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Objective: The engagement of patients and family caregivers in value assessment is pivotal since they provide valuable contributions to assessment acceptability and relevance. The proposed study aims to use patient-centered techniques and multicriteria decision analysis (MCDA) to evaluate the values of disease-modifying therapies (DMTs) for multiple sclerosis (MS) from the perspectives of patients and family caregivers living in three 'Deep South' States of the US—Alabama, Louisiana, and Mississippi. Methods: This study will follow guidance from the Patient-Centered Outcomes Research Institute (PCORI) for patient engagement and two best practice reports for MCDA from the Professional Society for Health Economics and Outcomes Research (ISPOR) to complete value assessment. Throughout the study, we will engage multiple stakeholders, including patients, family caregivers, healthcare providers, and payers. Forty patients with MS and their family caregivers from Alabama, Louisiana, and Mississippi will be invited to participate in this study. We will intensively train them for value assessment knowledge and MCDA before we engage them in MCDA to determine the value of DMTs for MS. Discussions: Our approach differs from common MCDA since we incorporated a patient-centered framework in this study. Unlike previous studies only briefly inform or prepare participants before the MCDA process, in this study, we will provide basic value assessment trainings for patients and family caregivers to ensure they can effectively engage throughout the patient-centered MCDA process. We expect this study will demonstrate that the patient-centered MCDA approach is feasible and likely leads to improved patients' and family caregivers' engagement in value assessment. [ABSTRACT FROM AUTHOR]

Introduction: Administration of intravenous (IV), high-efficacy treatments (HETs) for the treatment of multiple sclerosis (MS) poses a high resourcing and planning burden on infusion centres, resulting in treatment delays that may increase the risk of breakthrough disease activity. Simulation tools can be used to systematically analyse capacity scenarios and identify and better understand constraints, therefore enabling decision-makers to optimise patient care. We have previously applied ENTIMOS, a discrete event simulation model, to assess scenarios of patient flow and care delivery using real-life data inputs from the neurology infusion suite at Charing Cross Hospital London. The model predicted that, given current capacity and projected demand, patients would experience high-risk treatment delays within 30 months. Objective: This study aimed to address key healthcare challenges for MS patient care management as seen from a neurologist's perspective. We used ENTIMOS to predict the impact of several distinct and clinically plausible scenarios on patient waiting times at the same MS infusion suite and to quantify mitigation strategies needed to assure continuity of care. Methods: We used real-world experience of an expert neurologist to identify five clinical scenarios: (1) switching patients to a subcutaneous (SC) MS treatment of the same therapeutic agent, in the same hospital setting; (2) extending opening times to the weekend; (3) reducing the number of infusion chairs (to simulate social distancing measures applied during the coronavirus disease 2019 [COVID-19] pandemic); (4) increasing demand for infusions; and (5) increasing the scheduling approval time. Patient waiting time for next due infusion and time to high-risk treatment delays (≥ 30 days) were the main analysed model outputs. Previously published base case results were used as reference. All hypothetical scenarios were run over a 3-year horizon (with the exception of scenario 1, which was run over a 3- and 5-year horizon). Strategies to mitigate treatment delays were analysed and discussed. Results: Switching 50% of patients to SC treatment of the same therapeutic agent administered in hospital postponed the predicted high-risk treatment delays to shortly beyond the 3-year simulation timeframe (month 38). Weekend opening reduced waiting times from 20 days to 4 days and prevented treatment delays, however, at elevated labour costs. Reducing the infusion chairs increased waiting time to 53 days on average and 86 days at the end of the simulation, leading to high-risk treatment delays within 6 months. An increased demand for infusions increased waiting time to 26 days on average and 47 days at the end of the simulation, leading to high-risk treatment delays within 22 months. Prolonged scheduling approval time did not reduce the waiting time, nor postpone the high-risk treatment delays. Conclusion: Decision makers need transparency on capacity constraints to better plan resourcing at infusion suites and MS treatments. Our results showed that various mitigation measures, such as increasing capacity by additional infusion chairs per year and transferring patients to other infusion suites, may help prevent treatment delays. Switching patients from IV to an SC version of the same therapeutic agent reduced the waiting time moderately and postponed high-risk treatment delays. It was insufficient to prevent high-risk treatment delays in the long term. Plain Language Summary: Patients with multiple sclerosis and other neurological conditions receive therapies that are often given intravenously. Due to increasing demand for intravenous infusions, specialist infusion centres face challenges with scheduling and insufficient personnel numbers, which contributes to the increasing costs of care. Computer-based decision support tools can help hospital administrators predict demand for infusions, plan resources and estimate overall costs. We used a computer-based decision support tool, "ENTIMOS", to predict demand at a multiple sclerosis infusion suite in London and to simulate possible solutions. The tool predicted that over the next 3 years patients would face increasing waiting time for their treatment and many would experience high-risk treatment delays of 30 days or longer. We tested several different, realistic scenarios where treatment demand was exacerbated and alleviated: we tested what would happen if patients were discharged from the infusion suite (decreasing demand), if the centre opened for 7 days instead of 5 days a week (increasing capacity), if social distancing measures were in place (decreasing capacity), and other scenarios. We found that high-risk treatment delays could be avoided if the centre adds infusion chairs to the suite or switches patients out of the infusion suite (e.g. to a treatment administered at home). The most effective long-term solution would be to have treatment options for multiple sclerosis that could be taken by patients at home. These treatments would be required to have the same benefits and the same or lower risk as the intravenous infusion therapies that are used today. It would help reduce labour costs of healthcare and may enable patients with multiple sclerosis to manage their disease at home. [ABSTRACT FROM AUTHOR]

Aim: Multiple sclerosis (MS) is a central nervous system degenerative disease that can lead to life-long disability. The global prevalence of the disease has risen significantly. However, there is a lack of studies to assess this problem in Arab countries, including Palestine. Thus, this study aimed to determine the Palestinian community dwellers' knowledge about MS in the West Bank. Subjects and methods: A cross-sectional, descriptive correlational design was conducted in Jenin Governorate in West Bank. The data were collected using the Multiple Sclerosis Knowledge Questionnaire (MSKQ-25) in addition to demographic characteristics. A total of 715 community dwellers responded to the study during the period from February to April 2022. Results: Findings demonstrated that Palestinian community dwellers reported a low level of knowledge about multiple sclerosis, in which 74.0% were within the poor knowledge range. There was a significant difference in knowledge about multiple sclerosis according to educational level (p < 0.05). Conclusion: Knowledge about multiple sclerosis was below normal among Palestinian community dwellers, thus there is a need to improve their knowledge about multiple sclerosis by implementing various strategies and interventions, including use of public awareness campaigns through various media ensuring reliable information reach the public regarding early detection and management of this serious disease. [ABSTRACT FROM AUTHOR]

