研究者業績
基本情報
- 所属
- 千葉大学 医学部附属病院 脳神経内科
- 学位
- 千葉大学大学院医学薬学府 先端生命科学 博士課程(医学）(2012年3月 千葉大学)
- 研究者番号
- 10533317
- J-GLOBAL ID
- 201801017274232690
- researchmap会員ID
- B000346997
研究分野
1経歴
7-
2021年9月 - 現在
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2012年4月 - 2021年8月
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2008年10月 - 2012年3月
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2007年10月 - 2008年9月
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2006年4月 - 2007年9月
学歴
1-
2008年4月 - 2012年3月
受賞
12-
2024年6月
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2022年11月
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2022年11月
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2022年10月
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2018年5月
論文
253-
Journal of the neurological sciences 407 116419-116419 2019年12月15日The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.
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Journal of neuroimmunology 336 577021-577021 2019年11月15日 査読有りTo illustrate the accuracy of the fluorescence-activated cell sorting cell-based assay (FACS-CBA) and to detect anti-myelin oligodendrocyte glycoprotein (MOG) antibodies and ascertain the optimal method for positivity judgement, referencing the findings of microscopic CBA. We tested serum anti-MOG antibodies in 57 patients with central nervous system inflammatory disorders (CIDs), 30 healthy controls (HCs), and 63 disease controls (DCs) by FACS-CBA. To assess the diagnostic performance of 2 positive judgement methods for FACS-CBA, we evaluated the ratio of positive cells (RPC) and median fluorescence intensity (MFIratio); samples from 57 CIDs and 3 antiaquaporin-4 antibody-positive patients whose anti-MOG antibody levels were relatively high but negative by FACS-CBA were tested by microscopic CBA. Blinded to the RPC and MFIratio results, we classified the acquired dot plot into 3 patterns-"upright," "broadband," and "oblique"-as pattern analysis. The sample with the highest RPC in CIDs was subjected to serial dilution analysis. Finally, we analyzed the clinical and laboratory data of anti-MOG antibody-positive patients in the acute phase. Referencing results by microscopic CBA and receiver-operating characteristic curve analysis, the area under the curve, sensitivity, specificity, and cutoff value were 0.952, 92%, 94%, and 1.52 for RPC and 0.931, 79%, 94%, and 6.39 for MFIratio, respectively, suggesting the optimality of RPC for positive judgement. Titers by microscopic CBA analysis significantly correlated with RPC (P = .031). In the validation study, the positive rate of RPC for anti-MOG antibodies was 42.1% in CIDs, but 0% in HCs and DCs (both P < .001). In the pattern analysis, all anti-MOG antibody-positive patients but none of the HCs and DCs exhibited the "oblique" pattern. Serial dilution curve analysis fit a quaternary polymodal. FACS-CBA using RPC analysis for anti-MOG antibodies displayed relatively higher specificity, sensitivity, and semiquantitative property, indicating it could become another acceptable test to detect anti-MOG antibodies.
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Journal of the neurological sciences 404 157-158 2019年9月15日 査読有り
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Journal of the neurological sciences 403 78-84 2019年8月15日 査読有りLong term effect between disease-modifying drugs (DMDs) treatment duration and brain atrophy rate has not been fully investigated in patients with relapsing-remitting MS (RRMS). The aim of this study was to investigate whether DMDs could slow down the progression of brain atrophy in patients with RRMS by comparing DMDs-treated group with non-treated group during a certain period of time. This was a retrospective investigation. Forty-nine RRMS patients underwent two brain MRI scans more than one year apart. Between scans, patients were treated with fingolimod (n = 16), interferon-beta (n = 23) or not treated with DMD (n = 10). Correlations between clinical characteristics and brain volume were calculated by statistical parametric mapping-12. In all 49 patients, the total attack number before 1st MRI scan and the annualized rate of total lesion volume change between the two scans showed a positive correlation with annualized atrophy rate of grey matter volume (GMV) plus white matter volume (WMV). In patients with DMDs (n = 39), the period from drug initiation to 1st MRI scan was negatively correlated with the annualized atrophy rate of GMV + WMV and number of attacks between scans. The number of total previous attacks could be a predictor of subsequent MS progression. Early intervention by DMDs could prevent brain atrophy in patients with MS.
