今日の臨床サポート

重症筋無力症

著者: 鈴木重明 慶應義塾大学

監修: 高橋裕秀 昭和大学藤が丘病院 脳神経内科

著者校正/監修レビュー済:2022/11/24
参考ガイドライン:
  1. 日本神経学会:重症筋無力症/ランバート・イートン筋無力症候群診療ガイドライン2022
患者向け説明資料
薬価収載情報:2022年1月20日 ウィフガート 点滴静注400㎎(エフガルチギモド アルファ(遺伝子組換え) 抗FcRn抗体フラグメント製剤)

概要・推奨   

  1. 成人発症重症筋無力症(MG)の長期完全寛解は得難い(グレードC1)。治療が多くの場合、生涯にわたることを意識し、health-related quality of life(QOL)やメンタルヘルスを良好に保つように治療戦略をたてる(推奨度1C)
  1. MG治療における最初の治療目標は、「経口プレドニゾロン5mg/日以下でminimal manifestationsレベル(MM-5mg)」であり、これを早期達成するよう治療戦略を考える(推奨度1C)
  1. 漸増漸減による高用量経口ステロイド療法は様々な副作用やQOL阻害につながりやすく、かつ、完全寛解や早期MM-5mgに関連しないため推奨されない(推奨度1B)
アカウントをお持ちの方はログイン
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります 。閲覧にはご契約が必要 となります。閲覧に はご契約が必要とな ります。閲覧にはご契約が必要となります。閲覧にはご契約 が必要となります。閲 覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
鈴木重明 : 講演料(アレクシオンファーマ),研究費・助成金など(武田薬品工業)[2022年]
監修:高橋裕秀 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 重症筋無力症の治療ゴールを明記し、適切な免疫治療を選択できるように改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 重症筋無力症(MG)とは、神経筋接合部のアセチルコリンレセプター(AChR)あるいは筋特異的受容体型チロシンキナーゼ(MuSK)に対する自己抗体が原因となる臓器特異的な自己免疫疾患である。
  1. 2017年に受診したMG患者は全国で29,210人と推定され、10年間で2倍に増えている。
  1. 20~40歳代女性に好発するが、基本的には小児から高齢者まで発症し、特に高齢発症の頻度が増加傾向にある。近年、MGの治療法が確立し予後は著しく改善したが、ステロイドなどの免疫抑制薬の内服治療が必要であり、その副作用や長期間にわたるMGの管理が必要である。
  1. MGの治療には大きな変化があり、従来行われていた治療に加えて、分子標的薬が適応となった。胸腺摘除の有効性が期待でき、その施行が検討される非胸腺腫MGは、50歳未満の発症で、発病早期のAChR抗体陽性過形成胸腺例である[1]
  1. 重症筋無力症は、指定難病であり、ある一定の重症度基準を満たした場合などでは申請し認定されると保険料の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
病歴・診察のポイント  
  1. 神経診察で眼筋あるいは体幹・四肢近位筋の筋力低下の有無を確認する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

まずは15日間無料トライアル
本サイトの知的財産権は全てエルゼビアまたはコンテンツのライセンサーに帰属します。私的利用及び別途規定されている場合を除き、本サイトの利用はいかなる許諾を与えるものでもありません。 本サイト、そのコンテンツ、製品およびサービスのご利用は、お客様ご自身の責任において行ってください。本サイトの利用に基づくいかなる損害についても、エルゼビアは一切の責任及び賠償義務を負いません。 また、本サイトの利用を以て、本サイト利用者は、本サイトの利用に基づき第三者に生じるいかなる損害についても、エルゼビアを免責することに合意したことになります。  本サイトを利用される医学・医療提供者は、独自の臨床的判断を行使するべきです。本サイト利用者の判断においてリスクを正当なものとして受け入れる用意がない限り、コンテンツにおいて提案されている検査または処置がなされるべきではありません。 医学の急速な進歩に鑑み、エルゼビアは、本サイト利用者が診断方法および投与量について、独自に検証を行うことを推奨いたします。

文献 

Gil I Wolfe, Henry J Kaminski, Inmaculada B Aban, Greg Minisman, Hui-Chien Kuo, Alexander Marx, Philipp Ströbel, Claudio Mazia, Joel Oger, J Gabriel Cea, Jeannine M Heckmann, Amelia Evoli, Wilfred Nix, Emma Ciafaloni, Giovanni Antonini, Rawiphan Witoonpanich, John O King, Said R Beydoun, Colin H Chalk, Alexandru C Barboi, Anthony A Amato, Aziz I Shaibani, Bashar Katirji, Bryan R F Lecky, Camilla Buckley, Angela Vincent, Elza Dias-Tosta, Hiroaki Yoshikawa, Márcia Waddington-Cruz, Michael T Pulley, Michael H Rivner, Anna Kostera-Pruszczyk, Robert M Pascuzzi, Carlayne E Jackson, Guillermo S Garcia Ramos, Jan J G M Verschuuren, Janice M Massey, John T Kissel, Lineu C Werneck, Michael Benatar, Richard J Barohn, Rup Tandan, Tahseen Mozaffar, Robin Conwit, Joanne Odenkirchen, Joshua R Sonett, Alfred Jaretzki, John Newsom-Davis, Gary R Cutter, MGTX Study Group
Randomized Trial of Thymectomy in Myasthenia Gravis.
N Engl J Med. 2016 Aug 11;375(6):511-22. doi: 10.1056/NEJMoa1602489.
Abstract/Text BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone.
METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period.
RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003).
CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

