Strategy For Treatment Of Multiple Sclerosis Research Articles

Peripheral CD19+ B-cell counts and infusion intervals as a surrogate for long-term B-cell depleting therapy in multiple sclerosis and neuromyelitis optica/neuromyelitis optica spectrum disorders

BackgroundWith 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.ObjectiveWe 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.MethodsWe 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.ResultsCD19+ 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.ConclusionOur 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.

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

Background: Multiple sclerosis (MS) is a complex disease with new drugs becoming available in the past years. There is a need for a reference tool compiling current data to aid professionals in treatment decisions. Objectives: To develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS. Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients–Intervention–Comparator–Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion: The present guideline will enable homogeneity of treatment decisions across Europe.

ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis.

Multiple sclerosis (MS) is a complex disease of the central nervous system. As new drugs are becoming available, knowledge on diagnosis and treatment must continuously evolve. There is therefore a need for a reference tool compiling current data on benefit and safety, to aid professionals in treatment decisions and use of resources across Europe. The European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS) and the European Academy of Neurology (EAN) have joined forces to meet this need. The objective was to develop an evidence-based clinical practice guideline for the pharmacological treatment of people with MS to guide healthcare professionals in the decision-making process. This guideline has been developed using the GRADE methodology and following the recently updated EAN recommendations for guideline development. Clinical questions were formulated in PICO format (patient, intervention, comparator, outcome) and outcomes were prioritized according to their relevance to clinical practice. An exhaustive literature search up to December 2016 was performed for each question and the evidence is presented narratively and, when possible, combined in a meta-analysis using a random-effects model. The quality of evidence for each outcome was rated into four categories - very high, high, low and very low - according to the risk of bias. GRADE evidence profiles were created using GRADEprofiler (GRADEpro) software (Version 3.6). The recommendations with assigned strength (strong, weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panellists was reached by use of the modified nominal group technique. A total of 10 questions have been agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency at the time of publication. A total of 20 recommendations were agreed by the guideline working group members after three rounds of consensus.

Improved treatment satisfaction after switching therapy to rituximab in relapsing–remitting MS

Objective: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab. Method: A total of 75 patients with clinically stable relapsing–remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period. Results: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1–7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment (p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression. Conclusion: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

The future of multiple sclerosis treatments

ABSTRACTIntroduction: There are not many conditions in which the last few decades have brought such a major change in the landscape of treatments as is the case of multiple sclerosis (MS). A number of disease modifying treatments (DMTs) are presently available for the treatment of the inflammatory phase of this disabling disease; however, the need for treating neurodegeneration and halting the progression of disability is still unmet.Areas covered: In this paper we review the available information on existing and emerging DMTs and we discuss their place within the context of different treatment strategies in MS,Expert commentary: The future of MS treatments should include the development of new treatment strategies tackling disease progression, together with a better understanding of the side-effects and the best sequential strategy of implementation of available and emerging drugs.

Multiple sclerosis: Etiology, symptoms, incidence and prevalence, and implications for community living and employment.

This article presents an overview of multiple sclerosis (MS), one of the most common neurological disorders in the Western Hemisphere. We explore the impacts of MS on employment, career development, and community living, and the implications for rehabilitation professionals. The objective in this article is to provide a current and comprehensive review of the etiology and symptoms, incidence and prevalence, and current treatment strategies for MS, and the effects of MS on vocational and psychosocial outcomes. This analysis represents a comprehensive review of the relevant medical, vocational, community living, and rehabilitation research literature. Living with MS is associated with wide-ranging and unpredictable effects on employment, career development, and community independence. Effective responses by health and rehabilitation professionals require a comprehensive understanding of this progressive and complex condition and its psychosocial impacts. Customized interventions from allied health professionals and rehabilitation counselors that are grounded in the unique features of MS and that reflect current best practices in Vocational Rehabilitation are required to improve rehabilitation outcomes for people with MS.

