Multiple Sclerosis Therapy Research Articles

Dietary Polyphenols, Microbiome, and Multiple Sclerosis: From Molecular Anti-Inflammatory and Neuroprotective Mechanisms to Clinical Evidence.

Multiple sclerosis (MS) is a multifactorial, immune-mediated disease caused by complex gene-environment interactions. Dietary factors modulating the inflammatory status through the control of the metabolic and inflammatory pathways and the composition of commensal gut microbiota, are among the main environmental factors involved in the pathogenesis of MS. There is no etiological therapy for MS and the drugs currently used, often accompanied by major side effects, are represented by immunomodulatory substances capable of modifying the course of the disease. For this reason, nowadays, more attention is paid to alternative therapies with natural substances with anti-inflammatory and antioxidant effects, as adjuvants of classical therapies. Among natural substances with beneficial effects on human health, polyphenols are assuming an increasing interest due to their powerful antioxidant, anti-inflammatory, and neuroprotective effects. Beneficial properties of polyphenols on the CNS are achieved through direct effects depending on their ability to cross the blood-brain barrier and indirect effects exerted in part via interaction with the microbiota. The aim of this review is to examine the literature about the molecular mechanism underlying the protective effects of polyphenols in MS achieved by experiments conducted in vitro and in animal models of the disease. Significant data have been accumulated for resveratrol, curcumin, luteolin, quercetin, and hydroxytyrosol, and therefore we will focus on the results obtained with these polyphenols. Clinical evidence for the use of polyphenols as adjuvant therapy in MS is restricted to a smaller number of substances, mainly curcumin and epigallocatechin gallate. In the last part of the review, a clinical trial studying the effects of these polyphenols in MS patients will also be revised.

Bruton tyrosine kinase inhibitors for multiple sclerosis.

Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

Yoga vs Physical Therapy in Multiple Sclerosis: Results of Randomized Controlled Trial and the Training Protocol.

Yoga originated in the territory of modern India more than 3,000 years ago uses techniques for working with the musculoskeletal system, cardiorespiratory system, and attention. Currently, the effectiveness and safety of yoga in patients with various neurological disorders, including multiple sclerosis (MS), is of interest to many scientists and clinicians. The main aim of this study is to examine the effect of yoga on symptoms and quality of life in patients with MS vs physical therapy (exercise therapy) and no exercise. The patients were randomly assigned to three groups (yoga, physical therapy (PT), or waiting list). After 12 weeks of regular exercises (or the absence of them), the effect of yoga and PT on the functional status and quality of life of patients were evaluated. The data were collected during the patients' two visits to the study center - before the start of the study and at the end of the 12-week period. The in-person examination included a doctor's assessment of the Expanded Disability Status Scale (EDSS), the SF-36 quality of life questionnaire, the fatigue scale, the Berg balance scale, and the 6-min walking test. A total of 36 patients finished the clinical study: thirty women and six men. There was no statistically significant difference between the groups in terms of improvement in MS symptoms as measured by the balance, walking test, and fatigue scales. However, in the analysis of eight criteria of SF-36 quality-of-life questionnaire by the covariation analysis, statistically significant differences were found in favor of the yoga group in terms of physical functioning (PF) (p = .003), life activity (VT) (p < .001), mental health (MH) (p = 013), and social functioning (SF) (p = .028). Thus, regular yoga classes under the guidance of qualified staff are a promising method of non-drug rehabilitation of patients with MS with motor disorders.

