Attempt to elucidate the pathological mechanisms of myasthenic crisis

• Project/Area Number: 17K09780
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: International University of Health and Welfare
• Principal Investigator: Murai Hiroyuki 国際医療福祉大学, 医学部, 主任教授 (80325464)
• Co-Investigator(Kenkyū-buntansha): 槍澤 公明 公益財団法人総合花巻病院(臨床研究部), 脳神経内科, 脳神経内科部長 (00244913) ; 松下 拓也 九州大学, 大学病院, 講師 (00533001) ; 今井 富裕 札幌医科大学, 保健医療学部, 名誉教授 (40231162) ; 本村 政勝 長崎総合科学大学, 工学研究科, 教授 (70244093)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 重症筋無力症 / クリーゼ / 臨床疫学 / リスクファクター / メッセンジャーRNA

Outline of Final Research Achievements

The object of this study was to grasp the whole picture of myasthenic crisis and to elucidate the possible mechanisms of it. The first step was the clinico-epidemiological analyses. We analyzed the relationship between crisis and various clinical parameters. We divided generalized MG patients into two groups; with or without crisis. Positivity rate of AChR and MuSK antibodies were higher in crisis group. Early fast-acting treatment (EFT) was performed less frequently in crisis group. This may indicate that EFT contributes in reducing the crisis rate. Secondly, we identify the risk factors of myasthenic crisis applying the statistical procedure. A total of 10 articles were reviewed and meta-analyses identified several risk factors: bulbar symptoms, history of crisis, disease severity, and decreased vital capacity.

Academic Significance and Societal Importance of the Research Achievements

重症筋無力症のクリーゼの病態を解明することは神経筋組織に対する自己免疫疾患である重症筋無力症の重症化を予知することに繋がる。また、クリーゼに陥らないようにすることにより、患者の社会的生産性の低下を防止することも可能となる。

Research Products

• [Journal Article] Patient-reported burden of myasthenia gravis: baseline results of the international prospective, observational, longitudinal real-world digital study MyRealWorld-MG. (2023)
  • Author(s): Dewilde S, Philips G, Paci S, Beauchamp J, Chiroli S, Quinn C, Day L, Larkin M, Palace J, Berrih-Aknin S, Claeys KG, Muppidi S, Mantegazza R, Sacca F, Meisel A, Bassez G, Murai H, Janssen M.
  • Journal Title: BMJ Open Volume: 13 Issue: 1 Pages: e066445-e066445
  • DOI: 10.1136/bmjopen-2022-066445
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advances and ongoing research in the treatment of autoimmune neuromuscular junction disorders (2022)
  • Author(s): Verschuuren J, Palace J, Murai H, Tannemaat M, Kaminski H, Bril V
  • Journal Title: Lancet Neurol Volume: 21 Issue: 2 Pages: 189-202
  • DOI: 10.1016/s1474-4422(21)00463-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: Analysis of 1-year postmarketing surveillance. (2022)
  • Author(s): Murai H, Suzuki S, Fukamizu Y, Osawa T, Kikui H, Utsugisawa K:
  • Journal Title: Clin Exp Neuroimmunol Volume: 13 Issue: 4 Pages: 280-289
  • DOI: 10.1111/cen3.12716
  • Peer Reviewed / Open Access
• [Journal Article] Two-step nationwide epidemiological survey of myasthenia gravis in Japan 2018 (2022)
  • Author(s): Yoshikawa Hiroaki、Adachi Yumi、Nakamura Yosikazu、Kuriyama Nagato、Murai Hiroyuki、Nomura Yoshiko、Sakai Yasunari、Iwasa Kazuo、Furukawa Yutaka、Kuwabara Satoshi、Matsui Makoto
  • Journal Title: PLOS ONE Volume: 17 Issue: 9 Pages: e0274161-e0274161
