Seasonal fluctuations in serum levels of vitamin D in Japanese patients with multiple sclerosis.

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.

Disease Exacerbation after the Cessation of Fingolimod Treatment in Japanese Patients with Multiple Sclerosis.

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.

Beneficial effects of fingolimod in MS patients with high serum Sema4A levels.

We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-ß therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing-remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-ß therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels.

Fingolimod induces BAFF and expands circulating transitional B cells without activating memory B cells and plasma cells in multiple sclerosis.

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.

Once-daily glatiramer acetate decreases magnetic resonance imaging disease activity in Japanese patients with relapsing-remitting multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) prevalence, clinical patterns, and treatment responses vary between races and geographical latitudes. Glatiramer acetate (GA; Copaxone) has provided a safe, effective treatment option for relapsing-remitting MS patients in the USA, European nations, and other countries for decades. The objective of the present study was to assess the safety and efficacy of GA in reducing magnetic resonance imaging disease activity in Japanese patients with active relapsing-remitting MS. METHODS: This phase 2, multicenter, open-label, single-arm, 52-week study measured the effect of GA 20 mg once-daily on magnetic resonance imaging disease activity. GA efficacy was evaluated through week 36, and safety through week 52. The primary end-point was change in the mean number of T1-weighted gadolinium-enhancing (GdE) lesions from pretreatment (weeks -8, -4 and baseline) to weeks 28, 32 and 36. Secondary end-points included a change in mean number of new T2-weighted lesions, GdE lesion and T2 lesion volumes, annualized relapse rate, and Expanded Disability Status Scale scores. RESULTS: GA therapy reduced the number of new GdE lesions by 65.66% (95% CI 33.19-82.35%). The number of new T2 lesions and GdE lesion volume were also reduced from pretreatment. The annualized relapse rate was reduced by 42% compared with the 1 year before treatment. Changes in T2 lesion volume and Expanded Disability Status Scale scores were favorable, but less pronounced. Most common adverse events were injection-site reactions. CONCLUSIONS: The present study confirmed the well-established safety, tolerability and efficacy profile of GA in Japanese MS patients.

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis in Japan.

BACKGROUND: The Brief International Cognitive Assessment for MS (BICAMS) is a practical battery for measuring cognitive function in multiple sclerosis (MS). OBJECTIVES: We aimed to validate a Japanese version of the BICAMS in patients with MS and healthy controls. METHODS: The Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-Second Edition (CVLT2) and the Brief Visuospatial Memory Test Revised (BVMTR) were administered to 156 patients with MS and 126 healthy controls (HCs). The BICAMS was re-administered in a subset of 27 MS patients and 30 HCs. RESULTS: The mean (±SD) raw scores in the MS and HC groups were as follows: SDMT: MS 47.9 ± 14.0, HC 61.0 ± 9.5; CVLT2: MS 48.6 ± 12.6, HC 55.7 ± 10.5; BVMTR: MS 23.5 ± 8.4, HC 28.3 ± 5.4, respectively, and significant differences were found between the two groups on all tests (p < 0.0001). Cohen's d values were 1.07, 0.60, and 0.67 in SDMT, CVLT2, and BVMTR, respectively. The test-retest reliability coefficients for each test were as follows: SDMT: r = 0.93; CVLT2: r = 0.82; and BVMTR: r = 0.77 (p < 0.0001). CONCLUSIONS: This study provides results that support the reliability and validity of the BICAMS in Japan.

Fingolimod suppresses bone resorption in female patients with multiple sclerosis.

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.

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study.

BACKGROUND: Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. METHODS: We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. RESULTS: The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198). CONCLUSIONS: Living at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.

Lack of KIR4.1 autoantibodies in Japanese patients with MS and NMO.

OBJECTIVES: To examine anti-KIR4.1 antibodies by 2 different assays in Japanese patients with multiple sclerosis (MS) or neuromyelitis optica (NMO). METHODS: One hundred sixty serum samples from 57 patients with MS, 40 patients with NMO/NMO spectrum disorder (NMOSD), and 50 healthy controls (all were Japanese) were tested with ELISA using a synthetic peptide of the first extracellular portion of human KIR4.1. In addition, we attempted to detect anti-KIR4.1 immunoglobulin G in the serum by the luciferase immunoprecipitation systems (LIPS) with the full length of human KIR4.1 produced in a human cell line, which is highly sensitive to single or multiple epitopes. RESULTS: We failed to detect antibodies to the peptide fragment KIR4.1(83-120) in any case of MS and NMO/NMOSD using ELISA. Antibodies to the recombinant full length of KIR4.1 protein were detected in only 2 patients with MS and none in the patients with NMO/NMOSD by the LIPS assay. CONCLUSIONS: We developed 2 different methods (ELISA and LIPS) to measure autoantibodies to KIR4.1 in serum. We detected anti-KIR4.1 immunoglobulin G at a very low frequency in Japanese patients with MS or NMO/NMOSD. Serologic testing for human KIR4.1-specific antibodies is unlikely to improve the diagnosis of MS or NMO/NMOSD in Japanese patients.