The role of multiple sclerosis therapies on the dynamic of human gut microbiota

Gut microbiota, the total microorganisms in our gastrointestinal tract, might have an implication in multiple sclerosis (MS), a demyelinating neurological disease. Our study included 50 MS patients and 21 healthy controls (HC). Twenty patients received a disease modifying therapy (DMT), interferon beta1a or teriflunomide, 19 DMT combined with homeopathy and 11 patients accepted only homeopathy. We collected in total 142 gut samples, two for each individual: at the study enrolment and eight weeks after treatment. We compared MS patients' microbiome with HC, we analysed its evolution in time and the effect of interferon beta1a, teriflunomide and homeopathy. There was no difference in alpha diversity, only two beta diversity results related to homeopathy. Compared to HC, untreated MS patients had a decrease of Actinobacteria, Bifidobacterium, Faecalibacterium prauznitzii and increased Prevotella stercorea, while treated patients presented lowered Ruminococcus and Clostridium. Compared to the initial sample, treated MS patients had a decrease of Lachnospiraceae and Ruminococcus and an increased Enterococcus faecalis. Eubacterium oxidoreducens was reduced after homeopathic treatment. The study revealed that MS patients may present dysbiosis. Treatment with interferon beta1a, teriflunomide or homeopathy implied several taxonomic changes. DMTs and homeopathy might influence the gut microbiota.

Platelets and platelet-derived vesicles as an innovative cellular and subcellular platform for managing multiple sclerosis.

Multiple sclerosis (MS) is a progressive inflammatory autoimmune disease that involves young individuals. The drug delivery systems now are available for this disease have chronic and non-targeted effects on the patients. Because of the presence of BBB (blood-brain-barrier), their concentration in the CNS (central nervous system) is low. Because of this flaw, it is critical to use innovative active targeted drug delivery methods. Platelets are blood cells that circulate freely and play an important role in blood hemostasis. In this review, we emphasize the various roles of activated platelets in the inflammatory condition to recruit other cells to the injured area and limit inflammation. Besides, the activated platelets in the different stages of the MS disease play a significant role in limiting the progression of inflammation in the peripheral area and CNS. This evidence indicates that a platelet-based drug delivery system can be an efficient biomimetic candidate for drug targeting to the CNS and limiting the inflammation in the peripheral and central areas for MS therapy.

1,25(OH)2D3 Differently Modulates the Secretory Activity of IFN-DC and IL4-DC: A Study in Cells from Healthy Donors and MS Patients

Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNβ and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNβ/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNβ therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis.

Personalized Treatment for Multiple Sclerosis: The Role of Precision Medicine

Multiple Sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system. It is a complex and heterogeneous disease, and its pathogenesis is still not completely understood. Precision medicine, which involves the use of advanced technologies such as genomics, proteomics, metabolomics, and imaging to identify specific biomarkers and disease subtypes, is a promising approach to the management of multiple sclerosis. Precision medicine in MS includes the development of targeted therapies that aim to modulate specific immune pathways involved in MS pathogenesis. This review article aims to provide an overview of the current status and future directions of precision medicine in MS. The article discusses the importance of precision diagnostics in MS, including the identification of biomarkers and imaging techniques for MS, as well as the challenges and opportunities of personalized treatment in MS. Targeted therapies in MS are also discussed, including the challenges of developing and implementing these therapies. The article highlights the potential of combination therapies in MS, and the role of AI and ML in improving biomarker identification. The challenges of implementing precision medicine in clinical practice are also addressed, including the standardization of diagnostic criteria and treatment guidelines, and the ethical and legal considerations of personalized treatment. Overall, precision medicine represents a promising approach to the management of MS, with the potential to improve diagnosis, prognosis, and treatment outcomes. However, the implementation of precision medicine in MS clinical practice requires addressing several challenges, including the standardization of diagnostic criteria and treatment guidelines, and the development of affordable and accessible technologies and therapies. With continued research and advances in technology, precision medicine has the potential to transform the field of MS research and clinical practice.

Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1million USD fixed treatment budget. Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30μg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95%CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30μg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 withteriflunomide 7mg, $4737 withteriflunomide 14mg, $2178 withfingolimod, and $2793 withdimethyl fumarate. Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic.

The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

FGF/FGFR system in the central nervous system demyelinating disease: Recent progress and implications for multiple sclerosis.

