Japanese Multiple Sclerosis Patients Research Articles

Japanese translation and validation of the 12-item Multiple Sclerosis Walking Scale version 2

BackgroundDisability in ambulation has a critical impact on activities of daily living in patients with multiple sclerosis (MS). The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a self-reported instrument developed to assess the impact of MS on walking. The scale's 12 items assess various aspects of walking-related tasks during the past 2 weeks. MSWS-12 has been used in multiple clinical studies and translated into several languages. In the present study, we translated the MSWS-12 into Japanese and evaluated its psychometric properties in a cross-sectional study. MethodsThe original English MSWS-12 version 2 (v2) was translated into Japanese through a standard procedure. Sixty consecutive Japanese MS patients completed the newly prepared Japanese MSWS-12v2 questionnaire and repeated the test 14 days later. Physical disability was assessed by the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk (T25FW), and 9-hole Peg Test (9HPT). Cognitive performance was evaluated using the Processing Speed Test (PST). Fatigue and health-related quality of life were assessed using the Japanese versions of the Fatigue Severity Scale (FSS) and the Functional Assessment of MS (FAMS). ResultsThe mean age of the patients was 42.5 years, with median disease duration of 10 years, and median EDSS of 2.0 (range 0, 6.5). Forty-seven patients (78.3%) had relapsing-remitting, 9 (15.0%) had secondary-progressive, and 4 (6.7%) had primary-progressive phenotypes. The median score of the MSWS-12v2 was 5.95 (interquartile range 0, 50.6). Twenty-seven patients (45%) scored the lowest possible score (0 points), while one (1.7%) scored the highest possible score (100 points). Cronbach's alpha was 0.98 (95% confidence interval [CI] 0.97, 0.98), and the test-retest intraclass correlation was 0.95 (95%CI 0.94, 0.96). MSWS-12v2 score was strongly correlated with EDSS (Spearman's ρ = 0.73 [95%CI 0.58, 0.83]), T25FW (ρ = 0.70 [95%CI 0.55, 0.81]), and total FAMS score (ρ = –0.80 [95%CI –0.88, –0.69]), and moderately correlated with 9HPT (ρ = 0.65 [95%CI 0.47, 0.77] for the dominant hand; ρ = 0.62 [95%CI 0.43, 0.75] for the non-dominant hand), PST (ρ = –0.65 [95%CI –0.78, –0.47]), and FSS (ρ = 0.68 [95%CI 0.52, 0.80]). Among the subcomponents of FAMS, the mobility subcomponent showed the most robust correlation with MSWS-12v2 score (ρ = –0.91 [95%CI –0.94, –0.81]). In patients with minimal or no objective disability (EDSS < 3.0, n = 40), only the mobility subcomponent of FAMS was strongly correlated with MSWS-12v2 score (ρ = –0.76 [95% CI –0.87, –0.58]). In contrast, correlations of MSWS-12v2 score with EDSS and T25FW were weak in this subgroup (ρ = 0.28 [95%CI –0.03, 0.55] for EDSS; ρ = 0.25 [95%CI –0.06, 0.52] for T25FW). Response patterns for the single items showed that 32.5% of the patients with EDSS below 3.0 reported having problems with balance, followed by climbing stairs and standing while doing things (both 25%). ConclusionThe Japanese version of the MSWS-12v2 developed in this study is reliable, valid, and helpful for screening walking disability in Japanese MS patients, including those with minimal objective disability.

Mycobacterium avium subsp. paratuberculosis Antigens Elicit a Strong IgG4 Response in Patients with Multiple Sclerosis and Exacerbate Experimental Autoimmune Encephalomyelitis.