Patients experience existential themes as pivotal in their lives, in order to be able to live with a severe, chronic illness; however, physicians report a hesitative approach to existential communication. The current study investigated Nordic patients' experiences of existential communication with their physicians related to the treatment of multiple sclerosis or chronic pain. Semi-structured interviews with 23 patients were analyzed following Interpretative Phenomenological Analysis. Physicians focusing on medical aspects at the expense of psychological and existential aspects of being ill was experienced by patients as challenging their treatment and well-being. For making a shared decision with the physician on their treatment, patients needed a transition from being dependent to being autonomous. A holding environment and existential communication about transitional objects such as relationships with something bigger than themselves, as nature or religion, supported this autonomy. The analysis showed that existential communication not only supported patients in developing and regaining autonomy but also functioned as a moderator for illness-related distress, as a prevention of withdrawal from treatment, and as significant for patients in relation to living with chronic illness. Further education in existential communication is desirable, to support physicians integrating existential dimensions in consultations and shared decision-making with patients suffering from a severe, chronic illness. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is one of the most serious neurological diseases. It is the most frequent reason of non-traumatic disability among young adults. MS is an autoimmune disease wherein the central nervous system wrongly destructs the myelin sheath surrounding and protecting axons of nerve cells of the brain and the spinal cord which results in presence of lesions called plaques. The damage of myelin sheath alters the normal transmission of nerve flow at the plaques level, consequently, a loss of communication between the brain and other organs. The consequence of this poor transmission of nerve impulses is the occurrence of various neurological symptoms. MS lesions cause mobility, vision, cognitive, and memory disorders. Indeed, early detection of lesions provides an accurate MS diagnosis. Consequently, and with the adequate treatment, clinicians will be able to deal effectively with the disease and reduce the number of relapses. Therefore, the use of magnetic resonance imaging (MRI) is primordial which is proven as the relevant imaging tool for early diagnosis of MS patients. But, low contrast MRI images can hide important objects in the image such lesions. In this paper, we propose a new automated contrast enhancement (CE) method to ameliorate the low contrast of MRI images for a better enhancement of MS lesions. This step is very important as it helps radiologists in confirming their diagnosis. The developed algorithm called BDS is based on Brightness Preserving Dynamic Fuzzy Histogram Equalization (BPDFHE) and Singular Value Decomposition with Discrete Wavelet Transform (SVD-DWT) techniques. BDS is dedicated to improve the low quality of MRI images with preservation of the brightness level and the edge details from degradation and without added artifacts or noise. These features are essential in CE approaches for a better lesion recognition. A modified version of BDS called MBDS is also implemented in the second part of this paper wherein we have proposed a new method for computing the correction factor. Indeed, with the use of the new correction factor, the entropy has been increased and the contrast is greatly enhanced. MBDS is specially dedicated for very low contrast MRI images. The experimental results proved the effectiveness of developed methods in improving low contrast of MRI images with preservation of brightness level and edge information. Moreover, performances of both proposed BDS and MBDS algorithms exceeded conventional CE methods. [ABSTRACT FROM AUTHOR]

Social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are the non-medical factors that influence health outcomes. Evidence indicates that health behaviours, comorbidities and disease-modifying therapies all contribute to multiple sclerosis (MS) outcomes; however, our knowledge of the effects of social determinants - that is, the 'risks of risks' - on health has not yet changed our approach to MS. Assessing and addressing social determinants of health could fundamentally improve health and health care in MS; this approach has already been successful in improving outcomes in other chronic diseases. In this narrative Review, we identify and discuss the body of evidence supporting an effect of many social determinants of health, including racial background, employment and social support, on MS outcomes. It must be noted that many of the published studies were subject to bias, and screening tools and/or practical interventions that address these social determinants are, for the most part, lacking. The existing work does not fully explore the potential bidirectional and complex relationships between social determinants of health and MS, and the interpretation of findings is complicated by the interactions and intersections among many of the identified determinants. On the basis of the reviewed literature, we consider that, if effective interventions targeting social determinants of health were available, they could have substantial effects on MS outcomes. Therefore, funding for and focused design of studies to evaluate and address social determinants of health are urgently needed. [ABSTRACT FROM AUTHOR]

Objective: To compare the description of interventions defined as "usual care" in control groups with those provided in experimental groups in physiotherapy randomized clinical trials for multiple sclerosis.Methods: Two independent reviewers conducted a literature search and study selection from five databases from their inception to February 2021. Randomized clinical trials aimed to physiotherapy multiple sclerosis treatment and providing "usual care" in the control group were included. Intervention reporting was assessed using the TIDieR checklist. Word and reference counts for each group were extracted. The methodological quality was assessed by the PEDro scale.Results: Twenty-four articles were included. The TIDieR total scores, word, and reference count were statistically higher in the experimental group, when compared to the control group (p < 0.001). The TIDieR total score is not correlated with PEDro score, word, publication year, or reference counts.Conclusion: Control treatments identified as "usual care" are underdescribed when compared to experimental treatments, affecting the validity, generalizability, and interpretability of results. [ABSTRACT FROM AUTHOR]

Introduction: The concurrent presence of both central nervous system (CNS) tumors and multiple sclerosis (MS) poses various diagnostic and therapeutic pitfalls and makes the clinical management of such patients challenging.Methods: In this retrospective, single-center cohort study, we searched our clinical databases (2006-2019) for patients with concurrent CNS tumors and MS and described their disease courses. Age at diagnosis of the respective disease and probabilities for MS disease activity events (DAEs) with vs. without prior tumor-specific therapy were tested pairwise using t-test for dependent samples and exact binomial test.Results: N = 16 patients with concurrent CNS tumors and MS were identified. MS diagnosis preceded the CNS oncological diagnosis by an average of 9 years (p = 0.004). More DAEs occurred in patients without prior chemotherapy (83.3%) than in patients with prior chemotherapy (16.7%; p = 0.008). This effect did not reach significance for patients with prior radiation therapy/radiosurgery (66.7% vs. 33.3%, p = 0.238). The average interval between DAEs and the last documented lymphopenia was 32.25 weeks.Conclusions: This study describes the clinical and demographic features of patients with concurrent CNS tumors and MS and suggests several practical approaches to their clinical management. Our findings suggest that adding a disease-modifying MS therapy to the regimen of patients treated with chemotherapy is necessary only if the patient suffers from a highly active, aggressive course of MS. In view of the lack of prospective trials, individual risk assessments should remain the foundation of the decision on MS treatment in concurrent CNS tumor diseases. [ABSTRACT FROM AUTHOR]

During the past decade, research has revealed that the vast community of micro-organisms that inhabit the gut - known as the gut microbiota - is intricately linked to human health and disease, partly as a result of its influence on systemic immune responses. Accumulating evidence demonstrates that these effects on immune function are important in neuroinflammatory diseases, such as multiple sclerosis (MS), and that modulation of the microbiome could be therapeutically beneficial in these conditions. In this Review, we examine the influence that the gut microbiota have on immune function via modulation of serotonin production in the gut and through complex interactions with components of the immune system, such as T cells and B cells. We then present evidence from studies in mice and humans that these effects of the gut microbiota on the immune system are important in the development and course of MS. We also consider how strategies for manipulating the composition of the gut microbiota could be used to influence disease-related immune dysfunction and form the basis of a new class of therapeutics. The strategies discussed include the use of probiotics, supplementation with bacterial metabolites, transplantation of faecal matter or defined microbial communities, and dietary intervention. Carefully designed studies with large human cohorts will be required to gain a full understanding of the microbiome changes involved in MS and to develop therapeutic strategies that target these changes. [ABSTRACT FROM AUTHOR]

