研究者業績

鵜沢 顕之

ウザワ アキユキ  (Akiyuki Uzawa)

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

論文

 270
  • 大櫛 萌子, 常山 篤子, 安田 真人, 鵜沢 顕之, 森 雅裕, 桑原 聡, 島 さゆり, 武藤 多津郎
    千葉医学雑誌 96(2) 42-42 2020年4月  
  • 初鹿野 悦子, 狩野 裕樹, 櫻井 透, 仲野 義和, 鵜沢 顕之, 平野 成樹, 桑原 聡, 宇治 百合子
    千葉医学雑誌 96(2) 42-42 2020年4月  
  • Akiyuki Uzawa, Yukiko Ozawa, Manato Yasuda, Fumiko Oda, Yuta Kojima, Naoki Kawaguchi, Tetsuya Kanai, Keiichi Himuro, Satoshi Kuwabara
    Journal of neuroimmunology 339 577125-577125 2020年2月15日  
    Complement-dependent disruption of motor endplate is detected in anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). We measured serum AChR α1 subunit protein levels, which may be associated with neuromuscular damage, in 55 patients with MG (47 were seropositive and 8 were negative) and in 20 controls. Serum AChR α1 subunit protein concentrations were higher in patients with anti-AChR antibody-positive MG than those in controls (P = .04), were negatively correlated with MG activities of daily living score (P = .01), and tended to be higher in ocular MG than in generalized MG. AChR α1 subunit protein elevation may be related to seropositive MG pathogenesis, especially in the ocular type.
  • Jia Liu, Masahiro Mori, Kazuo Sugimoto, Akiyuki Uzawa, Hiroki Masuda, Tomohiko Uchida, Ryohei Ohtani, Satoshi Kuwabara
    Journal of neurology, neurosurgery, and psychiatry 91(2) 132-139 2020年2月  
    OBJECTIVE: To investigate the immunological characteristics and their clinical relevance in anti-myelin oligodendrocyte glycoprotein (MOG)-IgG-associated and anti-aquaporin-4 (AQP4)-IgG-associated disorders (MOGAD and AQPAD) and multiple sclerosis (MS). METHODS: We measured peripheral blood helper T cell subsets (Th1, Th2, Th17 and regulatory T cell (Treg)) in patients with MOGAD (n=26), AQPAD (n=32) and MS (n=28) in the attack and remission phases by flow cytometry with intracellular cytokine staining. We also studied their correlation with clinical parameters. Ten normal subjects served as healthy controls. RESULTS: In all the three disorders, Th17 significantly increased at attack, and downregulated in the remission phases, although still elevated compare with healthy controls. MOGAD and AQPAD patients shared the common T cell profiles, while the extent of Th17 shift was more prominent in AQPAD. Patients with MS showed decreased Th2 than ones with MOGAD and AQPAD at attack. In terms of clinical correlation, MS patients showed that higher Th1 and Th17 proportion was associated with more frequent relapse and more severe clinical disability, whereas in MOGAD, higher Treg was associated with milder clinical severity. In AQPAD, no obvious correlation of Th profiles with clinical manifestation was found. CONCLUSIONS: The present study first investigated intracellular cytokine levels among MOGAD, AQPAD and MS. The different patterns and extent of helper T cell profiles could reflect the pathogenesis of each disorders, and may affect disease severity and activity.
  • Hiroki Masuda, Masahiro Mori, Akiyuki Uzawa, Tomohiko Uchida, Ryohei Ohtani, Satoshi Kuwabara
    PloS one 15(4) e0224419 2020年  
    OBJECTIVE: To investigate the difference of fatigue and pain in patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: Data from the Modified Fatigue Impact Scale (MFIS) and Pain Effects Scale (PES) were compared between 51 NMOSD and 85 MS patients. Each score was compared in each disease group with or without clinical abnormalities. Since almost no MS patients are without brain magnetic resonance imaging abnormalities, volumetry analysis by the Lesion Segmentation Tool and statistical parametric mapping 12 were added to obtain total lesion volume and intracranial volume in MS patients, and the correlations between total lesion volume/intracranial volume and each score were investigated. RESULTS: Compared to the MS group, the NMOSD group showed a higher PES score (median, 15.0 vs. 7.0, P = 0.045), no difference in MFIS, and an increased percentage of patients with extended spinal cord lesions (58.8% vs. 8.2%, P < 0.001). Moreover, NMOSD and MS patients with extended spinal cord lesions tended to demonstrate higher PES scores than those without. A positive correlation between MFIS and PES were found in patients with NMOSD and MS. On the other hand, MS patients showed a higher percentage of brain abnormalities (80.4% vs. 97.6%, P = 0.001) and a positive correlation between total lesion volume/intracranial volume and MFIS (Spearman's ρ = 0.50, P = 0.033). CONCLUSIONS: The origin of fatigue may be associated with spinal cord lesions causing pain in NMOSD patients, but with brain lesions in MS patients.
  • Tomihiro Imai, Shigeaki Suzuki, Yuriko Nagane, Akiyuki Uzawa, Hiroyuki Murai, Kimiaki Utsugisawa
    Frontiers in neurology 11 868-868 2020年  
    Treatment with oral corticosteroids at high doses with an escalation and de-escalation schedule is effective against myasthena gravis (MG). In fact, the use of corticosteroids has led to a reduction in mortality to below 10% after the 1960s. However, long-term use of oral steroids above a certain dosage level is known to cause a number of problems. In 2014, the Japanese clinical guidelines for MG proposed that the first goal in MG treatment (treatment target) should be set at minimal manifestations (MM) with oral prednisolone (PSL) 5 mg/day or below, and that treatment strategies should strive to attain this level as rapidly as possible. In 2015, a multicenter, cross-sectional study revealed that higher PSL dose and longer PSL treatment do not ensure better outcome. In the absence of good response, the PSL dose should be decreased by combining with modalities such as plasma exchange/plasmapheresis and intravenous immunoglobulin (fast-acting treatments). In 2018, we conducted a multicenter, cross-sectional study in a large population of Japanese patients with generalized MG, aiming to elucidate the correlation between oral PSL regimens and achievement of treatment goals. The ORs for low vs. high dose to achieve treatment goals at 1, 2, and 3 years were 10.4, 2.75, and 1.86, respectively, whereas the corresponding ORs for low vs. medium dose were 13.4, 3.99, and 4.92. Early combination with fast-acting therapy (OR 2.19 at 2 years, 2.11 at 3 years) or combination with calcineurin inhibitors (OR 2.09 at 2 years, 2.36 at 3 years) were also positively associated with achieving treatment goals. These results indicate that early combination of low-dose PSL regimens with other therapies is the key for early achievement of treatment goals in generalized MG. However, even with this regimen, ~35% of patients did not achieve the treatment target after 3 years. These results suggest the limitation of the current oral corticosteroid therapy. We need to develop new treatment options to increase the rate of satisfactory outcome.