Neuroinflammation can be triggered by microbial products disrupting immune regulation. In this study, we investigated the levels of IgG1, IgG2, IgG3, and IgG4 subclasses against the heat shock protein (HSP)70533-545 peptide and lipopentapeptide (MAP_Lp5) derived from Mycobacterium avium subsp. paratuberculosis (MAP) in the blood samples of Japanese and Italian individuals with relapsing remitting multiple sclerosis (MS). Additionally, we examined the impact of this peptide on MOG-induced experimental autoimmune encephalomyelitis (EAE). A total of 130 Japanese and 130 Italian subjects were retrospectively analyzed using the indirect ELISA method. Furthermore, a group of C57BL/6J mice received immunization with the MAP_HSP70533-545 peptide two weeks prior to the active induction of MOG35-55 EAE. The results revealed a significantly robust antibody response against MAP_HSP70533-545 in serum of both Japanese and Italian MS patients compared to their respective control groups. Moreover, heightened levels of serum IgG4 antibodies specific to MAP antigens were correlated with the severity of the disease. Additionally, EAE mice that were immunized with MAP_HSP70533-545 peptide exhibited more severe disease symptoms and increased reactivity of MOG35-55-specific T-cell compared to untreated mice. These findings provide evidence suggesting a potential link between MAP and the development or exacerbation of MS, particularly in a subgroup of MS patients with elevated serum IgG4 levels.

Two-dimensional measurements with cut-off values are useful for assessing brain volume, physical disability, and processing speed in multiple sclerosis

BackgroundTwo-dimensional (2D) measures have been proposed as potential proxy measures for whole-brain volume in multiple sclerosis (MS); however, cut-off values that determine the degree of brain volume loss (BVL) have not been established. Since we had previously developed a system to categorize MS patients into clusters with significantly different degrees of BVL, we tried to identify cut-off values for 2D measurements that can discriminate MS patients on the basis of disease severity associated with brain atrophy. MethodsIn this cross-sectional analysis, ninety-one consecutive Japanese MS patients—clinically isolated syndrome (5%), relapsing-remitting MS (78%) and progressive MS (17%)—were categorized into two clusters (CL1 and CL2) with a significantly different degree of BVL using the method described in our previous study. MS patients were also evaluated for 2D measurements, namely, third ventricle width, lateral ventricle width (LVW), bicaudate ratio (BCR), and corpus callosum index (CCI). Thereafter, we performed receiver operating characteristic analysis to determine the cut-off values of the 2D measurements for categorizing the MS patients into two clusters. ResultsWe identified optimal cut-off values for each 2D measure with high specificity and sensitivity. The cut-off values for LVW, BCR, and CCI divided the MS patients into two subgroups, in which whole-brain and grey matter volume, EDSS, and processing speed were significantly different. ConclusionLVW, BCR, and CCI with particular cut-off values are useful to discriminate MS patients with decreased brain volume, physical disability, and processing speed.

Usefulness of two-dimensional measurements for the evaluation of brain volume and disability in multiple sclerosis.

BackgroundTwo-dimensional (2D) measures have been proposed as potential proxies for whole-brain volume in multiple sclerosis (MS).ObjectiveTo verify whether 2D measurements by routine MRI are useful in predicting brain volume or disability in MS.MethodsIn this cross-sectional analysis, eighty-five consecutive Japanese MS patients—relapsing-remitting MS (81%) and progressive MS (19%)—underwent 1.5 Tesla T1-weighted 3D MRI examinations to measure whole-brain and grey matter volume. 2D measurements, namely, third ventricle width, lateral ventricle width (LVW), brain width, bicaudate ratio, and corpus callosum index (CCI), were obtained from each scan. Correlations between 2D measurements and 3D measurements, the Expanded Disability Status Scale (EDSS), or processing speed were analysed.ResultsThe third and lateral ventricle widths were well-correlated with the whole-brain volume (p < 0.0001), grey matter volume (p < 0.0001), and EDSS scores (p = 0.0001, p = .0004, respectively).The least squares regression model revealed that 78% of the variation in whole-brain volume could be explained using five explanatory variables, namely, LVW, CCI, age, sex, and disease duration. By contrast, the partial correlation coefficient excluding the effect of age showed that the CCI was significantly correlated with the EDSS and processing speed (p < 0.0001).ConclusionVentricle width correlated well with brain volumes, while the CCI correlated well with age-independent (i.e. disease-induced) disability.

