Hirofumi Ochi

Genetic and infectious profiles influence cerebrospinal fluid IgG abnormality in Japanese multiple sclerosis patients.

Background Abnormal intrathecal synthesis of IgG, reflected by cerebrospinal fluid (CSF) oligoclonal IgG bands (OBs) and increased IgG index, is much less frequently observed in Japanese multiple sclerosis (MS) cohorts compared with Western cohorts. We aimed to clarify whether genetic and common infectious backgrounds influence CSF IgG abnormality in Japanese MS patients. Methodology We analyzed HLA-DRB1 alleles, and IgG antibodies against Chlamydia pneumoniae, Helicobacter pylori, Epstein-Barr virus nuclear antigen (EBNA), and varicella zoster virus (VZV) in 94 patients with MS and 367 unrelated healthy controls (HCs). We defined CSF IgG abnormality as the presence of CSF OBs and/or increased IgG index (>0.658). Principal Findings CSF IgG abnormality was found in 59 of 94 (62.8%) MS patients. CSF IgG abnormality-positive patients had a significantly higher frequency of brain MRI lesions meeting the Barkhof criteria compared with abnormality-negative patients. Compared with HCs, CSF IgG abnormality-positive MS patients showed a significantly higher frequency of DRB1*1501, whereas CSF IgG abnormality-negative patients had a significantly higher frequency of DRB1*0405. CSF IgG abnormality-positive MS patients had a significantly higher frequency of anti-C. pneumoniae IgG antibodies compared with CSF IgG abnormality-negative MS patients, although there was no difference in the frequency of anti-C. pneumoniae IgG antibodies between HCs and total MS patients. Compared with HCs, anti-H. pylori IgG antibodies were detected significantly less frequently in the total MS patients, especially in CSF IgG abnormality-negative MS patients. The frequencies of antibodies against EBNA and VZV did not differ significantly among the groups. Conclusions CSF IgG abnormality is associated with Western MS-like brain MRI features. DRB1*1501 and C. pneumoniae infection confer CSF IgG abnormality, while DRB1*0405 and H. pylori infection are positively and negatively associated with CSF IgG abnormality-negative MS, respectively, suggesting that genetic and environmental factors differentially contribute to MS susceptibility according to the CSF IgG abnormality status.

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 1u2009week 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 (−0.8u2009±u20090.9), second (−0.7u2009±u20090.9), and third (−0.7u2009±u20090.8) courses (pu2009<u20090.05), but not after the fourth (−0.3u2009±u20090.7) and fifth (−0.5u2009±u20090.6). However, decreased EDSS score was only significant after the first course (−0.5u2009±u20091.5, pu2009<u20090.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (pu2009<u20090.05), 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 (pu2009<u20090.05). 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.

Demyelinating diseases in Asia.

PURPOSE OF REVIEWnThe present review aims to discuss the recent advances in inflammatory demyelinating diseases of the central nervous system in Asia.nnnRECENT FINDINGSnPrevalence of multiple sclerosis (MS) in Asia is lower than that in Western countries, although it has been increasing recently. Meanwhile, there seems to be no major difference in neuromyelitis optica (NMO) prevalence in various regions or ethnicities. Thus, the ratios of NMO/NMO spectrum disorder (NMOSD) to MS are higher in Asia as compared with Western countries, indicating that the differential diagnosis between NMO/NMOSD and MS is a major challenge in Asia. Although the detection of aquaporin-4 (AQP4)-antibody is critical in distinguishing NMO/NMOSD from MS, some patients with NMO/NMOSD phenotype are seronegative for AQP4-antibody, and a fraction of those patients possess autoantibody against myelin oligodendrocyte glycoprotein. The clinical profile of Asian MS seems to be essentially similar to that in Western MS after careful exclusion of NMO/NMOSD, although some unique genetic and/or environmental factors may modify the disease in Asians.nnnSUMMARYnMS prevalence has been low but is increasing in Asia. In contrast, NMO/NMOSD prevalence seems relatively constant in the world. Asian MS is not fundamentally different from Western MS, but some genetic and/or environmental differences may cause some features unique to Asian patients.

