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Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51

Objectives Smoking is a known risk factor for the development and progression of autoimmune diseases. Previous studies in ocular myasthenia gravis (MG) patients showed that smoking is associated with the severity of symptoms and progression to generalized MG. However, whether smoking affects MG symptoms in patients with a broader clinical spectrum of presentations is unknown. Therefore, in this study, the associations of smoking with the clinical characteristics of MG were analyzed in a cohort of patients including those with generalized, seronegative, and thymoma-associated MG. Methods The smoking history was investigated in a cross-sectional study of 187 patients with MG followed in a referral hospital for neurology. The association of smoking with MG-activities of daily living score at survey, the presence of generalized manifestations, and the age of onset was assessed using multiple regression models. Results Neither current nor prior smoking habit was associated with the MG-activities of daily living score at survey. However, smoking exposure after MG onset was significantly associated with the presence of generalized manifestations during the disease course (odds ratio, 3.57; 95% confidence interval, 1.04, 12.3). The smoking history before or at onset of MG was not associated with the age of onset. Conclusion Smoking exposure after the onset is associated with generalized manifestations of MG in our cohort of patients with a broad clinical spectrum of presentations.

Background: Normal-appearing white matter (NAWM) lesions are known to be present in multiple sclerosis (MS); however, it is not easy to distinguish these lesions from others in MRI. This study aimed to investigate the most useful value for estimating NAWM damage using fractional anisotropy (FA) histograms analysis. Methods: Data from patients with relapsing-remitting MS and healthy controls were analyzed using a 1.5T MRI system with SENSE-Head-8 coil. FA maps with diffusion- weighted images were acquired using a single-shot echo-planar imaging sequence. The median, standard deviation (SD), kurtosis, and skewness of white matter (WM) of each subject were compared between MS and healthy controls using an in-house application. Results: FA decrease in 8 patients with MS was observed upon comparison with 12 controls and leaned toward the left side. While the SDs of the healthy controls were not significantly different from those of patients with MS, patients with MS expressed significantly lower median values, and higher kurtosis and skewness compared to healthy controls. A trend for inverse associations existed between median and expanded disability status scale scores. Conclusion: Our data suggests that median FA values can allow for distinguishing between patients with MS and healthy controls with high accuracy.

Neurological disabilities, especially physical issues, can adversely affect the daily lives of people with multiple sclerosis (MS) and negatively impact their health-related quality of life (HRQOL). On the other hand, physical and psychiatric symptoms are variable in people with MS, and QOL can be influenced by cultural and educational background. This study aimed to evaluate the association of HRQOL with disabilities, fatigue, and depression in Japanese subjects with MS.Evaluation of HRQOL, fatigue, and depression was performed in 184 Japanese individuals with MS, using the Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II), respectively.Multiple linear regression analysis demonstrated negative correlations of the Expanded Disability Status Scale (EDSS) with scores on the FAMS subscales of mobility, symptoms, thinking and fatigue, total FAMS, and additional concerns. The FSS score had negative correlations with mobility, symptoms, emotional well-being, thinking and fatigue, total FAMS, and additional concerns. There were negative correlations between BDI-II scores and all items of FAMS.HRQOL had relatively close correlations with disabilities and fatigue, and depression had an especially close relationship with HRQOL.