The dynamics of mucosal-associated invariant T cells in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination, gliosis and axonal loss in the Central Nervous System. Although the etiology of the disease has remained enigmatic, recent studies have suggested a role of the innate-like T cells, called Mucosal Associated Invariant T cells (MAITs) in the pathophysiology. In the present study, we have analyzed the relative frequency of MAITs and the expression of the cell surface antigens in MAITs to seek a possible link to the disease. RESULTS: There was little difference in the frequency of total MAITs between healthy donors (HDs) and untreated MS patients, whereas the latter harbored more CD8(lo/neg) (DN) MAITs concomitant with a decrease in CD8(high) MAITs and in CD4 MAITs compared with those in HDs. While the expression of CCR5, CCR6, CD95, CD127, and CD150 has increased in untreated subjects compared with that in HDs, CD45RO has declined in untreated subjects in both DN MAITs and CD8(hi) MAITs. FTY720 therapy has increased the relative frequency of total MAITs in a time-dependent fashion up to 2 years. Intriguingly, FTY720 therapy for 3 years reversed the above phenotype, engendering more CD8(high) MAITs accompanied with decreased DN MAITs. FTY720 therapy affected the cytokine production from CD4 T cells and also enhanced the relative frequency of cells producing both TNF-α and IFN-γ from MAITs, CD8 T cells, and CD4 T cells compared with that in untreated subjects. CONCLUSIONS: FTY 720 therapy enhanced the relative frequency of MAITs in MS patients in a time-dependent manner. Although the expression of CD8 in MAITs has been affected early by FTY720, longer treatment has reversed the phenotypic change. These data demonstrated that FTY720 induced dynamic change in the relative frequency and in the phenotype of MAITs in MS.

Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica.

BACKGROUND: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO). OBJECTIVE: To explain differences in treatment responses of MS and NMO patients to IVMP. METHODS: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases. RESULTS: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p < 0.05), but not after the fourth (-0.3 ± 0.7) and fifth (-0.5 ± 0.6). However, decreased EDSS score was only significant after the first course (-0.5 ± 1.5, p < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p < 0.05). CONCLUSION: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

Copy number variations in multiple sclerosis and neuromyelitis optica.

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.

Decreased serum vitamin D levels in Japanese patients with multiple sclerosis.

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.

Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis.

BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. CONCLUSIONS: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.

[Vitamin D and latitude as environmental factors in multiple sclerosis].

Multiple sclerosis (MS) shows a multifold increase in prevalence with an increase in latitudes, both north and south of the equator. One of the potential factors related to the difference of the prevalence is vitamin D, because the strength of ambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude. It is known that vitamin D has immunomodulatory functions and suppresses an animal model of MS. It is also considered that vitamin D-related genes are critical susceptible genes for MS. An approach from environmental and genetic aspects is needed to investigate the association between vitamin D and MS.

[Home hospice care, working support and rehabilitation for MS/NMO].

There are a huge amount of physical, mental and financial handicaps to patients with multiple sclerosis (MS) or neuromyelitis optica (NMO) and their family members, although treatment strategies have remarkably progressed recently. Among many important issues, to support them, here we make issues of home hospice care, working support and rehabilitation. We should consider social immaturity and ignorance to resolve the issues, and the key point to contribute useful support is consistent cooperation among medical teams and appropriate understanding of MS/NMO by all the people in our society as well as medical staffs.

Suppression of IL-10 production by calcitriol in patients with multiple sclerosis.

We investigated whether calcitriol (1,25-dihydroxyvitamin D) differentially modulates cytokine production by peripheral blood mononuclear cells from multiple sclerosis (MS) patients compared with that from healthy controls. In response to phytohemagglutinin (PHA) or lipopolysaccharide (LPS), cytokine level in a calcitriol-added sample was normalized to that in a calcitriol-absent sample, and this relative unit was compared. The relative unit of IL-12/23(p40) in LPS-stimulation was higher in MS patients. Moreover, the relative unit of IL-10 in PHA-stimulation was lower in MS patients, and negatively correlated with the Expanded Disability Status Scale. The anti-inflammatory response to vitamin D may be reduced in MS.

Suppressed pro-inflammatory properties of circulating B cells in patients with multiple sclerosis treated with fingolimod, based on altered proportions of B-cell subpopulations.

The chief therapeutic mechanism of fingolimod in multiple sclerosis (MS) is considered to be sequestration of pathogenic lymphocytes into secondary lymphoid tissues. B cells have recently been recognized as important immune regulators in MS. In this study, the effects of fingolimod on B cells in MS patients were analyzed. MS patients treated with fingolimod (MS-F) had a significantly lower number of B cells in the circulation. The remaining B cells in the blood of MS-F had a reduced proportion of memory B cells and an increased proportion of naïve B cells, expressed lower levels of the costimulatory molecule CD80, and produced less tumor necrosis factor-α and more interleukin-10. These observations in MS-F were based on an increased proportion of the transitional B-cell subpopulation within the naïve B-cell compartment. The observed findings in B cells of MS-F might be related to the therapeutic effect of this drug in MS.

Increased prevalence, incidence, and female predominance of multiple sclerosis in northern Japan.

OBJECTIVE: To carry out the third epidemiologic surveillance of multiple sclerosis (MS) in Tokachi province, on the northernmost island of Japan, and to compare the results of the present survey on the prevalence, incidence, and characteristics of MS and neuromyelitis optica (NMO) with those of previous surveys performed in 2001 and 2006. METHODS: A data processing sheet was sent to all MS-related institutions in Tokachi province, and all sheets were collected in March 2011. The criteria of Poser were used for diagnosing MS and the criteria proposed by Wingerchuk for diagnosing NMO. We then compared the results of the present survey with those of previous surveys performed in 2001 and 2006 in the same community. RESULTS: Fifty-seven patients diagnosed with MS according to the criteria of Poser were identified. The prevalence was 16.2/100,000 in 2011, which was higher than in the previous studies. The female/male ratio of MS was 2.63, 2.75, and 3.38 in 2001, 2006, and 2011, respectively. Three patients fulfilled the criteria for diagnosis of NMO in 2011; the prevalence of NMO was 0.9/100,000. CONCLUSIONS: The results of this study suggest that the prevalence and the female predominance of MS have been increasing, due to an increase in the incidence after 1990, and that the prevalence of NMO is relatively low in northern Japan.