  • Munenori Oyama, Kensuke Okada, Masayuki Masuda, Yuko Shimizu, Kazumasa Yokoyama, Akiyuki Uzawa, Naoki Kawaguchi, Ryotaro Ikeguchi, Yasunobu Hoshino, Taku Hatano, Yukiko Ozawa, Jin Nakahara, Hitoshi Aizawa, Kazuo Kitagawa, Nobutaka Hattori, Satoshi Kuwabara, Hiroyuki Murai, Shigeaki Suzuki
    Therapeutic advances in neurological disorders 13 1756286420904207-1756286420904207 2020年  査読有り
    Background: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated damage at the neuromuscular junction. Recently, the REGAIN study showed that eculizumab was effective and well tolerated in patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG). However, there is no consensus regarding which kind of patients with gMG are selected to preferentially receive eculizumab. Methods: Between January and December 2018, we followed 1388 patients with MG at seven hospitals located in Tokyo and Chiba. We evaluated the clinical features of MG and the patients' quality of life. Clinical status and severity were determined by the recommendations of the Myasthenia Gravis Foundation of America. Results: Of 1388 patients with MG, 12 (0.9%) patients received eculizumab. A total of 11 patients who were anti-acetylcholine receptor antibody-positive with refractory gMG (M:F = 3:8) completed the 26-week treatment with eculizumab. The disease subtypes represented included five cases of early onset MG, one of late-onset MG, and five of thymoma-associated MG. Overall, seven patients had experienced myasthenic crisis. The mean quantitative MG score ranged from 18.6 at baseline to 9.1 at week 26 (p = 0.008). Similarly, the mean MG activities of daily living score ranged from 10.8 at baseline to 4.2 at week 26 (p = 0.002). There were marked improvements in all patients' quality of life status. Overall, seven patients were able to reduce the dose of prednisolone at week 26. All but one patient did not require additional rescue treatment. Overall, one patient with early onset MG could not continue the eculizumab treatment due to nausea and vertigo. Conclusion: We demonstrate that eculizumab provided remarkable benefits for refractory gMG in practical real-world experience as well as in the REGAIN study. Patients with refractory gMG with myasthenia crisis and thymoma-associated MG are suitable for eculizumab administration.
  • Hiroyuki Murai, Akiyuki Uzawa, Yasushi Suzuki, Tomihiro Imai, Hirokazu Shiraishi, Hidekazu Suzuki, Meinoshin Okumura, Fanny O'Brien, Jing-Jing Wang, Kenji P Fujita, Kimiaki Utsugisawa
    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.
  • Kazuo Sugimoto, Masahiro Mori, Jia Liu, Satoru Tanaka, Kimihiko Kaneko, Satoru Oji, Toshiyuki Takahashi, Akiyuki Uzawa, Tomohiko Uchida, Hiroki Masuda, Ryohei Ohtani, Kyoichi Nomura, Takaki Hiwasa, Satoshi Kuwabara
    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.
  • 小澤 由希子, 鵜沢 顕之, 安田 真人, 織田 史子, 金井 哲也, 氷室 圭一, 川口 直樹, 桑原 聡
    臨床神経学 59(Suppl.) S253-S253 2019年11月  
  • 安田 真人, 鵜沢 顕之, 小澤 由希子, 織田 史子, 金井 哲也, 氷室 圭一, 川口 直樹, 桑原 聡
    臨床神経学 59(Suppl.) S360-S360 2019年11月  
  • 織田 史子, 鵜沢 顕之, 川口 直樹, 小澤 由希子, 安田 真人, 金井 哲也, 氷室 圭一, 桑原 聡
    臨床神経学 59(Suppl.) S361-S361 2019年11月  
  • 小澤 由希子, 鵜沢 顕之, 安田 真人, 織田 史子, 金井 哲也, 氷室 圭一, 川口 直樹, 桑原 聡
    神経治療学 36(6) S273-S273 2019年10月  
  • 織田 史子, 鵜沢 顕之, 小澤 由希子, 安田 真人, 桑原 聡
    神経治療学 36(6) S277-S277 2019年10月  
  • Tetsuya Kanai, Akiyuki Uzawa, Satoshi Kuwabara
    Journal of the neurological sciences 404 157-158 2019年9月15日  査読有り
  • 鵜沢 顕之, 織田 史子, 小澤 由希子, 安田 真人, Maimaitiming Bibinu, 金井 哲也, 川口 直樹, 氷室 圭一, 桑原 聡
    神経免疫学 24(1) 101-101 2019年9月  
  • 織田 史子, 鵜沢 顕之, 小澤 由希子, 安田 真人, 桑原 聡
    神経免疫学 24(1) 112-112 2019年9月  
  • 小澤 由希子, 鵜沢 顕之, 安田 真人, 織田 史子, 川口 直樹, 氷室 圭一, 桑原 聡
    神経免疫学 24(1) 129-129 2019年9月  
  • 安田 真人, 鵜沢 顕之, 小澤 由希子, 織田 史子, 金井 哲也, 氷室 圭一, 川口 直樹, 桑原 聡
    神経免疫学 24(1) 131-131 2019年9月  
  • 小島 雄太, 鵜沢 顕之, 安田 真人, 小澤 由希子, 織田 史子, 桑原 聡
    神経免疫学 24(1) 159-159 2019年9月  
  • Hiroki Masuda, Masahiro Mori, Shigeki Hirano, Kazuho Kojima, Akiyuki Uzawa, Tomohiko Uchida, Ryohei Ohtani, Satoshi Kuwabara
    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.