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Background: Uncertainty in model-based cost-utility analyses is commonly assessed in a probabilistic sensitivity analysis. Model parameters are implemented as distributions and values are sampled from these distributions in a Monte Carlo simulation. Bootstrapping is an alternative method that requires fewer assumptions and incorporates correlations between model parameters. Methods: A Markov model-based cost–utility analysis comparing oromucosal spray containing delta-9-tetrahidrocannabinol + cannabidiol (Sativex®, nabiximols) plus standard care versus standard spasticity care alone in the management of multiple sclerosis spasticity was performed over a 5-year time horizon from the Belgian healthcare payer perspective. The probabilistic sensitivity analysis was implemented using a bootstrap approach to ensure that the correlations present in the source clinical trial data were incorporated in the uncertainty estimates. Results: Adding Sativex® spray to standard care was found to dominate standard spasticity care alone, with cost savings of €6,068 and a quality-adjusted life year gain of 0.145 per patient over the 5-year analysis. The probability of dominance increased from 29% in the first year to 94% in the fifth year, with the probability of QALY gains in excess of 99% for all years considered. Conclusions: Adding Sativex® spray to spasticity care was found to dominate standard spasticity care alone in the Belgian healthcare setting. This study showed the use of bootstrapping techniques in a Markov model probabilistic sensitivity analysis instead of Monte Carlo simulations. Bootstrapping avoided the need to make distributional assumptions and allowed the incorporation of correlating structures present in the original clinical trial data in the uncertainty assessment. [ABSTRACT FROM AUTHOR]

Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing–remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82–15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p < 0.0001). This shows that low baseline sNfL values identify MS patients with higher probability of optimal response to DMF and of a reduction in effector immune cells. [ABSTRACT FROM AUTHOR]

MRI studies have provided valuable insights into the structure and function of neural networks, particularly in health and in classical neurodegenerative conditions such as Alzheimer disease. However, such work is also highly relevant in other diseases of the CNS, including multiple sclerosis (MS). In this Review, we consider the effects of MS pathology on brain networks, as assessed using MRI, and how these changes to brain networks translate into clinical impairments. We also discuss how this knowledge can inform the targeting of MS treatments and the potential future directions for research in this area. Studying MS is challenging as its pathology involves neurodegenerative and focal inflammatory elements, both of which could disrupt neural networks. The disruption of white matter tracts in MS is reflected in changes in network efficiency, an increasingly random grey matter network topology, relative cortical disconnection, and both increases and decreases in connectivity centred around hubs such as the thalamus and the default mode network. The results of initial longitudinal studies suggest that these changes evolve rather than simply increase over time and are linked with clinical features. Studies have also identified a potential role for treatments that functionally modify neural networks as opposed to altering their structure. [ABSTRACT FROM AUTHOR]

Standardization is necessary to ensure the reliability of clinical data and to enable longitudinal and cross-sectional comparisons of data obtained in different centres and countries. In patients with multiple sclerosis (MS), standardized clinical data are needed for monitoring of disability and for collecting real-world evidence for use in research. This Perspective describes attempts to improve the standardization and digitization of clinical data in MS, including digital electronic health recording systems and applications that attempt to offer a comprehensive assessment of patients' neurological deficits and their effects on daily life. Despite the challenges raised by regulatory, ethical and data-privacy considerations, the standardization and digitization of clinical data in MS is expected to generate new insights into the pathophysiology of the disease and to contribute to personalized patient care. [ABSTRACT FROM AUTHOR]

The long-term and potential rare side effects of new immunomodulating drugs for the treatment of multiple sclerosis (MS) are often not well known. Spontaneous case report systems of adverse drug effects are a valuable source in pharmacovigilance, but have several limitations. Primary data collections within registries allow a comprehensive analysis of potential side effects, but face several challenges. This article will outline the chances and challenges of registry-based adverse event reporting, using the example of the German immunotherapeutic registry REGIMS. REGIMS is an observational, clinical multicenter registry that aims to assess the incidence, type, and consequences of side effects of MS immunotherapies. Patients treated with an approved MS medication are recruited by their physicians during routine visits in hospitals, outpatient clinics, and MS-specialized practices. REGIMS incorporates an electronic physician-based documentation in each center and a paper-based patient documentation, both at baseline and regular follow-up visits. By the end of 2019, 43 REGIMS centers were actively recruiting patients and performing follow-up documentations. The majority of the first 1000 REGIMS patients were female (69.3%), had relapse-remitting MS (89.8%), and were treated with a second-line therapy. During the implementation of REGIMS, several logistic and procedural challenges had to be overcome, which are outlined in this paper. Pharmacovigilance registries such as REGIMS provide high-quality primary data from a specific patient population in a real-world care setting and enable pharmacovigilance research that cannot be carried out using secondary data. Despite the logistic and procedural challenges in establishing a multicenter pharmacovigilance registry in Germany, the advantages outweigh the drawbacks. [ABSTRACT FROM AUTHOR]

Background: Plasma exchange (PLEX) is a therapeutic option in the treatment of acute attacks of Demyelinating Diseases of the Central Nervous System (DDCNS). Factors related with PLEX response are not well established.Methods: Descriptive and retrospective study. We included patients treated with PLEX for acute attacks of DDCNS between 2008 and 2017. We recorded demographics, clinical and treatment-related data, and Expanded Disability Status Scale (EDSS) score at admission, at discharge, and at 6 months.Results: We included 64 patients. Forty-eight (75%) were female with a mean age of 48.28 ± 11.5 years. Half of our patients were diagnosed with multiple sclerosis. Clinical improvement was achieved in 51.6% at discharge and 62.5% at 6 months. The logistic regression model showed that EDSS score > 3 at admission (p = 0.04) and early clinical improvement with PLEX (p = 0.00) were predictors of good response to PLEX at discharge and at 6 months, respectively. No serious adverse effects were identified.Conclusions: PLEX is a safe and effective treatment for acute attacks of DDCNS. EDSS score at admission and early clinical improvement with PLEX were factors associated with good response to PLEX. [ABSTRACT FROM AUTHOR]