Serum neurofilament light is a sensitive biomarker that reflects grey matter volume in Japanese patients with multiple sclerosis

ObjectiveTo evaluate the degree of neuroaxonal injury in Japanese multiple sclerosis (MS) patients using serum neurofilament light (sNfL) and to investigate the relationship of sNFL with the degree of brain volume. MethodssNfL levels in 82 consecutive Japanese MS patients in remission were cross-sectionally evaluated using a single molecule array assay. Within this sample, cross-sectional volumetric brain MRI data was evaluated in 80 patients, and longitudinal data was evaluated in 63 patients. ResultsMS patients (female/male = 61/21), including those with relapsing-remitting MS (82%), secondary progressive MS (17%), and primary progressive MS (1%), were studied. The mean age of the patients was 41.2 ± 8.7 years, and 77 of the MS patients (94%) were treated with disease-modifying therapy (DMT). Their median sNfL level was 7.985 (IQR, 5.959–10.9), and their sNfL levels were significantly correlated with their grey matter volume and their age. A standard least squares regression model revealed that approximately 57% of the variation in grey matter volume could be explained by a regression equation using three explanatory variables: sNfL concentration, age, and sex. Moreover, the sNfL level multiplied by disease duration was significantly correlated with the Expanded Disability Status Scale (EDSS) scores and whole and grey matter volumes. ConclusionAlthough neuroaxonal injury appeared to be mild in our Japanese MS patients, their sNfL levels significantly reflected grey matter volume. Moreover, when multiplied by the disease duration, sNfL can reflect disability and brain volume.

Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod

BackgroundProgressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod.MethodsWe enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped.ResultsHLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023).ConclusionsHLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

Efficacy of dimethyl fumarate in Japanese multiple sclerosis patients: interim analysis of randomized, double-blind APEX study and its open-label extension.

BackgroundCurrent data for the use of dimethyl fumarate (DMF) in Japanese patients with relapsing–remitting multiple sclerosis (RRMS) is limited.ObjectivesTo assess the efficacy of DMF in Japanese patients with RRMS.MethodsThe phase 3, multinational APEX study (ClinicalTrials.gov identifier: NCT01838668) consisted of two parts: a 24-week double-blind part where subjects were randomized to receive DMF 240 mg or placebo twice daily in East Asian and Eastern European countries, and an open-label extension part where all subjects received DMF. The primary endpoint was the total number of new gadolinium-enhancing lesions in Weeks 12–24. In this interim analysis, we report efficacy data in the Japanese subgroup (DMF n = 56; placebo n = 58) over 72 weeks, including an extension phase.ResultsDMF reduced the total number of new gadolinium-enhancing lesions in Weeks 12–24 by 85% versus placebo (p < 0.0001). At Week 24, the annualized relapse rate was also reduced by 48% with DMF, versus placebo. DMF reduced the probability of relapse from Week 8 and was sustained. The number of gadolinium-enhancing lesions was maintained through 72 weeks.ConclusionsDMF demonstrated sustained efficacy in this Japanese subgroup. The results were consistent with those observed in studies of DMF enrolling primarily Caucasian patients.

Effect of dosage reduction on peripheral blood lymphocyte count in patients with multiple sclerosis receiving long-term fingolimod therapy

Of the 19 cases of fingolimod-associated progressive multifocal leukoencephalopathy (PML) reported worldwide by the end of 2017, 4 cases were from Japan. This may indicate that fingolimod sensitivity is higher in the Japanese population than in the western population because the fingolimod dosage used for the prevention of multiple sclerosis (MS) is the same in both populations. Therefore, the laboratory data of nine patients with MS receiving fingolimod treatment for more than 2 years were retrospectively collected. Moreover, the effect of drug holiday was compared between five patients who underwent at least 3 months of dosage reduction via drug holiday after receiving fingolimod for more than 2 years and three patients who underwent drug holiday after receiving fingolimod for less than 2 years. The total, CD3(+), CD4(+), C19(+) lymphocyte counts, the CD4(+)/CD8(+) cell ratio, and the serum IgG concentrations were similar between Japanese patients with MS receiving fingolimod for more than 2 years and Western patients from the previous reports. Recovery of lymphocyte counts in the peripheral blood after fingolimod dosage reduction was worse in some MS patients who received long-term fingolimod treatment than in MS patients who received short-term fingolimod treatment.My findings indicate that the currently used fingolimod dosage may be too high for some Japanese MS patients receiving long-term fingolimod treatment.

