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Multiple sclerosis (MS) is uncommon in China and the standard of care is underdeveloped, with limited utilization of disease-modifying treatment (DMT). An understanding of real-world disease burden (including direct medical, non-medical, and indirect costs, such as loss of productivity), is currently lacking in this population. To investigate the overall burden of managing patients with MS in China, a cross-sectional survey of physicians and their consulting patients with MS was conducted in 2021. Physicians provided information on healthcare resource utilization (HCRU; consultations, hospitalizations, tests, medication) and associated costs. Patients provided data on changes in their life, productivity, and impairment of daily activities due to MS. Results were stratified by disease severity using generalized linear models, with a p value < 0.05 considered statistically significant. Patients with more severe disease had greater HCRU, including hospitalizations, consultations and tests/scans, and incurred higher direct and indirect costs and productivity loss, compared with those with milder disease. However, the use of DMT was higher in patients with mild disease severity. With the low uptake and limited efficacy of non-DMT drugs, Chinese patients with MS experience a high disease burden and significant unmet needs. Therapeutic interventions could help save downstream costs and lessen societal burden., (© 2024. The Author(s).)

Background: The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians., Objective: Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching., Methods: Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021., Results: Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%)., Conclusions: Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs., Competing Interests: Declaration of Competing Interest Tarunya Arun has nothing to disclose. Carlos Capela has received consulting fees from Janssen, Merck and Roche, has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, has received support for attending meetings and/or travel from Almirall, Bayer, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, has participated on a Data Safety Monitoring Board or Advisory Board for Biogen, Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. Guy Laureys and/or his employer (UZ Ghent) have received financial compensation for congress attendance, consultancy, research and education by Almirall, Biogen, Celgene, Bristol Myers Squibb, Novartis, Roche, Sanofi, Teva. Pietro Iaffaldano and/or his institution has received medical writing support for present manuscript from Novartis, has received grants from Novartis, Biogen and Roche; has received consulting fees from Novartis, Biogen, Sanofi, genzyme, BMS, Merck and Roche; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Biogen, Sanofi and Merck; support for attending meetings and/or travel from Biogen, Sanofi and Merck and participated on a data safety monitoring board or advisory board for Novartis, Biogen, Sanofi, Genzyme, BMS, Merck and Roche. Eddie Jones is an employee of Adelphi Real World. Adelphi Real World received funds from Novartis in exchange for access to the MS DSP data set that was used for analysis. Eddie Jones did not receive any funding directly from Novartis. Patricia Dominguez-Castro, and Simone Hiltl are employees of Novartis Pharma AG. Gustavo Seifer was an employee of Novartis Pharma AG at the time of study design, execution, interpretation and submission. Rainel Sanchez-de la Rosa was an employee of Novartis Pharma AG at the time of study design and execution., (Copyright © 2023. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is a chronic progressive condition affecting the central nervous system. Progression of MS results in increased level of disability and most patients will eventually experience some degree of functional impairment and impaired mobility. Costs and burdens escalate as MS disability increases. However, there is a lack of recent data on the impact of MS disability on the cost and burden among patients in the US., Methods: Data for this study were drawn from a real world, cross-sectional survey undertaken between 2013 and 2014. Neurologists completed detailed patient report forms (PRF) for the most recent consulting patients with MS (age >18 years). Patient's perceptions of their diagnosis and health-related quality of life (HRQoL) were collected through a patient self-completion questionnaire (PSC). Regression analysis was used to evaluate the relationship between disability (determined by latest Expanded Disability Status Scale [EDSS] score) and current relapse and health care resource utilization, health care costs, HRQoL and work productivity., Results: PRF data were collected for 715 patients (335 also completed a PSC). Patients with higher disability scores (EDSS 3-5 and >5 vs <3 points) and current relapse (vs no current relapse) reported significantly greater health resource utilization for physician visits (p < 0.05) and hospitalizations (p < 0.05) in the preceding 12 months. In addition, they had poorer HRQoL (p < 0.05), were significantly more likely to be unemployed (p < 0.05) and to have had to stop working due to MS (p < 0.05). They also incurred significantly higher health care related costs, including costs for physician consultations, hospitalizations and therapy (p < 0.05). The total costs of care were $51,825, $57,889 and $67,116 for EDSS < 3, EDSS 3-5 and EDSS > 5 groups, respectively; $51,692 and $58,648 for non-relapse and relapse groups, respectively., Conclusions: For MS patients in the US, health resource utilization and healthcare care costs increase with progression of disability. As the disability worsens, patients also exhibit diminished HRQoL and lower work productivity. There is a need for treatments that slow down or delay disability progression among MS patients.

