Treatment Of Multiple Sclerosis Research Articles

Fingolimod, a sphingosine-1-phosphate receptor modulator, prevents neonatal bronchopulmonary dysplasia and subsequent airway remodeling in a murine model.

Neonatal bronchopulmonary dysplasia (BPD) is associated with alveolar simplification and airway remodeling. Airway remodeling leads to deformation of airways characterized by peribronchial collagen deposition and hypertrophy of airway smooth muscle, which contribute to the narrowing of airways. Poorly developed lungs contribute to reduced lung function that deteriorates with the passage of time. We have earlier shown that sphingosine kinase 1 (SPHK 1)/sphingosine-1-phosphate (S1P)/S1P receptor1 (S1PR1) signaling plays a role in the pathogenesis of BPD. In this study, we investigated the role of fingolimod or FTY720, a known S1PR1 modulator approved for the treatment of multiple sclerosis in the treatment of BPD. Fingolimod promotes the degradation of S1PR1 by preventing its recycling, thus serving as the equivalent of an inhibitor. Exposure of neonatal mice to hyperoxia enhanced the expression of S1PR1 in both airways and alveoli as compared with normoxia. This increased expression of S1PR1 in the airways persisted into adulthood, accompanied by airway remodeling and airway hyperreactivity (AHR) after neonatal hyperoxia. Intranasal fingolimod at a much lower dose compared with the intraperitoneal route of administration during neonatal hyperoxia improved alveolarization in neonates and reduced airway remodeling and AHR in adult mice associated with improved lung function. The intranasal route was not associated with the lymphopenia seen with the intraperitoneal route of administration of the drug. An increase in S1PR1 expression in the airways was associated with an increase in the expression of enzyme lysyl oxidase (LOX) in the airways following hyperoxia, which was suppressed by fingolimod. This association warrants further investigation.NEW & NOTEWORTHY The role of the S1P receptor1 modulator, fingolimod, as an FDA-approved drug in preventing the recurrence of multiple sclerosis is established. Fingolimod prevented bronchopulmonary dysplasia (BPD) and its sequela of airway remodeling in a neonatal murine model. This protection was associated with the downregulation of lysyl oxidase signaling pathway. Fingolimod could be repurposed for the therapy of BPD.

Real-World Experience with Diroximel Fumarate in Patients with Multiple Sclerosis: A Prospective Multicenter Study.

Current literature and a real-world study suggest that diroximel fumarate (DRF) is safer than dimethyl fumarate (DMF) in the treatment of multiple sclerosis (MS). However, no real-world study to date has significantly addressed the efficacy of this treatment. This study aims to elucidate the safety, tolerability, and efficacy of DRF in a real-world setting, utilizing data from a Spanish national registry of patients commencing DRF therapy post-market introduction. In this multicenter, prospective observational study, data were collected from MS patients who initiated DRF treatment. The study monitored demographic and clinical characteristics, safety outcomes (including adverse events, reasons for discontinuation, and lymphocyte counts), and efficacy outcomes (radiological and clinical activity). A total of 195 MS patients across 26 neurological departments were included, predominantly female (79.5%), with a mean age of 42.17 years, and a mean duration of treatment with DRF of 6.3 months. Most patients (70.3%) reported no adverse events, while gastrointestinal issues and flushing were the most common adverse events observed. The majority of patients (84.6%) continued with DRF treatment, with tolerability issues being the primary reason for discontinuation. Efficacy analysis showed low relapse rates post-DRF initiation, with most patients exhibiting stable or improved Expanded Disability Status Scale scores and radiological assessments demonstrating minimal activity. This comprehensive analysis provides valuable insights into the real-world application of DRF, confirming its safety and tolerability while offering preliminary evidence of its efficacy in managing MS.