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Journal of the neurological sciences 402 12-15 2019年7月15日 査読有りHigh-dose intravenous methylprednisolone (IVMP) is often used as a treatment for generalized myasthenia gravis (MG); however, little is reported about the efficacy of IVMP in ocular MG. We evaluated the efficacy and safety of IVMP therapy and compared results with those of conventional oral prednisolone (PSL) treatment in ocular MG. We retrospectively studied 18 patients with ocular MG. Clinical course and safety during 6 months in 10 patients who were treated with IVMP were compared with those of 8 who were treated with PSL. IVMP (1000 mg/day) was administered one to three times within 6 months, whereas oral PSL was administered at the dose of 5-10 mg/day. The score for MG activities of daily living profile (MGADL) was assessed at baseline and at 1, 3, and 6 months after treatment. Patients who received IVMP showed faster improvements than those receiving PSL; the median changes in the ocular scores on the MGADL was -2 versus 0 at 1 month (p = 0.03), -3 versus -1 at 3 months (p = 0.07), and -3 versus -2 (p = 0.86) at 6 months. No patient in either group developed initial worsening of symptoms or generalized weakness. In conclusion, IVMP results in more rapid improvement than oral PSL therapy and can be a treatment option for ocular MG.
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Muscle and Nerve 60(1) 14-24 2019年7月1日Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG REGAIN NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.
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European journal of neurology 2019年7月 査読有り
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European journal of neurology 27(1) 175-180 2019年7月 査読有り
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Brain and nerve = Shinkei kenkyu no shinpo 71(6) 565-570 2019年6月Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction mainly caused by anti-nicotinic acetylcholine receptor (AChR) antibodies. Complements are known to play a prominent role in the pathogenesis of MG. Long-term remission may not necessarily be achieved in MG patients with conventional therapies. Recently, complement inhibitor, the humanized monoclonal anti-C5 antibody eculizumab, complement inhibitor, was approved for patients with anti-AChR antibody-positive generalized refractory MG in Japan. In this review, we focus on the role of complements in the pathogenesis of MG and the action mechanism, efficacy, and future prospects of eculizumab.
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Brain and nerve = Shinkei kenkyu no shinpo 71(5) 525-530 2019年5月Myasthenia gravis (MG) is an inflammatory disorder caused by autoantibodies against the nicotinic acetylcholine receptor (AChR). New therapeutic options for MG are required because the conventional treatments cannot always achieve long-term remission in MG patients. We developed a fusion protein, AChR-Fc, as a novel therapeutic agent for patients with MG. It is composed of the extracellular domain of human AChR-α1 subunit and human IgG1. AChR-Fc exhibited dual activities: it neutralized anti-AChR antibodies and demonstrated an enhanced cytotoxicity against autoantibody-producing B cells. Therefore, AChR-Fc is a novel biomolecule that can be used in the treatment of patients with MG, and potentially overcomes the disorder.
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Journal of the neurological sciences 399 229 2019年4月 査読有り
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Multiple sclerosis (Houndmills, Basingstoke, England) 26(1) 1352458518808473-129 2018年10月 査読有り
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Journal of the neurological sciences 396 8-11 2018年10月 査読有り
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Clinical and experimental immunology 193(1) 47-54 2018年7月 査読有り
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Neurology 91(1) 45-46 2018年7月 査読有り
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Journal of Neurology, Neurosurgery and Psychiatry 89(9) 900 2018年6月5日 査読有り
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Journal of neurology, neurosurgery, and psychiatry 89(5) 513-517 2018年5月 査読有り
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Journal of Neurology 265(5) 1145-1150 2018年5月1日 査読有りBackground: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.