With millions of victims worldwide, multiple sclerosis is the second most common cause of disability among young adults. Although formidable advancements have been made in understanding the disease, the neurodegeneration associated with multiple sclerosis is only partially counteracted by current treatments, and effective therapy for progressive multiple sclerosis remains an unmet need. Therefore, new approaches are required to delay demyelination and the resulting disability and to restore neural function by promoting remyelination and neuronal repair. The article reviews the latest literature in this field. The fibroblast growth factor (FGF) signaling pathway is a promising target in progressive multiple sclerosis. FGF signal transduction contributes to establishing the oligodendrocyte lineage, neural stem cell proliferation and differentiation, and myelination of the central nervous system. Furthermore, FGF signaling is implicated in the control of neuroinflammation. In recent years, interventions targeting FGF, and its receptor (FGFR) have been shown to ameliorate autoimmune encephalomyelitis symptoms in multiple sclerosis animal models moderately. Here, we summarize the recent findings and investigate the role of FGF/FGFR signaling in the onset and progression, discuss the potential therapeutic advances, and offer fresh insights into managing multiple sclerosis.

Rhino-Sino-Cerebral Mucormycosis Associated with Long-Term Rituximab Therapy in Multiple Sclerosis: A Case Report and Review of the Literature

Introduction: Rituximab is a CD20 depleting agent, widely used as an off-label diseasemodifying treatment (DMT) in treating multiple sclerosis (MS). The present study aimed to report the first case of rhino-sino-cerebral mucormycosis in a patient with secondary progressive MS (SPMS), treated with rituximab. Case Report: The patient was a 38-year-old man with a history of SPMS treated with rituximab, who developed subacute left vision loss and impaired ocular movement. He also mentioned a concomitant severe headache and cheek swelling. Based on the brain and orbital magnetic resonance imaging (MRI) findings, rhino-sino-cerebral mucormycosis was suspected. Subsequent endoscopic examination confirmed the diagnosis. He underwent medical treatment with amphotericin B liposomal and surgical debridement leading to a significant clinical recovery. He was eventually discharged home with a solid recommendation to discontinue rituximab. Conclusion: The present report indicates a case of SPMS treated with rituximab, who developed rhino-sino-cerebral mucormycosis.

Exercise Therapy in Early Multiple Sclerosis Improves Physical Function But Not Cognition: Secondary Analyses From a Randomized Controlled Trial

Background Exercise positively affects multiple sclerosis (MS) symptoms, physiological systems, and potentially cognition. However, an uninvestigated “window of opportunity” exists for exercise therapy early in the disease. Objective This study presents secondary analyses from the Early Multiple Sclerosis Exercise Study, and aims to investigate the efficacy of exercise on physical function, cognition, and patient-reported measures of disease and fatigue impact early in the disease course of MS. Methods This randomized controlled trial (n = 84, time since diagnosis <2 years) included 48 weeks of aerobic exercise or an active control condition (health education) and between-group changes are based on repeated measurement mixed regression models. Physical function tests included measures of aerobic fitness, walking (6-minute walk, Timed 25-foot walk, Six-spot step test), and upper-limb dexterity. Tests of processing speed and memory evaluated cognition. The questionnaires Multiple Sclerosis Impact Scale and Modified Fatigue Impact Scale assessed perception of disease and fatigue impact. Results Following early exercise aerobic fitness showed superior between-group physiological adaptations (4.0 [1.7; 6.3] ml O2/min/kg; large effect size [ES = 0.90]). No other outcomes showed significant between-group differences, yet all measures of walking and upper-limb function showed small-to-medium effect sizes in favor of exercise (ES = 0.19−0.58). Overall disability status as well as cognition were unaffected by exercise, whereas perception of disease and fatigue impact were reduced in both groups. Conclusion In early MS, 48 weeks of supervised aerobic exercise seem to positively modify physical function, but not cognitive function. Perception of disease and fatigue impact may be modifiable by exercise in early MS. Trial registration: Clinicaltrials.gov (identifier: NCT03322761).