  • Yukiko Ozawa, Akiyuki Uzawa, Tetsuya Kanai, Fumiko Oda, Manato Yasuda, Naoki Kawaguchi, Keiichi Himuro, Satoshi Kuwabara
    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.
  • Srikanth Muppidi, Kimiaki Utsugisawa, Michael Benatar, Hiroyuki Murai, Richard J. Barohn, Isabel Illa, Saiju Jacob, John Vissing, Ted M. Burns, John T. Kissel, Richard J. Nowak, Henning Andersen, Carlos Casasnovas, Jan L. de Bleecker, Tuan H. Vu, Renato Mantegazza, Fanny L. O'Brien, Jing Jing Wang, Kenji P. Fujita, James F. Howard, Claudio Gabriel Mazia, Miguel Wilken, Fabio Barroso, Juliet Saba, Marcelo Rugiero, Mariela Bettini, Marcelo Chaves, Gonzalo Vidal, Alejandra Dalila Garcia, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, Rudy Mercelis, Délphine Mahieu, Linda Wagemaekers, Philip Van Damme, Annelies Depreitere, Caroline Schotte, Charlotte Smetcoren, Olivier Stevens, Sien Van Daele, Nicolas Vandenbussche, Annelies Vanhee, Sarah Verjans, Jan Vynckier, Ann D'Hondt, Petra Tilkin, Alzira Alves de Siqueira Carvalho, Igor Dias Brockhausen, David Feder, Daniel Ambrosio, Pamela César, Ana Paula Melo, Renata Martins Ribeiro, Rosana Rocha, Bruno Bezerra Rosa, Thabata Veiga, Luiz Augusto da Silva, Murilo Santos Engel, Jordana Gonçalves Geraldo, Maria da Penha Ananias Morita, Erica Nogueira Coelho, Gabriel Paiva, Marina Pozo, Natalia Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Gustavo Duran, Tamires Cristina Gomes da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Tomás Augusto Suriane Fialho, Luciana Renata Cubas Volpe, Luciana Souza Duca, Maurício André Gheller Friedrich, Alexandre Guerreiro, Henrique Mohr, Maurer Pereira Martins, Daiane da Cruz Pacheco, Luciana Ferreira, Ana Paula Macagnan, Graziela Pinto, Aline de Cassia Santos, Acary Souza Bulle Oliveira, Ana Carolina Amaral Andrade, Marcelo Annes, Liene Duarte Silva, Valeria Cavalcante Lino, Wladimir Pinto, Natália Assis, Fernanda Carrara, Carolina Miranda, Iandra Souza, Patricia Fernandes, Zaeem Siddiqi, Cecile Phan, Jeffrey Narayan, Derrick Blackmore, Ashley Mallon, Rikki Roderus, Elizabeth Watt, Stanislav Vohanka, Josef Bednarik, Magda Chmelikova, Marek Cierny, Stanislava Toncrova, Jana Junkerova, Barbora Kurkova, Katarina Reguliova, Olga Zapletalova, Jiri Pitha, Iveta Novakova, Michaela Tyblova, Ivana Jurajdova, Marcela Wolfova, Thomas Harbo, Lotte Vinge, Susanne Krogh, Anita Mogensen, Joan Højgaard, Nanna Witting, Anne Ostergaard Autzen, Jane Pedersen, Juha-Pekka Eralinna, Mikko Laaksonen, Olli Oksaranta, Tuula Harrison, Jaana Eriksson, Csilla Rozsa, Melinda Horvath, Gabor Lovas, Judit Matolcsi, Gyorgyi Szabo, Gedeonne Jakab, Brigitta Szabadosne, Laszlo Vecsei, Livia Dezsi, Edina Varga, Monika Konyane, Giovanni Antonini, Antonella Di Pasquale, Matteo Garibaldi, Stefania Morino, Fernanda Troili, Laura Fionda, Allessandro Filla, Teresa Costabile, Enrico Marano, Francesco Saccà, Angiola Fasanaro, Angela Marsili, Giorgia Puorro, Carlo Antozzi, Silvia Bonanno, Giorgia Camera, Alberta Locatelli, Lorenzo Maggi, Maria Pasanisi, Angela Campanella, Amelia Evoli, Paolo Emilio Alboini, Valentina D'Amato, Raffaele Iorio, Maurizio Inghilleri, Vittorio Frasca, Elena Giacomelli, Maria Gori, Diego Lopergolo, Emanuela Onesti, Maria Gabriele, Akiyuki Uzawa, Tetsuya Kanai, Naoki Kawaguchi, Masahiro Mori, Yoko Kaneko, Akiko Kanzaki, Eri Kobayashi, Katsuhisa Masaki, Dai Matsuse, Takuya Matsushita, Taira Uehara, Misa Shimpo, Maki Jingu, Keiko Kikutake, Yumiko Nakamura, Yoshiko Sano, Yuriko Nagane, Ikuko Kamegamori, Tomoko Tsuda, Yuko Fujii, Kazumi Futono, Yukiko Ozawa, Aya Mizugami, Yuka Saito, Hidekazu Suzuki, Miyuki Morikawa, Makoto Samukawa, Sachiko Kamakura, Eriko Miyawaki, Hirokazu Shiraishi, Teiichiro Mitazaki, Masakatsu Motomura, Akihiro Mukaino, Shunsuke Yoshimura, Shizuka Asada, Seiko Yoshida, Shoko Amamoto, Tomomi Kobashikawa, Megumi Koga, Yasuko Maeda, Kazumi Takada, Mihoko Takada, Masako Tsurumaru, Yumi Yamashita, Yasushi Suzuki, Tetsuya Akiyama, Koichi Narikawa, Ohito Tano, Kenichi Tsukita, Rikako Kurihara, Fumie Meguro, Yusuke Fukuda, Miwako Sato, Meinoshin Okumura, Soichiro Funaka, Tomohiro Kawamura, Masayuki Makamori, Masanori Takahashi, Namie Taichi, Tomoya Hasuike, Eriko Higuchi, Hisako Kobayashi, Kaori Osakada, Tomihiro