Purpose: Hopelessness theory predicts that negative attributional style will interact with negative life events over time to predict depression. The intention of this study was to test this in a population who are at greater risk of negative life events, people with Multiple Sclerosis (MS)., Method: Data, including measures of attributional style, negative life events, and depressive symptoms, were collected via postal survey in 3 phases, each one a year apart., Results: Responses were received from over 380 participants at each study phase. Negative attributional style was consistently able to predict future depressive symptoms at low to moderate levels of association; however, this ability was not sustained when depressive symptoms at Phase 1 were controlled for. No substantial evidence to support the hypothesised interaction of negative attributional style and negative life events was found., Conclusions: Findings were not supportive of the causal interaction proposed by the hopelessness theory of depression. Further work considering other time frames, using methods to prime attributional style before assessment and specifically assessing the hopelessness subtype of depression, may prove to be more fruitful. Intervention directly to address attributional style should also be considered.

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.

Background: Multiple sclerosis (MS) is a chronic progressive neurological disease and the majority of patients will experience some degree of impaired mobility. We evaluated the prevalence, severity and burden of walking and mobility problems (WMPs) in 5 European countries., Methods: This was a cross-sectional, patient record-based study involving 340 neurologists who completed detailed patient record forms (PRF) for patients (>18 years) attending their clinic with MS. Patients were also invited to complete a questionnaire (PSC). Information collected included demographics, disease characteristics, work productivity, quality of life (QoL; EuroQol-5D and Hamburg Quality of Life Questionnaire Multiple Sclerosis [HAQUAMS]) and mobility (subjective patient-reported and objectively measured using the timed 25 foot walk test [T25FW]). Relationships between WMPs and disease and other characteristics were examined using Chi square tests. Analysis of variance was used to examine relationships between mobility measures and work productivity., Results: Records were available for 3572 patients of whom 2171 also completed a PSC. WMPs were regarded as the most bothersome symptom by almost half of patients who responded (43%; 291/683). There was a clear, independent and strong directional relationship between severity of WMPs (subjective and objective) and healthcare resource utilisation. Patients with longer T25FW times (indicating greater walking impairment) were significantly more likely to require additional caregiver support (p < 0.0001), visit a variety of healthcare professionals including their primary care physicians (p = 0.0044) and require more long-term non-disease modifying drugs (p = 0.0001). A similar pattern was observed when subjective reporting of the severity of WMPs was considered. Work productivity was also markedly impacted by the presence of WMPs with fewer patients working full time and a reduction in weekly working hours as T25FW times and the subjective severity of WMPs increased., Conclusions: In Europe, WMPs in MS represent a considerable personal and social burden both financially and in terms of quality of life. Interventions to improve mobility could have significant benefits for patients and society as a whole.

The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

Epidemiological and genetic data have consistently identified associations with HLA class II alleles in many autoimmune diseases. In multiple sclerosis (MS), an autoimmune disease targeting central nervous system (CNS) myelin, the DR2 haplotype (DRB1*1501, DRB5*0101 and DQB1*0602) remains the strongest identified genetic risk factor in Caucasians. However, it is hard to tease apart the precise contributions of its constituent individual alleles and their modes of action remain poorly understood, due in part to the strong linkage disequilibrium in this region. Recent work in humanized mice indicates functional epistatic interactions whereby DRB5*0101 directly modulates the severity of the ensuing disease through activation-induced cell death (AICD) of encephalitogenic T cells which are restricted by DRB1*1501. Complementary structural studies help to explain how these alleles may facilitate thymic escape of autoreactive T cells and contribute to peripheral T cell activation via suboptimal binding interactions and mechanisms of molecular mimicry. Here we discuss the emerging role of the constituent alleles of the DR2 haplotype and our ongoing efforts to uncover the mechanisms by which they influence MS pathogenesis.

The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4(+) T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8(+) T cells are controversial. We have generated humanized mice expressing the multiple sclerosis-associated MHC class I alleles HLA-A(*)0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A(*)0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8(+) T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3-restricted CD8(+) T cells in induction of multiple sclerosis-like disease and for CD4(+) T cells in its progression, and we also define a possible mechanism for HLA-A(*)0201-mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8(+) T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis.