Changes in Retinal Thickness and Brain Volume during 6.8-Year Escalating Therapy for Multiple Sclerosis

Background. Different disease-modifying therapies (DMT) for multiple sclerosis (MS) have disparate effects on disability outcomes. Sweden has a leading position globally in initiating high-efficacy DMT instead of escalating DMT from 1st-line to high-efficacy DMT. With optical coherence tomography (OCT), retinal changes can be measured at a few micrometer level. OCT has been increasingly applied in diagnosing MS and monitoring disease course and therapeutic effect. Objective. We investigate the effects of 1st-line versus high-efficacy DMT for MS on retinal and brain atrophy and on functional outcomes during 6.8 years of escalating DMT. Materials and Methods. In this prospective longitudinal observational study, 18 MS patients were followed up for 6.8 years. Twelve of the patients were untreated at baseline. All patients underwent 1st-line DMT for median duration of 2.4 years and then switched to high-efficacy DMT for a median duration of 2.9 years. Findings from neurological examinations, MRI, and OCT measures were registered 2-4 times per year. Results. Ganglion cell-inner plexiform layer (GCIPL) thickness was significantly reduced during 1st-line DMT (73.75 μm, p &lt; 0.01 ) compared to baseline (76.38 μm). During high-efficacy DMT, thickness reduction was slower (73.27 μm, p &lt; 0.05 ), and MRI contrast-loading lesions vanished ( p &lt; 0.01 ). However, brain parenchymal fraction (BPF) decreased during high-efficacy DMT compared to 1st-line DMT. Estimated models showed similar results. Conclusion. GCIPL decline was most profound during 1st-line DMT and diminished during high-efficacy DMT. MRI contrast lesions vanished during high-efficacy DMT. However, brain atrophy continued regardless of high-efficacy DMT.

Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis.

Multiple sclerosis is a complex autoimmune disease, and several therapies for multiple sclerosis have been developed and widely used. However, existing medications for multiple sclerosis were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for multiple sclerosis prevention are still needed. We performed Mendelian randomization to explore potential drug targets for multiple sclerosis using summary statistics from the International Multiple Sclerosis Genetics Consortium (nCase = 47 429, nControl = 68 374) and further replicated in UK Biobank (nCase = 1356, nControl = 395 209) and FinnGen cohorts (nCase = 1326, nControl = 359 815). Genetic instruments for 734 plasma and 154 CSF proteins were obtained from recently published genome-wide association studies. The reverse causality detection using bidirectional Mendelian randomization analysis and Steiger filtering, Bayesian co-localization, and phenotype scanning that searched previously reported genetic variant-trait associations were implemented to consolidate the Mendelian randomization findings further. In addition, the protein-protein interaction network was performed to reveal potential associations among proteins and/or present multiple sclerosis medications. At Bonferroni significance (P < 5.63 × 10-5), Mendelian randomization analysis revealed six protein-multiple sclerosis pairs. In plasma, per standard deviation increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratios for the proteins above were 0.83 (95% CI, 0.79-0.89), 0.59 (95% CI, 0.48-0.71) and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of multiple sclerosis, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six proteins had reverse causality. Bayesian co-localization suggested that FCRL3 [coloc.abf-posterior probability of hypothesis 4 (PPH4) = 0.889], TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930) and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with multiple sclerosis. FCRL3, TYMP and SLAMF7 interacted with target proteins of current multiple sclerosis medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1 and SLAMF7 had causal effects on multiple sclerosis risk. These findings suggested those five proteins might be promising drug targets for multiple sclerosis and warrant further clinical investigation, especially FCRL3 and SLAMF7.

Impact of COVID-19 on prescribing patterns and treatment selection of disease modifying therapies in multiple sclerosis.