Introduction: The main objective of this study was to examine discontinuation rates associated with delayed-release dimethyl fumarate (DMF) when used for the treatment of relapsing multiple sclerosis (MS) in a real-world, clinical practice setting. Methods: Data were collected retrospectively from charts of adult patients with relapsing–remitting MS treated at a single large institution in Australia, who completed at least 6 months of continuous therapy, either with DMF or another MS medication administered following DMF discontinuation. The primary endpoint was overall discontinuation rate. Secondary endpoints included discontinuation rate 6 months after initiation of DMF therapy; incidence of adverse events, particularly gastrointestinal events; discontinuation rate because of adverse events; and use of concomitant medications by patients during administration of DMF. Results: A total of 100 patients initially prescribed DMF between October 1, 2013 and June 30, 2014 were included in the analysis. The mean age of the patients was 43 years and 80% were female. The overall discontinuation rate was 13%, with 9% discontinuing because of gastrointestinal tolerability issues, within the first 6 months. Dose changes as a result of adverse events occurred in 15% of patients, and none of the adverse events reported were serious. Only one patient discontinued owing to lack of efficacy. Conclusion: This study, conducted shortly after the approval of DMF in Australia when first-hand clinical experience was still limited, demonstrated that DMF has an acceptable tolerability profile in the real-world setting that is similar to that demonstrated in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: The present small semi-controlled feasibility study investigated a possible efficacy of a combined upper limb and breathing exercise programme in managing pain in ambulatory and non-ambulatory patients with EDSS from 0.0-8.0.Method: People with MS (N = 19) were enrolled in this single-blind randomized controlled study and divided into 2 groups: exercise group (5 ambulatory, 5 non-ambulatory; Expanded Disability Status Scale (EDSS), 1.0-8.0) and related control group that performed no exercise (4 ambulatory, 5 non-ambulatory; EDSS, 1.0-7.5). The exercise group performed combined upper limb and breathing exercises in a group led by a physiotherapist (2 days/week, 60 min/session) accompanied by independent home exercises (3 days/week, ≥ 20 min/session). Participants underwent measures of pain level (visual analogue scale) for physical pain, functional independence of daily activities (Barthel index) and handgrip strength (HGS) for dominant (D) and non-dominant (ND) hand evaluated by a dynamometer before and after the 4-week period by the blinded assessor.Results: The VAS for pain showed statistically significant group-by-time interaction only in non-ambulatory (p = .049) individuals, but with large intervention effects on both subgroups (ambulatory, p = .159; non-ambulatory, d = 0.97). Functional independence in daily activities (Barthel index) showed statistically non-significant group-by-time interaction in ambulatory (p = .195, d = 0.89) and non-ambulatory (p = .102, d = 1.64) individuals, but despite the absence of statistical significance, there were large intervention effects. Handgrip strength was significantly improved for both hands in ambulatory (D, p = .012; d = 2.07; ND, p = .025, d = 1.77) and only non-dominant hand in non-ambulatory individuals (D, p = .288, d = 0.83; ND, p = .012, d = 2.21).Conclusion: This small pilot study provides preliminary proof-of-concept data supporting low-intensity upper limb and breathing exercise programme for potential reduction of pain and improvement of functional independence in both ambulatory and non-ambulatory individuals with MS in a larger sample and that strengthening the upper limbs might be an additional pain relief mechanism.Trial Registration: NTC03222596. [ABSTRACT FROM AUTHOR]

New so-called immune reconstitution therapies (IRTs) have the potential to induce long-term or even permanent drug-free remission in people with multiple sclerosis (MS). These therapies deplete components of the immune system with the aim of allowing the immune system to renew itself. Haematopoietic stem cell transplantation, the oral formulation cladribine and the monoclonal antibodies alemtuzumab, rituximab and ocrelizumab are frequently categorized as IRTs. However, the evidence that IRTs indeed renew adaptive immune cell repertoires and rebuild a healthy immune system in people with MS is variable. Instead, IRTs might foster the expansion of those cells that survive immunosuppression, and this expansion could be associated with acquisition of new functional phenotypes. Understanding immunological changes induced by IRTs and how they correlate with clinical outcomes will be instrumental in guiding the optimal use of immune reconstitution as a durable therapeutic strategy. This Perspectives article critically discusses the efficacy and potential mechanisms of IRTs in the context of immune system renewal and durable disease remission in MS. [ABSTRACT FROM AUTHOR]

Background: Physical, cognitive and mood-behavioral disturbances are very common in people with multiple sclerosis (MS) representing a relevant disease burden. Recently, in this field, several studies investigated the role of music therapy (MT) as a complementary therapeutic approach especially in terms of rehabilitation strategy.Objectives: The aim of this review is to report and discuss the effectiveness of various music-based interventions (MBIs) for clinical outcomes in MS patients.Data Sources: All English medical papers registered in the Web of Knowledge, PubMed, Google Scholar, and ScienceDirect from March 1999 to March 2019.Inclusion and Exclusion Criteria: We selected all the articles concerning MBIs in MS including papers that dealt with human samples and excluding non-human samples, reviews and case reports.Results: Out of 46 articles, we selected 24 papers of which 13 completely following the inclusion criteria were evaluated for the present analysis.Discussion: We explored the efficacy of several MT programs, taking into account the different aspects of application feasibility in the clinical management of MS patients and the future challenges. [ABSTRACT FROM AUTHOR]

Biologic immunotherapies have transformed the treatment landscape of multiple sclerosis. Such therapies include recombinant proteins (interferon beta), as well as monoclonal antibodies (natalizumab, alemtuzumab, daclizumab, rituximab and ocrelizumab). Monoclonal antibodies show particular efficacy in the treatment of the inflammatory phase of multiple sclerosis. However, the immunological perturbations caused by biologic therapies are associated with significant immunological adverse reactions. These include development of neutralising immunogenicity, secondary immunodeficiency and secondary autoimmunity. These complications can affect the balance of risks and benefits of biologic agents, and 2018 saw the withdrawal from the market of daclizumab, an anti-CD25 monoclonal antibody, due to concerns about the development of severe, unpredictable autoimmunity. Here we review established and emerging risks associated with multiple sclerosis biologic agents, with an emphasis on their immunological adverse effects. We also discuss the specific challenges that multiple sclerosis biologics pose to drug safety systems, and the potential for improvements in safety frameworks. [ABSTRACT FROM AUTHOR]

Background: No postmarketing randomised clinical trials are available about alemtuzumab, and real-world data are limited. We aimed to analyse the efficacy and safety of alemtuzumab in a single-centre cohort of patients with relapsing–remitting MS. Methods: Patients who took alemtuzumab were enrolled. We collected the following data: age, sex, MS history, expanded disability status scale (EDSS), relapses, magnetic resonance imaging (MRI) parameters after alemtuzumab, and adverse events. EDSS scores before alemtuzumab and at the last follow-up were compared by Wilcoxon test. Time to first relapse was analysed after dividing the cohort on the basis of previous treatment. Results: Ninety patients were enrolled [women 74.4%; naïve 7; mean follow-up 27 months (SD 23)]. The EDSS was reduced from a median of 2.5 (IQR 1.5–4) before alemtuzumab to 2.0 (IQR 1.5–3.5) after (p = 0.025). The time to first relapse was shorter in patients shifting from a second-line therapy (p = 0.011). Over 2 years, 43.7% had no evidence of disease activity. We observed infusion-related reactions in 95.5% patients, including 11.1% with pneumonitis, thyroiditis in 11%, and thrombocytopenia in 3.3%. Conclusions: We confirmed the clinical and MRI efficacy of alemtuzumab in the clinical setting and the frequency of infusion-related reactions. Compared with that in clinical trials, higher number of patients developed pneumonitis during infusion. [ABSTRACT FROM AUTHOR]