Cognitive dysfunction occurs in a substantial proportion of patients with multiple sclerosis (MS), negatively affects their daily activities, and is associated with poor prognosis. Cognitive dysfunction in MS can extend across multiple cognitive domains, depending on the patterns and extent of the brain regions affected. Therefore, a combination of tests, including the Brief International Cognitive Assessment for MS (BICAMS), that assess different aspects of cognition is recommended to capture the full picture of cognitive impairment in each patient. However, the temporal relationships between the progression of the MS brain pathology and the performances in different cognitive tests remain unclear.Global and regional brain volume data were obtained based on T1-weighted magnetic resonance imaging from 61 patients with MS, and hierarchical cluster analysis was performed using these brain volume data. Cognitive function was assessed using the three subcomponents of the BICAMS: the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test Second Edition (CVLT2), and Brief Visuospatial Memory Test-Revised (BVMTR). Clinical characteristics, patterns of regional brain volume loss, and cognitive test scores were compared among clusters.Cluster analysis of the global and regional brain volume data classified patients into three clusters (Clusters 1, 2, and 3) in order of decreasing global brain volume. A comparison of the clinical profiles of the patients suggested that those in Clusters 1, 2, and 3 are in the early, intermediate, and advanced stages of MS, respectively. Pair-wise analysis of regional brain volume among the three clusters suggested brain regions where volume loss starts early and continues throughout the disease course, occurs preferentially at the early phase, or evolves relatively slowly. SDMT scores differed significantly among the three clusters, with a decrease from Clusters 1 to 3. BVMTR scores also declined in this order, whereas the CVLT2 was significantly impaired only in Cluster 3.Our results suggest that SDMT performance declines in conjunction with brain volume loss throughout the disease course of MS. Performance in the BVMTR also declines in line with the brain volume loss, but impairment in the CVLT2 becomes particularly apparent at the late phase of MS.

Eight disease-modifying drugs have been approved for treating multiple sclerosis in Japan., The drugs show some differences in for the degree to which they prevent relapses; among them, natalizumab and ofatumumab are significantly effective in preventing relapses. If relapses are not suppressed when treated with natalizumab, the presence of anti-natalizumab antibodies should be investigated. When relapses cannot be suppressed with natalizumab, the patient should be treated with ofatumumab and vice versa. If relapses cannot be suppressed with both natalizumab and ofatumumab, then the diagnosis of multiple sclerosis should be thoroughly reassessed. In cases with atypical symptoms and/or exhibiting factors such as multiple sclerosis, oral steroids, and/or immunosuppressive agents can be administered to prevent relapses.

Different treatment strategies can have varying effects on disability and whole brain volume in patients with multiple sclerosis (MS). However, the association between regional brain volume and treatment efficacy is currently unclear. Our objective was to determine whether whole brain volume, as well as the regional volume of cortical and subcortical grey matter, differ with the administration of high-efficacy therapy (HET) versus low-efficacy therapy (LET).We evaluated clinical data and change in regional brain volume in 44 patients with relapse-onset MS, who underwent HET (n = 19) or LET (n = 25). Regional brain volume was determined with three-dimensional T1-weighted magnetic resonance imaging using FreeSurfer. The association between volume change and treatment type was assessed via generalised linear mixed models (GLMMs).During the observation period (2.0 ± 0.16 years), the proportion of patients with a "no evidence of disease activity-3″ status was significantly greater in those who underwent HET versus LET (p = 0.012). HET was positively associated with volume changes in the cortex (β = 0.64, p = 0.0499), left (β = 0.98, p = 0.0033) and right (β = 0.77, p = 0.019) caudate and right putamen (β = 0.87, p = 0.0077), after adjusting for age, sex, and MS severity scores in the GLMMs. Further correction for multiple comparisons by false discovery rate revealed that HET was consistently associated with the volume changes of the left caudate (p = 0.049) and right putamen (p = 0.049).HET can improve the mid-term prognosis of Japanese patients with relapse-onset MS by reducing disease activity and regional brain volume loss.

Background : This study aimed to evaluate the association between cognitive impairment and health-related quality of life (HRQOL), fatigue, and depression in Japanese patients with multiple sclerosis (MS). Methods : The Brief International Cognitive Assessment for MS (BICAMS) was performed in 184 Japanese patients with MS. The Functional Assessment of MS (FAMS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-Second Edition (BDI-II) were used to evaluate HRQOL, fatigue, and depression, respectively. Results : Multiple linear regression analysis demonstrated positive correlations of the Symbol Digit Modalities Test (SDMT) with the scores on the FAMS subscales of mobility, symptoms, emotional well-being, and additional concerns and with the total FAMS score even after controlling for the Expanded Disability Status Scale score, age at examination, and duration of education. The SDMT score in the BICAMS battery had negative correlations with the BDI-II score, as revealed by multiple linear regression analysis. None of the three tests in the BICAMS had any correlation with the FSS score. Conclusion : The SDMT has a significant relationship with HRQOL and depression in Japanese patients with MS.