Differences in Treatment Strategies in Multiple Sclerosis According to Experience: A Survey of Multiple Sclerosis Experts and General Neurologists (P3.230)

Differences in Treatment Strategies in Multiple Sclerosis According to Experience: A Survey of Multiple Sclerosis Experts and General Neurologists (P3.230)

Lack of effect of Theiler’s murine encephalomyelitis virus infection on system xc−

Changes in the expression of xCT, the specific subunit of system xc− or the cystine/glutamate antiporter, have been associated with several neurological disorders and system xc− was recently proposed as a potential target for the development of new treatment strategies for multiple sclerosis (MS). In this study we used Theiler's murine encephalomyelitis virus (TMEV) infection, both in vitro and in vivo, as a model to further evaluate the involvement of system xc− in MS. Protein levels of xCT, as well as activity of system xc− were unaffected in RAW264.7 macrophages after infection with the demyelinating DA strain of TMEV. Also, protein expression of xCT remained stable in spinal cord and brain of FVB mice 1–2 and 6 weeks after intracranial injection of the DA strain of TMEV. These results demonstrate that TMEV infection of macrophages or FVB mice has no effect on system xc− and as such cannot be used as a model to study the involvement of system xc− in MS.

Treatment strategies for multiple sclerosis: When to start, when to change, when to stop?

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies.

Therapeutic Administration of Mesenchymal Stem Cells Abrogates the Relapse Phase in Chronic Relapsing-Remitting EAE

Multiple Sclerosis (MS) is a neuroinflammatory and immune-mediated chronic disease of the Central Nervous System which progressively damages the axonal myelin sheath, leading to axonal transmission impairment and to the development of neurological symptoms. Most MS cases are characterized by a relapsing-remitting course, and current therapies rely only on the use of immunomodulating drugs which are, however, unable to reverse disease progression. Among the newly proposed alternative therapies, Mesenchymal Stem Cells (MSCs) are considered suitable for MS treatment due to their capacity to modulate the immune response and to modify the pattern of the released cytokines. So far, encouraging results have been obtained with the administration of MSCs before disease onset, mainly in animal models of acute Experimental Autoimmune Encephalomyelitis (EAE) in which MSCs were able to reduce inflammation, thus ameliorating also the disease’s clinical symptoms. On the contrary, only a very small number of studies have investigated the effect of MSCs on relapsing-remitting models of the disease. Here, we investigated the therapeutic potential of MSC administration, both before and after the disease’s onset, in an animal model of MS represented by Dark Agouti rats affected by chronic Relapsing-Remitting EAE. Our results demonstrated that in chronic Relapsing-Remitting EAE the administration of MSCs after the clinical disease’s appearance is able to completely abrogate the relapsing phase and to strongly reduce spinal cord demyelination. These encouraging results have demonstrated that MSCs can provide a protective and reparative strategy for MS treatment.

Dendritic cells are specifically affected by different immunomodulatory treatment strategies in multiple sclerosis

Dendritic cells are specifically affected by different immunomodulatory treatment strategies in multiple sclerosis

Decreased Level of sRAGE in the Cerebrospinal Fluid of Multiple Sclerosis Patients at Clinical Onset

Objectives: Receptor for advanced glycation end products (RAGE) ligands/RAGE interactions have been proposed to have a pathogenic role in neuroinflammatory disorders. Our study aimed to assess changes in high-mobility group box (HMGB)1 and its receptor RAGE in peripheral blood (PBL) and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) at the disease onset compared with control subjects. Methods: PBL and CSF were collected from control subjects (n = 30) and MS patients (n = 27) at clinical onset. Soluble RAGE (sRAGE), HMGB1, S100 calcium-binding protein A12 (S100A12), interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured in the CSF and plasma by enzyme-linked immunosorbent assay. Gene expression in PBL mononuclear cells (PBMCs) was detected by quantitative PCR for RAGE, HMGB1, S100A12 and several proinflammatory/immunoregulatory cytokines. Results: We found a significantly lower expression of IL-10 (p = 0.031) in the PBMCs of MS patients. The level of sRAGE in the CSF of MS patients was lower (p = 0.021), with the ability to discriminate between MS patients and control subjects. Moreover, PBMC gene expression for HMGB1 and S100A12 positively correlated with IL-6. Conclusions: Our study confirmed that the cytokine network is disturbed in PBL and CSF at MS clinical onset. The deregulated HMGB1/RAGE axis found in our study may present an early pathogenic event in MS, proposing sRAGE as a possible novel therapeutic strategy for MS treatment.