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BMC Neurology 18(1) 52 2018年4月25日 査読有りBackground: To present our findings in a case of convulsive seizures and loss of consciousness that developed during recording electroretinograms (ERG). Case presentation: A 34-year-old man had reduced vision in his left eye for about 15 years, and night blindness for about two years. His visual acuity was 20/15 in the right eye and 20/50 in the left eye. The fundus was normal but the sensitivity in the macular region of the left eye was decreased. Optical coherence tomography (OCT) showed partial loss of the interdigitation zone. Upon completion of the flicker ERG recording, a paralysis developed in both upper limbs, then convulsions of the lower limbs followed by a loss of consciousness. The convulsions disappeared after an intravenous injection of diazepam. After that incident, he reported that he had had previous conscious-loss seizures. Conclusions: Photosensitive epileptic seizures can occur with the light stimuli used for conventional ERG recordings. We recommended that clinicians request information on any prior seizure episodes of the patients and their family members before ERG recordings.
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Journal of Pharmacovigilance 6(2) 1.00E+06 2018年4月 査読有り
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Journal of neuroimmunology 316 117-120 2018年3月15日 査読有りSerum soluble CD40 ligand (sCD40L) has been reported to positively correlate with the albumin quotient, a marker of blood-brain barrier (BBB) breakdown, in patients with multiple sclerosis (MS). To clarify the mechanisms of sCD40L in MS pathophysiology, sCD40L was administered to experimental autoimmune encephalomyelitis (EAE) mice and a human brain microvascular endothelial cell (HBMEC)-based BBB model. The high-dose sCD40L group showed a worse EAE score than the low-dose and control groups. BBB permeability was increased by administering sCD40L in a HBMEC-based BBB model. Thus, sCD40L induces more severe inflammation in the central nervous system by disrupting the BBB.
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Journal of the Neurological Sciences 385 64-68 2018年2月15日 査読有りFatigue and pain are disabling symptoms in patients with neuromyelitis optica spectrum disorder (NMOSD). The Modified Fatigue Impact Scale (MFIS) has not yet been validated in patients with NMOSD, and anti-interleukin-6 (IL-6) receptor antibody was reported to decrease pain and fatigue in patients with NMOSD. The aim of this study was to validate MFIS and to investigate the relationships among fatigue, pain and serum IL-6 levels in patients with NMOSD. MFIS and the Multidimensional Fatigue Inventory (MFI), an established scale for fatigue, were administered to patients with NMOSD and age- and sex-matched healthy controls (HCs). The Pain Effects Scale score and serum IL-6 levels were also measured in patients with NMOSD. Correlations among clinical characteristics, laboratory data and each score were investigated. To validate MFIS in patients with NMOSD, MFIS was administered twice within 4 days from the first administration. Fifty-one patients answered the first MFIS, and 26 patients answered the second MFIS. There was no difference between the first and second MFIS scores. Patients with NMOSD had higher MFIS and MFI scores than HCs. No correlations were observed between serum IL-6 levels and either score. MFIS was validated in patients with NMOSD. Serum IL-6 levels may not be involved in the pathogenesis of fatigue and pain in patients with NMOSD.
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Oncotarget 9(5) 5600-5613 2018年 査読有りTransient ischemic attack (TIA) is a predictor for cerebral infarction (CI), and early diagnosis of TIA is extremely important for the prevention of CI. We set out to identify novel antibody biomarkers for TIA and CI, and detected matrix metalloproteinase 1 (MMP1), chromobox homolog 1 (CBX1), and chromobox homolog 5 (CBX5) as candidate antigens using serological identification of antigens by recombinant cDNA expression cloning (SEREX) and Western blotting to confirm the presence of serum antibodies against the antigens. Amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) revealed that serum antibody levels were significantly higher in patients with TIA or acute-phase CI (aCI) compared with healthy donors (P < 0.01). Spearman's correlation analysis and multivariate logistic regression analysis demonstrated that levels of anti-MMP1, anti-CBX1, and anti-CBX5 antibodies were associated with age, cigarette-smoking habits, and blood pressure. Thus, serum levels of antibodies against MMP1, CBX1, and CBX5 could potentially serve as useful tools for diagnosing TIA and predicting the onset of aCI.
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Multiple sclerosis journal - experimental, translational and clinical 4(1) 2055217318759692 2018年1月 査読有り
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The Lancet Neurology 16(12) 976-986 2017年12月1日 査読有りBackground Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II–IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3 1200 mg at week 4 and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5] rank-based treatment difference −11·7, 95% CI −24·3 to 0·96 p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result further research into the role of complement is needed. Funding Alexion Pharmaceuticals.