Imai, Emiko Tsuda, Shun Shimohama, Takashi Hayashi, Shin Hisahara, Jun Kawamata, Takashi Murahara, Masaki Saitoh, Shuichiro Suzuki, Daisuke Yamamoto, Yoko Ishiyama, Naoko Ishiyama, Mayuko Noshiro, Rumi Takeyama, Kaori Uwasa, Ikuko Yasuda, Anneke van der Kooi, Marianne de Visser, Tamar Gibson, Byung-Jo Kim, Chang Nyoung Lee, Yong Seo Koo, Hung Youl Seok, Hoo Nam Kang, HyeJin Ra, Byoung Joon Kim, Eun Bin Cho, MiSong Choi, HyeLim Lee, Ju-Hong Min, Jinmyoung Seok, JiEun Lee, Da Yoon Koh, JuYoung Kwon, SangAe Park, Eun Hwa Choi, Yoon-Ho Hong, So-Hyun Ahn, Dae Lim Koo, Jae-Sung Lim, Chae Won Shin, Ji Ye Hwang, Miri Kim, Seung Min Kim, Ha-Neul Jeong, JinWoo Jung, Yool-hee Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, Miju Shin, Maria Antonia Alberti Aguilo, Christian Homedes-Pedret, Natalia Julia Palacios, Laura Diez Porras, Valentina Velez Santamaria, Ana Lazaro, Exuperio Diez Tejedor, Pilar Gomez Salcedo, Mireya Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez de Rivera, Maria Sastre, Josep Gamez, Pilar Sune, Maria Salvado, Gisela Gili, Gonzalo Mazuela, Elena Cortes Vicente, Jordi Diaz-Manera, Luis Antonio Querol Gutierrez, Ricardo Rojas Garcia, Nuria Vidal, Elisabet Arribas-Ibar, Fredrik Piehl, Albert Hietala, Lena Bjarbo, Ihsan Sengun, Arzu Meherremova, Pinar Ozcelik, Bengu Balkan, Celal Tuga, Muzeyyen Ugur, Sevim Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Nazire Pinar Acar, Ezgi Yilmaz, Yagmur Caliskan, Gulsah Orsel, Husnu Efendi, Seda Aydinlik, Hakan Cavus, Ayse Kutlu, Gulsar Becerikli, Cansu Semiz, Ozlem Tun, Murat Terzi, Baki Dogan, Musa Kazim Onar, Sedat Sen, Tugce Kirbas Cavdar, Adife Veske, Fiona Norwood, Aikaterini Dimitriou, Jakit Gollogly, Mohamed Mahdi-Rogers, Arshira Seddigh, Giannis Sokratous, Gal Maier, Faisal Sohail, Girija Sadalage, Pravin Torane, Claire Brown, Amna Shah, Sivakumar Sathasivam, Heike Arndt, Debbie Davies, Dave Watling, Anthony Amato, Thomas Cochrane, Mohammed Salajegheh, Kristen Roe, Katherine Amato, Shirli Toska, Gil Wolfe, Nicholas Silvestri, Kara Patrick, Karen Zakalik, Jonathan Katz, Robert Miller, Marguerite Engel, Dallas Forshew, Elena Bravver, Benjamin Brooks, Sarah Plevka, Maryanne Burdette, Scott Cunningham, Mohammad Sanjak, Megan Kramer, Joanne Nemeth, Clara Schommer, Scott Tierney, Vern Juel, Jeffrey Guptill, Lisa Hobson-Webb, Janice Massey, Kate Beck, Donna Carnes, John Loor, Amanda Anderson, Robert Pascuzzi, Cynthia Bodkin, John Kincaid, Riley Snook, Sandra Guingrich, Angela Micheels, Vinay Chaudhry, Andrea Corse, Betsy Mosmiller, Andrea Kelley, Doreen Ho, Jayashri Srinivasan, Michal Vytopil, Jordan Jara, Nicholas Ventura, Stephanie Scala, Cynthia Carter, Craig Donahue, Carol Herbert, Elaine Weiner, Sharmeen Alam, Jonathan McKinnon, Laura Haar, Naya McKinnon, Karan Alcon, Kaitlyn McKenna, Nadia Sattar, Kevin Daniels, Dennis Jeffery, Miriam Freimer, Joseph Chad Hoyle, Julie Agriesti, Sharon Chelnick, Louisa Mezache, Colleen Pineda, Filiz Muharrem, Chafic Karam, Julie Khoury, Tessa Marburger, Harpreet Kaur, Diana Dimitrova, James Gilchrist, Brajesh Agrawal, Mona Elsayed, Stephanie Kohlrus, Angela Andoin, Taylor Darnell, Laura Golden, Barbara Lokaitis, Jenna Seelback, Neelam Goyal, Sarada Sakamuri, Yuen T. So, Shirley Paulose, Sabrina Pol, Lesly Welsh, Ratna Bhavaraju-Sanka, Alejandro Tobon Gonzales, Lorraine Dishman, Floyd Jones, Anna Gonzalez, Patricia Padilla, Amy Saklad, Marcela Silva, Sharon Nations, Jaya Trivedi, Steve Hopkins, Mohamed Kazamel, Mohammad Alsharabati, Liang Lu, Kenkichi Nozaki, Sandi Mumfrey-Thomas, Amy Woodall, Tahseen Mozaffar, Tiyonnoh Cash, Namita Goyal, Gulmohor Roy, Veena Mathew, Fatima Maqsood, Brian Minton, H. James Jones, Jeffrey Rosenfeld, Rebekah Garcia, Laura Echevarria, Sonia Garcia, Michael Pulley, Shachie Aranke, Alan Ross Berger, Jaimin Shah, Yasmeen Shabbir, Lisa Smith, Mary Varghese, Laurie Gutmann, Ludwig Gutmann, Nivedita Jerath, Christopher Nance, Andrea Swenson, Heena Olalde, Nicole Kressin, Jeri Sieren, Mazen Dimachkie, Melanie Glenn, April McVey, Mamatha Pasnoor, Jeffery Statland, Yunxia Wang, Tina Liu, Kelley Emmons, Nicole Jenci, Jerry Locheke, Alex Fondaw, Kathryn Johns, Gabrielle Rico, Maureen Walsh, Laura Herbelin, Charlene Hafer-Macko, Justin