Structural equation modeling of factors contributing to quality of life in Japanese patients with multiple sclerosis.

BackgroundTo improve quality of life (QOL) in patients with multiple sclerosis (MS), it is important to decrease disability and prevent relapse. The aim of this study was to examine the causal and mutual relationships contributing to QOL in Japanese patients with MS, develop path diagrams, and explore interventions with the potential to improve patient QOL.MethodsData of 163 Japanese MS patients were obtained using the Functional Assessment of MS (FAMS) and Nottingham Adjustment Scale-Japanese version (NAS-J) tests, as well as four additional factors that affect QOL (employment status, change of income, availability of disease information, and communication with medical staff). Data were then used in structural equation modeling to develop path diagrams for factors contributing to QOL.ResultsThe Expanded Disability Status Scale (EDSS) score had a significant effect on the total FAMS score. Although EDSS negatively affected the FAMS symptom score, NAS-J subscale scores of anxiety/depression and acceptance were positively related to the FAMS symptom score. Changes in employment status after MS onset negatively affected all NAS-J scores. Knowledge of disease information improved the total NAS-J score, which in turn improved many FAMS subscale scores. Communication with doctors and nurses directly and positively affected some FAMS subscale scores.ConclusionsDisability and change in employment status decrease patient QOL. However, the present findings suggest that other factors, such as acquiring information on MS and communicating with medical staff, can compensate for the worsening of QOL.

Altered T cell phenotypes associated with clinical relapse of multiple sclerosis patients receiving fingolimod therapy

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease. Fingolimod, a highly effective disease-modifying drug for MS, retains CCR7+ central memory T cells in which autoaggressive T cells putatively exist, in secondary lymphoid organs, although relapse may still occur in some patients. Here, we analyzed the T cell phenotypes of fingolimod-treated, fingolimod-untreated patients, and healthy subjects. The frequency of CD56+ T cells and granzyme B-, perforin-, and Fas ligand-positive T cells significantly increased during fingolimod treatment. Each T cell subpopulation further increased during relapse. Interestingly, T cells from fingolimod-treated patients exhibited interferon-γ biased production, and more myelin basic protein-reactive cells was noted in CD56+ than in CD56− T cells. It is likely that the altered T cell phenotypes play a role in MS relapse in fingolimod-treated patients. Further clinical studies are necessary to investigate whether altered T cell phenotypes are a biomarker for relapse under fingolimod therapy.

Efficacy of methylprednisolone pulse therapy for acute relapse in Japanese patients with multiple sclerosis and neuromyelitis optica: A multicenter retrospective analysis – 1. Whole group analysis

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.

Signaling via toll-like receptor 4 and CD40 in B cells plays a regulatory role in the pathogenesis of multiple sclerosis through interleukin-10 production

BACKGROUNDnB cells play an important role in the development of multiple sclerosis (MS), but can also exhibit regulatory functions through IL-10 production. Toll-like receptors (TLR) and CD40 signaling are likely to be involved in this process.nnnOBJECTIVEnTo investigate the ability of MS B cells to produce IL-10 in response to TLR stimulation in the presence or absence of CD40 co-stimulation.nnnMETHODSnPeripheral blood mononuclear cells obtained from 34 MS patients and 24 matched healthy participants (HS) were stimulated through either TLR4 or TLR9 alone, or together with CD40. Intracellular cytokine production was analyzed by flow cytometry.nnnRESULTSnThe frequency of IL-10-producing cells in total B cells after either TLR9 or CD40 stimulation was significantly lower in MS than HS, regardless of disease phase. The frequency of IL-10 producing B cells after TLR4 stimulation did not differ significantly between HS and MS, regardless of disease phase. TLR4 and CD40 co-stimulation synergistically increased the frequency of IL-10-producing but not pro-inflammatory cytokine-producing B cells at MS relapse. This effect was observed in both CD27- naïve and CD27+ memory B cells. The frequency of IL-10-producing B cells following CD40 stimulation was significantly higher in interferon-β responders than non-treated MS patients. Finally, we confirmed that the frequency of IL-10-producing B cells positively correlated with IL-10 production quantity by B cells using magnetic-isolated B cells.nnnCONCLUSIONSnCross-talk between TLR4 and CD40 signaling plays a crucial role in regulating IL-10 production by B cells during MS relapses, which may promote recovery from relapse. CD40 signaling in B cells is involved in the response to interferon-β in MS. Collectively, TLR4 and CD40 signaling in B cells may provide a promising target for MS therapy.