CXCL10 chemokine is a member of CXC chemokine family. It is secreted from a variety of cells in response to IFN-γ and stimulates a range of inflammatory responses via binding to its receptor, CXCR3. CXCL10 has a pivotal role in the pathogenesis of various infectious diseases, cancers, and inflammatory and autoimmune diseases. It has been put forward as a potential biomarker and therapeutic target in diagnosis and treatment of these diseases. In the present study, production of camel heavy chain antibodies (HCAbs) specific for the CXCL10 is reported. In this regard, recombinant CXCL10 was used for immunization of camel and subsequently the CXCL10 HCAbs were obtained. Afterwards, three subclasses of IgG were separated using protein A and protein G affinity columns, characterized with SDS-PAGE and confirmed for specific binding to the CXCL10 using ELISA. These IgG subclasses successfully recognized CXCL10 and a strong and specific reactivity towards CXCL10 were observed. Therefore, the selected HCAbs and their corresponding expression library could be used to develop a recombinant variable domain of these HCAbs (nanobody or VHH) as a new possible strategy for treatment of multiple sclerosis and other autoimmune diseases. [ABSTRACT FROM AUTHOR]

Introduction: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns. Methods: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns. Results: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies. Conclusion: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence. Trial Registration: NCT02776072. Funding: Biogen (Cambridge, MA, USA). [ABSTRACT FROM AUTHOR]

Multiple sclerosis is an inflammatory neurodegenerative disease of the central nervous system (CNS) and the most frequent cause of non-traumatic disability in adults in the Western world. Currently, several drugs have been approved for the treatment of multiple sclerosis. While the newer drugs are more effective, they have less favourable safety profiles. Thus, there is a need to identify new targets for effective and safe therapies, particularly in patients with progressive disease for whom no treatments are available. One such target is granulocyte-macrophage colony-stimulating factor (GM-CSF) or its receptor. In this article we review data on the potential role of GM-CSF and GM-CSF inhibition in MS. We discuss the expression and function of GM-CSF and its receptor in the CNS, as well as data from animal studies and clinical trials in MS. [ABSTRACT FROM AUTHOR]

The prevalence of multiple sclerosis (MS) and the age of affected patients are increasing owing to increased longevity of the general population and the availability of effective disease-modifying therapies. However, ageing presents unique challenges in patients with MS largely as a result of their increased frequency of age-related and MS-related comorbidities as well as transition of the disease course from an inflammatory to a neurodegenerative phenotype. Immunosenescence (the weakening of the immune system associated with natural ageing) might be at least partly responsible for this transition, which further complicates disease management. Currently approved therapies for MS are effective in preventing relapse but are not as effective in preventing the accumulation of disability associated with ageing and disease progression. Thus, ageing patients with MS represent a uniquely challenging population that is currently underserved by existing therapeutic regimens. This Review focuses on the epidemiology of MS in ageing patients. Unique considerations relevant to this population are discussed, including the immunology and pathobiology of the complex relationship between ageing and MS, the safety and efficacy of disease-modifying therapies, when discontinuation of treatment might be appropriate and the important role of approaches to support wellness and cognition. [ABSTRACT FROM AUTHOR]

Objective: The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations. Methods: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions. Results: The significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs. Conclusions: The treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies. [ABSTRACT FROM AUTHOR]

Personalized treatment is ideal for multiple sclerosis (MS) owing to the heterogeneity of clinical features, but current knowledge gaps, including validation of biomarkers and treatment algorithms, limit practical implementation. The contemporary approach to personalized MS therapy depends on evidence-based prognostication, an initial treatment choice and evaluation of early treatment responses to identify the need to switch therapy. Prognostication is directed by baseline clinical, environmental and demographic factors, MRI measures and biomarkers that correlate with long-term disability measures. The initial treatment choice should be a shared decision between the patient and physician. In addition to prognosis, this choice must account for patient-related factors, including comorbidities, pregnancy planning, preferences of the patients and their comfort with risk, and drug-related factors, including safety, cost and implications for treatment sequencing. Treatment response has traditionally been assessed on the basis of relapse rate, MRI lesions and disability progression. Larger longitudinal data sets have enabled development of composite outcome measures and more stringent standards for disease control. Biomarkers, including neurofilament light chain, have potential as early surrogate markers of prognosis and treatment response but require further validation. Overall, attainment of personalized treatment for MS is complex but will be refined as new data become available. [ABSTRACT FROM AUTHOR]

The benefits provided by disease-modifying treatments in multiple sclerosis have been demonstrated in clinical trials, but the extent to which they can be extrapolated to everyday care is less clear, as are the long-term benefits of treatment. The objective of this prospective observational cohort study performed in France was to evaluate the effectiveness and safety of glatiramer acetate in patients with relapsing-remitting multiple sclerosis over a 5-year period. All neurologists in France were invited to participate and enroll adult patients starting a first treatment with brand glatiramer acetate 20 mg. Given the observational nature of the study, no fixed study visits were imposed; consultations took place according to the investigator's normal practice. Occurrence of disease exacerbations and adverse events was documented and neurological disability evaluated with the EDSS at each consultation. Overall, 852 patients were analysable and 269 took glatiramer acetate continuously for 5 years. Median treatment duration was 3.4 years. Principal reasons for discontinuation were inadequate efficacy (38.9%), local tolerability (22.6%) and personal convenience (21.3%). Age, employment status, baseline EDSS score and number of previous exacerbations were variables associated with treatment persistence. The annualised exacerbation rate (5 years) was 0.41 [95% CI 0.39-0.44]; 316 patients (37.2%) remained exacerbation-free throughout. The risk of confirmed disability worsening (5 years) was 43.8% [95% CI 39.9-47.9%]. The most frequent adverse drug reactions were local injection site reactions (584 patients; 68.5%) and systemic immediate post-injection reactions (168 patients; 19.7%). Overall, these findings are consistent with those of previous clinical trials. [ABSTRACT FROM AUTHOR]