It is generally accepted that MHC II molecules confer susceptibility to inflammatory diseases because of the different abilities they possess for binding and presenting peptides to T cells. A new study suggests that the level of MHC II gene expression is also a risk factor for such diseases. It shows that a polymorphism in the promoter of the MHC II transactivator (MHC2TA) gene (which encodes CIITA), leads to reduced MHC2TA expression, and hence reduced production of MHC II molecules. This predisposes to rheumatoid arthritis, multiple sclerosis and myocardial infarction.

Multiple sclerosis (MS) is an autoimmune disease with an important genetic component. The strongest genetic association is with the major histocompatibility complex (MHC) region. Several MHC alleles predispose to the disease, the most prominent of which are certain alleles in the HLA-DR2 haplotype. Functional and structural studies have helped to explain the molecular basis of these associations. Although there is currently no curative treatment for MS, an increased understanding of the disease has aided the design of immunotherapies that act on the immune system more specifically than the longstanding drugs. Many of these therapies work at the antigen-specific level, disrupting the interaction between T-cell receptors and MHC molecules that leads to disease.

The multiple sclerosis (MS)-associated HLA major histocompatibility complex (MHC) class II alleles DRB1*1501, DRB5*0101 and DQB1*0602 are in strong linkage disequilibrium, making it difficult to determine which is the principal MS risk gene. Here we show that together the DRB1 and DRB5 loci may influence susceptibility to MS. We demonstrate that a T cell receptor (TCR) from an MS patient recognized both a DRB1*1501-restricted myelin basic protein (MBP) and DRB5*0101-restricted Epstein-Barr virus (EBV) peptide. Crystal structure determination of the DRB5*0101-EBV peptide complex revealed a marked degree of structural equivalence to the DRB1*1501-MBP peptide complex at the surface presented for TCR recognition. This provides structural evidence for molecular mimicry involving HLA molecules. The structural details suggest an explanation for the preponderance of MHC class II associations in HLA-associated diseases.

Patients with chronic progressive multiple sclerosis (MS) have alterations of T cell regulation that can be measured by in vitro assays and include decreases of the autologous mixed lymphocyte reaction (AMLR). Whether a defect in cytokine secretion was involved in the altered AMLR was investigated in 29 MS patients and 13 age- and sex-matched controls. The response of CD4+ T cell populations to irradiated non-T cells was decreased in MS as compared to control subjects. As previously reported, decreases in the AMLR were similarly observed with whole T cells of MS subjects as compared to controls. The addition of recombinant interleukin (IL)-1 to cultures of either whole T cells or CD4+ T cells with irradiated non-T cells in the AMLR corrected the immune defect in subjects with MS but had no effect on the AMLR in control subjects. In contrast, addition of rIL-2 or rIL-4 to the AMLR did not correct the decreased AMLR in MS patients as compared to controls. The lymphokines IFN-gamma and TGF-beta 2 both decreased the AMLR in MS patients and controls while TNF had no effect. Further, the magnitude of the AMLR response corresponded to IL-1 secretion induced by LPS in the non-T cell population. These studies indicate that defects in IL-1 may be related to immune defects of suppression in MS patients. Selective correction of immunoregulatory defects using lymphokines or their inducers in subjects with autoimmune diseases such as MS may be possible.