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ANNALS OF NEUROLOGY 82(5) 841-849 2017年11月 査読有りObjectiveMyasthenia gravis (MG) is an autoimmune disease mostly caused by autoantibodies against acetylcholine receptor associated with thymus abnormalities. Thymectomy has been proven to be an efficacious treatment for patients with MG, but postoperative myasthenic crisis often occurs and is a major complication. We aimed to develop and validate a simple scoring system based on clinical characteristics in the preoperative status to predict the risk of postoperative myasthenic crisis. MethodsWe studied 393 patients with MG who underwent thymectomy at 6 tertiary centers in Japan (275 patients for derivation and 118 for validation). Clinical characteristics, such as gender, age at onset and operation, body mass index, disease duration, MG subtype, severity, symptoms, preoperative therapy, operative data, and laboratory data, were reviewed retrospectively. A multivariate logistic regression with LASSO penalties was used to determine the factors associated with postoperative myasthenic crisis, and a score was assigned. Finally, the predictive score was evaluated using bootstrapping technique in the derivation and validation groups. ResultsMultivariate logistic regression identified 3 clinical factors for predicting postoperative myasthenic crisis risk: (1) vital capacity<80%, (2) disease duration<3 months, and (3) bulbar symptoms immediately before thymectomy. The postoperative myasthenic crisis predictive score, ranging from 0 to 6 points, had areas under the curve of 0.84 (0.66-0.96) in the derivation group and 0.80 (0.62-0.95) in the validation group. InterpretationA simple scoring system based on 3 preoperative clinical characteristics can predict the possibility of postoperative myasthenic crisis. Ann Neurol 2017;82:841-849
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JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88(8) 620-620 2017年8月 査読有り
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PLOS ONE 12(8) e0184012 2017年8月 査読有りObjective Brain regions responsible for cognitive dysfunction in MS and neuromyelitis optica spectrum disorder (NMOSD) are not known. Our aim of this study was to investigate whether cognitive function and brain volume differed between MS and NMOSD in Japanese patients. Methods Brain MRI and neuropsychological tests including the Wechsler Adult Intelligence Scale-III (WAIS-III), Wechsler Memory Scale-Revised (WMS-R), Trail Making Test (TMT) and Clinical Assessment for Attention (CAT) were performed. Parametric grey matter (GM) and white matter (WM) volumes determined from lesion-filled T1-weighted images using wholebrain voxel-based morphometry (VBM) were compared by two-tailed t test. Results Twenty relapsing-remitting MS and sixteen NMOSD patients were included. MS patients were younger than NMOSD patients. Processing speed intelligence quotient (IQ), general memory, verbal memory and delayed recall were significantly worse in MS patients than in NMOSD patients. Furthermore, left superior temporal gyrus (STG) GM volume was smaller in MS patients than in NMOSD patients (P < 0.05, family-wise error [FWE] corrected, Zmax = 4.97, 62 voxel). The left STG GM volume tended to be positively correlated with delayed recall in MS patients. Conclusions Despite being younger, MS patients demonstrated worse performance in certain cognitive variables than NMOSD patients, which might be associated with left STG GM volume loss.
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MULTIPLE SCLEROSIS JOURNAL 23(8) 1072-1084 2017年7月 査読有りBackground: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood-brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).
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MUSCLE & NERVE 55(6) 794-801 2017年6月 査読有りIntroduction: In this study we sought to clarify the effects of early fast-acting treatment (EFT) strategies on the time course for achieving the treatment target in generalized myasthenia gravis (MG). Methods: This retrospective study of 923 consecutive MG patients analyzed 688 generalized MG patients who had received immunotherapy during the disease course. The time to first achieve minimal manifestations (MM) or better while receiving prednisolone at <= 5 mg/day for >= 6 months (MM-or-better-5mg) up to 120 months after starting immunotherapy was compared between EFT and non-EFT patients. Results: Achievement of MM-or-better-5mg was more frequent and earlier in the EFT group (P = 0.0004, Wilcoxon test; P = 0.0001, log-rank test). Multivariate Cox regression analysis calculated a hazard ratio of 1.98 (P < 0.0001) for utilization of EFT. Dosing regimens of oral steroids in EFT produced no differences in the time course. Conclusions: EFT strategies are advantageous for early achievement of MM-or-better-5mg.