B‐cell‐targeted therapy in multiple sclerosis

Multiple sclerosis (MS) is a complex immune‐mediated disease of the central nervous system. Traditionally, it has been considered to be mediated primarily by T cells, and the contribution of B cells in the pathogenesis of MS has long been debated. However, clinical trial results of B‐cell depletion therapies have established the central role of B cells in the pathogenesis of MS and their contribution to MS disease activity through antibody‐independent pro‐inflammatory function. One of the monoclonal antibodies targeting the B‐cell surface antigen CD20, ocrelizumab, has shown efficacy in both relapsing–remitting and primary progressive MS in phase III clinical trials, whereas the potential role of B cells in compartmentalized central nervous system inflammation that might underlie tissue injury in progressive MS still continues to be debated. Furthermore, the failure of atacicept, which targets the B‐cell survival factors and a proliferation‐inducing ligand, suggests that B cells potentially have a dual role in the pathogenesis of MS, and the role of B cells in MS is highly complex. In the present review, we discuss the role of B cells in the pathogenesis of MS and review available clinical efficacy data on B‐cell‐targeted therapy in MS.

Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway

We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35–55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

Insights on diagnosis and therapeutic decision-making patterns for multiple sclerosis treatment: cross-sectional opinion survey results from Japanese neurologists

BackgroundThere are few reports about the actual state of diagnosis for multiple sclerosis (MS) in Japan. In addition, in late years multiple disease-modifying drugs (DMDs) were released in Japan, but there are few reports of the actual treatment situation including the choice of DMD as well. Therefore, we conducted a questionnaire survey involving neurologists across Japan to investigate the current practices of diagnosing and determining the treatment strategy for MS.MethodsA case-based survey was conducted among Japanese neurologists currently treating MS patients with DMD to understand the current situation of MS diagnosis and treatment policy determination in Japan. Respondents were divided into tertiles, group 1 (one to three), group 2 (four to nine) and group 3 (≥ ten) by the number of MS patients under management. Results were evaluated as the whole and in each group. Consensus opinion was defined a priori as at least 75% agreement.ResultsEffective responses were obtained from 205 neurologists by web-based survey. 86.3% of the respondents answered that they are able to diagnose MS in accordance with the 2010 revised McDonald criteria for MS. This proportion increased in accordance with the abundance of experience gained treating MS patients (trend test: pxa0<u20090.014). All the respondents answered that magnetic resonance imaging (MRI) was to be used for all suspected clinical relapse regardless of the presence or absence of new signs on any neurological examinations, and even when no neurological exams were performed, suggesting that they value MRI testing as a key criterion for diagnosing MS regardless of treatment experience. While no consensus was achieved on DMD selection to treat naïve patients with different disease activities, most of the respondents answered to choose either IFNβ products or fingolimod. The neurologists with abundant treatment experience (group 3) would change DMD as the disease activity increased, whereas the less experienced groups (group 1 and 2) replied that they would choose the same DMDs regardless of disease activity level.ConclusionsThe present study shed light on diagnosis and treatment decision-making patterns for MS in Japan.