Evidence⁃based evaluation of treatment strategy for multiple sclerosis

Objective To formulate the best treatment plan for multiple sclerosis (MS) patients by evaluating the therapeutic efficacy and side effect of various evidence ⁃ based programs. Methods Key words were defined as multiple sclerosis, immunomodulatory therapy and therapy, etc. We searched MEDLINE, Cochrane Library, Wanfang data bases for Scientific Journals in China and National Knowledge Infrastructure for Chinese Scientific Journals Database. Additionally, we applied manual searching and screened out conference paper and academic dissertation, etc, from various references. After that we obtained and evaluated by Jadad scales on systematic reviews, randomized controlled trials, controlled clinical trials and observational study cases about glucocorticoids, plasmapheresis, intravenous immunoglobulin, IFN ⁃ β, glatiramer acetate, mitoxantrone, natalizumab, fingolimod. Results After screening, all seventeen selected resources included systematic reviews 6 articles, randomized controlled trials 7 articles, controlled clinical trials 2 articles, observational study cases 2 articles, among which fifteen articles were proved to be high quality (according to Jadad scoring system, five score 4, six score 5, four score 7), two chapters were judged to be low quality scoring 3. Finally, we summerize that: 1) The first choice of treatment for acute relapses is glucocorticoids and we suggest that plasmapheresis or intravenous immunoglobulin may be tried as an alternative therapy in acute MS relapse, especially in case of contraindications to intravenous methylprednisolone. 2) Immunomodulatory or immunosuppressive treatment (IFN ⁃ β, glatiramer acetate, mitoxantrone, natalizumab) can be an option to prevent new relapses and progression of disability. 3) Fingolimod is an oral treatment for multiple sclerosis to improve treatment adherence. Conclusion Using evidence⁃based medicine methods can provide us best clinical evidence on MS treatment. DOI：10.3969/j.issn.1672⁃6731.2012.02.012

Current Treatment Strategies for Multiple Sclerosis - Efficacy Versus Neurological Adverse Effects

Recent years have broadened the spectrum of therapeutic strategies and specific agents for treatment of multiple sclerosis (MS). While immune-modulating drugs remain the first-line agents for MS predominantly due to their benign safety profile, our growing understanding of key processes in initiation and progression of MS has pioneered development of new agents with specific targets. One concept of these novel drugs is to hamper migration of immune cells towards the affected central nervous system (CNS). The first oral drug approved for MS therapy, fingolimod inhibits egress of lymphocytes from lymph nodes; the monoclonal antibody natalizumab prevents inflammatory CNS infiltration by blocking required adhesion molecules. The second concept is to deplete T cells and/or B cells from the peripheral circulation using highly specific monoclonal antibodies such as alemtuzumab (anti-CD52) or rituximab/ocrelizumab (anti-CD20). All of these novel, highly effective agents are a substantial improvement in our therapeutic armamentarium; however, they have in common to potentially lower the abundance of immune cells within the CNS, thereby collaterally affecting immune surveillance within this well-controlled compartment. In this review, we aim to critically evaluate the risk/benefit ratio of therapeutic strategies in treatment of MS with a specific focus on infectious neurological side effects.

Adult mesenchymal stem cell therapy for myelin repair in Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating immune-mediated disease of the central nervous system (CNS). It is the most frequent neurological disease in young adults and affects over 2 million people worldwide. Current treatments reduce the relapse rate and the formation of inflammatory lesions in the CNS, but with only temporary and limited success. Despite the presence of endogenous oligodendroglial progenitors (OPCs) and of spontaneous remyelination, at least in early MS its levels and its qualities are apparently insufficient for a sustained endogenous functional repair. Therefore, novel MS therapies should consider not only immunemodulatory but also myelin repair activities. Mesenchymal stem cells (MSCs) represent an attractive alternative to develop a cell-based therapy for MS. MSCs display stromal features and exert bystander immunemodulatory and neuroprotective activities. Importantly, MSCs induce oligodendrocyte fate decision and differentiation/maturation of adult neural progenitors, suggesting the existence of MSC-derived remyelination activity. Moreover, transplanted MSCs promote functional recovery and myelin repair in different MS animal models. Here, we summarize the current knowledge on endogenous mechanisms for remyelination and proposed autologous MSC therapy as a promising strategy for MS treatment.