PMID 27509100
R M Pascuzzi, H B Coslett, T R Johns
Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients.
Ann Neurol. 1984 Mar;15(3):291-8. doi: 10.1002/ana.410150316.
Abstract/Text One hundred sixteen patients, aged 8 to 82 years, with myasthenia gravis were treated with prednisone, 60 to 80 mg daily, until the onset of improvement, followed by lower-dose alternate-day therapy of several years' duration. Of all patients, 80.2% achieved either remission (27.6%) or marked improvement (52.6%). Moderate improvement occurred in 14.7%, and 5.2% showed no improvement. Increasing age correlated with a favorable outcome, but sex, duration of illness prior to treatment, severity and distribution of weakness at the time of onset of treatment, and presence of thymoma were not factors in the response to therapy.

PMID 6721451
E Arsura, N G Brunner, T Namba, D Grob
High-dose intravenous methylprednisolone in myasthenia gravis.
Arch Neurol. 1985 Dec;42(12):1149-53.
Abstract/Text Corticosteroids have been useful in the management of myasthenia gravis (MG), but their efficacy has been limited by the slow onset of improvement, initial worsening of MG, refractoriness of some patients, and side effects of large daily doses. High-dose intravenous methylprednisolone pulses have been reported to produce rapid improvement in several immunologic disorders. In this study we administered 2 g of methylprednisolone intravenously every five days to 15 consecutive patients who had exacerbation of generalized MG. Satisfactory improvement occurred in ten of 15 patients after two courses and in two of five patients after a third course. Onset of improvement began a mean (+/- SD) of 3 +/- 1.1 days after the first infusion, 2.1 +/- 1 days after the second, and 2.4 +/- 1 days after the third, and reached its maximum level 8.9 +/- 6.1 days after the last infusion. A decrease in strength occurred in three patients 1.43 +/- 1.30 days after each infusion, was not marked, and lasted three days, following which improvement generally occurred. Side effects were minimal. After improvement, a daily dose of prednisone (30 mg) was used to maintain improvement. Use of pulse therapy at five-day intervals for the management of severe MG seems to have an advantage in that it produces less initial worsening and more rapid improvement in MG, enabling smaller daily maintenance doses to be employed, with fewer side effects.

PMID 4062612
K Utsugisawa, Y Nagane, S Suzuki, N Suzuki
Monitoring treatment with cyclosporine microemulsion in myasthenia gravis.
Eur J Neurol. 2008 Jun;15(6):598-604. doi: 10.1111/j.1468-1331.2008.02130.x. Epub 2008 Apr 9.
Abstract/Text PURPOSE: To examine whether the monitoring of cyclosporine (CsA) blood concentrations is of benefit in CsA microemulsion pre-concentrate (MEPC) therapy for myasthenia gravis (MG).
METHODS: We measured CsA blood concentrations both 2 h after administration (C2) and immediately before administration (C0) and examined associations with changes to clinical parameters in 20 MG patients treated with CsA MEPC in an unblinded, 6-month prospective open trial.
RESULTS: Initial dose of CsA MEPC (4.7 +/- 0.5 mg/kg/day) provided both high C2 levels and safe C0 levels. Disease severity, daily dose of prednisolone, acetylcholine receptor-antibody titre levels and levels of interleukin-2 production by peripheral blood mononuclear cells were significantly reduced following treatment with CsA MEPC. A significant correlation existed between C2 levels following the initial dose and clinical improvement in responder MG patients. C0 levels were significantly higher in patients who exhibited increased serum creatinine or hypertension compared with patients free from side effects. Body mass index of individual patients was significantly correlated with C0 level, and may thus offer a useful marker to predict C0 levels.
DISCUSSION: CsA MEPC was effective at suppressing symptoms and T-cell-dependent pathogenesis of MG, and monitoring of C2 and C0 levels can be useful to estimate efficacy and safety of the drug.

PMID 18410372
Hiroaki Yoshikawa, Takahiro Kiuchi, Takahiko Saida, Masaharu Takamori
Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis.
J Neurol Neurosurg Psychiatry. 2011 Sep;82(9):970-7. doi: 10.1136/jnnp-2011-300148. Epub 2011 Jul 22.
Abstract/Text OBJECTIVES: To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study.
METHODS: Patients being treated with oral prednisolone at doses equivalent to 10-20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.
RESULTS: Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p = 0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted.
CONCLUSIONS: This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients.
CLINICAL TRIAL REGISTRATION NUMBER: NCT00309088. Name of the trial registry: FK506 Phase 3 STUDY: A STUDY for Steroid Non-Resistant MG Patients.