Dimethyl fumarate (DMF) is an oral, disease-modifying agent for the treatment of relapsing–remitting multiple sclerosis (RRMS). However, details regarding its mode of action are still emerging. It is believed that the mode of action of DMF involves both nuclear factor erythroid-derived 2-related factor (Nrf2)–dependent and independent pathways, which lead to an anti-inflammatory immune response due to type II myeloid cell and Th2 cell differentiation and neuroprotection. In this review, we will focus on the molecular and signaling effects of DMF that lead to changes in peripheral immune cell composition and function, alteration in CNS cell-specific functions, and effect on the blood-brain barrier. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the feasibility of a combined upper limb and breathing exercise for a home-based program and to explore its effect on primary fatigue and quality of life in ambulatory and non-ambulatory individuals with multiple sclerosis (MS) in a short time.Method: Nineteen individuals with MS were assigned into semi-controlled pre-post feasibility study based on Expanded Disability Status Scale (EDSS) status and divided into two groups: exercise (five ambulatory, five non-ambulatory; EDSS 1.0-8.0) and related control with no exercise (four ambulatory, five non-ambulatory; EDSS 1.0-7.5). Exercise group performed combined upper limb and breathing exercise in a controlled group (2 days/week, 60 min/session) accompanied by independent home exercise (3 days/week, ≥ 20 min/session). Participants underwent measures of fatigue impact (Modified Fatigue Impact Scale (MFIS) and quality of life (RAND Medical outcomes study 36-item short-form health survey (SF-36)) before and after a 4-week period.Results: The MFIS (physical, psychosocial, total) showed statistically significant group-by-time interaction in ambulatory (p = 0.033, d = 1.60; p = 0.039, d = 1.59; p = 0.033, d = 1.62) and non-ambulatory individuals (p = 0.009, d = 2.42; p = 0.018, d = 1.96; p = 0.0008, d = 3.92). Physical functioning (SF-36) showed statistically significant group-by-time interaction in ambulatory (p = 0.014, d = 2.14) but no significance in non-ambulatory (p = 0.368, d = 0.68) individuals. Despite the absent statistical significance, there were large intervention effects on MFIS cognitive scores for ambulatory (d = 1.28) and non-ambulatory (d = 1.47), and on other SF-36 scores for ambulatory (general health: d = 1.76 and pain: d = 1.02) and non-ambulatory (physical limitation: d = 1.03 and emotional well-being: d = 0.94) individuals.Conclusion: Our 4-week program reduced some aspects of fatigue and improved some aspects of quality of life in a small group of ambulatory and non-ambulatory individuals with MS. Good feasibility and significant positive changes from baseline warrant further exploratory work.Trial Registration: Name of the registry: The Impact of Exercise Training on Living Quality in Multiple Sclerosis. Registration: The study was registered at www.clinicaltrial.gov on July 14, 2017. First participant enrollment: August 28, 2017. URL: 602-01/17-01-147; Trial registration ID: NTC03222596. [ABSTRACT FROM AUTHOR]

Background: Autologous hematopoietic stem-cell transplantation (AHSCT) has been utilized as a treatment option for multiple sclerosis (MS) since 1995. However, this procedure has not been widely implemented in clinical practice owing to its mortality risk. Here, we conduct a meta-analysis to evaluate the long-term efficacy and safety of AHSCT in MS treatment, aiming to optimize the benefit/risk ratio of this therapeutic strategy.Methods: We searched the PubMed Web site and clinicaltrials.gov databases. The efficacy endpoints were progression-free survival (PFS) and disease activity-free survival. The safety outcomes were transplant-related mortality (TRM) and overall deaths.Results: Eighteen eligible studies with a total of 732 participants were enrolled. The PFS was 75% (95% CI, 0.69-0.81), and the estimate of disease activity-free survival was 61% with 48-month follow-up. Subgroups analysis showed that low- and intermediate-intensity regimens were associated with higher PFS 80%. Relapsing remitting MS (RRMS) benefited more from AHSCT than other MS subtypes with PFS 85%. Patients with Gd+ lesions at baseline MRI responded better to AHSCT with PFS 77%. The estimate of TRM was 1.34% (95% CI, 0.39-2.30), and the overall mortality was 3.58%. TRM was significantly higher in high-intensity regimen studies (3.13%) and in older studies (1.93%) performed before 2006.Conclusions: This meta-analysis provides evidences that AHSCT can induce long-term remissions for MS patients with a high degree of safety. We indicate low- and intermediate-intensity regimens and RRMS patients with the presence of Gd+ lesions at baseline MRI can obtain the optimal benefit/risk ratio from AHSCT. [ABSTRACT FROM AUTHOR]

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group's review of the company's evidence submission for cladribine and the Appraisal Committee's final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group's main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company's cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company's economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources. [ABSTRACT FROM AUTHOR]

Cladribine Tablets (MAVENCLAD®) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450-mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk. [ABSTRACT FROM AUTHOR]

The use of monoclonal antibodies in multiple sclerosis (MS) patients is in a transitional period. Studies regarding well-established, effective antibodies such as natalizumab and alemtuzumab focus more and more on long-term efficacy and safety, risk management, and treating complications. Primary progressive MS, a disease that was long considered to be unmodifiable, is currently in focus following ocrelizumab being approved as the first drug with a proven beneficial effect on the disease course. Conversely, post-marketing safety mechanisms have also proven to function as daclizumab has been suspended after a series of relevant serious adverse events. Currently, new therapies are emerging that promise more convenience and an improved safety profile (ofatumumab) or remyelinating potential with clinical improvement (opicinumab). While it is very unlikely that monoclonal antibodies will ever cure MS, they have become very valuable therapeutic tools to better patient outcomes. This review focuses on developments of monoclonal antibodies used in the past, present, and near future in MS patients. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS). One of the most promising recent medications for MS is teriflunomide. Its primary mechanism of action is linked to effects on the peripheral immune system by inhibiting dihydroorotate dehydrogenase (DHODH)-catalyzed de novo pyrimidine synthesis and reducing the expansion of lymphocytes in the peripheral immune system. Some in vitro studies suggested, however, that it can also have a direct effect on the CNS compartment. This potential alternative mode of action depends on the drug's capacity to traverse the blood-brain barrier (BBB) and to exert an effect on the complex network of brain biochemical pathways. In this paper, we demonstrate the application of high-resolution/high-accuracy matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry for molecular imaging of the mouse brain coronal sections from animals treated with teriflunomide. Specifically, in order to assess the effect of teriflunomide on the mouse CNS compartment, we investigated the feasibility of teriflunomide to traverse the BBB. Secondly, we systematically evaluated the spatial and semi-quantitative brain metabolic profiles of 24 different endogenous compounds after 4-day teriflunomide administration. Even though the drug was not detected in the examined cerebral sections (despite the high detection sensitivity of the developed method), in-depth study of the endogenous metabolic compartment revealed noticeable alterations as a result of teriflunomide administration compared to the control animals. The observed differences, particularly for purine and pyrimidine nucleotides as well as for glutathione and carbohydrate metabolism intermediates, shed some light on the potential impact of teriflunomide on the mouse brain metabolic networks.Graphical Abstract [ABSTRACT FROM AUTHOR]

Background: Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce.Objective: To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ.Methods: We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation.Results: 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26-4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time).Conclusion: Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ. [ABSTRACT FROM AUTHOR]