Certain classes of multiple sclerosis (MS) disease modifying therapies (DMTs) have been associated with an increased risk of severe COVID-19, resulting in prescribers considering changes in their practice habits during the COVID-19 pandemic. This study assessed for differences in prescribing patterns of DMTs along with the reason(s) for modification of therapy over time. A retrospective review of medical records at Johns Hopkins Health System was performed. The timeframe of the study, April 2019 to December 2021, was divided into three subcategories: pre-pandemic (April 2019-March 2020), pre-vaccine availability (April 2020-March 2021), and post-vaccine availability (April 2021-December 2021). Patients were identified through dispense reports from the pharmacy dispensing system, and prescribing report from the health-system electronic health record (EHR). The health-system EHR was also utilized to conduct chart reviews for a subset of patients that had a modification in their therapy during the specified timeframes. The study included adult patients that were prescribed at least one DMT through the Johns Hopkins Pharmacy Services during the study timeframe and those who stayed on their DMT for at least 2 months without tolerability issues. Descriptive statistics were used to compare the prescribing practices during the timeframes with the percentage of prescribing for each type of treatment and to assess the percentage of patients that switched therapies in the different time periods. Based on prescribing report data, 670 patients were prescribed a DMT during the pre-pandemic period with infusion therapies being the most prescribed therapies during this timeframe (38%), followed by oral therapies at 35%. In comparison, a total of 620 patients were prescribed a DMT during pre-vaccine pandemic and the percentage of prescriptions of infusion therapies decreased to 28% (-10%) during this timeframe, whereas oral prescriptions increased to 42% (+7%). These trends continued during the post-vaccine timeframe where infusion therapies decreased to 26% (-12%) and oral therapies increased to 43% (+8%) in reference to the pre-pandemic period. Prescribing patterns of self-injectable therapies remained stable throughout the 3 timeframes. A dispensing report cohort of 500 patients were randomly selected for chart reviews to assess therapy modifications due to COVID-19. The percentage of therapy change due to COVID-19 increased to 45.2% during pre-vaccine period and remained at 38.4% during post-vaccine period when compared to the pre-pandemic reference period. The majority of changes due to COVID-19 were delays in infusion therapies (96% during pre-vaccine, and 94% during post-vaccine), not medication changes. Prescribing patterns and therapy modifications of DMTs for MS patients were impacted by COVID-19, with the greatest changes observed for the infusion therapies, including reduction in percentage of infusion prescriptions and delays in infusion therapies. Prescribing patterns of lower efficacy self-injectable therapies (interferon-beta and glatiramer acetate) remained stable. The outcomes of this study provide background for future outcomes-focused research studies in MS.

Factors Associated with Therapeutic Adherence in Multiple Sclerosis in Spain.

Adherence to disease-modifying therapies (DMTs) in multiple sclerosis (MS) is a complex and multidimensional phenomenon. Identifying the predictors of therapeutic adherence in MS will guide the design of interventions to improve health outcomes. Our aim was to assess the degree of adherence to pharmacological treatments, assess the relationship between patient-related factors and pharmacological adherence and to identify predictors of adherence to pharmacological treatments in patients with MS in Spain. A cross-sectional nationwide study was carried out in Spain between December 2020 and September 2021. The web-based evaluation protocol consisted of a self-questionnaire survey designed ad hoc and the application of validated questionnaires to assess adherence, as well as beliefs about medication and quality of life. Predictor variables of adherence to MS treatment were assessed using multivariate analysis. A total of 152 patients with MS participated (mean age: 44 years; 64% were female; and 78% had relapsing-remitting MS). Seventy-three percent of the patients reported being adherent to their pharmacological treatment for MS. Forgetfulness was the most common cause of non-adherence. Necessity beliefs and concerns beliefs were not statistically associated with adherence. The adherent group shows statistically significant better levels of quality of life in the cognitive function subscale than the non-adherent participants (p=0.040). Role limitations-emotional, emotional well-being and overall quality of life were not significantly associated with adherence. Predictors with a statistical association with adherence to treatment were years of education (OR=0.79; 95% CI: 0.65-0.96; p=0.020) and intravenous treatment (OR=3.17; 95% CI: 1.07-9.45; p=0.038). We found an adequate adherence to pharmacological treatment. Low education and intravenous treatment were significant predictors of adherence to DMTs.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR]=0.52, 95% confidence interval [CI]=0.45-0.60), 46% lower risk of disability worsening (HR=0.54, 95% CI=0.41-0.71), and 32% greater chance of disability improvement (HR=1.32, 95% CI=1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Patient and Clinician Perspectives of Physical Therapy for Walking Difficulties in Multiple Sclerosis.