Since the initial observation of increased immunoglobulin concentrations in the cerebrospinal fluid of multiple sclerosis (MS) patients in the 1940s, B cells have been considered to participate in the pathology of MS through the production of autoantibodies reactive against central nervous system antigens. However, it is now recognized that B cells contribute to MS relapses via antibody-independent activities, including the presentation of antigens to T cells and the release of pro-inflammatory cytokines. In addition, the recent identification of B cell-rich follicle-like structures in the meninges of progressive MS patients suggests that the pathogenic roles of B cells also exist at the progressive phase of this disease. Recently, large-scale clinical trials have demonstrated the efficacy of B-cell depletion therapy using anti-CD20 antibodies in relapsing as well as primary progressive MS. B-cell depletion therapy has become an essential treatment option for MS based on its unique benefit to risk balance in relapsing MS, and because it is the only drug that has been shown to be effective in primary progressive MS to date.

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. There are neither diagnostic tests nor markers for MS. Other causes must be excluded thoroughly before an MS diagnosis is considered definitive. The relapsing-remitting type is a major clinical course in MS. Most disease-modifying drugs (DMDs) target this clinical type. Many clinical studies have demonstrated that early intervention with DMDs may prevent disease progression and transition from relapsing-remitting MS to the secondary progressive type. There are windows of opportunity for DMDs. An adequate DMD should be used for the appropriate patient at the optimal time.

We explored the presence of seasonal fluctuations in serum vitamin D levels and potential relationship between vitamin D levels and disease severity or prognosis in patients with multiple sclerosis (MS) in northern Japan. Serum levels of 25(OH)D in spring were significantly lower than in summer and autumn, whereas no differences in 1,25(OH)2D levels were demonstrated among four seasons. Seasonal fluctuations in 25(OH)D were demonstrated in patients with EDSS ≤3.5, but not in those with EDSS≥4.0. Negative correlations between 25(OH)D and EDSS or MSSS were found in each season. Seasonal fluctuations in 25(OH)D levels may be affected by physical disabilities.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype–phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype–phenotype correlations are unclear in NMOSD.

Objective In Japan, following the launch of dimethyl fumarate (DMF) after fingolimod as a disease-modifying drug in multiple sclerosis (MS), some patients switched from fingolimod to DMF. The aim of this study was to determine the follow-up status of MS patients who switched to DMF after fingolimod cessation. Methods Clinical and magnetic resonance imaging (MRI) data in 19 patients with MS who switched to DMF were collected for at least for 6 months after fingolimod cessation. Results Ten patients (52.6%) experienced clinical or MRI exacerbation after fingolimod cessation. The peripheral blood lymphocyte counts at the time of fingolimod cessation in those with disease exacerbation were significantly lower than in those without exacerbation. The patients with disease exacerbation were further classified into three groups based on MRI findings: those with some new T2-weighted lesions with or without gadolinium (Gd) enhancement (group I), those with more new and/or enlarged T2-weighted lesions with Gd enhancement compared to pre-fingolimod induction (group II), and those with multifocal tumefactive demyelinating lesions. In group II, the clinical disease activity, which was similar to that at fingolimod initiation in group I, was higher than the clinical disease activity observed before fingolimod initiation. Conversely, group III exhibited unexpected new MRI findings that were not evident before fingolimod initiation. Conclusion Cessation of fingolimod might precipitate rebound or reactivation of clinical disease in patients with MS, and careful follow-up is necessary for patients who discontinue fingolimod.