Medicinal cannabis delivery systems: A perspective

In recent years, cannabis derivatives have been proposed for the treatment of various medical conditions, including pain, inflammation, epilepsy, sleep disorders, multiple sclerosis, anorexia, schizophrenia, neurodegenerative diseases, nausea, and cancer. While the benefits of cannabis derivatives, primarily cannabinoids, have been demonstrated and continue to be studied, their use presents various challenges associated with their low water solubility, rapid metabolism, erratic and poor bioavailability, and erratic pharmacokinetics, which directly affect their efficacy. In this context, a great deal of research is being carried out to overcome these drawbacks by designing delivery systems capable of improving solubility/bioavailability, potency, and efficacy, while addressing the purity and quality issues required by the pharmaceutical industry. This article aims to critically review the major trends and challenges in designing controlled-release cannabinoid delivery systems and their potential application in the pharmaceutical industry.

Inflammation-Targeted Biomimetic Nano-Decoys via Inhibiting the Infiltration of Immune Cells and Effectively Delivering Glucocorticoids for Enhanced Multiple Sclerosis Treatment.

Excessive infiltration of neutrophil and inflammatory cytokines accumulation as well as the inadequate delivery of drugs to the targeted site are key pathological cascades in multiple sclerosis (MS). Herein, inflammation-targeting biomimetic nano-decoys (TFMN) is developed that inhibit the infiltration of immune cells and effectively deliver glucocorticoids to lesions for enhanced MS treatment. Nano-decoys encapsulated with the glucocorticoid methylprednisolone (MPS) are prepared by coating neutrophil membrane (NM) on nanoparticles formed by the self-assembly of tannic acid and poloxamer188/pluronic68. Benefiting from the natural inflammation-targeting ability of activated neutrophil membranes, TFMN can target the lesion site and prevent neutrophils infiltration by adsorbing and neutralizing elevated neutrophil-related cytokines, subsequently modulating the inflammatory microenvironment in experimental autoimmune encephalomyelitis mice. TFMN exhibits a strong antioxidant capacity and scavenged excessive reactive oxygen species to enhance neuronal protection. Furthermore, at the inflammation site, perforin, discharged by cytotoxic T-lymphocytes, triggered the controlled release of MPS within the TFMN through perforin-formed pores in the NM. Simultaneously, this mechanism protected neurons from perforin-induced toxicity. The MPS liberated at the targeted site achieves optimal drug accumulation, thereby enhancing therapeutic efficacy. In conclusion, the innovative system shows potential for integrating various therapeutic agents, offering a novel strategy for CNS disorders.

MOG-specific CAR Tregs: a novel approach to treat multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients.

Efficacy and safety of cladribine tablets in multiple sclerosis in real-world clinical practice

Cladribine has a well-defined activity against lymphocytes, leading to their selective depletion.Objective: to determine the efficacy and safety of cladribine in the treatment of multiple sclerosis (MS) in real-world clinical practice.Material and methods. The study involved 82 patients (57 women and 25 men, mean age 36.4±9.3 years) with a disease duration of 2.2±1.5 years. Seven (9%) patients had secondary progressive MS (SPMS), 6 (7%) had rapidly progressive MS (RPMS) and 69 (84%) had highly active MS (HAMS). According to the instructions for use, oral therapy with cladribine was administered in two short courses (up to 10 days per year) to achieve a long-term effect on the immune system. The dose of cladribine was calculated based on the body weight.Results. The average frequency of exacerbations per year before starting therapy was 1.6, while it decreased to 0.2 during cladribine therapy. An exacerbation was observed in 18 patients (22%) at the end of the first course of cladribine treatment and in one patient (2.6%) after the second treatment course. Thus, the number of exacerbations decreased by 78% after the first year of treatment and by 97.4% after the second year of treatment. The mean EDSS score was 3.2±2.5 points before the start of treatment, 3.6±2.5 points after the first course of treatment and 3.4±2.5 points after the second course (p>0.05). MRI results showed a decrease in disease activity by 83% after the first course of cladribine therapy and by 97.4% after the second course. No serious adverse events occurred in any of the patients.Conclusion. We demonstrated efficacy and safety of cladribine in real-life clinical practice in MS patients with frequent exacerbations and rapid disability progression (SPMS, RPMS, HAMS).

RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.

Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS. Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration. We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases. hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.

Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis.

To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events. A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores. Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high. Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.

Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.

Correlation between MRI utilization and therapy switches in disease-modifying treatments for multiple sclerosis.

Studies measuring the role of magnetic resonance imaging (MRI) in therapeutic decision-making are rare in people with multiple sclerosis (pwMS). This study aimed to measure the association between MRI utilization and disease-modifying therapy (DMT) switches in pwMS. This retrospective cohort study identified pwMS in 2018 from a de-identified national claims database. PwMS who received MRI in 2018 were compared to pwMS not receiving MRI in 2018. PwMS were observed for six months to assess the incidence of DMT switches. The study sample consisted of 11,972 pwMS. 3,931 (32.8%) pwMS received at least one MRI in 2018. Overall, MRI utilization increased the odds of switching DMT (OR = 1.49, 1.79, and 3.01 for 1, 2, and ≥ 3 CNS locations imaged). For those on injectable or platform DMT, any MRI utilization increased the odds of switching DMT (OR = 1.54, 2.00, and 3.48 for 1, 2, and ≥ 3 locations imaged). For those on oral DMT, only receiving MRI of 2 or ≥ 3 locations increased the odds of a DMT switch (OR = 1.36, 1.89, and 2.40 for 1, 2, and ≥ 3 locations). Finally, for pwMS on infusible therapies, there was little evidence that MRI changed the odds of a DMT switch. Among pwMS on injectable or oral DMT, imaging more CNS locations increased the odds of switching DMT after adjusting for age and relapse incidence. For pwMS on high-efficacy infusible DMTs, MRI did not change the odds of switching DMT but remains essential for safety monitoring.

Sex differences in use of potentially teratogenic disease modifying treatments for multiple sclerosis and degree of hormonal contraception overlap in women between 2007–2021: An Australian population-based study

BackgroundDisease modifying treatments (DMTs) for multiple sclerosis (MS) have varying levels of teratogenic potential, but whether this influences DMT prescribing patterns by sex or concurrent use of hormonal contraception in women is unknown. This study aimed to examine patterns in dispensing of DMTs in women and men with MS, and hormonal long-acting reversible contraceptive (LARC) overlap at DMT initiation among women. MethodsPopulation cohort study using 10% random sample of the Australian Pharmaceutical Benefits Scheme dispensing data (2007–2021). DMT dispensing data were evaluated separately for women and men aged 18–49 years. Hormonal LARC overlap was determined by receipt of contraceptive dispensing where the expected duration of efficacy overlapped with the DMT dispensing date. ResultsDMTs with teratogenic potential (cladribine, sphingosine-1-phosphates and teriflunomide) were less likely to be commenced in women than men aged 18–39 (OR 0.70, 0.51–0.96), but not in those aged 40–49 (OR 0.93, 0.60–1.43). Hormonal LARC overlap was higher among those commenced DMTs with teratogenic potential compared with interferons (aOR 2.52, 1.14, 5.55). ConclusionSex and age differences in DMT utilisation were observed based on teratogenic potential. Hormonal LARC overlap appears higher in those receiving potentially teratogenic DMTs, but overall rates remain low.

The effect of metabolic syndrome in patients with type 2 diabetes mellitus: Review

A group of metabolic abnormalities known as the metabolic syndrome (MS) are typified by a number of cardiovascular risk factors that are typically linked to central fat buildup and insulin resistance. Insufficient dietary modifications and weight loss, linked to consistent physical exercise, are regarded as primary and first-choice treatments for multiple sclerosis (MS). These interventions help decrease visceral fat and belly circumference, enhance insulin sensitivity, lower plasma glucose and triglyceride concentrations, increase high-density lipoprotein levels, and ultimately lower the risk factors that lead to type 2 diabetes. The MS is a topic of study in the medical community right now since it is associated with conditions that not only have a high death rate globally but also exhibit rising occurrence. Deregulation of the proteins, fats, and carbohydrates involved in metabolism causes type 2diabetes, which can lead to reduced insulin production, insulin resistance, or a combination of the two. With 90% of cases, type 2 diabetes is the most common of the three kinds of the disease. Being a chronic and complicated illness, diabetes necessitates close medical monitoring in order to lower risks and develop control techniques. Given its rapid epidemic expansion on a global scale in recent years, it is regarded as one of the pandemics of the twenty-first century. This review was non-systematic and advanced, examining the MS in individuals with type 2 diabetes by consulting multiple literatures and analyzing some new publications.