Kwan, Lindsay Zilliox, Karen Callison, Valerie Young, Beth DiSanzo, Kerry Naunton, Martin Bilsker, Khema Sharma, Anne Cooley, Eliana Reyes, Sara-Claude Michon, Danielle Sheldon, Julie Steele, Manisha Chopra, Rebecca Traub, Lara Katzin, Terry McClain, Brittany Harvey, Adam Hart, Kristin Huynh, Said Beydoun, Amaiak Chilingaryan, Victor Doan, Brian Droker, Hui Gong, Sanaz Karimi, Frank Lin, Krishna Pokala, Akshay Shah, Anh Tran, Salma Akhter, Ali Malekniazi, Rup Tandan, Michael Hehir, Waqar Waheed, Shannon Lucy, Michael Weiss, Jane Distad, Susan Strom, Sharon Downing, Bryan Kim, Tulio Bertorini, Thomas Arnold, Kendrick Hendersen, Rekha Pillai, Ye Liu, Lauren Wheeler, Jasmine Hewlett, Mollie Vanderhook, Daniel Dicapua, Benison Keung, Aditya Kumar, Huned Patwa, Kimberly Robeson, Irene Yang, Joan Nye, Hong Vu, for the Regain Study Group
    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 &lt 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 &lt 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019.
  • Nishida Y, Takahashi YK, Kanai T, Nose Y, Ishibashi S, Sanjo N, Uzawa A, Oda F, Ozawa Y, Kuwabara S, Noguchi E, Suzuki S, Nakahara J, Suzuki N, Ogawa T, Yokoyama K, Hattori N, Konno S, Fujioka T, Kawaguchi N, Hatanaka Y, Sonoo M, Kaneko J, Ogino M, Nishiyama K, Nomura K, Yokota T
    European journal of neurology 2019年7月  査読有り
  • Uzawa A, Kanai T, Oda F, Ozawa Y, Yasuda M, Kawaguchi N, Himuro K, Yoshino I, Kuwabara S
    European journal of neurology 27(1) 175-180 2019年7月  査読有り
  • Akiyuki Uzawa, Satoshi Kuwabara
    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.
  • Akiyuki Uzawa, Junji Yamashita, Satoshi Kuwabara
    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.
  • Kanai T, Uzawa A, Kuwabara S
    Journal of the neurological sciences 399 229 2019年4月  査読有り
  • Aoyama S, Mori M, Uzawa A, Uchida T, Masuda H, Ohtani R, Kuwabara S
    Multiple sclerosis (Houndmills, Basingstoke, England) 26(1) 1352458518808473-129 2018年10月  査読有り
  • Kanai T, Uzawa A, Kawaguchi N, Oda F, Ozawa Y, Himuro K, Kuwabara S
    Journal of the neurological sciences 396 8-11 2018年10月  査読有り
  • Uzawa A, Mori M, Masuda H, Ohtani R, Uchida T, Kuwabara S
    Clinical and experimental immunology 193(1) 47-54 2018年7月  査読有り
  • Uzawa A, Furuya T, Ohtori S, Kuwabara S
    Neurology 91(1) 45-46 2018年7月  査読有り
  • Akiyuki Uzawa, Masahiro Mori, Satoshi Kuwabara
    Journal of Neurology, Neurosurgery and Psychiatry 89(9) 900 2018年6月5日  査読有り
  • Imai T, Utsugisawa K, Murai H, Tsuda E, Nagane Y, Suzuki Y, Minami N, Uzawa A, Kawaguchi N, Masuda M, Konno S, Suzuki H, Akaishi T, Aoki M
    Journal of neurology, neurosurgery, and psychiatry 89(5) 513-517 2018年5月  査読有り
  • Shinji Aoyama, Masahiro Mori, Akiyuki Uzawa, Tomohiko Uchida, Hiroki Masuda, Ryohei Ohtani, Satoshi Kuwabara
    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.
  • Yuko Hayashi, Gen Miura, Akiyuki Uzawa, Takayuki Baba, Shuichi Yamamoto
    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.
  • Kawaguchi N, Nakatani K, Uzawa A, Nemoto Y, Himuro K, Kuwabara S
    Journal of Pharmacovigilance 6(2) 1.00E+06 2018年4月  査読有り
  • Hiroki Masuda, Masahiro Mori, Kenta Umehara, Tomomi Furihata, Tomohiko Uchida, Akiyuki Uzawa, Satoshi Kuwabara
    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.
  • Hiroki Masuda, Masahiro Mori, Akiyuki Uzawa, Tomohiko Uchida, Ryohei Ohtani, Shigeo Kobayashi, Satoshi Kuwabara
    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.
  • Hao Wang, Xiao-Meng Zhang, Go Tomiyoshi, Rika Nakamura, Natsuko Shinmen, Hideyuki Kuroda, Risa Kimura, Seiichiro Mine, Ikuo Kamitsukasa, Takeshi Wada, Akiyo Aotsuka, Yoichi Yoshida, Eiichi Kobayashi, Tomoo Matsutani, Yasuo Iwadate, Kazuo Sugimoto, Masahiro Mori, Akiyuki Uzawa, Mayumi Muto, Satoshi Kuwabara, Minoru Takemoto, Kazuki Kobayashi, Harukiyo Kawamura, Ryoichi Ishibashi, Koutaro Yokote, Mikiko Ohno, Po-Min Chen, Eiichiro Nishi, Koh Ono, Takeshi Kimura, Toshio Machida, Hirotaka Takizawa, Koichi Kashiwado, Hideaki Shimada, Masaaki Ito, Ken-Ichiro Goto, Katsuro Iwase, Hiromi Ashino, Akiko Taira, Emiko Arita, Masaki Takiguchi, Takaki Hiwasa
    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 &lt 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.