PMID 21784757
D Grob, D Simpson, H Mitsumoto, B Hoch, F Mokhtarian, A Bender, M Greenberg, A Koo, S Nakayama
Treatment of myasthenia gravis by immunoadsorption of plasma.
Neurology. 1995 Feb;45(2):338-44.
Abstract/Text We treated 16 patients with moderately severe to severe generalized myasthenia gravis (MG) by immunoadsorption (perfusion through a resin that adsorbs proteins) of 2,500 ml plasma on each of four alternate days. Fourteen patients who completed treatment all had significant improvement in strength (6 excellent, 6 good, and 2 fair), which began a mean of 42 hours after the first immunoadsorption, reached a maximum 4 days after the fourth immunoadsorption (mean, 250% of baseline strength), and returned to baseline over a mean of 2 months. Thirty-seven grams of plasma proteins were removed during each immunoadsorption, which required no replacement, compared with 175 grams during plasma exchange, which requires replacement with albumin. Serum or plasma concentration of all proteins fell, more so for most of the larger proteins than for the smaller ones: acetylcholine receptor antibody (AChR Ab) fell to a mean of 23% of original level, fibrinogen to 26%, C4 to 29%, IgM to 33%, IgG to 35%, CH50 to 41%, C3 to 42%, IgA to 54%, and albumin to 76%. All proteins, including AChR Ab, returned to their original levels within 1 to 3 weeks after the last immunoadsorption, while improvement in strength lasted a mean of 6 weeks longer. One seronegative patient had excellent improvement lasting more than a month. Activated complement C5a and white blood cell count rose during each immunoadsorption, while activated complement C3a fell, and each returned to its original level within hours. Eight patients had transient symptomatic hypotension attributable to withdrawal of blood more rapidly than it was returned; this hypotension was prevented or ameliorated by intravenous saline.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7854536
P Gajdos, S Chevret, B Clair, C Tranchant, C Chastang
Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group.
Ann Neurol. 1997 Jun;41(6):789-96. doi: 10.1002/ana.410410615.
Abstract/Text We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (i.v.Ig) or plasma exchange (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of i.v.Ig. Eighty-seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or i.v.Ig (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the i.v.Ig group, p = 0.65). Similar efficacy, although slightly reduced in the 5-day group was observed with both i.v.Ig schedules. The tolerance of i.v.Ig was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the i.v.Ig group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for i.v.Ig. i.v.Ig is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with i.v.Ig and to determine the optimal dosage of i.v.Ig.

PMID 9189040
A I Qureshi, M A Choudhry, M S Akbar, Y Mohammad, H C Chua, A M Yahia, J A Ulatowski, D A Krendel, R T Leshner
Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis.
Neurology. 1999 Feb;52(3):629-32.
Abstract/Text We performed a retrospective multicenter chart review to compare the efficacy and tolerance of plasma exchange (PE) and intravenous immunoglobulin (i.v.Ig) in treatment of 54 episodes of myasthenic crisis. After adjustment for other variables, PE (compared with i.v.Ig) was associated with a superior ventilatory status at 2 weeks (partial F = 6.2, p = 0.02) and 1 month functional outcome (partial F = 4.5, p = 0.04). However, the complication rate was higher with PE compared with i.v.Ig (13 versus 5 episodes, p = 0.07).

PMID 10025801
R B Stricker, B J Kwiatkowska, J A Habis, D D Kiprov
Myasthenic crisis. Response to plasmapheresis following failure of intravenous gamma-globulin.
Arch Neurol. 1993 Aug;50(8):837-40.
Abstract/Text Myasthenic crisis is a potentially life-threatening complication of myasthenia gravis that requires aggressive therapy. We describe four patients in whom myasthenic crisis developed and who failed to respond to initial treatment with intravenous gamma-globulin. All four patients subsequently responded to intensive plasma exchange. Based on our experience, plasmapheresis appears to be superior to intravenous gamma-globulin for the treatment of myasthenic crisis in certain patients. Prognostic factors that determine the effectiveness of intravenous gamma-globulin vs plasmapheresis in these patients merit further investigation.

PMID 8352670
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
Suitable indications of eculizumab for patients with refractory generalized myasthenia gravis.
Ther Adv Neurol Disord. 2020;13:1756286420904207. doi: 10.1177/1756286420904207. Epub 2020 Mar 18.
Abstract/Text 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.

© The Author(s), 2020.
PMID 32215054

ページ上部に戻る

戻る

さらなるご利用にはご登録が必要です。

こちらよりご契約または優待日間無料トライアルお申込みをお願いします。

(※トライアルご登録は1名様につき、一度となります)


ご契約の場合はご招待された方だけのご優待特典があります。

以下の優待コードを入力いただくと、

契約期間が通常12ヵ月のところ、14ヵ月ご利用いただけます。

優待コード: (利用期限:まで)

ご契約はこちらから