Introduction The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS. Methods Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded. Results Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups. Conclusion The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports. Trial Registration ClinicalTrials.gov identifier NCT01838668. Funding Biogen Japan Ltd. Electronic supplementary material The online version of this article (10.1007/s12325-018-0788-8) contains supplementary material, which is available to authorized users.

Patients with multiple sclerosis (MS) who are treated with fingolimod have an increased proportion of transitional B cells in the circulation, but the underlying mechanism is not known. We hypothesized that B cell-activating factor of the tumor necrosis factor family (BAFF) is involved in the process. Compared with healthy controls and untreated MS patients, fingolimod-treated MS patients had significantly higher serum concentrations of BAFF, which positively correlated with the proportions and the absolute numbers of transitional B cells in blood. Despite the elevated concentrations of BAFF in fingolimod-treated MS patients, serum levels of soluble transmembrane activator and calcium-modulating cyclophilin ligand interactor, and B cell maturation antigen were not elevated. Our results show that fingolimod induces BAFF in the circulation and expands transitional B cells, but does not activate memory B cells or plasma cells in MS, which is favorable for the treatment of this disease.

Objective:To clarify the prevalence and clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) in Japan and compare them with those in other ethnic populations.Methods:Data processing sheets were sent to all related institutions in northern Japan and were collected from April to May 2016. Prevalence was determined on March 31, 2016, using the 2015 International Panel for NMO Diagnosis criteria.Results:The crude prevalence was 4.1/100,000 (95% confidence interval 2.2–6.9) for NMOSD in northern Japan, with a significantly higher number of female than male patients (female: male 12:2). The positivity for anti-aquaporin-4 antibody was 78.6%, and the mean age at onset was 45.2 years. All patients were subjected to preventive therapy in the form of treatment with steroids or immunosuppressive agents.Conclusions:Our results showed that the prevalence of NMOSD in the Japanese population is similar to that in Caucasians.

Magnetic resonance imaging has improved the diagnosis and evaluation of disease activity in multiple sclerosis (MS), and its widespread use has contributed to creating the concept of radiologically isolated syndrome (RIS) to describe patients without symptoms of MS whose magnetic resonance imaging findings suggest they might be at risk of future demyelinating events. Indeed, using the revised McDonald criteria now allows some patients who would have been diagnosed with clinically isolated syndrome (CIS) in the era of Poser criteria to be diagnosed as having MS before a second episode. The present review discusses the current concepts of RIS and CIS, and the risk factors for conversion from these conditions to MS. Clinical trials involving participants with CIS at high risk of developing clinically definite MS have shown that disease-modifying drugs significantly suppressed the conversion from CIS to MS, and that early treatment with these drugs could improve future disease prognosis in patients who subsequently developed MS. When a patient presents with RIS or CIS, the primary concern for the physician and patient should be the probability of conversion to MS, and the patient should be followed up taking into consideration the risk factors for conversion from RIS or CIS to MS.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. In the past few decades, several disease-modifying drugs including interferon (IFN)-β have become available for treating MS. IFN-β belongs to the type I IFN family, and thus is an endogenous molecule whose primary role is thought to be host defense against viruses. In addition, type I IFN are constitutively produced at low amounts and involved in the homeostasis of various tissues. In contrast, it is suggested that type I IFN play a pathogenic role in other autoimmune diseases, such as lupus. Several lines of evidence from studies using MS samples and animal models suggest the protective role of endogenous type I IFN in MS. Correspondingly, MS patients with a higher endogenous type I IFN signature show lower disease activity. Paradoxically, these patients have been shown to respond poorly to IFN-β therapy. In addition, an animal model with a defective regulatory mechanism in type I IFN signaling has been shown to develop augmented central nervous system autoimmunity, suggesting that type I IFN responses need to be appropriately regulated in MS. Multiple endogenous molecules participate in the regulation of type I IFN responses, but their roles in MS have not been studied extensively. Further study delineating the role of endogenous type I IFN and their regulatory mechanisms in MS should enhance our understanding of the disease, and could lead to improvements in the therapeutic effects of IFN-β in MS.