Gait speed is frequently the primary efficacy endpoint in clinical trials of interventions targeting mobility in people with multiple sclerosis (MS). However, it is unclear whether increased gait speed is a meaningful outcome for people living with MS. The purpose of this study was to identify the most important aspects of mobility for people with MS and physical therapists and to explore how patients and clinicians perceive whether physical therapy has been effective. Forty-six people with MS and 23 physical therapy clinicians participated in a focus group, one-on-one interview, or electronic survey. The focus group and interview data were transcribed and coded to identify themes. Free-text survey responses were also coded, and multiple-choice options were analyzed for frequency. Among people with MS, falls and difficulties getting out into the community were identified as highly important mobility limitations. Clinicians also identified falls and safety as a priority. Walking speed was infrequently described as a problem, and although gait speed is often measured by clinicians, improving gait speed is rarely a treatment goal. Despite their emphasis on safety, clinicians lacked certainty about how to objectively measure improvements in safety. People with MS evaluated physical therapy effectiveness based on the ease by which they can do things and acknowledged that "not getting worse" is a positive outcome. Clinicians evaluated effectiveness based on the amount of change in objective outcome measures and by patient and caregiver reports of improved function. These findings indicate that gait speed is not of major importance to people with MS or physical therapy clinicians. People with MS want to be able to walk further and without an assistive device, and they want to avoid falls. Clinicians want to maximize safety while improving functional ability. Clinicians and patients may differ in their expected outcomes from physical therapy.

Real-World Effectiveness of Natalizumab Extended Interval Dosing in a French Cohort.

Natalizumab, a therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of - 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (- 1.3 to 9.8%); p < 0.001 for non-inferiority. There were no significant differences between relapse rates (0.043 vs. 0.083 per year, respectively; p = 0.14) or Expanded Disability Status Scale mean scores (2.43 vs. 2.72, respectively; p = 0.18); anti-JC virus index values were similar (p = 0.23); and no instances of PML were reported. The comparisons using IPTW (n = 306) and PSM (n = 204) were consistent. These results support the pertinence of using an EID strategy for RRMS patients treated with natalizumab. gov identifier (NCT04580381).

High-throughput screening for myelination promoting compounds using human stem cell-derived oligodendrocyte progenitor cells

Promoting myelination capacity of endogenous oligodendrocyte precursor cells (OPCs) is a promising therapeutic approach for CNS demyelinating disorders such as Multiple Sclerosis (MS). To aid in the discovery of myelination-promoting compounds, we generated a genome-engineered human pluripotent stem cell (hPSC) line that consists of three reporters: identification-and-purification tag, GFP, and secreted-NanoLuc, driven by the endogenous PDGFRA, PLP1, and MBP genes, respectively. Using this cell line, we established a high-throughput drug screening platform and performed a small-molecule screen, which identified at least two myelination-promoting small-molecule (Ro1138452 and SR2211) that target prostacyclin (IP) receptor and retinoic acid receptor-related orphan receptor γ (RORγ), respectively. Single-cell-transcriptomic analysis of differentiating OPCs treated with these molecules further confirmed that they promote oligodendrocyte differentiation and revealed several pathways that are potentially modulated by them. The molecules and their target pathways provide promising targets for the possible development of remyelination-based therapy for MS and other demyelinating disorders.