Disease-modifying Treatments For Multiple Sclerosis Research Articles

Multi-actor system dynamics in access to disease-modifying treatments for multiple sclerosis in Southeast Asia: A regional survey and suggestions for improvement

BackgroundDespite the global availability of multiple sclerosis (MS) treatments, accessing and financing them in Southeast Asia (SEA) remains a challenge. This descriptive survey-based study aimed to describe the current state of MS treatment access and local access dynamics within this region. MethodsThe survey questionnaire, comprising of 15 closed-ended and five open-ended questions, was developed by three neurologists with expertise in MS and routine MS patient management, or had training in neuroimmunology. Questionnaire development was guided by the recent Atlas of MS and in alignment with the Access to Treatment framework, focusing on MS diagnosis and treatment issues in SEA. Fifteen neurologists experienced in managing MS across the region were identified as key informants for this study. ResultsAll fifteen neurologists participated in the survey via email and videoconferencing between January 2020 and February 2023, which included the following countries: Brunei, Cambodia, Indonesia, Malaysia, Myanmar, Lao PDR, Philippines, Singapore, Thailand, Timor-Leste, and Vietnam. All had at least five years of experience in managing MS patients and six had previously completed a neuroimmunology fellowship programme. SEA countries showed disparities in healthcare financing, availability of neurologists, MS treatments, and investigative tools. Access to MS disease-modifying treatments (DMTs) is hindered by high cost, lack of MS specialists, and weak advocacy efforts. On-label DMTs are not listed as essential medicines regionally except for interferon beta1a and teriflunomide in Malaysia. On-label monoclonals are available only in Malaysia, Singapore, and Thailand. Generic on-label DMTs are unavailable due to lack of distributorship and expertise in using them. Off-label DMTs (azathioprine, methotrexate, and rituximab) predominate in most SEA countries. Other challenges include limited access to investigations, education, and knowledge about DMTs among general neurologists, and absence of registries and MS societies. Patient champions, communities, and MS organisations have limited influence on local governments and pharmaceutical companies. Despite its increasing prevalence, there is a lack of concerted priority setting due to MS being perceived as a rare, non-communicable disease. ConclusionThis study highlights the distinct dynamics, challenges, and research gaps within this region, and provides suggestions to improve MS diagnosis, education, and medicine access.

Effects of disease-modifying drugs in multiple sclerosis on the gut microbiome

Over the past decade, the scientific research has shown that the community of microorganisms that inhabit the gut, known as the gut microbiota, is closely linked to human health and disease, in part as a result of its influence on the systemic immune responses. The accumulated evidence suggests that these effects on the immune system are significant in neuroinflammatory diseases such as multiple sclerosis, and that modulation of the gut microbiota may be a potential therapeutic target in these conditions. In recent years, more and more studies have been appearing devoted to the role of microbiota in the development of various pathological processes in the central nervous system, including multiple sclerosis, through the brain-gut axis. In this regard, the question of finding ways to influence the microbiome is interesting. In addition to the existing attempts through the use of probiotics and fecal microbiota transplantation, of particular interest is the search for other ways of influencing the microbiome, including the effect of multiple sclerosis modifying therapies on the microbiota’s composition. The purpose of this review is to summarize the current evidence investigating the effects of disease-modifying treatment on the gut microbiome.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

Migraine in multiple sclerosis patients: potential links and treatment approach

ABSTRACT Introduction Migraine has been reported to be twice as prevalent in patients with multiple sclerosis (MS) compared to the non-MS population. However, prospective, controlled studies that could lead to robust conclusions are still lacking. Areas covered Treatment of migraine in patients with MS can be challenging. Comorbidities need to be assessed and managed early, and preventive treatment should be initiated when indicated. Caution is warranted regarding the selection of the preventive medication since certain agents can magnify MS symptoms and particularly cognitive symptoms. This paper aims to discuss the association of MS and migraine, shed light on distinguishing points and red flags, as well as offer practical advice on the selection of treatment according to patients’ characteristics. Expert opinion A holistic approach including pharmacological and non-pharmacological modifications is required to treat migraine in patients with MS effectively. Anti-CGRP monoclonal antibodies are a promising option due to limited drug-to-drug interactions; however, larger prospective studies are required to draw robust conclusions on the concomitant use of anti-CGRPs with MS disease modifying treatments. Early migraine preventive treatment might be needed to reduce the burden of disease in patients with MS.

Natalizumab Treatment of Relapsing Remitting Multiple Sclerosis Has No Long-Term Effects on the Proportion of Circulating Regulatory T Cells.