Association of innate immune activation with latent Epstein-Barr virus in active MS lesions

To determine whether the activation of innate immune responses, which can be elicited by pathogenic and endogenous triggers, is associated with the presence of Epstein-Barr virus (EBV) infection in the multiple sclerosis (MS) brain. White matter postmortem MS (n = 10) and control tissue (n = 11) was analyzed for the expression of the proinflammatory cytokine interferon α (IFNα) by immunohistochemistry and for EBV by using the highly sensitive method of EBV-encoded RNA (EBER) in situ hybridization. We detected overexpression of IFNα in active areas of white matter MS lesions but not in inactive MS lesions, normal-appearing white matter, or normal brains. The presence of IFNα in macrophages and microglia (expressing human leukocyte antigen class II) is suggestive of local production as part of an acute inflammatory process. Interestingly, EBERs were also specifically detected in areas where IFNα was overexpressed in these preselected active MS lesions. EBER+ cells were also found in CNS lymphoma and stroke cases, but were absent in other control brains. We next addressed a potential mechanism, e.g., the role of EBERs in eliciting IFNα production, and transfected EBERs into human embryonic kidney (HEK) cells. We used HEK cells that stably expressed Toll-like receptor-3, which recognizes double-stranded RNAs, associated with many viral infections. EBERs elicited IFNα production in vitro. These findings suggest that latent EBV infection may contribute to the inflammatory milieu in active MS lesions by activating innate immune responses, e.g., IFNα production. Unraveling the underlying mechanisms may help in uncovering causal pathways and developing better treatment strategies for MS and other neuroinflammatory diseases.

Novel Agents and Emerging Treatment Strategies in Multiple Sclerosis

In the past decade, the treatment of multiple sclerosis has undergone a significant paradigm shift. Weekly to daily self-injections of moderate benefit are making way for more effective therapies with improved relapse and disability impact with more appealing routes and frequencies of administration. Some such therapies, like natalizumab, belong to the monoclonal antibody family, while others offer novel immunomodulatory mechanisms and the much sought after oral route of administration. While novel and more powerful immune mechanisms present new issues with respect to adverse effects, these new therapies offer significant advances in the quality of patient care.

Novel Agents and Emerging Treatment Strategies in Multiple Sclerosis. What Role for Cladribine?

Multiple sclerosis (MS), a chronic inflammatory-degenerative illness of the central nervous system (CNS), remains at the moment a treatable but incurable disease. Currently available disease-modifying agents (DMA-s), the majority of which are being injected, mainly relieve the inflammatory phase of MS with little beneficial effect, if any, in halting neurodegeneration. Cladribine is an immunosuppressive agent that can be administered orally and by cycles of short-course dosing as opposed to continuous administration. Cladribine has been shown to be effective in reducing inflammatory activity of MS but much remains unknown regarding its potential beyond the control of CNS inflammation. In addition, knowledge on the safety profile of cladribine in MS is limited. Data from on going clinical studies and registries on its safety profile will shed more light on the actual benefit/risk ratio of cladribine.

Immunomodulatory treatment strategies in multiple sclerosis

Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young adults. The mainstays in the immunomodulatory therapy of MS are currently interferon beta and glatiramer acetate, both of which have proven to be clinically and paraclinically effective. Current clinical evidence indicates that treatment should be initiated as early as possible. In this review we summarize available data from clinical studies on clinical efficacy of immunomodulatory drugs for treating patients with multiple sclerosis.

Multiple Sclerosis: Etiology and Treatment Strategies

To review the etiology and treatment strategies for multiple sclerosis (MS). Published information on MS and targeted treatment strategies extending back to 1955. The search terms multiple sclerosis and pathology, prevalence, genetics, and each of the common symptoms of MS were used. Seventy-two studies were reviewed based on level 1, 2, and 3 search strategies. Level 1 search strategy targeted evidence-based trials of large sample size (N > 100) with a randomized, double-blind, placebo-controlled design. A level 2 search targeted additional trials with some of the traits of evidence-based trials. A level 3 search compared key findings in reports of very small (N < 15) poorly designed trials with the results of well-designed trials. MS affects each patient differently, making a definitive diagnosis and management of symptoms very difficult. Effective symptom management requires an interprofessional team approach. Despite all the research dedicated to this disease, there is still no cure. The treatments currently available function at best only to slow the disease progression and mitigate symptoms. Using the skills and knowledge available from a team of health care professionals will help patients navigate the trials and tribulations that follow throughout a life with MS.