroprotective properties and its modulation has the potential of being a therapeutic target in Multiple Sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS, which has immunomodulatory effects although its mechanism of action is not yet fully understood. Objectives: To test if DMF could modulate the ECS in Peripheral Blood Mononuclear Cells (PBMCs) from MS patients. Methods: PBMCs from 11 Healthy Donors (HC) and 20 MS patients (at baseline and after 1 year of DMF treatment) were obtained by Ficoll density gradient centrifugation. Patients were clinically followed for 2 years; disease activity was assessed annually. The levels of the endocannabinoids 2-Arachidonoylglycerol (2-AG), Anandamide (AEA), Oleoylethanolamine (OEA) and Palmitoylethanolamine (PEA) were determined by Liquid chromatography–mass spectrometry (LC-MS), and normalized to the total amount of protein. Results: The median values (in pmol/g protein) of 2-AG and AEA were both similar between HC (361.42 for 2-AG; 63.62 for AEA) and patients at baseline (269.26 for 2-AG; 58.70 for AEA). After 1 year of treatment, no differences were found compared to baseline. However, there was a trend (p=0.07) towards an increase of 2-AG in patients that did not reach NEDA 3 on follow-up at 2 years. OEA and PEA levels were both lower at baseline (61.83 for OEA, p=0.01; 541.0 for PEA, p=0.001) compared to HC (190.35 for OEA; 1140.51 for PEA). After 1 year, PEA levels were unchanged (449.50, p=0.68), but OEA (115.39, p=0.04) increased to levels similar to those of HC. Conclusions: Our results confirm the dysregulation of the ECS in MS. Furthermore, they shed light on a new mechanism of action of DMF in MS, as it can modulate the ECS through OEApre-print110 K

Características clínico-epidemiológicas em pacientes com estenose hipertrófica do piloro. Estudo de 15 anos em um centro terciário

La estenosis hipertrófica del píloro está caracterizada por una hipertrofia e hiperplasia de las fibras musculares y estrechamiento del canal pilórico, que provoca vómitos no biliosos, dando lugar a una de las causas más comunes de tratamiento quirúrgico en la etapa de recién nacido. Se realizó un estudio descriptivo retrospectivo en 119 pacientes con el diagnóstico de estenosis hipertrófica del píloro en el Hospital Pediátrico Universitario “William Soler” desde el año 2000 al 2015. El 70,6% de los niños tenía entre tres y cinco semanas de nacido y el 83,2% un peso al diagnóstico entre 2500 g a 4500 g. El vómito estuvo presente en todos los pacientes, las alteraciones del peso corporal en 79,8% y los desequilibrios hidroelectrolíticos y acido básico en el 53,8%. El sexo masculino, apariencia racial blanca, ser primogénito y la lactancia artificial o mixta, fueron factores de riesgos prevalentes significativos asociados a la enfermedad (p<0.05). La estenosis hipertrófica del píloro se diagnosticó con mayor frecuencia a la 4ta semana de vida y en niños con un peso entre 3000 a 4500 g. Las variaciones ponderales denotan la importancia del seguimiento de la curva de peso en estos pacientes.Hypertrophic pyloric stenosis is characterized by hypertrophy and hyperplasia of the muscle fibers and narrowing of the pyloric canal, which causes non-bilious vomiting, giving rise to one of the most common causes of surgical treatment in the newborn stage. A retrospective descriptive study was carried out in 119 patients with a diagnosis of hypertrophic pyloric stenosis at the “William Soler” University Pediatric Hospital from 2000 to 2015. 70.6% of the children were between three and five weeks old and 83.2% a weight at diagnosis between 2500 g to 4500 g. Vomiting was present in all patients, alterations in body weight in 79.8% and hydroelectrolyte and basic acid imbalances in 53.8%. Male sex, white racial appearance, being first-born, and artificial or mixed breastfeeding were significant prevalent risk factors associated with the disease (p <0.05). Hypertrophic pyloric stenosis was most frequently diagnosed at the 4th week of life and in children weighing between 3000 and 4500 g. The weight variations denote the importance of following the weight curve in these patients.A estenose hipertrófica do piloro é caracterizada por hipertrofia e hiperplasia das fibras musculares e estreitamento do canal pilórico, que causa vômitos não biliosos, sendo uma das causas mais comuns de tratamento cirúrgico na fase neonatal. Um estudo descritivo retrospectivo foi realizado em 119 pacientes com diagnóstico de estenose pilórica hipertrófica no Hospital Pediátrico da Universidade “William Soler” de 2000 a 2015. 70,6% das crianças tinham entre três e cinco semanas de idade e 83,2% com peso ao diagnóstico entre 2500 ga 4500 g. Vômito esteve presente em todos os pacientes, alteração do peso corporal em 79,8% e desequilíbrio hidroeletrolítico e ácido básico em 53,8%. Sexo masculino, raça branca, primogênito e amamentação artificial ou mista foram fatores de risco prevalentes e significativos associados à doença (p <0,05). A estenose hipertrófica do piloro foi diagnosticada com maior frequência na 4ª semana de vida e em crianças com peso entre 3.000 e 4.500 g. As variações de peso denotam a importância de seguir a curva de peso nesses pacientes

Endocannabinoid levels in peripheral blood mononuclear cells of multiple sclerosis patients treated with dimethyl fumarate.