Natalizumab (NTZ), a monoclonal antibody against the integrin α4β1 (VLA-4) found on activated T cells and B cells, blocks the interaction of this integrin with adhesion molecules of central nervous system (CNS) endothelial cells and lymphocyte migration through the blood-brain barrier, effectively preventing new lesion formation and relapses in multiple sclerosis (MS). Whether NTZ treatment has additional effects on the peripheral immune system cells, and how its actions compare with other MS disease-modifying treatments, have not been extensively investigated. In particular, its effect on the proportions of circulating regulatory T cells (Treg) is unclear. In this study, we investigated the effect of NTZ treatment in 12 patients with relapsing MS, at 6 and 12months after the start of treatment. We evaluated the proportions of regulatory T cells (Treg), defined by flow cytometry as CD4+CD25++FoxP3+cells and CD4+CD25++CD127- cells at these intervals. As an exploratory study, we also investigated the NTZ effects on the proportions of bulk T and B lymphocyte populations, and of those expressing novel the markers CD195 (CCR5), CD196 (CCR6), or CD161 (KLRB1), which are involved in MS pathogenesis but have been studied less in the context of MS treatment. The effects of NTZ were compared to those obtained with 11 patients under interferon-beta-1a (IFN-β1a) treatment, and against 9 healthy volunteers. We observed a transient increment in the proportion of Treg cells at 6months, which was not sustained at 12months. We observed a reduction in the proportion of T cells expressing CD195 (CCR5) and CD161 (KLRB1) subsets of T cells. We conclude that NTZ does not have an effect on the proportion of Treg cells over 1year, but it may affect the expression of molecules important for some aspects MS pathogenesis, in a manner that is not shared with IFN-β1a.

Adverse side effects of Glatiramer acetate and Interferon beta-1a in patients with multiple sclerosis: A systematic review of case reports.

Background: Glatiramer acetate (GA) and Interferon (IFN) beta-1a are used as first-line disease-modifying treatments for multiple sclerosis (MS). In this systematic review, we summarized case reports and case series of adverse side effects of GA and IFN beta-1a in MS patients. Methods: Without any restrictions, PubMed, Scopus, Web of Sciences, and Embase databases, and gray literature were systemically searched until June 2022. Articles were screened and data were extracted based on a predefined table by two independent reviewers. The risk of bias was assessed using the Joanna Briggs Institute (JBI) tool. Results: We identified 2103 records from the preliminary search. After deduplication and screening, 172 articles were included in the systematic review. In total, 229 individuals (52 men, 173 women, and 4 unknown) were included in the study. The most common adverse events were cutaneous (32.75%), hepatic (13.54%), allergic (8.3%), and neurological (5.68%) side effects. Furthermore, most reported side effects were related to autoimmune diseases or hypersensitivity reactions. Conclusion: GA and IFN beta-1a are associated with several side effects which may be related to the immunomodulatory function of medication or other injection-related reactions.

Do clinical trials prepare to fail by failing to prepare? An examination of MS trials and recommendations for patient-reported outcome measure selection.

Many clinical trials use patient-reported outcome (PRO) measures, which can influence treatment decision-making, drug approval and label claims. Given that many PRO measure options exist, and there are conceptual and contextual complexities with PRO measurement, we aimed to evaluate how and why specific PRO measures have been selected for pivotal multiple sclerosis (MS) clinical trials. Specifically, we aimed to identify the reasons documented for PRO measure selection in contemporary phase III MS disease-modifying treatment (DMT) clinical trials. We searched for phase III clinical trials of MS DMTs published between 2015 and 2021 and evaluated trial protocols, or primary publications where available, for PRO measure selection information. Specifically, we examined study documents for their clarification of clinical concepts measured, definitions of concepts measured, explanations of which PRO measures were considered, why specific PRO measures were chosen, and trade-offs in PRO measure selection. We identified 1705 abstracts containing 61 unique phase III MS DMT clinical trials. We obtained and examined 27/61 trial protocols. Six protocols were excluded: four contained no mention of PRO measures and two contained redacted sections preventing adequate assessment, leaving 21 protocols for assessment. For the remaining 34 trials (61-27), we retrieved 31 primary publications; 15 primary publications mentioned the use of a PRO measure. None of the 36 clinical trials that mentioned the use of PRO measures (21 protocols and 15 primary publications) documented clear PRO or clinical outcome assessment (COA) measurement strategies, provided clear justifications for PRO selection, or reasons why specific PRO measures were selected when alternatives existed. PRO measure selection for clinical trials is not evidence-based or underpinned by structured systematic approaches. This represents a critical area for study design improvement as PRO measure results directly affect patient care, PRO measurement has conceptual and contextual complexities, and there is a wide range of options when selecting a PRO measure. We recommend trial designers use formal approaches for PRO measure selection to ensure PRO measurement-based decisions are optimised. We provide a simple, logical, five-stage approach for PRO measure selection in clinical trials.