  • Ohtani R, Mori M, Uchida T, Uzawa A, Masuda H, Liu J, Kuwabara S
    Multiple sclerosis journal - experimental, translational and clinical 4(1) 2055217318759692 2018年1月  査読有り
  • James F Howard, REGAIN Study Group, Kimiaki Utsugisawa, Michael Benatar, Hiroyuki Murai, Richard J Barohn, Isabel Illa, Saiju Jacob, John Vissing, Ted M Burns, John T Kissel, Srikanth Muppidi, Richard J Nowak, Fanny O'Brien, Jing-Jing Wang, Renato Mantegazza, Claudio Gabriel Mazia, Miguel Wilken, Carolina Ortea, Juliet Saba, Marcelo Rugiero, Mariela Bettini, Gonzalo Vidal, Alejandra Dalila Garcia, Phillipa Lamont, Wai-Kuen Leong, Heidi Boterhoven, Beverly Fyfe, Leslie Roberts, Mahi Jasinarachchi, Natasha Willlems, Julia Wanschitz, Wolfgang Löscher, Jan De Bleecker, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, Rudy Mercelis, Linda Wagemaekers, Delphine Mahieu, Philip Van Damme, Charlotte Smetcoren, Olivier Stevens, Sarah Verjans, Ann D'Hondt, Petra Tilkin, Alzira Alves de Siqueira Carvalho, Rosa Hasan, Igor Dias Brockhausen, David Feder, Daniel Ambrosio, Ana Paula Melo, Rosana Rocha, Bruno Rosa, Thabata Veiga, Luiz Augusto da Silva, Jordana Gonçalves Geraldo, Maria da Penha Morita Ananias, Erica Nogueira Coelho, Gabriel Paiva, Marina Pozo, Natalia Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Erica Coelho, Luciana Renata Cubas Volpe, Gustavo Duran, Tamires Cristina Gomes da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Luciana Souza Duca, Tomás Augusto Suriane Fialho, Maurício André Gheller Friedrich, Alexandre Guerreiro, Henrique Mohr, Maurer Pereira Martins, Daiane da Cruz Pacheco, Ana Paula Macagnan, Aline de Cassia Santos, Acary Souza Bulle Oliveira, Ana Carolina Amaral de Andrade, Marcelo Annes, Valeria Cavalcante Lino, Wladimir Pinto, Carolina Miranda, Fernanda Carrara, Iandra Souza, Angela Genge, Rami Massie, Natasha Campbell, Vera Bril, Hans Katzberg, Mehran Soltani, Eduardo Ng, Zaeem Siddiqi, Celile Phan, Derrick Blackmore, Stanislav Vohanka, Josef Bednarik, Magda Chmelikova, Marek Cierny, Stanislava Toncrova, Jana Junkerova, Barbora Kurkova, Katarina Reguliova, Olga Zapletalova, Jiri Pitha, Iveta Novakova, Michaela Tyblova, Marcela Wolfova, Ivana Jurajdova, Henning Andersen, Thomas Harbo, Lotte Vinge, Anita Mogensen, Joan Højgaard, Nanna Witting, Anne Mette Autzen, Jane Pedersen, Markus Färkkilä, Sari Atula, Anne Nyrhinen, Juha-Pekka Erälinna, Mikko Laaksonen, Olli Oksaranta, Jaana Eriksson, Tuula Harrison, Claude Desnuelle, Sabrina Sacconi, Marie-Hélène Soriani, Sonia Decressac, Julie Moutarde, Pauline Lahaut, Guilhem Solé, Gwendal Le Masson, Anne-Cécile Wielanek-Bachelet, Morgane Gaboreau, Caroline Moreau, Amy Wilson, Christophe Vial, Françoise Bouhour, Helene Gervais-Bernard, Hélène Merle, Caroline Hourquin, Arnaud Lacour, Olivier Outteryck, Patrick Vermersch, Hélène Zephir, Edouard Millois, Michel Deneve, Fabienne Deruelle, Benedikt Schoser, Stephan Wenninger, Martin Stangel, Sascha Alvermann, Stefan Gingele, Thomas Skripuletz, Kurt-Wolfram Suehs, Corinna Trebst, Karin Fricke, Sotirios Papagiannopoulos, Sevasti Bostantzopoulou, Nicholas Vlaikidis, Martha Zampaki, Nikoletta Papadopoulou, Dimos-Dimitrios Mitsikostas, Eleni Kasioti, Efstathia Mitropoulou, Despoina Charalambous, Csilla Rozsa, Melinda Horvath, Gabor Lovas, Judit Matolcsi, Gyorgyi Szabo, Brigitta Szabadosne, Laszlo Vecsei, Livia Dezsi, Edina Varga, Monika Konyane, Bella Gross, Olga Azrilin, Nelly Greenbereg, Hila Bali Kuperman, Giovanni Antonini, Matteo Garibaldi, Stefania Morino, Fernanda Troili, Antonella Di Pasquale, Alessandro Filla, Teresa Costabile, Enrico Marano, Francesco Sacca, Angela Marsil, Giorgia Puorro, Michelangelo Maestri Tassoni, Anna De Rosa, Silvia Bonanno, Carlo Antozzi, Lorenzo Maggi, Angela Campanella, Corrado Angelini, Paola Cudia, Valentina Pegoraro, Elena Pinzan, Francesca Bevilacqua, Daniele Orrico, Domenico Marco Bonifati, Amelia Evoli, Paolo Emilio Alboini, Valentina D'Amato, Raffaele Iorio, Maurizio Inghilleri, Laura Fionda, Vittorio Frasca, Elena Giacomelli, Maria Gori, Diego Lopergolo, Emanuela Onesti, Maria Gabriele, Francesco Patti, Andrea Salvatore Caramma, Silvia Messina, Ester Reggio, Cinzia Caserta, Akiyuki Uzawa, Tetsuya