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CLINICA CHIMICA ACTA 469 144-149 2017年6月 査読有りBackground: Elevation of cerebrospinal fluid (CSF) interleukin (IL)-6 has been reported in various neurological disorders but has never been systematically analyzed. Our main objectives are to compare the CSF IL-6 levels among various neurological disorders and to evaluate the significance of CSF IL-6 measurements for the diagnosis of neuromyelitis optica (NMO). Methods: We retrospectively investigated the IL-6 levels of 572 consecutive CSF samples in patients with various neurological disorders. Additionally, the associations between clinical manifestations in NMO patients and CSF IL-6 levels were closely investigated. Results: Among the neurological disorders, patients with NMO had the highest CSF IL-6 level. Receiver operating characteristic analysis found the optimal cutoff CSF IL-6 value for diagnosing NMO as 7.8 pg/ml, and the sensitivity and specificity were 0.7317 and 0.7694, respectively. In NMO, CSF IL-6 levels were correlated with the length of the spinal cord lesion and anti-aquaporin-4 antibody-positivity and decreased after treatment. Conclusion: CSF IL-6 can be high in various inflammatory and non-inflammatory CNS disorders, but its upregulation appears to be the most remarkable in NMO. (C) 2017 Elsevier B.V. All rights reserved.
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JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88(4) 283-283 2017年4月 査読有り
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JOURNAL OF NEUROIMMUNOLOGY 305 102-107 2017年4月 査読有りSoluble CD40 ligand (sCD4OL) is reported to disrupt the blood-brain barrier (BBB). Cerebrospinal fluid (CSF) and serum sCD4OL levels were measured in 29 multiple sclerosis (MS), 29 neuromyelitis optica spectrum disorder (NMOSD), and 27 disease control (DC) patients. In MS, serum sCD4OL levels were higher than in DCs and positively correlated with the CSF/serum albumin ratio (Qalb). In NMOSD, CSF sCD4OL levels were significantly increased compared to DCs, and were correlated to Qalb, CSF cell counts, protein concentrations, and interleukin-6 levels. sCD4OL could be involved in BBB disruption in MS, whereas it may contribute to CNS inflammation in NMOSD. (C) 2017 Elsevier B.V. All rights reserved.
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JOURNAL OF NEUROIMMUNOLOGY 305 131-134 2017年4月 査読有りPreviously, we identified anti-Talin-1 antibodies in the serum of MS. In this case, we measured the serum soluble Talin-1 (sTalin-1) levels by enzyme-linked immunosorbent assay. The serum sTalin-1 levels were significantly higher in 40 patients with MS than in 43 normal controls and in the acute phase of disease than in the remission phase. Interestingly, serum sTalin-1 levels were associated with a sustained increase in disability after MS attack but not with serum anti-Talin-1 antibody levels. sTalin-1 may be a biomarker for the acute phase of MS and may be used for the short-term prognosis of MS. (C) 2017 Elsevier B.V. All rights reserved.
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EUROPEAN JOURNAL OF NEUROLOGY 24(2) 270-275 2017年2月 査読有りBackground and purposeA single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti-acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment. MethodsThe trough tacrolimus concentration in 51 patients with MG (positive for anti-AChR antibody, n = 48; negative for anti-AChR and anti-muscle-specific tyrosine kinase antibodies, n = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively. ResultsThe median trough tacrolimus concentration was 5.4 (range, 2.9-7.6) ng/mL, which was correlated with minimal manifestation or better status' (P = 0.0190, r = 0.3273) and the reduction in anti-AChR antibody 1 year after tacrolimus initiation (P = 0.0170, r = 0.3465). When the cut-off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (4.8 ng/mL) showed more reduction in anti-AChR antibody titers and more improvement in MG-related activities in daily life scores. More patients with adequate tacrolimus concentration achieved minimal manifestation or better status' compared with those with low tacrolimus concentration. ConclusionsAn adequate tacrolimus concentration is required for better MG prognosis.