Cortical lesions (CLs) have a low prevalence and are associated with physical disabilities in Japanese patients with multiple sclerosis (MS). However, the contribution of CLs to cognitive impairment remains unclear in Asian MS. Sixty-one prospectively enrolled MS patients underwent three-dimensional double inversion recovery MR imaging, the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Apathy Scale (AS), the Fatigue Questionnaire (FQ), and the Hospital Anxiety and Depression Scale (HADS) within a 1-week period. The cognitive impairment index (CII) score was calculated to measure patients’ overall cognitive impairment. MS patients with CLs had poorer scores than those without CLs in most BRB-N tests, but scored comparably in the FQ, AS, and HADS. The number of CLs correlated negatively with all BRB-N test scores and positively with total CII scores. Leukocortical lesions were more extensively associated with cognitive dysfunction in various domains than intracortical lesions. Stepwise multiple regression analysis revealed that potential confounding factors for the highest quartile of CII score were the number of CLs (odds ratio 2.38, p = 0.0070) and the Expanded Disability Severity Scale score (odds ratio 2.13, p = 0.0003). Our results demonstrate that the presence and number of CLs are robustly associated with cognitive dysfunction in Asian MS patients.

Fingolimod is a sphingosine-1-phosphate receptor agonist used to inhibit the inflammatory activity of multiple sclerosis (MS), and has been shown to suppress osteoporosis in mouse models. In this study, levels of bone turnover markers were quantified in serum and urine samples from MS patients treated with fingolimod. Compared with untreated MS patients and healthy controls, fingolimod-treated MS patients had a significantly lower level of the bone resorption marker type I collagen cross-linked N-telopeptide in urine. This finding was prominent in female but was not seen in male subjects. Our results suggest that fingolimod may have a beneficial effect on bone mass loss in female MS patients.

The development of multiple sclerosis (MS) is based on complex interactions between genetic and environmental factors. Epigenetic regulation is a biological phenomenon defined as the modification of gene expression without alteration of the DNA sequence, and is currently thought to underlie the interactions between the genetic and environmental risks of MS. The molecular mechanisms of epigenetics include DNA methylation, histone modification, and microRNAs. Observational data obtained from epidemiological studies of MS, such as the parent-of-origin effect and the longitudinal increase in female patients, suggest that epigenetic mechanisms are involved in MS development, although the molecular basis remains unclear. Interestingly, environmental factors related to the development of MS, such as Epstein-Barr virus, smoking, and vitamin D, have been shown to regulate gene expression through epigenetic mechanisms in some experimental settings. One study showed no reproducible differences among DNA methylation profiles in peripheral blood CD4+ T cells between three monozygotic twin pairs discordant for MS. However, several studies have shown that dysregulated DNA methylation of genes is related to abnormal immune reactions and post-translational modifications of myelin proteins in MS brain samples. In addition, abnormal microRNA profiles have been reported in brain tissues and peripheral blood immune cells obtained from MS patients. In this article, we will review the studies on the epigenetics of MS and discuss the perspectives for future research.

Since the initial observation of increased immunoglobulin concentrations in the cerebrospinal fluid of patients with multiple sclerosis (MS) in the 1940s, B cells have been considered to participate in the pathology of MS through the production of autoantibodies reactive against central nervous system antigens. However, it is now recognized that B cells contribute to MS relapses by antibody-independent activities, including presenting antigens to T cells and releasing pro-inflammatory cytokines. In addition, the recent identification of B cell-rich follicle-like structures in the meninges of patients with MS suggests that pathogenic roles of B cells also exist at the progressive phase. Recently, large-scale clinical trials have demonstrated the efficacy of B-cell depletion therapy using ocrelizumab, an anti-CD20-antibody, in relapsing-remitting as well as primary progressive MS; these findings have led to the approval of ocrelizumab by the Food and Drug Administration and the European Medical Agency for treating these conditions. B-cell depletion therapy is an important treatment option for MS based on its favorable benefit to risk balance in relapsing remitting MS, and as it is the only drug that has currently been demonstrated to be effective in treating primary progressive MS.