Long-term modifications of the peripheral immune repertoire after switching from sequestering disease-modifying treatments in multiple sclerosis.

Scarce data are available on the long-term immunological effects of multiple sclerosis (MS) disease-modifying treatments (DMTs). This study aimed to investigate the long-term modifications of the peripheral immune repertoire on interruption of a sequestering DMT (natalizumab, fingolimod) and switch to another high-efficacy DMT. Lymphocyte subpopulations were assessed, every 6 months up to 48 months, in patients switched from fingolimod or natalizumab to ocrelizumab, and in patients switched from fingolimod to natalizumab, compared to patients switched to ocrelizumab or natalizumab from a moderate-efficacy DMT and to naive patients. We included 389 MS patients (200 ocrelizumab and 189 natalizumab). After adjusting for baseline variables, patients switched from fingolimod to ocrelizumab showed lower CD3 + and CD4 + lymphocytes up to 48 months after switch (with lower percentage of naive CD4 +), and increased odds of total, CD3+, CD4+ lymphopenia. Patients switched from natalizumab to ocrelizumab showed higher CD3 + lymphocytes up to 36 months after switch, and higher CD4+, CD8+ lymphocytes up to 24 months. The frequency of infections was not influenced by previous treatment. A long-term persistence of the residual effects of the exposure to sequestering DMTs (fingolimod and less natalizumab) on the peripheral immune repertoire was observed after switching to another high-efficacy DMT.

MyMS: An Interface for Patient-Reported Outcomes for Finnish Individuals With Multiple Sclerosis.

Patient-generated data are a cornerstone of individualized multiple sclerosis (MS) treatment. MyMS, an interface for patient-reported outcomes (PROs) was developed by the Finnish MS Register to enable systematic collection of PROs. MyMS collects data on demographics, lifestyle factors, disease-related factors, and validated questionnaires, including the Quality of Life Questionnaire (15D), the Multiple Sclerosis Impact Scale (MSIS-29), and the Fatigue Severity Scale (FSS). At the end of 2020, the patient-reported Expanded Disability Status Scale (PREDSS), the EuroQOL-5 Dimension (EQ-5D), the Fatigue Scale for Motor and Cognitive Functions (FSMC), and the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) were added. As of January 1, 2023, 1201 individuals with MS (79% female) have added data to MyMS. Of the validated PRO measures (PROMs), the 15D, MSIS-29, and FSS are the most used. The mean PREDSS score is 3.0 and median disease duration is 6.4 years. According to the existing PROMs, patients report mildly compromised quality of life and problems with fatigue and cognition. The patient interface of the Finnish MS Register consists of data from 17 of 21 counties with well-being services. The interface is used by 10% of Finnish individuals with MS. The addition of the PREDSS, EQ-5D, FSMC, and MSNQ to the interface has increased health care professional and patient interest in the use of PROMs. We suggest that PROs should be integrated into electronic health records to improve shared decision-making and diminish documentation burden.