Background: With ocrelizumab another drug is available for the treatment of multiple sclerosis (MS). Little is known on the long-term use of ocrelizumab on immune cell subsets, and no surrogate markers are available. Rituximab (RTX) has been in off-label use for the treatment of MS, neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorder (NMOSD) for > 10 years.Objective: We evaluated the long-term depletion and repopulation rate of peripheral CD19+ B-cells as a potential surrogate for the clinical outcome, and whether it may serve for dosage and time-to-infusion decision making.Methods: We evaluated the CD19+ and CD4+/8+ T-cell counts in n = 153 patients treated with RTX (132 MS, 21 NMO/NMOSD). The dosages ranged from 250 to 2000 mg RTX. Depletion/repopulation rates of CD19+ B-cells as well as long-term total lymphocyte cell counts, were assessed and corroborated with EDSS, ARR (annualized relapse rate), MRI, and time to reinfusion.Results: CD19+ B-cells' repopulation rate significantly varied depending on the dosage applied leading to individualized application intervals (mean 9.73 ± 0.528 months). Low/absent CD19+ B-cell counts were associated with reduced ARR, EDSS, and GD+-MRI-lesions. Long-term B-cell-depleting therapy led to a transiently skewed CD4+/8+ T-cell ratio due to reduced CD4+ T-cells and absolute lymphocyte counts, which recovered after the second cycle.Conclusion: Our data suggest that CD19+ B-cell repopulation latency may serve as surrogate marker for individualized treatment strategies in MS and NMO/NMOSD, which proved clinically equally effective in our cohort as evaluated by previous studies. [ABSTRACT FROM AUTHOR]

Objective: There is an association between latitude, relative vitamin D deficiency and risk of multiple sclerosis (MS), and an association between vitamin D and disease progression. We have performed a meta-analysis with the aim of investigating the role of therapeutic vitamin D in MS.Methods: A systematic search of databases was performed to identify clinical trials assessing vitamin D in patients with relapsing-remitting MS. Studies were selected based on inclusion and exclusion criteria. Analysis was performed using RevMan 5.3 software.Results: Twelve studies involving 950 patients were included in the final analysis. Studies were divided into four groups because of heterogeneity in study design. Studies were judged to be at low or unclear risk of bias, except in three studies, and this was confirmed by funnel plots. No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures, particularly when only placebo-controlled studies were included. Dose comparison studies showed a significant increase in annualised relapse rate (mean difference 0.15 [95%CI 0.01-0.30]) and non-significant trends of increased Expanded Disability Status Scale and gadolinium-enhancing lesions for the higher-dose arms.Conclusion: These findings suggest that vitamin D supplementation may have a therapeutic role in the treatment of MS. However, there is uncertainty with regard to the most appropriate dose, with high doses potentially being associated with worse outcomes. There remains the need for further well-performed randomised, dose-ranging, placebo-controlled trials of vitamin D in MS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a progressive autoimmune disease of the central nervous system that is often disabling and for which there is currently no cure, though disease-modifying treatment is now available. The aim of this study is to describe the current values of the direct costs of multiple sclerosis (MS) in the Czech Republic.Methods: Attention is focused on direct medical costs. The costs were monitored in the Czech Republic among 5673 patients in the period between 2011 and 2015. These costs included complex, special and targeted visits at the neurologist, blood collection and the costs of hospitalisation. The results refer to the diagnoses according to the International Statistical Classification of Diseases and Related Health Problems. The attention is focused on MS G35 (NS; brain stem; spinal cord; disseminated; generalised).Results: The average total direct costs per patient per year are 4838.1 €. Not every patient has to be hospitalised during the year, and not every patient has prescribed medication. According to the above data, 12% of patients are hospitalised and 55% of patients are prescribed medication. The minimum average cost per patient without medication and hospitalisation is 54.1 €.Conclusion: Cost evaluation across countries is difficult due to the different evidence. If only selected direct costs considered in this study are compared, the absolute economics burden increases over time. The only statistically significant difference in the average price and the time spent is between 2012 and 2013, where the correlation value is 0.597. [ABSTRACT FROM AUTHOR]

The management and treatment of multiple sclerosis (MS) is becoming more and more complex as many medications are now available, with different routes of administration, mechanisms of action, and effectiveness and safety profiles. The decision-making process to choose the right medication is a complex task requiring a careful evaluation of the results of clinical and post-marketing studies, and the capability to translate data from clinical studies to patients in everyday clinical practice. Two European neurological societies, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and European Academy of Neurology (EAN), and the American Academy of Neurology (AAN) have recently delivered guidelines for MS treatment, helping neurologists to address the most common clinical issues related to this topic. The two guidelines offer a similar view and similar recommendations for the most relevant and common questions of clinical practice. For some aspects of MS treatment the statements are slightly different, in particular regarding pregnancy management in relation to treatments, the use of mitoxantrone, and the treatment of secondary progressive MS (SP-MS). [ABSTRACT FROM AUTHOR]

Background: Clinical deterioration of relapsing-remitting MS (RR-MS) patients reflects not only the number and severity of overt inflammatory and demyelinating episodes, but also subtle central damage caused by persistent exposure to inflammatory molecules.Objective: To explore the correlation between levels of CSF inflammatory molecules at the time of diagnosis and both demographic and clinical characteristics of a large sample of RR-MS patients, as well as the predictive value of cytokine levels on their prospective disease course.Methods: In 205 patients diagnosed with RR-MS, we measured at the time of diagnosis the CSF levels of inflammatory molecules. Clinical and MRI evaluation was collected at the time of CSF withdrawal and during a median follow-up of 3 years.Results: The time interval between the first anamnestic episode of focal neurological dysfunction and RR-MS diagnosis was the main factor associated with high CSF levels of IL-6 and IL-8. Furthermore, elevated CSF levels of these cytokines correlated with enhanced risk of clinical and radiological disease reactivation, switch to second-line treatments, and with disability progression in the follow-up.Conclusions: Delayed diagnosis and treatment initiation are associated with higher CSF levels of IL-6 and IL-8 in RR-MS, leading to worsening disease course and poor response to treatments. [ABSTRACT FROM AUTHOR]

Background: Two phase III trials have demonstrated the clinical and radiological efficacy of delayed-release dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS). However, data on its safety and effectiveness in real-world practice are still limited.Objectives: The aim of our study was to explore the safety and tolerability profile of DMF in RRMS. We also tried to identify individual variables associated with better clinical and radiological outcomes.Methods: We collected the clinical and magnetic resonance imaging (MRI) data of patients with RRMS who started DMF between 2012 and 2017 in seven MS clinics in central Italy. We first evaluated DMF discontinuation rates and the incidence of adverse events and side effects. We then assessed the annualized relapse rate (ARR), the number of patients with clinical relapses or disability worsening and the presence of radiological activity. Third, we investigated which baseline variables were associated with clinical and radiological outcomes.Results: We collected data for 1089 patients with a mean on-treatment follow-up of 17 ± 8 months; 331 (30.4%) of these patients were treatment naïve. In total, 210 (19.5%) patients discontinued DMF mainly because of poor tolerability (n = 103) and disease activity (n = 63), and 166 (16.5%) patients presented with lymphopenia. The ARR reduced from 0.55 to 0.13. Mean change in Expanded Disability Status Scale (EDSS) score was 0.08 ± 0.44 per year. The occurrence of clinical and/or radiological activity during follow-up was associated with younger age [hazard ratio (HR) 0.97; p < 0.001], higher EDSS score (HR 1.18; p < 0.001), greater number of Gd-enhancing lesions at baseline scan (HR 1.14; p = 0.003) and prior exposure to MS treatments (HR 1.43; p = 0.02).Conclusion: This post-marketing data confirms the short-term safety, tolerability and effectiveness of DMF, supporting its use as an early treatment in MS. [ABSTRACT FROM AUTHOR]