Objective To clarify the potential association of copy number variations (CNVs) with multiple sclerosis (MS) and neuromyelitis optica (NMO) in Japanese cases. Methods Genome-wide association analyses of CNVs among 277 MS patients, 135 NMO/NMO spectrum disorder (NMOSD) patients, and 288 healthy individuals as a discovery cohort, and among 296 MS patients, 76 NMO/NMOSD patients, and 790 healthy individuals as a replication cohort were performed using high-density single nucleotide polymorphism microarrays. Results A series of discovery and replication studies revealed that most identified CNVs were 5 to 50kb deletions at particular T cell receptor (TCR) gamma and alpha loci regions. Among these CNVs, a TCR gamma locus deletion was found in 16.40% of MS patients (p = 2.44E-40, odds ratio [OR] = 52.6), and deletion at the TCR alpha locus was found in 17.28% of MS patients (p = 1.70E-31, OR = 13.0) and 13.27% of NMO/NMOSD patients (p = 5.79E-20, OR = 54.6). These CNVs were observed in peripheral blood T-cell subsets only, suggesting the CNVs were somatically acquired. NMO/NMOSD patients carrying the CNV tended to be seronegative for anti–aquaporin-4 antibody or had significantly lower titers than those without CNV. Interpretation Deletion-type CNVs at specific TCR loci regions contribute to MS and NMO susceptibility. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696

Vitamin D receptors (VDRs), which are responsible for most vitamin D functions, are expressed on various immune cells. Vitamin D is considered to be a potent immunomodulator. A variety of cells in the central nervous system (CNS) also express VDRs; thus, vitamin D may play a role in the regulation of neurodegeneration and repair processes within the CNS. Considered together with epidemiological studies, low vitamin D status is reckoned to be one of the risk factors for multiple sclerosis (MS). Further, vitamin D is considered to be a possible treatment for MS. However, previous clinical trials with small cohorts have not demonstrated significant effects of vitamin D in MS. Current ongoing clinical trials with large cohorts could provide answers with respect to the clinical effects of vitamin D in MS. However, genetic studies have suggested that genes associated with vitamin D, including VDRs, are susceptible genes for MS. Vitamin D needs to be considered from the perspective of the interaction between vitamin-D-related genetic factors and environmental factors affecting vitamin D levels.

Data regarding vitamin D in multiple sclerosis (MS) in Asia are limited. We investigated whether Japanese MS patients show decreased serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and vitamin D-binding protein (DBP) during winter. Mean serum 25(OH)D and 1,25(OH)2D levels were significantly lower in MS patients than in controls. There were no significant differences in serum 25(OH)D, 1,25(OH)2D, and DBP levels between patients or between controls from northern Japan (Hokkaido) and southern Japan (Kyushu). Serum vitamin D levels were low in Japanese MS patients but did not differ in patients from northern and southern Japan.

B cells have been implicated in the pathology of multiple sclerosis (MS) since the initial observation in the 1940s and 50s of increased immunoglobulin concentrations in the cerebrospinal fluid of MS patients. Until recently, B cells have been considered to participate in MS pathology through the secretion of antibodies specific to central nervous system antigens. However, the successful targeting of B cells with anti-CD20 monoclonal antibodies without affecting immunoglobulin levels suggests that B cells have antibody-independent functions in immune regulation in MS. Furthermore, the recent identification of B cell-rich follicle-like structures in the meninges of patients with secondary progressive MS indicates that B cells also have pathogenic roles within the central nervous system, where they contribute to disease progression by inducing cortical injury. These observations suggest that B cells are key players in the pathogenesis of MS, and are therefore attractive targets for therapeutic intervention. In addition to CD20, several other molecules and pathways related to B cell function are being evaluated as therapeutic targets in other autoimmune diseases. Furthermore, based on the increased understanding of the molecular mechanisms underlying B cell effector function, particularly those involved in MS, therapeutic strategies for specifically inhibiting the pro-inflammatory activity of B cells while preserving or even enhancing their role in protective immune response are under active investigation. Here, we review recent advances in molecular targeted therapies against B cells for MS, and discuss perspectives for future therapies targeting B cells and related molecules.