Kanai, Masahiro Mori, Yoko Kaneko, Akiko Kanzaki, Eri Kobayashi, Katsuhisa Masaki, Dai Matsuse, Takuya Matsushita, Taira Uehara, Misa Shimpo, Maki Jingu, Keiko Kikutake, Yumiko Nakamura, Yoshiko Sano, Yuriko Nagane, Ikuko Kamegamori, Yuko Fujii, Kazumi Futono, Tomoko Tsuda, Yuka Saito, Hidekazu Suzuki, Miyuki Morikawa, Makoto Samukawa, Sachiko Kamakura, Hirokazu Shiraishi, Teiichiro Mitazaki, Masakatsu Motomura, Akihiro Mukaino, Shunsuke Yoshimura, Shizuka Asada, Tomomi Kobashikawa, Megumi Koga, Yasuko Maeda, Kazumi Takada, Mihoko Takada Takada, Yumi Yamashita, Seiko Yoshida, Yasushi Suzuki, Tetsuya Akiyama, Koichi Narikawa, Kenichi Tsukita, Fumie Meguro, Yusuke Fukuda, Miwako Sato, Hidenori Matsuo, Takayasu Fukudome, Yuichiro Gondo, Yasuhiro Maeda, Akiko Nagaishi, Shunya Nakane, Yoshinori Okubo, Meinoshin Okumura, Soichiro Funaka, Tomohiro Kawamura, Masayuki Makamori, Masanori Takahashi, Tomoya Hasuike, Eriko Higuchi, Hisako Kobayashi, Kaori Osakada, Namie Taichi, Emiko Tsuda, Takashi Hayashi, Shin Hisahara, Tomihiro Imai, Jun Kawamata, Takashi Murahara, Masaki Saitoh, Shun Shimohama, Shuichiro Suzuki, Daisuke Yamamoto, Shingo Konno, Tomomi Imamura, Masashi Inoue, Mayumi Murata, Hiroshi Nakazora, Ritsu Nakayama, Yasuko Ikeda, Miki Ogawa, Maoko Shirane, Takashi Kanda, Motoharu Kawai, Michiaki Koga, Junichi Ogasawara, Masatoshi Omoto, Yasuteru Sano, Hideki Arima, Sachie Fukui, Shigemi Shimose, Hirokazu Shinozaki, Masanori Watanabe, Chieko Yoshikawa, Anneke van der Kooi, Marianne de Visser, Tamar Gibson, Jos Maessen, Marc de Baets, Catherine Faber, Maria Johanna Keijzers, Monique Miesen, Anna Kostera-Pruszczyk, Anna Kaminska, Byung-Jo Kim, Chang Nyoung Lee, Yong Seo Koo, Hung Youl Seok, Hoo Nam Kang, HyeJin Ra, Byoung Joon Kim, Eun Bin Cho, HyeLim Lee, Ju-Hong Min, Jinmyoung Seok, Da Yoon Koh, JuYoung Kwon, JiEun Lee, SangAe Park, Yoon-Ho Hong, Jae-Sung Lim, MiRi Kim, Seung Min Kim, Yool-hee Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, MiJu Shin, Denis Sazonov, Asya Yarmoschuk, Larisa Babenko, Nadezhda Malkova, Anna Melnikova, Denis Korobko, Evgeniya Kosykh, Dmitry Pokhabov, Yulia Nesterova, Vladislav Abramov, Victor Balyazin, Carlos Casasnovas Pons, Maria Alberti Aguilo, Christian Homedes-Pedret, Natalia Julia Palacios, Ana Lazaro, Exuperio Diez Tejedor, Mireya Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez de Rivera, Maria Salvado Figueras, Josep Gamez, Maria Salvado, Elena Cortes Vicente, Jordi Diaz-Manera, Luis Querol Gutierrez, Ricardo Rojas Garcia, Nuria Vidal, Elisabet Arribas-Ibar, Fredrik Piehl, Albert Hietala, Lena Bjarbo, Christopher Lindberg, Daniel Jons, Blanka Andersson, Ihsan Sengun, Pinar Ozcelik, Celal Tuga, Muzeyyen Ugur, Cavit Boz, Didem Altiparmak, Sibel Gazioglu, Cigdem Ozen Aydin, Sevim Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Ezgi Yilmaz, Nazire Pinar Acar, Yagmur Caliskan, Husnu Efendi, Seda Aydinlik, Hakan Cavus, Cansu Semiz, Ozlem Tun, Murat Terzi, Baki Dogan, Musa Kazim Onar, Sedat Sen, Tugce Kirbas Cavdar, Fiona Norwood, Aikaterini Dimitriou, Jakit Gollogly, Mohamed Mahdi-Rogers, Arshira Seddigh, Gal Maier, Faisal Sohail, Sivakumar Sathasivam, Heike Arndt, Debbie Davies, Dave Watling, Michael Rivner, J. Edward Hartmann, Brandy Quarles, Nicole Smalley, Anthony Amato, Thomas Cochrane, Mohammed Salajegheh, Kristen Roe, Katherine Amato, Shirli Toska, Gil Wolfe, Nicholas Silvestri, Kara Patrick, Karen Zakalik, Jonathan Katz, Robert Miller, Marguerite Engel, Elena Bravver, Benjamin Brooks, Sarah Plevka, Maryanne Burdette, Mohammad Sanjak, Megan Kramer, Joanne Nemeth, Clara Schommer, Vern Juel, Jeffrey Guptill, Lisa Hobson-Webb, Kate Beck, Donna Carnes, John Loor, Amanda Anderson, Dale Lange, Eliz Agopian, Jonathan Goldstein, Erin Manning, Lindsay Kaplan, Shara Holzberg, Nicole Kassebaum, Robert Pascuzzi, Cynthia Bodkin, John Kincaid, Riley Snook, Sandra Guinrich, Angela Micheels, Vinay Chaudhry, Andrea Corse, Betsy Mosmiller, Doreen Ho, Jayashri Srinivasan, Michael Vytopil, Nicholas Ventura, Stephanie Scala, Cynthia Carter, Craig Donahue, Carol Herbert, Elaine Weiner, Jonathan McKinnon, Laura Haar, Naya McKinnon, Karan Alcon, Kevin Daniels, Nadia Sattar, Dennis Jeffery, Kaitlyn McKenna, Amanda