Lack of Rebound Disease Activity in Participants with Relapsing Multiple Sclerosis Following Placebo Run-out in the Tolebrutinib Phase 2b Trial (P6-3.006)

Lack of Rebound Disease Activity in Participants with Relapsing Multiple Sclerosis Following Placebo Run-out in the Tolebrutinib Phase 2b Trial (P6-3.006)

Monitoring response to disease-modifying treatment in multiple sclerosis

BackgroundStandard criteria for defining suboptimal response to disease-modifying treatment (DMT) in patients with multiple sclerosis (MS) are lacking. Decision-making on how and when DMTs should be switched is challenging. The objective of the study was to identify areas of agreement on which and when specific assessments should be conducted to monitor patient response to DMT. MethodsA survey comprising 54 statements in nine categories was drafted by eight MS experts after gathering insight during four previous meetings of a total of 25 MS experts. For each statement, results were classified as being in general agreement (≥66.6% responded “Strongly agree” or “Agree”) or general disagreement (≥66.6% responded “Strongly disagree” or “Disagree”). ResultsThe survey was sent to 790 MS neurologists, 151 of whom participated (19%), and 98 (65%) completed it. General agreement and disagreement were reached for 45 and 2 statements, respectively, on different aspects of MS management, including treatment response, MS relapses, progression, disease activity measured by imaging and biomarkers, neuropsychological evaluation, brain volume loss, DMT switches due to lack of response and applicability to clinical practice. ConclusionsThis study aims to provide guidance for the early identification of suboptimal response to DMT and for improving MS patient monitoring and treatment.

Omics approaches to understanding the efficacy and safety of disease-modifying treatments in multiple sclerosis.

From the perspective of precision medicine, the challenge for the future is to improve the accuracy of diagnosis, prognosis, and prediction of therapeutic responses through the identification of biomarkers. In this framework, the omics sciences (genomics, transcriptomics, proteomics, and metabolomics) and their combined use represent innovative approaches for the exploration of the complexity and heterogeneity of multiple sclerosis (MS). This review examines the evidence currently available on the application of omics sciences to MS, analyses the methods, their limitations, the samples used, and their characteristics, with a particular focus on biomarkers associated with the disease state, exposure to disease-modifying treatments (DMTs), and drug efficacies and safety profiles.

Comparative effectiveness of cladribine tablets versus other oral disease-modifying treatments for multiple sclerosis: Results from MSBase registry

Background: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. Objectives: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. Methods: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). Results: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54–6.32), 7.04 (4.16–11.93), and 6.52 (3.79–11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. Conclusion: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

Use of follow-on disease-modifying treatments for multiple sclerosis: Consensus recommendations

Background: As patents for multiple sclerosis (MS) therapies expire, follow-on disease-modifying treatments (FO-DMTs) become available at reduced cost. Concerns exist that cheaper FO-DMTs are used simply to reduce healthcare costs. However, the well-being of people with MS should take priority. Objectives: To identify best practices for FO-DMT development and use by agreeing on principles and consensus statements through appraisal of published evidence. Methods: Following a systematic review, we formulated five overarching principles and 13 consensus statements. Principles and statements were voted on by a multidisciplinary panel from 17 European countries, Argentina, Canada and the United States. Results: All principles and statements were endorsed by >80% of panellists. In brief, FO-DMTs approved within highly regulated areas can be considered effective and safe as their reference products; FO-DMTs can be evaluated case by case and do not always require Phase III trials; long-term pharmacovigilance and transparency are needed; there is lack of evidence for multiple- and cross-switching among FO-DMTs; and education is needed to address remaining concerns. Conclusion: Published data support the use of FO-DMTs in MS. The consensus may aid shared decision-making. While our consensus focused on Europe, the results may contribute to enhanced quality standards for FO-DMTs use elsewhere.