Background and purpose The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been globally reported for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in Tokachi province of Hokkaido, northern Japan, from 2001 to 2016. Methods Prevalence was determined on March 31, 2016. Data processing sheets were collected from all MS-related institutions in Tokachi province. Herein, we applied the Poser's diagnostic criteria for MS as that used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded. Results In 2016, the crude MS prevalence was 18.6/100,000 (95% confidence interval, 14.3–23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6, and 16.2, in 2001, 2006, and 2011, respectively. The female/male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary-progressive, relapsing-remitting, and secondary-progressive MS types were 2%, 84%, and 14%, respectively. Conclusion Our results demonstrated consistent increase in the MS prevalence among the northern Japanese, particularly in females, and the relatively lower rates of progressive MS in northern Japan than in Western countries. This article is protected by copyright. All rights reserved.

Epidemiological studies have suggested an association between multiple sclerosis (MS) risk and vitamin D deficiency, whereas genome-wide association studies have identified several allelic variants of vitamin D-associated genes as possible risk factors. Vitamin D is a multifunctional immune system modulator; therefore, there is a strong interest in its therapeutic potential against MS. Indeed, vitamin D suppresses experimental autoimmune encephalopathy, a major animal model of MS. Although previous clinical trials have not demonstrated substantial benefits, vitamin D may potentiate the effects of other disease-modifying drugs. Furthermore, previous trials may be limited by insufficient dose, short duration, and patient heterogeneity. This chapter discusses the possible contributions of vitamin D insufficiency or dysregulation to MS pathogenesis and reevaluates the therapeutic potential of vitamin D supplementation.

Objective The aim of the present study was to investigate the association of magnetic resonance imaging (MRI) findings and social activity with cognitive function in Japanese patients with multiple sclerosis (MS). Methods The Brief Repeatable Battery of Neuropsychological tests (BRB-N) was carried out in 184 Japanese patients with MS, and 163 controls matched for age, sex and education. MRI findings of cerebral, brainstem, and cerebellar lesions and social activities of MS patients were further examined. Results MS patients with higher numbers of cerebral lesions on MRI had lower scores in most BRB-N tests. BRB-N scores in the majority of tests were significantly lower in patients with brainstem and cerebellar lesions. Data from an analysis of variance model in which only the main effects of cerebral, brainstem and cerebellar lesions were hypothesized showed an association of cerebral lesions with decreased scores in all BRB-N tests, except symbol digit modalities test (SDMT) and paced auditory serial addition test (PASAT). In contrast, cerebellar lesions were associated with decreased SDMT and PASAT scores. Patients categorized as “unemployed because of MS” had lower BRB-N scores than other social activity groups. Lower SDMT scores had an effect on the “unemployed because of MS” group, whereas the Expanded Disability Status Scale had a significantly greater negative impact on patients in this social category. Conclusions Higher numbers of brain lesions on MRI could have an impact on cognitive function in patients with MS, and impairment of information processing appears significantly associated with cerebellar lesions. Cognitive impairment affects the employment status of patients with MS.

Fingolimod functions as a modulator of sphingosine-1-phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing-remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first-line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second-line option, because the long-term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti-aquaporin-4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.