Long‐term, single‐arm, open‐label, multicenter phase 2/4 study of glatiramer acetate by subcutaneous injection in Japanese patients with relapsing–remitting multiple sclerosis

AbstractObjectiveGlatiramer acetate (GA) has been shown to be a well‐tolerated and effective treatment for patients with multiple sclerosis (MS) with relapse. The present open‐label study aimed to evaluate the efficacy and safety of long‐term treatment with GA.MethodsJapanese patients with relapsing–remitting MS received up to 52‐weeks’ treatment with GA 20 mg/mL once daily in the phase 2 study. In phase 4, patients continued to receive treatment after marketing approval in Japan until commercial availability. Key end‐points were safety and tolerability of GA. Other analyses included numbers and volumes of gadolinium‐enhancing and T2‐weighted (T2) lesions.ResultsOf 17 patients initially treated, 13 completed 52 weeks’ therapy and 10 completed the phase 4 extension (efficacy assessment: 104 weeks; maximum treatment period/long‐term safety assessment: up to 5 years). No new safety signals were observed; most adverse events were mild or moderate, with injection site reactions being the most common. The number of T1 gadolinium‐enhancing lesions declined from 2.9 (baseline) to 1.3 (week 104), and the number of T2 lesions increased from 1.7 to 6.7. T1 and T2 lesion volume changes were not clinically meaningful (changes of −0.090 and 0.088 mL, respectively, by week 104). The mean annualized relapse rate was 2.01 (baseline) and 1.78 (week 104); the mean Expanded Disability Status Scale scores indicated reduced levels of disability.ConclusionsThese findings suggest the favorable tolerability and safety profile of GA in Japanese patients, and provide supportive evidence for the efficacy of GA in reducing MS recurrence and improving disability in Japanese MS patients.

Japanese guidelines for dimethyl fumarate

AbstractA multicenter, randomized, double‐blind, placebo‐controlled, efficacy and safety study of BG00012 in participants from the Asia–Pacific region and other countries with relapsing–remitting multiple sclerosis (APEX), including Japan, established the efficacy of dimethyl fumarate (DMF) in preventing relapses and disease progression in patients with multiple sclerosis (MS). Consequently, in December 2016, DMF was approved as the second oral disease‐modifying drug for MS in Japan. However, the new Japanese guidelines for MS and neuromyelitis optica published in 2017 did not include DMF. Later, after the committee discussed a guideline for DMF, a supplement of the new guidelines for MS and neuromyelitis optica, which included DMF, was published in June 2018; this supplement comprised the following four clinical questions: (i) is DMF effective in preventing relapses in patients with MS?; (ii) is DMF effective in preventing disease progression in patients with MS?; (iii) how to use DMF?; and (iv) what adverse events does DMF possibly cause? Furthermore, the supplement comprised answers to the questions and comments. Overall, this supplement is anticipated to contribute toward the treatment of Japanese MS patients with DMF.

Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity.

No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale = 1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-β (n= 6), IFN-β, or azathioprine followed by fingolimod (n= 4), fingolimod (n= 4), and IFN-β followed by natalizumab (n= 1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as ≥ 0.4% per year. Importantly, these nine patients included all patients receiving IFN-β therapy (n= 6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-β did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN-β therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts.

Serum anti-JCV antibody indexes in Japanese patients with multiple sclerosis: elevations along with fingolimod treatment duration.

The risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis (MS) patients is related to serum anti-JCV antibody (JCVAb) index. However, the correlation of JCVAb index with other disease-modifying treatments (DMTs) is not well understood. In this study, we investigated the JCVAb seropositivity rate/JCVAb indexes and its correlation with clinical profiles in Japanese MS patients, and the relationship between JCVAb indexes and DMTs. JCVAb indexes were measured in 149 serum samples from 105 patients with MS. JCVAb indexes and seropositivity, and their correlation with age, sex, disease duration, Kurtzke expanded disability status scale and the duration of the DMTs were evaluated in each patient. JCVAb was positive in 73 of 105 MS patients. Within 40 fingolimod-treated patients, 27 were positive for JCVAb and JCVAb indexes were positively correlated with the duration of fingolimod treatment. No significant relation was found between JCVAb indexes and the duration of treatment for the other disease-modifying drugs. JCVAb seropositivity was comparatively high in Japanese MS patients. Fingolimod treatment is likely to increase serum JCVAb index, possibly leading to the development of PML. Therefore, it is advised that JCVAb index should be serially monitored during fingolimod treatment to decrease PML risk.