  • DOI: 10.1371/journal.pone.0274161
  • Peer Reviewed / Open Access
• [Journal Article] Immunotherapy for ocular myasthenia gravis: an observational study in Japan (2022)
  • Author(s): Narita Tomoko; Nakane Shunya, Nagaishi Akiko, Minami Naoya, Niino Masaaki, Kawaguchi Naoki, Murai Hiroyuki, Kira Jun-Ichi, Shimizu Jun, Iwasa Kazuo, Yoshikawa Hiroaki, Hatanaka Yuki, Sonoo Masahiro, Shimizu Yuko, Matsuo Hidenori
  • Journal Title: Therapeutic advances in neurological disorders Volume: 16 Pages: 1-12
  • DOI: 10.1177/17562864231163819
  • Peer Reviewed / Open Access
• [Journal Article] Safety and effectiveness of eculizumab in Japanese patients with generalized myasthenia gravis: Interim analysis of post-marketing surveillance (2021)
  • Author(s): Murai H, Suzuki S, Hasebe M, Fukamizu Y, Rodrigues E, Utsugisawa K
  • Journal Title: Ther Adv Neurol Disord Volume: 14
  • DOI: 10.1177/17562864211001995
  • Peer Reviewed / Open Access
• [Journal Article] Zilucoplan: an investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody- positive generalized myasthenia gravis (2021)
  • Author(s): Howard JF, Vissing J, Gilhus NE, Leite MI, Utsugisawa K, Duda PW, Farzaneh-Far R, Murai H, Wiendl H
  • Journal Title: Expert Opin Investig Drugs Volume: 30 Issue: 5 Pages: 483-493
  • DOI: 10.1080/13543784.2021.1897567
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficacy, Safety, and Tolerability of Efgartigimod in Patients with Generalized Myasthenia Gravis (gMG): Analysis of the Randomized Phase 3 ADAPT Study (2021)
  • Author(s): Howard JF, Bril V, Vu T, Karam C, Peric S, Margania T, Murai H, Bilinska M, Shakarishvili R, Smilowski M, Guglietta A, Ulrichts P, Vangeneugden T, Utsugisawa K, Verschuuren J, Mantegazza R, ADAPT Investigator Study Group
  • Journal Title: Lancet Neurol Volume: 20 Issue: 7 Pages: 526-536
  • DOI: 10.1016/s1474-4422(21)00159-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The patient-reported impact of myasthenia gravis in the real world: protocol for a digital observational study (MyRealWorld MG) (2021)
  • Author(s): Berrih-Aknin S, Claeys KG, Law N, Mantegazza R, Murai H, Sacca F, Dewilde S, Janssen MF, Bagshaw E, Kousoulakou H, Larkin M, Beauchamp J, Leighton T, Paci S
  • Journal Title: BMJ Open Volume: 11 Issue: 7 Pages: e048198-e048198
  • DOI: 10.1136/bmjopen-2020-048198
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update (2021)
  • Author(s): Narayanaswami P, Sanders DB, Wolfe GI, Benatar M, Cea G, Evoli A, Gilhus NE, Illa I, Kuntz N, Massey JM, Melms A, Murai H, Nicolle M, Palace J, Richman DP, Verschuuren J
  • Journal Title: Neurology Volume: 96 Issue: 3 Pages: 114-122
  • DOI: 10.1212/wnl.0000000000011124
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Response to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study (2020)
  • Author(s): Jacob S, Murai H, Utsugisawa K, Nowak RJ, Wiendl H, Fujita KP, O’Brien F, Howard JF
  • Journal Title: Ther Adv Neurol Disord Volume: 13 Pages: 1-8
  • DOI: 10.1177/1756286420911784
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis (2020)