Ways to improve adherence to long-term injection therapy in multiple sclerosis using the example of pegylated interferon-β1a (sampeginterferon β-1a)

Patient adherence to therapy with multiple sclerosis disease-modifying treatments (MS DMTs) in many cases determine the effectiveness of therapy. The review discusses the reasons for low adherence to DMTs, ways to increase it. Among the most effective ways is to reduce the frequency of administration of the drug while maintaining its high efficiency. To illustrate this, the increase in adherence to treatment with interferon-β drugs due to pegylation is discussed. Without losing its effectiveness, sampeginterferon beta-1a (samPEG-IFN-β1a) administration reduces the frequency of local adverse reactions, partly due to reducing the frequency of injections, which contributes to higher adherence to the treatment.

Temporal trends of epilepsy in multiple sclerosis.

Epilepsy is associated with advanced multiple sclerosis (MS). We aimed to investigate whether the incidence of epilepsy in MS has been affected by the introduction of disease-modifying treatments (DMT) for MS. This retrospective study included 14,557 patients from the Swedish MS register with MS onset between 1991 and 2018. Incident diagnoses of epilepsy or any seizure were identified through cross-linkage with the National Patient Register. Next, yearly prevalence of epilepsy as well as 5- and 10 years incidence of epilepsy or any seizure for consecutive years of MS onset were estimated, the latter with Kaplan-Meier analysis. Cox regression was used to adjust the association between the year of MS onset and incidence of epilepsy for baseline variables. Prevalence of epilepsy in the MS cohort increased from 0.34% in 1991 to 2.54% in 2018 (yearly odds: 1.26 [1.22, 1.29]). The 5 years incidence rate of epilepsy, ranging from 0.4% (95% CI 0.008-0.79%) to 1.3% (95% CI 0.71-1.89%), and the 10 years incidence rate of epilepsy, ranging from 1.1% (95% CI 0.31-1.88%) to 2.6% (95% CI 1.22-3.97%) showed no significant trends (p=.147 and p=.418, respectively). Similarly, no significant trends were found for the incidences of any seizure. The incidence trends of epilepsy remained not significant after adjusting for sex, MS onset type (relapsing or progressive onset), or age at MS onset. Our findings do not support the hypothesis that the introduction of novel DMT for MS has reduced the incidence of epilepsy among MS patients.

Promoting exogenous repair in multiple sclerosis: myelin regeneration.

Despite the significant progress in the development of disease-modifying treatments for multiple sclerosis (MS), repair of existing damage is still poorly addressed. Current research focuses on stem cell-based therapies as a suitable alternative or complement to current drug therapies. Myelin damage is a hallmark of multiple sclerosis, and novel approaches leading to remyelination represent a promising tool to prevent neurodegeneration of the underlying axon. With increasing evidence of diminishing remyelination capacity of the MS brain with ageing and disease progression, exogenous cell transplantation is a promising therapeutic approach for restoration of oligodendrocyte precursor cell pool reserve and myelin regeneration. The present review summarizes recent developments of remyelinating therapies in multiple sclerosis, focusing on exogenous cell-based strategies and discussing related scientific, practical, and ethical concerns.

Real-world Comparative Effectiveness and Persistence of Cladribine Tablets and Other Oral Disease-Modifying Treatments for Multiple Sclerosis from GLIMPSE: Results from the MSBase Registry (P12-4.003)

Real-world Comparative Effectiveness and Persistence of Cladribine Tablets and Other Oral Disease-Modifying Treatments for Multiple Sclerosis from GLIMPSE: Results from the MSBase Registry (P12-4.003)

How important are COVID-19 vaccine responses in patients with MS on disease-modifying therapies?

How important are COVID-19 vaccine responses in patients with MS on disease-modifying therapies?

Decreasing Multiple Sclerosis Treatment Expenditures and Improving Quality at the Health System Level.

ObjectiveThis study was undertaken to evaluate a multicomponent health system intervention designed to reduce escalating disease‐modifying treatment (DMT) expenditures and improve multiple sclerosis (MS) outcomes by increasing use of preferred formulary and highly effective DMTs (HETs).MethodsWe conducted a trend study of treatment utilization and expenditure outcomes prior to (2009–2011) and during (2012–2018) MS Treatment Optimization Program (MSTOP) implementation in Kaiser Permanente Southern California (KPSC) compared to a Kaiser Permanente region of similar size. Annual relapse rates (ARRs) were obtained from KPSC's electronic health records.ResultsAdherence to preferred formulary DMTs increased from 25.4% in 2011 to 72.2% in 2017 following MSTOP implementation in KPSC and 22.1% to 43.8%, respectively, in the comparator. KPSC's annual DMT expenditures in 2018 were less than in 2011 despite an 11.3% increase in DMT‐treated members. The decline in average per patient per year of treatment expenditures from a peak of $43.1 K in 2014 to $26.3 K in 2018 in KPSC was greater than the comparator, which peaked at $52.1 K and declined to $40.0 K in 2018. Over the 7 years following initiation of MSTOP, cumulative MS DMT expenditures were $161.6 million less than the comparator. HET use increased to 62.5% of per patient treatment‐years versus 32.4% in the comparator. This corresponded to a 69% decline in adjusted ARR (95% confidence interval = 64.1–73.2%; p < 0.0001) among DMT‐treated patients in KPSC.InterpretationA novel, expert‐led health system intervention reduced MS DMT expenditures despite rising prices while simultaneously reducing MS relapse rates. Our focus on health system progress toward meaningful, measurable targets could serve as a model to improve quality and affordability of MS care in other settings. ANN NEUROL 2022;92:164–172