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BMJ OPEN 7(2) e013278 2017年2月 査読有りObjectives: To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. Design: Cross-sectional study. Setting and participants: We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. Outcome measures: All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose >= 20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at <= 5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. Results: We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was >= 50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. Conclusions: Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.
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NEUROTHERAPEUTICS 14(1) 191-198 2017年1月 査読有りMost patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AChR-Fc can be a novel therapeutic biomolecule for patients with MG.
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Clinical and Experimental Neuroimmunology 7(4) 357-360 2016年11月1日 査読有りObjective: Damage-associated molecular patterns (DAMP) and cytokines can play a crucial role in inflammation at neuromuscular junctions in myasthenia gravis (MG). However, the relationship between DAMP and cytokine levels in MG pathogenesis remains unknown. To clarify this, we examined the relationship between serum levels of DAMP and cytokines in MG patients. Methods: Using serum data from 26 patients with anti-acetylcholine receptor antibody-positive MG, we investigated the relationship between the levels of DAMP (high-mobility group box 1 [HMGB1] and peroxiredoxin 5) and cytokines (interleukin [IL]-4, IL-15, IL-19, IL-20, IL-28A, IL-35, a proliferation-inducing ligand [APRIL] and vascular endothelial growth factor), which were reported to be significantly elevated in MG. Results: Serum levels of APRIL (r = 0.4789, P = 0.0133), IL-19 (r = 0.5496, P = 0.0036) and IL-35 (r = 0.5396, P = 0.0044) were correlated with those of HMGB1, but no cytokine levels were correlated with peroxiredoxin 5 levels. When we carried out multivariate analyses, only APRIL (P = 0.0244) and IL-19 (P = 0.0009) levels were correlated with HMGB1 levels. Conclusions: HMGB1 might be related with upregulation of IL-19 and APRIL levels in MG immunopathogenesis. These molecules could play a key role in controlling autoimmune inflammatory response, and represent a potent therapeutic target in MG.
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BMC NEUROLOGY 16(1) 225 2016年11月 査読有りBackground: We have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment. Methods: A total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti-muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared. Results: As a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status. Conclusions: Differences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.
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Seronegative neuromyelitis optica spectrum disorder patients diagnosed using new diagnostic criteriaMULTIPLE SCLEROSIS JOURNAL 22(10) 1371-1375 2016年9月 査読有りBackground: Recently, new diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) were published. Objective: Our primary aim was to evaluate the usefulness of the new diagnostic criteria in anti-aquaporin 4 (AQP4) antibody-negative cases. Methods: Consecutive 471 patients whose anti-AQP4 antibody was measured at Chiba University were reviewed. Results: Four anti-AQP4 antibody negative-patients, who fulfilled the new diagnostic criteria for NMOSD but not 2006 diagnostic criteria for neuromyelitis optica (NMO), were identified. They showed high cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels, an absence of oligoclonal bands and/or cloud-like enhancement on magnetic resonance imaging, which are compatible findings for NMO. Conclusion: The new diagnostic criteria are clinically useful in seronegative NMOSD.
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Recovery from optic neuritis attack in neuromyelitis optica spectrum disorder and multiple sclerosisJOURNAL OF THE NEUROLOGICAL SCIENCES 367 375-379 2016年8月 査読有りBackground: Both neuromyelitis optica spectrum disorder (NMOsd) and multiple sclerosis (MS) patients experience optic neuritis (ON) attacks characterized by rapidly reduced best-correct visual acuity (BCVA) and slow recovery. Prognosis and effects of recurrence on recovery may differ between disorders but remain unclear. Objective: To compare ON severity, time and degree of recovery and effects of previous ON between NMOsd and MS patients. Methods: Retrospective chart review was performed. BCVA measurements acquired before ON, at nadir and during recovery were retrospectively reviewed. Records were obtained on 69 ON attacks in 36 NMOsd patients and 43 attacks in 28 MS patients, including first episodes and recurrences. Results: NMOsd patients exhibited significantly lower BCVA values at all time points after attack (P <0.05), reached nadir earlier (P = 0.014) and regained a smaller fraction of baseline BCVA than MS patients (P < 0.001). In NMOsd, relapsed ON resulted in worse recovery and tended to reach nadir earlier than first-episode ON (P = 0.030 and 0.059, respectively). In MS, relapsed ON also reached nadir earlier (P = 0.042); however, there was no difference in recovery. Conclusions: Recovery from ON was poorer in NMOsd than in MS and was negatively affected by previous ON attacks. (C) 2016 Elsevier B.V. All rights reserved.