The endocannabinoid system (ECS), a signalling network with immunomodulatory properties, is a potential therapeutic target in multiple sclerosis (MS). Dimethyl fumarate (DMF) is an approved drug for MS whose mechanism of action has not been fully elucidated; the possibility exists that its therapeutic effects could imply the ECS. With the aim of studying if DMF can modulate the ECS, the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were determined by liquid chromatography-mass spectrometry in peripheral blood mononuclear cells from 21 healthy donors (HD) and 32 MS patients at baseline and after 12 and 24 months of DMF treatment. MS patients presented lower levels of 2-AG and PEA compared to HD. 2-AG increased at 24 months, reaching HD levels. AEA and PEA remained stable at 12 and 24 months. OEA increased at 12 months and returned to initial levels at 24 months. Patients who achieved no evidence of disease activity (NEDA3) presented the same modulation over time as EDA3 patients. PEA was modulated differentially between females and males. Our results show that the ECS is dysregulated in MS patients. The increase in 2-AG and OEA during DMF treatment suggests a possible role of DMF in ECS modulation.post-print1392 K

Risk and outcomes of COVID-19 in patients with multiple sclerosis

Background and purpose Limited information is available on incidence and outcomes of COVID-19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS-CoV-2 infection and COVID-19-related outcomes in patients with MS, and compared these with the general population. Methods A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID-19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. Results Two-hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID-19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease-modifying treatment and hospitalization risk. Conclusions Patients with MS do not appear to have greater risks of SARS-CoV-2 infection or severe COVID-19 outcomes compared with the general population. The decision to start or continue disease-modifying treatment should be based on a careful risk–benefit assessment.post-print996 K

Tolerability and safety of Dimethyl fumarate in relapsing multiple sclerosis: A prospective observational post-marketing study

Sin financiación4.849 JCR (2020) Q1, 52/208 Clinical Neurology1.541 SJR (2020) Q1, 33/165 NeurologyNo data IDR 2020UE

Dimethyl fumarate treatment in relapsing multiple sclerosis: a prospective observational postmarketing study of effectiveness

Sin financiación5.649 JCR (2018) Q1, 23/199 Clinical Neurology1.742 SJR (2018) Q1, 25/171 NeurologyNo data IDR 2018UE

Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A Prospective Multicenter Real-World Study

Background: Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. Objective: The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. Methods: We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. Results: Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6-41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. Conclusions: Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.Sin financiación5.754 JCR (2020) Q1, 36/208 Clinical Neurology1.565 SJR (2020) Q1, 61/372 Neurology (clinical)No data IDR 2020UE

Early predictive risk factors for dimethyl fumarate-associated lymphopenia in patients with multiple sclerosis

Background: Lymphopenia is a major concern in MS patients treated with dimethyl-fumarate (DMF) as it increases the risk of progressive multifocal leukoencephalopathy. A pronounced reduction in absolute lymphocyte counts (ALCs) early after treatment initiation has been suggested to be associated with the occurrence of lymphopenia thereafter. Objectives: To identify risk factors for DMF-induced lymphopenia and evaluate whether the degree of decrease in the ALCs three months after initiation of DMF treatment is a predictor of the subsequent development of lymphopenia. Methods: In this real-world Spanish prospective multicenter study conducted in MS patients who started DMF between 2014 and 2019, we analyzed the association between DMF-related lymphopenia and the percentage of early ALCs decline using regression models, considering both, significant lymphopenia (grades 2 + 3) and severe lymphopenia (grade 3). The cutoff values of early ALCs declines were obtained using the ROC curve. Results: Among 532 MS patients treated with DMF, 193 (36.3%) developed any grade of lymphopenia. Older age and lower ALCs at treatment onset predicted the risk for lymphopenia but the best predictive risk factor was the reduction of ALCs within the three first months of treatment. Specifically, a reduction in ALCs≥21.2% was associated with a 6.5-fold higher risk of developing significant lymphopenia, and a decrease in ALCs≥40.2% with a 12.7-fold higher risk of developing severe lymphopenia. Conclusions: A pronounced reduction in ALCs early after initiation of DMF in MS patients is the best predictive risk factor for the subsequent development of significant lymphopenia.Sin financiación4.808 JCR (2021) Q2, 64/212 Clinical Neurology1.006 JCR (2021) Q1, 472/2489 Medicine (miscellaneous)No data IDR 2020UE

The Need for the Closer Monitoring of Novel Drugs in MS: A Siponimod Retrospective Cohort Study (Realhes Study)

Background: Severe cases of lymphopenia have been reported during siponimod clinical trials, which may negatively impact its benefit/risk profile. Objective: We aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice. The secondary objectives included the analysis of factors predisposing to and the clinical relevance of lymphopenia events. Methods: In this multicenter retrospective cohort study, information collected from the medical records of 129 patients with MS from 15 tertiary hospitals in Spain who initiated treatment with Siponimod were followed-up for at least 3 months, including at least one lymphocyte count evaluation per patient. Results: Of the 129 patients, 121 (93.6%) reported lymphopenia events, including 110 (85.3%) with grade <= 3 and 11 (8.5%) with grade 4 lymphopenia, higher than those reported in the pivotal clinical trial (73.3% and 3.3% for grade <= 3 and grade 4 lymphopenia, respectively). The study included an unexpectedly high proportion of male subjects (72.9%), which might have led to an underestimation of the actual magnitude of the risk. Conclusions: In this study, the incidence and severity of lymphopenia after starting siponimod treatment were higher than those reported in previous clinical trials. Therefore, our results reinforce the need for the closer monitoring of novel MS drugs in clinical practice, as well as larger and longer follow-up studies to properly characterize this risk

Seroprevalence of SARS-CoV-2 in Patients with Multiple Sclerosis under Disease-Modifying Therapies: A Multi-Centre Study

Background: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs. Methods: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed. Results: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable. Conclusion: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population