Dietary zinc status is associated with ZnT3 (SLC30A3), IL-6 gene expressions and spinal cord tissue damage in spinal cord tissue in a cuprizone-induced rat Multiple Sclerosis model

The aim of this study was to investigate the effects of dietary zinc status on spinal cord tissue damage and ZnT3, IL-6 gene expressions in a cuprizone-induced rat Multiple Sclerosis (MS) model. The study was carried out on 46 adult male rats of the genus Wistar. The animals used in the study were divided into 5 groups (G) (Control 6, other groups 10). G1, Control. G2, Sham-MS: Carboxy-methyl-cellulose (KMS) solution in which Cuprizon was dissolved was given to rats by gavage daily for 8 weeks at the rate of 1 % of daily feed consumption. MS was formed by giving 1 % of the daily feed consumption cuprizon in KMS solution by gavage to the animals in G3, 4 and 5 for 8 weeks. G4 was fed with a zinc deficient (50 µg/kg zinc) diet. G5 was given intraperitoneal (ip) zinc sulfate (5 mg/kg/day) supplementation. MS formation in animals was determined by Rotarod tests and Myelin Basic Protein (MBP) gene expression analysis. ZNT3 and IL-6 gene expression levels in spinal cord tissue samples of animals by Real-Time-PCR method; MDA and GSH levels were determined by ELISA method. The highest spinal cord MDA and IL-6 levels were obtained in G3 and G4 (P<0.05). Zinc supplementation in G5 prevented the increase in the mentioned parameters and turned them into control values (P<0.05). The spinal cord GSH and ZnT3 levels of G3 and G4 were lower than all other groups (P<0.05). Zinc supplementation prevented suppression in the same parameters in G5 and reached the control values (P<0.05). The findings of the current study suggest that zinc supplementation in addition to treatment for MS may be beneficial in reducing the severity of the disease.

Liposome-Assisted Drug Delivery in the Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the nervous system that leads to neurological dysfunctions and severe disabilities. It is worth noting that conventional pharmacotherapy is poorly selective and causes toxicity problems and several systemic side effects. Thus, there is a need to develop new approaches to this medical challenge. The use of nanocarriers for drug delivery represents a good strategy to overcome several issues such as high therapeutic drug doses with side effects, such as diarrhea, nausea, and abdominal pain, and drug degradation processes; in addition, nanocarriers can provide controlled and targeted drug release. This review describes the application of liposomes for the delivery of pharmaceutical actives to target MS. Firstly, MS is explained. Then, liposomes are described along with their preparation, characterization, and stability. The literature about the use of liposomes for the treatment of MS is then analyzed.

Academic outcomes before and after clinical onset of acquired demyelinating syndromes in children: a matched cohort data linkage study.

It is unknown if cognition is impaired before clinical onset of paediatric acquired demyelinating syndromes. We conducted a matched cohort study using prospectively collected educational data in multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) patients (n = 60) and controls (pooled n = 449,553). Academic performance at ages 10-11 was impaired in MOGAD (-1.27 adjusted z-score [95% CI: -1.81 to -0.73], P < 0.001) and preclinical MS (-0.40 [-0.80 to -0.0003], P = 0.0498). Moderate/high-efficacy MS treatment was associated with better final academic performance (0.92 [0.28-1.57], P = 0.005). After clinical onset MS patients missed 8.7% of school (controls 2.9%, P < 0.001) and MOGAD patients 11.9% (controls 2.0%, P < 0.001).

Enhancing Quality of Life in Multiple Sclerosis Patients Through Coadministration of FDA-Approved Immunomodulators and Melatonin

Objective: The primary goal of this study was to assess the binding characteristics and affinities of melatonin and certain U.S. Food and Drug Administration (FDA)-approved lipophilic drugs used in the treatment of multiple sclerosis (MS) with the brain and muscle Arnt-like 1 (BMAL1) clock protein. Additionally, the study aimed to investigate their potential as modulators of BMAL1 activity for therapeutic applications in MS.Methods: Molecular docking and simulation studies were conducted to investigate the interactions between the BMAL1 protein and the selected agents as ligands. Docking simulations were performed using AutoDock Vina, and key interactions were analyzed with Biovia Discovery Studio Visualizer. A molecular dynamics simulation was conducted using GROMACS 2020.4 and the binding free energies were calculated using the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method. The pharmacokinetic properties of the ligands were predicted using the BOILED-Egg model implemented in the SwissADME web tool.Results: Melatonin demonstrated the highest binding affinity (-8.5 kcal/mol) and most favorable binding free energy (-245.26±1.27 kJ/mol) with BMAL1, suggesting its potential synergistic activity with other FDA-approved drugs in MS therapy. The pharmacokinetic analysis indicated that all three ligands were likely to cross the blood-brain barrier and exhibit high gastrointestinal absorption, with teriflunomide and melatonin potentially achieving a better profile.Conclusion: This study highlights the potential of concomitant use of melatonin to modulate BMAL1 activity, providing a foundation for developing targeted chronotherapeutic strategies in MS treatment.

