Immunosuppressive agents for myasthenia gravis

  • Review
  • Intervention

Authors


Abstract

Background

The benefits of different immunosuppressants for myasthenia gravis (MG) are unclear.

Objectives

Assessment of immunosuppressant drug efficacy in MG.

Search methods

We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to July 2007), EMBASE (from January 1980 to July 2007), review and trial bibliographies and contacted trial authors.

Selection criteria

Types of studies: Randomised and quasi-randomised controlled trials.

Types of participants: Any age, any type or severity of MG regardless of concomitant treatment.

Types of interventions: Any immunosuppressive agent.

Types of outcome measures:

Primary:
(1) Improvement or not at six months

Secondary:
(1) Improvement or not at one year
(2) Need for other treatment, for example corticosteroid dose, at six months
(3) Number of exacerbations during the first year
(4) Acetylcholine receptor antibody titre after at least six months
(5) Occurrence of one or more adverse events at any time after the introduction of treatment.

Data collection and analysis

One author extracted and two checked the data.

Main results

Seven trials are included but few reported the outcomes selected for this review. A meta-analysis of ciclosporin versus placebo from two trials (59 participants) - one as monotherapy (20 participants) and the other with corticosteroids (39 participants) - showed that it resulted in improvement of participants in the ciclosporin group compared with those in the placebo group, with a relative rate of improvement of 2.44 (95% confidence interval (CI) 1.13 to 5.27). In addition the weighted mean difference in QMG score between the ciclosporin and placebo groups was -0.34 (95% CI -0.52 to -0.17). Azathioprine (plus prednisolone for first month) had no significant benefit over prednisolone alone (41 participants). The effects of azathioprine plus prednisolone versus prednisolone plus placebo were similar (34 participants). Cyclophosphamide was reported to be statistically more efficacious than placebo at 12 months in corticosteroid-dependent participants (23 participants), but no raw data were available. Trials of mycophenolate mofetil and tacrolimus did not provide relevant endpoint data for this review. All trials had low numbers of participants. Adverse event reporting was variable. Trial protocol heterogeneity prevented comparison of the different immunosuppressants.

Authors' conclusions

In generalised MG, limited evidence from small RCTs suggests that ciclosporin, as monotherapy or with corticosteroids, or cyclophosphamide with corticosteroids, significantly improve MG.
Limited evidence from RCTs shows no significant benefit from azathioprine (as monotherapy or with steroids), mycophenolate mofetil (as monotherapy or with either corticosteroids or ciclosporin) or tacrolimus (with corticosteroids or plasma exchange). Bigger, better-designed, longer trials are needed.

摘要

背景

重症肌無力的免疫抑制劑療法

不同的免疫抑制劑對重症肌無力的益處還不是很清楚

目標

評估免疫抑制劑對重症肌無力的效果

搜尋策略

我們搜尋了Cochrane Neuromuscular Disease Group Trials Register, MEDLINE(從1月 1966 到7月 2007), EMBASE (從1月 1980 到7月 2007),回顧試驗的參考書目,並且連絡試驗的作者.

選擇標準

研究的類型:隨機和半隨機的對照組試驗.受試者的類型:任何年齡,任何類型或嚴重度的肌無力,不論有沒有接受治療.治療的類型:任何免疫抑制劑.結果方法學的類型:主要的: 1.在第6個月有沒有改善. 次要的:1.在一年後有沒有改善 2.在第6個月需要其他治療方式,例如類固醇的劑量 3.在第一年內惡化的次數 4.在至少6個月後的乙醯膽鹼受器的抗體數值 5.在開始治療後的任何時間有沒有發生一個或多個副作用.

資料收集與分析

一個作者擷取資料而兩個作者核對資料

主要結論

7個試驗被選取,但被選定在這項回顧的結果很少被報告出來.從兩個試驗的方析來比較ciclosporin和安慰劑(59個受試者)其中一個是單一治療(20個受試者),而另一個是加上類固醇(39個受試者)顯示在使用ciclosporin這一組的受試者比安慰劑組這一組有改善,改善的相對比率是2.44(95% confidence interval (CI) 1.13 to 5.27).此外,在ciclosporin和安慰劑之間的加權均數差在QMG score是 −0.34 (95% CI −0.52 to −0.17). Azathioprine(第一個月加上類固醇)比單獨使用類固醇(41個受試者)並沒有明顯的益處. azathioprine加上類固醇和類固醇加上安慰劑的效果是相似的(34個受試者). Cyclophosphamide在對類固醇依賴的受試者身上使用12個月後的效果明顯比安慰劑較佳(23個受試者),但沒有原始的資料. Mycophenolate mofetil和 tacrolimus的試驗在這項回顧裡並沒有相關最後的數據.所有試驗受試者的人數都很少.報告的副作用很多種.試驗協定的異質性讓不同的免疫抑制劑無法比較.