  • Author(s): Oyama M, Okada K, Masuda M, Shimizu Y, Yokoyama K, Uzawa A, Kawaguchi N, Ikeguchi R, Hoshino Y, Hatano T, Ozawa Y, Nakahara J, Aizawa H, Kitagawa K, Hattori N, Kuwabara S, Murai H, Suzuki S
  • Journal Title: Therapeutic Advances in Neurological Disorders Volume: 13 Pages: 1-9
  • DOI: 10.1177/1756286420904207
  • Peer Reviewed / Open Access
• [Journal Article] Long-term safety and efficacy of eculizumab in generalized myasthenia gravis. (2019)
  • Author(s): Muppidi S, Utsugisawa K, Benatar M, Murai H, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Nowak RJ, Andersen H, Casasnovas C, de Bleecker JL, Vu TH, Mantegazza R, O'Brien FL, Wang JJ, Fujita KP, Howard JF Jr; Regain
  • Journal Title: Muscle Nerve. Volume: - Issue: 1 Pages: 14-24
  • DOI: 10.1002/mus.26447
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study (2019)
  • Author(s): Murai H, Uzawa A, Suzuki Y, Imai T, Shiraishi H, Suzuki H, Okumura M, O’Brien F, Wang JJ, Fujita KP, Utsugisawa K
  • Journal Title: Journal of the Neurological Sciences Volume: 407 Pages: 116419-116419
  • DOI: 10.1016/j.jns.2019.08.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical burden and healthcare resource utilization associated with myasthenia gravis: assessments from a Japanese claims database (2019)
  • Author(s): Murai H, Hasebe M, Murata A, Utsugisawa K
  • Journal Title: Clin Exp Neuroimmunol Volume: 10 Issue: 1 Pages: 61-68
  • DOI: 10.1111/cen3.12495
  • Peer Reviewed / Open Access
• [Journal Article] Rationale for the clinical guidelines for myasthenia gravis in Japan (2018)
  • Author(s): Murai H, Utsugisawa K, Nagane Y, Suzuki S, Imai T, Motomura M
  • Journal Title: Annals of the New York Academy of Sciences Volume: 1413 Issue: 1 Pages: 35-40
  • DOI: 10.1111/nyas.13544
  • Peer Reviewed / Open Access
• [Journal Article] Oral corticosteroid dosing regimen and long-term prognosis in generalised myasthenia gravis: a multicentre cross-sectional study in Japan (2018)
  • Author(s): Imai Tomihiro、Utsugisawa Kimiaki、Murai Hiroyuki、Tsuda Emiko、Nagane Yuriko、Suzuki Yasushi、Minami Naoya、Uzawa Akiyuki、Kawaguchi Naoki、Masuda Masayuki、Konno Shingo、Suzuki Hidekazu、Akaishi Tetsuya、Aoki Masashi
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: in press Issue: 5 Pages: 513-517
  • DOI: 10.1136/jnnp-2017-316625
  • Peer Reviewed / Open Access
• [Presentation] Long-Term Safety, Tolerability, and Efficacy of Efgartigimod in Patients With Generalized Myasthenia Gravis: Interim Results of the ADAPT+ Study. (2022)
  • Author(s): Howard JF, Bril V, Vu T, Karam C, Peric S, De Bleecker JL, Murai H, Meisel A, Beydoun S, Pasnoor M, Guglietta A, Ulrichts P, T’joen C, Utsugisawa K, Verschuuren J, Mantegazza R:
  • Organizer: 74th Annual Meeting of American Academy of Neurology
  • Int'l Joint Research
• [Presentation] Real-world effectiveness of eculizumab in generalized myasthenia gravis in Japan: 1-year post-marketing surveillance data (2022)
  • Author(s): Murai H, Suzuki S, Fukamizu Y, Osawa T, Kikui H, Utsugisawa K:
  • Organizer: 第63回日本神経学会学術大会
• [Presentation] Long-Term Safety and Efficacy of Efgartigimod in Patients With Generalized Myasthenia Gravis: Interim Results of the ADAPT+ Study (2022)