Anticancer Effects of BAF312 (Siponimod) in Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) is a lethal disease that is the fifth leading cause of cancer-related death in women. BAF312 (siponimod) is a potent and selective sphingosine-1-phosphate (S1P) receptor modulator that has been approved as a treatment for multiple sclerosis. In addition to its immunomodulatory action, BAF312 shows preclinical antitumor effects in several cancer types. This study sought to determine whether BAF312 had anticancer properties against EOC using in vitro and in vivo models. EOC cell lines A2780, SKOV3ip1, A2780-CP20, and SKOV3-TR were treated with BAF312 and tested for cell proliferation, apoptosis, and migration using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, fluorescence-activated cell sorting, and migration assays. We investigated the expression of sphingosine-1-phosphate receptor 1 (S1PR1) in most EOC cell lines through western blot analysis. To investigate potential mechanisms, western blot analysis was used to assess the expression of AKT serine/threonine kinase 1 (AKT) and extracellular-regulated kinase (ERK) after BAF312 treatment. We also created poly(D,L-lactide-co-glycolide) nanoparticles encapsulating BAF312 (PLGA-NP-BAF312) for in vivo therapy. The average size and zeta potential of PLGA-NP-BAF312 were determined using dynamic light scattering. The therapeutic efficacy of PLGA-NP-BAF312 was tested in an A2780 tumor-bearing orthotopic mouse model of EOC. S1PR1 was overexpressed in most EOC cell lines. BAF312 significantly reduced cell proliferation and migration while inducing significant apoptosis in all EOC cell lines. PLGA-NP-BAF312 treatment significantly reduced tumor weights in A2780 tumor-bearing mice. Furthermore, the anticancer effects of BAF312 were associated with reduced phosphorylation of ERK and AKT. Our findings show that BAF312 has significant anticancer effects in EOC cells by inhibiting the ERK and AKT pathways, and might potentially be used to treat EOCs.

The recurrence of disease activity after ocrelizumab discontinuation in multiple sclerosis

IntroductionOcrelizumab (OCR) is a highly effective treatment of multiple sclerosis (MS), and B cell repopulation profiles suggest that it might be used as an immune reconstitution therapy. However, data on disease recurrence after stopping treatment with OCR are scarce. Our objective was to evaluate the recurrence of disease activity after OCR discontinuation. MethodsIn this multicenter retrospective cohort study, we included MS patients who discontinued OCR, without switching to another treatment, for twelve months or more, after having received at least one full dosage of 600 mg. We defined focal inflammation as the occurrence of a clinical relapse or significant MRI activity (≥3 new T2 lesions or ≥2 contrast-enhancing lesions). ResultsWe included 53 MS patients; 41 relapsing remitting (RRMS), 5 secondary progressive (SPMS) and 7 primary progressive (PPMS) patients. Median follow-up period after OCR discontinuation was 16 months. We only observed focal inflammation after discontinuation in RRMS patients; 2.4 % (1/41) patients presented with significant MRI activity and matching clinical symptoms, and 7.3 % (3/41) patients presented with a suspected clinical relapse without radiological activity: a total of 9.8 % (4/41) at a median time of 17 months after the last infusion. DiscussionWe found focal inflammation after discontinuation of OCR in 4 (9.8 %) of the RRMS patients, of which 1 was radiologically confirmed. Our observations highlight that recurrence of focal inflammation seems low but discontinuation may not be appropriate for everyone. Further larger studies are important to determine the immune reconstitution therapy potential of OCR.