Drug‐induced progressive multifocal leukoencephalopathy in multiple sclerosis: A comprehensive review

AbstractProgressive multifocal leukoencephalopathy (PML) is a rare and severe demyelinating disease of the white matter in the central nervous system (CNS), and is caused by the John Cunningham virus. Most PML cases occur in immunocompromised patients, particularly those with impaired cell‐mediated immunity. There is no specific therapy for PML; the main therapeutic approach is restoring host adaptive immune responses. In 2005, PML was described in two multiple sclerosis (MS) patients treated with natalizumab. MS is a chronic inflammatory demyelinating disease of the CNS that has been suggested to be associated with attacks by autoreactive lymphocytes. Disease‐modifying therapies have recently been shown to reduce the frequency and severity of clinical relapse, and slow the development of disability. Although freedom from disease activity has become the primary aim of the treatment of MS, these therapies increase the risk of PML. Natalizumab is a monoclonal immunoglobulin antibody directed toward α4 integrin adhesion molecules. To date, 731 natalizumab‐associated PML cases (728 MS and three Crohn's disease) have been reported, including one case of PML in a Japanese patient with MS. Fingolimod is a sphingosine 1‐phosphate receptor modulator that prevents the egress of lymphocytes from lymphatic tissue. There have been 15 confirmed fingolimod‐associated PML cases, including four cases in Japanese MS patients. Dimethyl fumarate is the methyl ester of fumaric acid. The anti‐inflammatory mechanism of dimethyl fumarate has not yet been elucidated in detail. A total of 21 cases of PML have been reported in patients receiving dimethyl fumarate, among which five were MS patients. Dimethyl fumarate‐associated PML has not been documented in Japan. In the era of disease‐modifying therapies for the treatment of MS, neurologists need to consider drug‐induced PML in MS.

Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity

No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale = 1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-β (n = 6), IFN-β, or azathioprine followed by fingolimod (n = 4), fingolimod (n = 4), and IFN-β followed by natalizumab (n = 1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as ≥ 0.4% per year. Importantly, these nine patients included all patients receiving IFN-β therapy (n = 6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-β did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN-β therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts.

HLA–DRB1*04:05 is associated with intracortical lesions on 3-dimensional double inversion recovery imaging in Japanese patients with multiple sclerosis

Background: The frequently observed cortical lesions (CLs) contribute to disability in Caucasian patients with multiple sclerosis (MS). However, it remains unclear about the frequency of CLs in Japanese MS patients and the association of genetic risk factors such as HLA-DRB1*15:01 and -DRB1*04:05.

HLA-DRB1*04:05 allele is associated with intracortical lesions on three-dimensional double inversion recovery images in Japanese patients with multiple sclerosis

Background: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients. Objective: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients. Methods: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients. Results: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1%, 26.1%, and 28.3% of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs. Conclusion: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.

Whole brain and grey matter volume of Japanese patients with multiple sclerosis

We evaluated the brain volume and rate of atrophy in 85 Japanese patients with multiple sclerosis (MS). The mean brain volume was smaller and the rate of atrophy appeared to be more rapid in MS patients than in normal subjects. The brain atrophy seemed to exist from the early stage of MS and was prominent in the grey matter. Patients with progressive MS showed severer atrophy. We show the existence of pathological brain atrophy in Japanese MS patients for the first time, although the rate of atrophy may be much slower than in Caucasian patients.