  • Author(s): Meisel A, Bril V, Vu T, Karam C, Peric S, De Bleecker JL, Murai H, Beydoun S, Pasnoor M, Guglietta A, Ulrichts P, T’joen C, Utsugisawa K, Verschuuren J, Mantegazza R, Howard JF:
  • Organizer: 8th Congress of the European Academy of Neurology
  • Int'l Joint Research
• [Presentation] Efficacy of Efgartigimod in Generalized Myasthenia Gravis: Myasthenia Gravis Composite Score Analysis From ADAPT. (2022)
  • Author(s): De Bleecker JL, Meisel A, Howard JF, Vu T, Bril V, Ulrichts P, Guglietta A, T’joen C, Murai H, Utsugisawa K, Mantegazza R:
  • Organizer: 17th International Congress on Neuromuscular Diseases
  • Int'l Joint Research
• [Presentation] LUMINESCE: Phase 3 study of satralizumab, a therapeutic recycling antibody targeting the IL-6 receptor, in patients with generalised myasthenia gravis. (2022)
  • Author(s): Kaminski H, Zhao C, Meyer zu Horste G, O’Connor KC, Klingelschmitt G, Krumova P, Bolt S, Vodopivec I, Lennon-Chrimes S, Murai H:
  • Organizer: 27th Annual Congress of the World Muscle Society
  • Int'l Joint Research
• [Presentation] Analysis of Efgartigimod Efficacy Across Patient Populations and Myasthenia Gravis Specific Scales (2021)
  • Author(s): Murai H, Bril V, Vu T, Karam C, Peric S, Imai T, Takahashi M, Uzawa A, Guglietta A, Ulrichts P, Vangeneugden T, Utsugisawa K, Mantegazza R, Howard J
  • Organizer: 第62回日本神経学会学術大会
• [Presentation] Real-world experience with refractory generalized myasthenia gravis (2021)
  • Author(s): Murai H
  • Organizer: 16th International Congress on Neuromuscular Diseases
  • Int'l Joint Research / Invited
• [Presentation] COVID-19時代におけるMGのマネージメント (2021)
  • Author(s): 村井弘之
  • Organizer: 第33回日本神経免疫学会
  • Invited
• [Presentation] 抗補体薬ソリリスの位置づけ (2021)
  • Author(s): 村井弘之
  • Organizer: 第33回日本神経免疫学会
  • Invited
• [Presentation] エクリズマブ投与時の全身型重症筋無力症患者の病態生理特性に関する多施設共同臨床研究（中間解析） (2021)
  • Author(s): 村井弘之, 鈴木靖士, 永田栄一郎, 望月秀樹, 横山和正, 大崎康史, 関口兼司, 玉岡晃, 中嶋秀人, 丹羽淳一,野村恭一, 阪田麻友美, 増田眞之, 南尚哉, 岡村和美, 深水裕二, 小原崇史, 鈴木重明
  • Organizer: 第33回日本神経免疫学会
• [Presentation] REAL-WORLD PATIENT-REPORTED IMPACT OF MYASTHENIA GRAVIS: INITIAL DATA FROM THE MYREALWORLD MG STUDY (2021)
  • Author(s): Murai H, Claeys K, Friconneau M, Larkin M, Shao J
  • Organizer: 第39回日本神経治療学会
• [Presentation] 難治性重症筋無力症に対するエクリズマブの適応 (2020)
  • Author(s): 大山宗徳、岡田健佑、増田真之、清水優子、横山和正、川口直樹、鵜沢顕之、中原仁、村井弘之、鈴木重明
  • Organizer: 第117回日本内科学会総会
• [Presentation] 日本におけるエクリズマブの全身型重症筋無力症に関する製造販売後調査の中間解析 (2020)
  • Author(s): 村井弘之、鈴木重明、長谷部美紀、深水裕二、ロドリゲスエマ、槍澤公明
  • Organizer: 第61回日本神経学会学術大会
• [Presentation] Safety and effectiveness of eculizumab for patients with generalized myasthenia gravis in Japan: Interim analysis of post-marketing surveillance (2020)
  • Author(s): Murai H, Suzuki S, Hasebe M, Fukamizu Y, Rodriguez E, Utsugisawa K
  • Organizer: The 6th European Academy of Neurology
  • Int'l Joint Research
• [Presentation] ADAPT: A Randomized Phase 3 Study of the FcRn antagonist, Efgartigimod, in Myasthenia Gravis (2020)
  • Author(s): Howard JF, Vu T, Bril V, De Bleecker J, Verschuuren J, Mantegazza R, Meisel A, Peric S, de Haard H, Parys W, Guglietta A, Ulrichts P, Murai H.