SUMMARY Remarkable progress has recently been made regarding new therapies for multiple sclerosis, especially in the form of disease-modifying drugs that can be administered either intravenously or orally. However, responses to drugs, including efficacy and adverse reactions, vary considerably between individuals. Although it is preferable to predict these responses prior to commencing therapy, biomarkers and genetic factors for disease-modifying drugs are not available for routine clinical use. Newer techniques and methods of analysis will result in improved screening of individual benefit/risk balances for multiple sclerosis treatments.

Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Department of Neurology, Kushiro Rosai Hospital, Kushiro, Japan Department of Neurology, Brain Science Center, Sapporo City General Hospital, Sapporo, Japan Department of Clinical Research, Hokkaido Medical Center, Sapporo, Japan Department of Pathology, Kushiro Rosai Hospital, Kushiro, Japan Department of Neurology, Kanazawa Medical University, Uchinada, Japan

Several genetic and environmental factors are thought to be associated with an increased risk of multiple sclerosis (MS), the influence of which can differ between ethnicities. One of the most important risk factors for MS is low serum levels of vitamin D, and these levels also differ between ethnicities, probably mainly because of differences in skin pigmentation. Furthermore, genetic influences in vitamin D-related genes might also vary between ethnicities, reflecting different genetic backgrounds. The present review article discusses the association between vitamin D and MS, with a focus on Asians and Caucasians.

Objectives There has been no large-scale study of methylprednisolone pulse therapy in Asian patients with multiple sclerosis (MS) or neuromyelitis optica (NMO), despite it being widely used for acute relapse. We aimed to clarify treatment response of MS and NMO patients to methylprednisolone pulse therapy and post-pulse oral corticosteroids in real clinical practice in a multicenter study in Japan. Methods Investigators at 28 institutions collected changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of completion of methylprednisolone pulse therapy carried out in 2010, and after post-pulse oral corticosteroids therapy, by retrospective review of medical records. Results In 345 patients (95.1% of all registered patients), 457 series of methylprednisolone pulse therapy were carried out for treatment of acute relapse. EDSS scores improved by 0.8 ± 1.1 (mean ± SD) after the first course. The second and third courses also produced sufficient improvements (by 0.7 and 0.6, respectively), but much smaller improvements were observed thereafter. The target neurological symptoms and signs improved in 79.5% of patients. Improvement rates were 5–20% lower after a course of pulse therapy than after a series of pulse therapy. A half dose (500 mg/day) produced less improvement than a standard dose (1000 mg/day; 65.9 vs 79.5%). During post-pulse oral corticosteroid therapy, EDSS scores decreased by 0.6 ± 0.9. No significant adverse effects were observed. Conclusions Methylprednisolone pulse therapy is beneficial in nearly 80% of Japanese MS and NMO patients, and EDSS score improvements after therapy are compatible with those in Western MS patients.

Objective Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS. Methods Serum levels of 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), and vitamin D-binding protein (DBP) were measured in 29 patients with relapsing-remitting (RR) and secondary-progressive (SP) MS, and in 34 healthy controls. Results The serum levels of 25(OH)D in SPMS patients were significantly decreased compared with those of controls and RRMS patients at remitting phase (7.9 ± 7.2 nM vs 24.2 ± 14.2 nM vs 22.5 ± 13.2 nM, respectively; P

Many patients with multiple sclerosis (MS) suffer from neuropsychological impairments such as cognitive dysfunction, apathy, fatigue, and depression. However, physical disabilities in MS remain the main focus of daily clinical practice and of research into symptoms of the disease. In patients with MS, cognitive impairment typically involves domain-specific deficits rather than global cognitive decline, and sustained attention and information-processing speed are prominently affected. On the other hand, cognitive impairment in MS patients is often associated with other neuropsychological disorders, and its pathophysiology is complex. Neuropsychological impairments can influence activities of daily living and social activities in patients with MS. It has been suggested that cognitive impairment begins in the very early stages of the disease, but no established treatments are currently available. Urgent investigation into the treatment of neuropsychological impairments in MS is warranted, and challenges to conquer these widely neglected symptoms of the disease are continuing.