作者結論

在全身型重症肌無力,從小的隨機對照組試驗(RCTs)中有限的證據顯示ciclosporin不論是單一治療或加上類固醇,或是cyclophosphamide加上類固醇可以明顯改善肌無力.從RCTs有限的證據顯示azathioprine(單一治療或加上類固醇),或是mycophenolate mofetil(單一治療或加上類固醇或ciclosporin),或是tacrolimus(加上類固醇或血漿交換),並沒有顯著的益處.更大,設計更好,更久的試驗是需要的.

翻譯人

本摘要由新光醫院李建欣翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

一項對使用抑制免疫系統的藥物(免疫抑制劑)在重症肌無力的回顧.重症肌無力是因為免疫系統產生的抗體破壞了傳到肌肉的神經衝動所導致.它導致了肌肉無力,特徵是無力會有波動.每年大約每10000−50000人中會有一個人有肌無力.這個疾病的典型自然病程是會有一連串的惡化和恢復.嚴重時會造成生命危險,因為影響到吞嚥的肌肉造成嗆到,影響到呼吸的肌肉造成呼吸困難.在肌無力的病人,免疫抑制劑主要減少抗體的製造.在本回顧裡包括有7個隨機對照組試驗.每個試驗比較在全身型肌無力的不同治療方式:1.azathioprine 加上一開始的類固醇和類固醇比較 41個受試者;2.azathioprine加上類固醇和類固醇加上安慰劑比較(仿造的治療)  34個受試者;3.ciclosporin單一治療和安慰劑比較 20個受試者;4.ciclosporin 加上類固醇和類固醇加上安慰劑作比較 39個受試者;5.cyclophosphamide加上類固醇和類固醇加上安慰劑比較23個受試者;(6) mycophenolate mofetil 加上 ciclosporin或prednisolone或沒有免疫抑制劑 和 安慰劑加上ciclosporin或prednisolone或沒有免疫抑制劑比較14個受試者;(7) tacrolimus加上類固醇加上有或沒有血漿交換和沒有tacrolimus加上類固醇加上有或沒有血漿交換比較34位受試者.在這些少數的,和通常是短期的隨機對照組試驗中要下一個有用的臨床結論是困難的.每一個試驗包括很少的受試者而且不同的試驗使用不同的研究設計方法.有限的證據發現肌無力在使用ciclosporin(單獨或者加上類固醇)或cyclophosphamide(加上類固醇)和安慰劑比較有顯著的改善.從隨機對照組試驗中,沒有清楚的證據顯示任何普遍在肌無力的病人身上使用的免疫抑制劑有益處azathioprine(單獨或加上類固醇), mycophenolate mofetil (單獨治療或加上類固醇或ciclosporin)或者 tacrolimus (加上類固醇或血漿交換或是加上兩者).在肌無力病人身上沒有使用methotrexate的隨機對照組試驗.對於長期研究這些藥物在肌無力病人身上潛在的可怕毒性副作用是缺乏的.  

Plain language summary

A review of the use of drugs that suppress the immune system (immunosuppressants) in myasthenia gravis.

Myasthenia gravis (MG) is caused by antibodies produced by the immune system that impair the transmission of nerve impulses to muscles. This results in muscle weakness that characteristically fluctuates. About one person in every 10 000 - 50 000 develops MG each year. The natural history of the disorder is typically a series of exacerbations and remissions. Severe attacks can be life-threatening because of weakness of muscles involved in swallowing causing choking, and chest muscles causing difficulty with breathing. In MG, immunosuppressant drugs act mainly by reducing the production of antibodies.

There were seven randomised controlled trials to include in this review. Each trial compared different interventions in generalised MG: (1) azathioprine plus initial prednisolone versus prednisolone - 41 participants; (2) azathioprine plus prednisolone versus prednisolone plus placebo (dummy treatment) - 34 participants; (3) ciclosporin monotherapy versus placebo - 20 participants; (4) ciclosporin plus prednisolone versus prednisolone plus placebo - 39 participants; (5) cyclophosphamide plus prednisolone versus prednisolone plus placebo - 23 participants; (6) mycophenolate mofetil plus either ciclosporin or prednisolone or no immunosuppressants versus placebo plus either ciclosporin or prednisolone or no immunosuppressants trial - 14 participants; (7) tacrolimus plus corticosteroids with or without plasma exchange versus no tacrolimus plus corticosteroids with or without plasma exchange trial - 34 participants.

It is difficult to draw useful clinical conclusions from this small number of often short-term, randomised controlled trials. Each trial had relatively few participants and different trials used different study designs. The limited evidence available found that MG improved significantly with either ciclosporin (alone or in combination with corticosteroids) or cyclophosphamide (in combination with corticosteroids) compared with placebo. There is no clear evidence from randomised controlled trials of benefit for any of the immunosuppressant drugs used more commonly in MG - azathioprine (alone or in combination with corticosteroids), mycophenolate mofetil (as monotherapy or in combination with either corticosteroids or ciclosporin) or tacrolimus (in combination with corticosteroids or plasma exchange or both). There is no randomised controlled trial of methotrexate in MG. Long-term studies of the potentially formidable toxic effects of all of these drugs are lacking in MG.

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