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SCIENTIFIC REPORTS 6 25886 2016年5月 査読有りMyasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation- inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late- onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.
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JOURNAL OF THE NEUROLOGICAL SCIENCES 363 116-118 2016年4月 査読有りBackground: Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients. Methods: We included 58 MG patients with anti-acetylcholine receptor antibody (AChR + MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK + MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR + MG was classified into the three subgroups: early-onset MG (EOMG; n = 11), late-onset MG (LOMG; n = 20), and thymoma-associated MG (n = 27). Healthy volunteers (n = 100) served as controls. Results: A significant positive association was observed between MuSK + MG with the DRB1*14 [57.1%, MuSK + MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK + MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles. Conclusion: HLA-DRB1*14 and DQB1*05 were associated with MuSK + MG, therefore these alleles may play important roles in developing MuSK + MG across the races. (C) 2016 Elsevier B.V. All rights reserved.
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Clinical and Experimental Neuroimmunology 7(1) 52-58 2016年2月1日 査読有り© 2015 Japanese Society for Neuroimmunology. Objective It is well-known that bladder dysfunction is common in patients with multiple sclerosis (MS). Voiding dysfunction is remarkable in neuromyelitis optica (NMO). However, the difference in the urinary symptoms between MS and NMO remain unknown. We planned to elucidate the differences between the two conditions using a urinary symptoms questionnaire. Methods We recruited 34 patients with MS and 14 patients with NMO, who were examined at the Department of Neurology, Chiba University Hospital. We administered the following urinary symptom questionnaires: (i) Overactive Bladder Symptom Score (OABSS); and (b) International Prostate Symptom Score (IPSS). Neurological (Evaluation of the Expanded Disability Status Scale) and neuroradiological examinations were also carried out. Results The mean score of OABSS and IPSS tended to be higher in patients with NMO without statistical significance. The score of IPSS quality of life was significantly higher in patients with NMO. A positive correlation was found between the Evaluation of the Expanded Disability Status Scale and IPSS scores in patients with MS, whereas a negative correlation was found between the Evaluation of the Expanded Disability Status Scale and IPSS scores in patients with NMO. Multiple linear regression analysis showed that the presence of a cervical spinal cord lesion and the central lesion involving gray matter was associated with the severity of urinary symptoms. Conclusions The urinary symptoms tended to be more severe in patients with NMO as compared with patients with MS. The urinary symptoms and neurological disabilities seemed to be differentially correlated between patients with MS and those with NMO. The urinary symptoms and neurological disabilities seemed to be differentially correlated between patients with MS and those with NMO. Cervical spinal cord lesions and the central lesion involving gray matter are responsible for the urinary symptoms in patients with MS and NMO.