Prescription trends of disease-modifying treatments for multiple sclerosis in Iran over the past 30 years

BackgroundIran, as a middle income country, is one of the places with high and rising prevalence of multiple sclerosis (MS). Regarding the substantial economic burden, reviewing the trend in prescribed disease modifying treatments (DMTs) could be of help. Here we studied the DMT information of nearly 14000 MS cases and its trends change for 30 years to improve health services to patients. MethodsThe population base of this descriptive-analytical (cross-sectional) study consisted of all MS patients in the nationwide MS registry of Iran (NMSRI), up to August 1, 2021. Registrars from 15 provinces, 24 cities, 13 hospitals,8 MS associations, 16 private offices, and 7 clinics had entered the data. ResultsOverall, 14316 cases were enrolled. The majority (76.1%) were female. The youngest and eldest patients were 5 and 78 years old, respectively. Diagnosis delay was under one year in most cases (median: 0, IQR: 0 – 1). Most (61.4%) had RRMS. Generally, platform injectables (IFN beta, glatiramer acetate) were the most used DMTs until 2010. It seems that introduction of newer agents (antiCD20s and oral DMTs) resulted in a decrease in the use of former drugs since around 2015. Some unusual practices are prominent such as using not approved DMTs for PPMS over the years, or administering high efficacy drugs like natalizumab for CIS. The results indicate the remaining popularity of first line injectable DMTs in female and pediatric patients. DiscussionMean age (SD) at onset in our study (29 ± 8.8) is near the statistics in Asia and Oceania (28 ± 0.7). Concerns about COVID-19 had a noticeable impact on administering high efficacy drugs like rituximab and fingolimod. However, in male patients this approach has not been the case. It may be related to more aggressive disease course in this group. The other possible explanation could be planning for pregnancy in female cases. The popularity of platform injectable drugs in pediatric MS may be related to its favorable safety profile over the years. Another point in this group, is the superiority of rituximab over other highly efficient medications.

The Multiple Sclerosis Treatment Optimization Program.

ObjectiveTo design and implement a health system level intervention to reduce escalating multiple sclerosis (MS) disease modifying treatment (DMT) expenditures and improve outcomes.MethodsWe conducted stakeholder meetings, reviewed pharmacy utilization data, and abstracted information in subsets of persons with MS (pwMS) from the electronic health record to identify gaps in, and barriers to improving, quality, and affordability of MS care in Kaiser Permanente Southern California. These results informed the development and implementation of the MS Treatment Optimization Program (MSTOP).ResultsThe two main gaps identified were under‐prescribing of highly effective DMTs (HET, 4.9%) and the preferred formulary DMT (20.9%) among DMT‐treated pwMS. The main barriers identified were prescribers’ fear of rare but serious HET side effects, lack of MS‐specific and health systems science knowledge, Pharma influence, evidence gaps, formulary decisions‐based solely on costs, and multidirectional mistrust between neurologists, practice leaders, and health plan pharmacists. To overcome these barriers MSTOP developed four strategies: (1) risk‐stratified treatment algorithm to increase use of HETs; (2) an expert‐led ethical, cost‐sensitive, risk‐stratified, preferred formulary; (3) proactive counter‐launch campaigns to minimize uptake of new, low‐value DMTs; and (4) discontinuation of ineffective DMTs in progressive, non‐relapsing MS. The multicomponent MSTOP was implemented through education, training, and expanding access to MS‐trained providers, audit and feedback, and continual evidence reviews.InterpretationThe causes of wasteful spending on MS DMTs are complex and require multiple strategies to resolve. We provide herein granular details of how we designed and implemented our health system intervention to facilitate its adaption to other settings and conditions.