Ocrelizumab (Ocrevus®) is a humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). In the two identically designed, 96-week OPERA I and II trials in patients with RMS, ocrelizumab significantly reduced annualized relapse rates versus interferon β-1a. In the ≥ 120-week ORATORIO trial in patients with PPMS, ocrelizumab significantly reduced the risk of ≥ 12-week confirmed disability progression relative to placebo. These primary endpoint results were supported by a number of secondary outcomes, including disease activity in the brain assessed by magnetic resonance imaging. Ocrelizumab was generally well tolerated in these studies, with infusion-related reactions and infections being the most common adverse events, which were mostly mild to moderate in severity. In summary, ocrelizumab is a novel high-efficacy disease-modifying therapy for RMS that is more effective than interferon β-1a and also a valuable new treatment option for delaying progression in early PPMS. It offers a convenient once every 6 months treatment regimen, with no need for routine monitoring. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism of action of fingolimod within the central nervous system and its efficacy in reducing/preventing both focal and diffuse grey matter (GM) damage in active multiple sclerosis (MS) are not completely understood.Methods: In this longitudinal, 2-year prospective, phase IV, single-blind study, 40 MS patients treated with fingolimod and 39 untreated age, gender, and disability-matched MS patients were enrolled. Each patient underwent a neurological examination every 6 months and a 3T MRI at the beginning of the treatment and after 24 months. The accumulation of new cortical lesions (CLs) and the progression of regional GM atrophy were compared between the two groups.Results: At the end of the study (T24), the percentage of patients with new CLs (13.5 vs. 89%, p < 0.001) and the percentage of GM volume change was lower in the treated group (p < 0.001). The regional analysis revealed that the treated group had also less volume loss in thalamus, caudatus, globus pallidus, cingulate cortex, and hippocampus (p < 0.001), as well as in, cerebellum, superior frontal gyrus, and insular-long gyrus (p < 0.05). Patients with no evidence of disease activity were 60% in the treated group and 10% in the untreated group (p < 0.001).Conclusions: These results suggest a possible protective effect of fingolimod on focal and diffuse GM damage. [ABSTRACT FROM AUTHOR]

Interferon beta (IFNβ) is transiently expressed in response to viral infections and widely used to treat relapsing-remitting multiple sclerosis (MS). We introduced mutations in the IFNβ gene (in the 27th and 101st codons and in the Kozak sequence, and also deletion of 3′ and 5′ unstable, untranslated region, UTR) with the aim of increasing the expression of IFNβ. Computational analyses of mutant and wild-type RNAs and proteins of IFNβ by RNAfold, ASAView, HOPE and Ramachandran plot, and iStable web servers showed that the mutations could decrease RNA stability, protein solvent accessibility, and protein stability but could not change correct folding. Two recombinant IFNβ101 and IFNβ101+27 constructs were designed by site-directed mutagenesis. The wild-type IFNβ gene also was used as a control. In vitro experiments by quantitative real-time PCR, dot blot, SDS-PAGE, and Western blot assays showed an increased expression level of recombinant IFNβs. 79.9-fold, 99.7-fold, and 190-fold elevations in the mRNA expression of IFNβw, IFNβ101, and IFNβ101+27 were seen, respectively, in comparison with the endogenous IFNβ mRNA in untransfected HEK293T cells. The IFNβ mRNA expression was increased 2.38-fold and 1.25-fold for 101+27 and 101 mutated forms, respectively, in comparison with the IFNβ wild-type construct. An elevation in IFNβ protein production was also clearly detected in the transfected HEK293T cell containing recombinant IFNβ101 and IFNβ101+27 constructs. Finally, these directed mutations in the IFNβ gene successfully elevated protein and mRNA production but in silico analyses of mutant mRNAs showed decreased mRNA stability, unlike previous studies, in comparison with the wild-type mRNA. [ABSTRACT FROM AUTHOR]

Background: Optical coherence tomography (OCT) is a technique that allows for the assessment of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV), which reflect neuroaxonal integrity within the retina. As such it has been used in multiple sclerosis (MS) to study neurodegeneration. Glatiramer acetate (GA) is a widely used treatment for MS, which is suggested to have a possible neuroprotective role.Objective: The aim of this study was to assess RFNLT and TMV changes in relapsing-remitting MS (RRMS) patients who started treatment with GA and were followed for a 24-month period.Methods: A cohort of 60 RRMS patients and 40 healthy controls (HCs) were imaged with OCT at baseline and follow-up. All subjects also underwent clinical and neurological examination. Measurements were compared between the RRMS patients and HCs as well as between optic neuritis (ON)-affected and ON-unaffected eyes.Results: At baseline, MS patients showed lower average RNFLT (p = 0.046) and TMV (p = 0.013) when compared with HCs. No significant differences in the evolution of OCT measures were detected over the follow-up between MS patients and HCs. MS patients with both affected and unaffected eyes showed significantly lower average RNFLT, temporal inferior RNFLT, and TMV at baseline, compared with HCs. No significant differences between ON-affected and ON-unaffected eyes in MS patients were detected over the follow-up, except for the nasal superior RNFLT (p = 0.019).Conclusions: This study suggests a beneficial role of GA on retinal axonal degeneration in MS, and further confirms the utility of OCT to monitor the neuroprotective effect of disease-modifying treatment. [ABSTRACT FROM AUTHOR]

Background: Dimethyl-fumarate (DMF) demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials.Objectives: To track and evaluate post-market DMF profile in real-world setting.Materials and methods: Patients receiving DMF referred to Italian MS centres were enrolled and prospectively followed, collecting demographic clinical and radiological data.Results: Among the 735 included patients, 45.4% were naïve to disease-modifying therapies, 17.8% switched to DMF because of tolerance, 27.4% switched to DMF because of lack of efficacy, and 9.4% switched to DMF because of safety concerns. Median DMF exposure was 17 months (0-33). DMF reduced the annual relapse rate (ARR) by 63.2%. At 12 and 24 months, 85 and 76% of patients were relapse-free. NEDA-3 status after 12 months of DMF treatment was maintained by 47.5% of patients. 89 and 70% of patients at 12 and 24 months regularly continued DMF. Most frequent adverse events (AEs) were flushing (37.2%) and gastro-enteric AEs (31.1%).Conclusion: Our post-market study corroborated that DMF is a safe and effective drug. Additionally, the study suggested that naïve patients strongly benefit from DMF and that DMF improved ARR also in patients who were horizontally switched from injectable therapies due to tolerability and efficacy issues. [ABSTRACT FROM AUTHOR]

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary. [ABSTRACT FROM AUTHOR]

Background: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs.Aims: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY).Patients and Methods: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans.Results: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D ≥ 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05).Conclusions: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient. [ABSTRACT FROM AUTHOR]