Alexander Keenan,1 Hoa H Le,1 Kavita Gandhi,2 Lola Adedokun,3 Eddie Jones,4 Mia Unsworth,4 James Pike,5 Emily Trenholm4 1Scientific Affairs, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 2Research and Development, Janssen Pharmaceuticals Inc., Titusville, NJ, USA; 3Research and Development, Janssen-Cilag Ltd, High Wycombe, UK; 4Central Nervous System, Adelphi Real World, Bollington, Cheshire, UK; 5Statistics & Data Analytics, Adelphi Real World, Bollington, Cheshire, UKCorrespondence: Mia Unsworth, Adelphi Real World, Adelphi Mill, Grimshaw Lane, Macclesfield, Bollington, Cheshire, SK10 5JB, United Kingdom, Tel +441625578677, Email mia.unsworth@adelphigroup.comIntroduction: Multiple sclerosis (MS) is a neurodegenerative disease characterized by progressive deterioration of cognitive and physical functioning, reducing activities of daily living and quality of life (QoL). Several treatments are available that modify the course of the disease and reduce the frequency of relapses. Although effective, all treatment options are accompanied by adverse events, and this study aimed to assess the extent to which patients were involved in the choice of treatment.Methods: Data were drawn from the Adelphi Multiple Sclerosis Disease Specific Program (DSP)™, a cross-sectional survey of healthcare practitioners (HCP) and their patients with MS in real-world clinical settings in Europe and the United States (US) between December 2020 and July 2021. HCPs reported patient demographics, clinical characteristics, current and previous treatment, and treatment outcomes. Patients voluntarily completed questionnaires reporting the physical and psychological impact of their MS and its treatment. Regression analysis with inverse probability of treatment weighting was used to compare treatment outcomes in patients actively involved in their current treatment choice with those who were not.Results: Of a total of 692 patients, median age 40 years and 64% female, mostly diagnosed with relapsing-remitting MS, those who were involved in shared decision-making tended to choose oral therapies such as dimethyl fumarate more often than HCPs. MS had greater impact on physical and psychological functioning in patients whose HCP made treatment decisions solely. Patients involved in decision-making reported greater satisfaction with their treatment and a better QoL.Discussion: Because no single optimal therapy exists for patients with MS, treatments should be individualized with consideration of patients’ preferences. Our study shows that shared decision-making is under-utilized in the management of MS and supports the benefits of patient involvement.Conclusion: Patients who have an active role in treatment decision-making show improved wellbeing and QoL, and overall treatment satisfaction.Plain Language Summary: Multiple sclerosis (MS) is a disease that affects the brain, causing symptoms such as blurred vision and problems with movements, thoughts, and feelings. MS is a lifelong condition that becomes worse over time and limits the activities that people can do. There are many treatments that can help to reduce relapses (when symptoms become worse), but all have their benefits and drawbacks. It is often the physician who decides which treatment to use, but we wanted to know if patients would feel better if they were involved in the decision.Using our standardized and validated questionnaires, we surveyed physicians and nurses who treat patients with MS in Europe and the United States of America between December 2020 and July 2021, to assess how they felt about the treatment they chose and its effect on the patient. We also asked the patients themselves how they felt about their illness and treatment, whether they were given the chance to choose which treatment to take, and how their treatment affected their symptoms and overall quality of life.The information provided by both the physicians and their patients was used to compare how patients responded when they were involved in the treatment decisions. We found that patients who were involved in choosing their treatment were more satisfied with their treatment and responded better than those whose physicians decided alone. Therefore, it is important for physicians treating patients with MS to consider their patients’ preferences when deciding which treatment is best for them.Keywords: multiple sclerosis, patient preference, decision-making, shared, multinational, survey

The major known genetic risk factors in multiple sclerosis reside in the major histocompatibility complex (MHC) region. Although there is strong evidence implicating MHC class II alleles and CD4+ T cells in multiple sclerosis pathogenesis, possible contributions from MHC class I genes and CD8+ T cells are controversial. We have generated humanized mice expressing the multiple sclerosis–associated MHC class I alleles HLA-A*0301 (encoding human leukocyte antigen-A3 (HLA-A3)) and HLA-A*0201 (encoding HLA-A2) and a myelin-specific autoreactive T cell receptor (TCR) derived from a CD8+ T cell clone from an individual with multiple sclerosis to study mechanisms of disease susceptibility. We demonstrate roles for HLA-A3–restricted CD8+ T cells in induction of multiple sclerosis–like disease and for CD4+ T cells in its progression, and we also define a possible mechanism for HLA-A*0201–mediated protection. To our knowledge, these data provide the first direct evidence incriminating MHC class I genes and CD8+ T cells in the pathogenesis of human multiple sclerosis and reveal a network of MHC interactions that shape the risk of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Natalizumab is a highly efficacious disease modifying treatment (DMT) for RRMS patients. This study compares healthcare resource use (HCRU) and work productivity and activity impairment (WPAI) in RRMS patients who received 1L Natalizumab treatment vs. patients who received 1L platform DMTs and later switched to Natalizumab (delayed). [Extracted from the article]

This study evaluates work and activity impairment among patients with multiple sclerosis (MS) treated with ocrelizumab vs other disease-modifying therapies (DMTs). Outcomes were assessed using the patient-reported Work Productivity and Activity Impairment questionnaire, which measures loss of productivity at work and impairment in daily activities over the past 7 days. [Extracted from the article]