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EUROPEAN JOURNAL OF NEUROLOGY 23(2) 276-281 2016年2月 査読有りBackground and purposeAntinuclear antibody-positive multiple sclerosis (MS) patients have shorter disease duration and lower Expanded Disability Status Scale (EDSS) scores. The aim of this study was to compare clinical and laboratory features between MS and neuromyelitis optica (NMO) patients with and without autoantibodies and to investigate the prognosis of NMO in patients with and without autoantibodies. MethodsThe frequencies of antinuclear, anti-Sjogren's syndrome A (SSA)/Ro, anti-Sjogren's syndrome B (SSB)/La and anti-thyroid peroxidase (TPO) antibodies in the sera of 75 NMO patients and 131 MS patients were compared. Clinical and laboratory profiles were also compared between NMO patients with and without autoantibodies, including annual relapse rate and time from onset of NMO to EDSS scores of 4.0 (limited walking but without aid) and 6.0 (walking with unilateral aid). ResultsMore NMO than MS patients had antinuclear and anti-SSA/Ro antibodies (31% vs. 10%, P<0.001, and 21% vs. 3%, P<0.001, respectively). Antinuclear antibody-positive NMO patients had a lower annual relapse rate from disease onset to serum sampling compared with antinuclear antibody-negative NMO patients, independent of treatment regimen. Antinuclear antibody-negative NMO patients reached an EDSS score of 6.0 earlier than antinuclear antibody-positive NMO patients (P=0.026). Cerebrospinal fluid cell counts were higher in anti-SSA/Ro-positive than in anti-SSA/Ro-negative NMO patients. More anti-TPO antibody-positive than anti-TPO antibody-negative NMO patients had oligoclonal immunoglobulin G bands (60% vs. 11%, P=0.048). ConclusionsAutoantibodies possibly modulate the pathophysiology of NMO. Antinuclear antibody may be associated with less severe disease activity or less disability in NMO. Click to view the accompanying paper in this issue.
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CLINICA CHIMICA ACTA 453 131-133 2016年1月 査読有りBackground: Complement activation is important in multiple sclerosis (MS) and is essential for anti-aquaporin 4 antibodies to damage the central nervous system in neuromyelitis optica (NMO). Little is known about the role of cerebrospinal fluid (CSF) regulators of complement activation in NMO and MS. We determined whether CSF CD59, which is a complement regulator and C5b-9 formation inhibitor, is involved in the pathogenesis of NMO and MS. Methods: We analyzed CSF levels of CD59 in 30 patients with NMO, 22 patients with MS, and 24 patients with non-inflammatory neurological disorders (NINDs). Possible correlations between CSF CD59 levels and the clinical and laboratory variables in patients with NMO and MS were also reviewed. Results: CSF CD59 levels in patients with NMO and MS were higher than those in patients with NINDs (p < 0.001), and those in patients with NMO decreased after treatment. No significant correlations were found between CSF CD59 levels and clinical and laboratory parameters in NMO and MS. Conclusion: High CSF CD59 levels in NMO and MS may reflect inflammation, damage, and/or complement activation in the central nervous system. (C) 2015 Elsevier B.V. All rights reserved.
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INTERNAL MEDICINE 55(12) 1645-1647 2016年 査読有りProgressive multifocal leukoencephalopathy (PML) is a demyelinating disease that favors the cerebrum and typically occurs in immunosuppressed patients. We herein report the case of a 66-year-old man with PML, idiopathic CD4(+) T lymphocytopenia (ICL), and chronic renal failure. Cranial magnetic resonance imaging (MRI) showed a crescent-shaped lesion in the left cerebellum, brainstem, and middle cerebellar peduncle. Although the patient did not present with HIV infection, collagen diseases, or tumors, JC virus DNA was detected in the cerebrospinal fluid. Clinicians should consider PML and ICL in the differential diagnosis if the patient develops progressive ataxia and a crescent-shaped cerebellar lesion on MRI.
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臨床神経学 55(Suppl.) S288-S288 2015年12月
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clinical and experimental neuroimmunology 6(s1) 70-77 2015年12月
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Clinical & Experimental Neuroimmunology 6(4) 409-412 2015年11月 査読有り
MISC
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神経免疫疾患のエビデンスに基づく診断基準・重症度分類・ガイドラインの妥当性と患者QOLの検証 令和4年度 総括・分担研究報告書(Web) 2023年
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神経免疫疾患のエビデンスに基づく診断基準・重症度分類・ガイドラインの妥当性と患者QOLの検証 令和4年度 総括・分担研究報告書(Web) 2023年
講演・口頭発表等
2共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2022年4月 - 2025年3月
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日本学術振興会 科学研究費助成事業 挑戦的研究(萌芽) 2021年7月 - 2023年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2019年4月 - 2022年3月
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日本学術振興会 科学研究費助成事業 基盤研究(C) 2018年4月 - 2021年3月
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日本学術振興会 科学研究費助成事業 若手研究(B) 2017年4月 - 2019年3月