Guidon, William David, Christina Dheel, Mark Levine-Weinberg, Catherine Nigro, Ericka Simpson, Stanley H Appel, Eugene Lai, Luis Lay, Milvia Pleitez, Sharon Halton, Casey Faigle, Lisa Thompson, Mark Sivak, Susan Shin, Joan Bratton, Daniel Jacobs, Gavin Brown, Ibrez Bandukwala, Morris Brown, Jennifer Kane, Ira Blount, Miriam Freimer, J. Chad Hoyle, Julie Agriesti, Julie Khoury, Tessa Marburger, Harpreet Kaur, Diana Dimitrova, Michelle Mellion, George Sachs, Brigid Crabtree, Roseann Keo, Ele Kim Perez, Sandra Taber, James Gilchrist, Angela Andoin, Taylor Darnell, Neelam Goyal, Sarada Sakamuri, Yuen T So, Lesly Welsh Welsh, Ratna Bhavaraju-Sanka, Alejandro Tobon Gonzalez, Floyd Jones, Amy Saklad, Sharon Nations, Jaya Trivedi, Steve Hopkins, Mohamed Kazamel, Mohammad Alsharabati, Liang Lu, Sandi Mumfrey-Thomas, Amy Woodall, David Richman, Janelle Butters, Molly Lindsay, Tahseen Mozaffar, Tiyonnoh Cash, Namita Goyal, Gulmohor Roy, Veena Mathew, Fatima Maqsood, Brian Minton, H. James Jones, Jeffrey Rosenfeld, Rebekah Garcia, Sonia Garcia, Laura Echevarria, Michael Pulley, Shachie Aranke, Alan Ross Berger, Jaimin Shah, Yasmeen Shabbir, Lisa Smith, Mary Varghese, Laurie Gutmann, Ludwig Gutmann, Andrea Swenson, Heena Olalde, Charlene Hafer-Macko, Justin Kwan, Lindsay Zilliox, Karen Callison, Beth DiSanzo, Kerry Naunton, Martin Bilsker, Khema Sharma, Eliana Reyes, Anne Cooley, Sara-Claude Michon, Julie Steele, Chafic Karam Karam, Manisha Chopra, Shawn Bird, Jacob Kaufman, Nichole Gallatti, Tuan Vu, Lara Katzin, Terry McClain, Brittany Harvey, Adam Hart, Kristin Huynh, Said Beydoun, Amaiak Chilingaryan, Brian Droker, Frank Lin, Akshay Shah, Anh Tran, Salma Akhter, Ali Malekniazi, Rup Tandan, Michael Hehir, Waqar Waheed, Shannon Lucy, Michael Weiss, Jane Distad, Sharon Downing, Susan Strom, Robert Lisak, Evanthia Bernitsas, Omar Khan, Shitiz Kumar Sriwastava, Alexandros Tselis, Kelly Jia, Tulio Bertorini, Thomas Arnold, Kendrick Henderson, Rekha Pillai, Ye Liu, Lauren Wheeler, Jasmine Hewlett, Mollie Vanderhook, Daniel Dicapua, Benison Keung, Aditya Kumar, Huned Patwa, Kimberly Robeson, Joan Nye, Hong Vu
    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.
  • Tetsuya Kanai, Akiyuki Uzawa, Yasunori Sato, Shigeaki Suzuki, Naoki Kawaguchi, Keiichi Himuro, Fumiko Oda, Yukiko Ozawa, Jin Nakahara, Norihiro Suzuki, Yuko K. Takahashi, Satoru Ishibashi, Takanori Yokota, Takashi Ogawa, Kazumasa Yokoyama, Nobutaka Hattori, Shoko Izaki, Satoru Oji, Kyoichi Nomura, Juntaro Kaneko, Kazutoshi Nishiyama, Ichiro Yoshino, Satoshi Kuwabara
    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&lt;80%, (2) disease duration&lt;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
  • Masahiro Mori, Akiyuki Uzawa, Satoshi Kuwabara
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88(8) 620-620 2017年8月  査読有り
  • Hiroki Masuda, Shigeki Hirano, Nobuyoshi Takahashi, Etsuko Hatsugano, Akiyuki Uzawa, Tomohiko Uchida, Ryohei Ohtani, Satoshi Kuwabara, Masahiro Mori
    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 &lt; 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.
  • Tomohiko Uchida, Masahiro Mori, Akiyuki Uzawa, Hiroki Masuda, Mayumi Muto, Ryohei Ohtani, Satoshi Kuwabara
    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).
  • Kimiaki Utsugisawa, Yuriko Nagane, Tetsuya Akaishi, Yasushi Suzuki, Tomihiro Imai, Emiko Tsuda, Naoya Minami, Akiyuki Uzawa, Naoki Kawaguchi, Masayuki Masuda, Shingo Konno, Hidekazu Suzuki, Hiroyuki Murai, Masashi Aoki
    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 &lt;= 5 mg/day for &gt;= 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 &lt; 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.
  • Akiyuki Uzawa, Masahiro Mori, Hiroki Masuda, Ryohei Ohtani, Tomohiko Uchida, Setsu Sawai, Satoshi Kuwabara
    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.
  • Satoshi Kuwabara, Akiyuki Uzawa, Masahiro Mori
    JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY 88(4) 283-283 2017年4月  査読有り
  • Hiroki Masuda, Masahiro Mori, Tomohiko Uchida, Akiyuki Uzawa, Ryohei Ohtani, Satoshi Kuwabara
    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.

MISC

 254

講演・口頭発表等

 2

共同研究・競争的資金等の研究課題

 9