  • Organizer: AANEM 2020 Annual Meeting (American Association of Neuromuscular & Electrodiagnostic Medicine)
  • Int'l Joint Research
• [Presentation] 重症筋無力症に対するエクリズマブ治療：これまでにわかったこと、わからないこと (2019)
  • Author(s): 村井弘之
  • Organizer: 第60回日本神経学会学術大会
  • Invited
• [Presentation] Response to eculizumab in patients with myasthenia gravis recently treated with chronic intravenous immunoglobulin (2019)
  • Author(s): Genge A, Jacob S, Murai H, Utsugisawa K, Nowak RJ, Wiendl H, Fujita KP, O’Brien F, Howard JF
  • Organizer: The 54th Canadian Neurological Sciences Federation Congress
  • Int'l Joint Research
• [Presentation] Relieving the burden of myasthenia gravis: eculizumab reduces exacerbation, hospitalization and rescue therapy rates (2019)
  • Author(s): Siddiqi Z, Howard JF, Jacob S, Guptill JT, Meisel A, Wiendl H, Murai H, Utsugisawa K, Nowak RJ, Fujita KP, O’Brien F, Patra K, Muppidi S
  • Organizer: The 54th Canadian Neurological Sciences Federation Congress
  • Int'l Joint Research
• [Presentation] 重症筋無力症：新時代の治療戦略 (2019)
  • Author(s): 村井弘之
  • Organizer: 第60回日本神経病理学会総会学術研究会
  • Invited
• [Presentation] 重症筋無力症の新しい分類と治療戦略 (2019)
  • Author(s): 村井弘之
  • Organizer: 第37回日本神経治療学会学術集会
  • Invited
• [Presentation] Response to eculizumab in patients with AChR+ refractory myasthenia gravis recently treated with chronic IVIg (2018)
  • Author(s): Jacob S, Murai H, Utsugisawa K, Nowak RJ, Wiendl H, Fujita KP, O’Brien F, Howard JF
  • Organizer: The 15th International Congress on Neuromuscular Diseases
  • Int'l Joint Research
• [Presentation] MGクリーゼに遭遇したら (2018)
  • Author(s): 村井弘之
  • Organizer: 第36回日本神経治療学会
  • Invited
• [Presentation] 重症筋無力症の診断から治療までの最前線 (2018)
  • Author(s): 村井弘之
  • Organizer: 第30回日本神経免疫学会
  • Invited
• [Presentation] Updates on antibodies in myasthenia gravis (2017)
  • Author(s): Murai H
  • Organizer: Asean Neurological Association Biennial Convention 2017
  • Int'l Joint Research / Invited
• [Presentation] Early fast-acting treatment strategy against generalized myasthenia gravis (2017)
  • Author(s): Utsugisawa K, Nagane Y, Akaishi T, Suzuki Y, Imai T, Tsuda E, Minami N, Uzawa A, Kawaguchi N, Masuda M, Konno S, Suzuki H, Murai H, Aoki M
  • Organizer: The 23rd World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Open label extension trial of REGAIN to evaluate the safety and efficacy of eculizumab in patients from Japan with refractory generalized myasthenia gravis (2017)
  • Author(s): Murai H, Uzawa A, Suzuki Y, Imai T, Shiraishi H, Tsuda E, Suzuki H, Okumura M, Utsugisawa K
  • Organizer: The 23rd World Congress of Neurology
  • Int'l Joint Research
• [Book] 今日の処方（改訂第6版） (2019)
  • Author(s): 浦部 晶夫、島田 和幸、川合 眞一
  • Total Pages: 904
  • Publisher: 南江堂
  • ISBN: 9784524251193