Natalizumab for Achieving Relapse-Free, T1 Gadolinium-Enhancing-Lesion-Free, and T2 Lesion-Free Status in Japanese Multiple Sclerosis Patients: A Phase 2 Trial Subanalysis

IntroductionIn a phase 2 trial of natalizumab in Japanese patients with relapsing-remitting multiple sclerosis (RRMS), treatment-related changes in relapses, brain lesions, and disability worsening were found to be comparable with those observed in the phase 3 studies of natalizumab in primarily non-Asian RRMS patients.MethodsThis subanalysis of the placebo-controlled phase 2 trial of natalizumab in Japanese RRMS patients (n = 94) evaluated the effects of natalizumab versus placebo on the proportion of patients who achieved relapse-free, T1 gadolinium-enhancing (Gd+) lesion-free, and new/newly enlarged T2 lesion-free status, defined as “no evidence of inflammatory disease activity” (NEDA)–like status, after 24 weeks of treatment.ResultsIn this subanalysis, significantly more natalizumab-treated than placebo-treated patients achieved NEDA-like status (76.6% vs. 31.9%; P < 0.0001). In addition, the odds ratio (95% confidence interval) for patients on natalizumab to reach NEDA-like status was 6.98 (2.80–17.38) compared with placebo patients.ConclusionThese results confirm previous findings indicating that natalizumab is efficacious in Japanese patients with RRMS.FundingBiogen. Trial Registration: ClinicalTrials.gov identifier, NCT01440101.

Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomized controlled trial and open-label pharmacokinetic study

BackgroundNatalizumab, an anti-α4 integrin monoclonal antibody, has demonstrated efficacy in phase 2 and 3 studies of predominantly Caucasian patients with relapsing-remitting multiple sclerosis (RRMS). ObjectiveTo evaluate the efficacy, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of natalizumab in Japanese RRMS patients. MethodsThis multicenter, phase 2 study included an open-label PK/PD study in 12 patients (part A) and a double-blind, placebo-controlled, randomized (computer-generated sequence) study in 94 patients (part B). For part B, patients received intravenous natalizumab 300mg (n=47) or placebo (n=47) every 4 weeks. The primary efficacy endpoint was the rate of development of new active lesions (gadolinium-enhancing or new/enlarging T2 lesions) over 24 weeks. Clinical relapses and safety were also assessed. ResultsNew active lesions developed at a significantly lower mean rate in natalizumab-treated patients (0.06 lesions/24 weeks) than in placebo-treated patients (0.35 lesions/24 weeks) (p<0.001). The annualized relapse rate was 0.53 for natalizumab and 1.73 for placebo (p<0.001). Twice as many natalizumab-treated patients (79%) as placebo-treated patients (38%) were relapse-free (p<0.001). The safety, PK, and PD profiles of natalizumab in this study were consistent with data in Caucasian RRMS patients. ConclusionsIn Japanese RRMS patients, natalizumab treatment every 4 weeks for 24 weeks was well tolerated and reduced the development of new brain lesions and relapses (Funded by Biogen; ClinicalTrials.gov identifier: NCT01440101).

Humoral response against host-mimetic homologous epitopes of Mycobacterium avium subsp. paratuberculosis in Japanese multiple sclerosis patients.

Several works have demonstrated the existence of a link between Mycobacterium avium subsp. paratuberculosis (MAP) and MS in Italy. In this study, we analyzed the serology of MAP in a Japanese population while looking at several markers of MAP. Fifty MS patients, 12 clinically isolated syndrome (CIS) patients, 30 other neurological disorders (OND) patients, and 50 healthy controls (HCs) were tested using ELISA for the presence of IgG antibodies toward immunodominant epitopes MAP_0106c121-132, homologues MBP85-98, homologues IRF5424-432, MAP_402718-32, and MAP_2694295-303. MAP-positive patients were also analyzed in relation to their clinical/demographic characteristics. Amongst all peptides, only antibodies against MAP_2694295-303 were more prevalent in MS patients (30%), as compared to OND patients (3%) (p = 0.009; area under roc curve (AUC) = 0.61) and HCs (2%) (p = 0.0004; AUC = 0.65) and in CIS patients (25%) compared to HCs (p = 0.023; AUC = 0.55). Logistic regression analysis showed a higher frequency of anti-MAP_2694295-303 antibodies in the sera of oligoclonal bands positive MS patients (p = 0.2; OR = 2, 95%CI: 0.55–7.7). These findings support the view that MAP could act as a risk factor or a triggering agent of MS in some Japanese patients with a genetic susceptibility to the mycobacterium.