Azathioprine for multiple sclerosis

  • Review
  • Intervention

Authors

  • Ilaria Casetta,

    Corresponding author
    1. Universita degli Studi di Ferrara, Sezione di Clinica Neurologica; Dip.to di Discipline Medico Chirurgiche della Comunicazione e del Comportamento, Ferrara, Italy
    • Ilaria Casetta, Sezione di Clinica Neurologica; Dip.to di Discipline Medico Chirurgiche della Comunicazione e del Comportamento, Universita degli Studi di Ferrara, Corso della Giovecca, 203, Ferrara, 44100, Italy. cti@unife.it.

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  • Gerardo Iuliano,

    1. Ospedali Riuniti di Salerno, U.O. Neurologia, Salerno, Italy
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  • Graziella Filippini

    1. Fondazione I.R.C.C.S. - Istituto Neurologico C.Besta, Neuroepidemiology Unit, Milano, Italy
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Abstract

Background

Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis (MS). It is an alternative to interferon beta for treating MS also because it is less expensive. Concerns about its safety, mainly a possible increased risk of malignancy, has limited its use.

Objectives

To compare azathioprine versus placebo. To determine the effect of azathioprine on major clinical outcomes, i.e., disability progression and relapses in patients with MS.

Search methods

We searched The Cochrane Multiple Sclerosis Group Trials Register (2006), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2006), MEDLINE (PubMed) (1966 to December 2006), EMBASE (1980 to December 2006), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE - searched 28.12.06) Journals and reference lists were hand searched for relevant articles both to benefit and adverse effects. Regulatory agencies were additional sources of information for adverse effects.

Selection criteria

All parallel group randomised controlled trials (RCTs) comparing azathioprine treatment of a least one year duration with placebo for patients with MS. Cohorts, case controls, case series and case reports were also used to assess adverse effects.

Data collection and analysis

Potentially relevant references were evaluated and all data extracted by two independent authors.

Main results

The five trials that met our criteria included 698 patients: data from 499 (71.5%) were available for analysis of relapse frequency at one year's, from 488 (70%) at two years' and from 415 (59.5%) at three years' follow-up. Azathioprine reduced the number of patients who had relapses during the first year of treatment (relative risk reduction [RRR] =20%; 95% CI = 5% to 33%), at two years' (RRR =23%; 95% CI = 12% to 33%) and three years' (RRR =18%; 95% CI = 7% to 27%) follow-up. These results were consistent in sensitivity analysis. There was no heterogeneity among the studies.
Data from only three small trials with a total of 87 patients were available to calculate the number of patients who progressed during the first two to three years. There was a statistically significant benefit (RRR = 42%; 95% CI = 7% to 64%) of azathioprine therapy at three years' follow-up; this result was robust after sensitivity analyses and there was no heterogeneity among the trials.
Gastrointestinal disturbances, bone marrow suppression and hepatic toxicity were greater in the azathioprine group rather than in the placebo group; they were anticipated, and, by monitoring and dosage adjustment, were easily managed. Withdrawals due to adverse effects were few, occurring mostly during the first year of azathioprine treatment and mainly due to gastrointestinal intolerance (5%).
Data from the trials and from cohort and case controls studies available in the literature did not show an increase in risk of malignancy from azathioprine. A possible long-term risk of cancer from azathioprine may be related to a treatment duration above ten years and cumulative doses above 600 g.

Authors' conclusions

Azathioprine is an appropriate maintenance treatment for patients with MS who frequently relapse and require steroids. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy. Considering the trade off between the benefits and harms, azathioprine is a fair alternative to interferon beta for treating MS. A logical next step for future trials would seem the direct comparison of azathioprine and interferon beta. In fact the direct comparison between these two widely used treatments in MS has not been made.

摘要

背景

多發性硬化症的Azathioprine療法

Azathioprine是最被廣泛使用於治療多發性硬化症的免疫抑制劑。因為該藥比較便宜,遂被視為多發性硬化症beta干擾素療法之外的代替治療。當考量到它的可能增加致癌風險,即會限制它的使用。這篇系統性整理主要目的是決定在多發性硬化症使用azathioprine的好處和風險的權衡。

目標

本研究主要目標為比較azathioprine和對照組的差異及確認使用azathioprine的主要臨床結果,例如:多發性硬化症病人失能的進展和復發。

搜尋策略

The Multiple Sclerosis Group's Trials Register, The Cochrane Central Register of Controlled Trials (CENTRALIssue 4, 2006), Cochrane Database of Systematic Reviews (CDSR  Issue 4, 2006), Database of Abstracts of Reviews of Effectiveness (DARE  searched 28.12.06) MEDLINE (PubMed) (1966 to December2006), EMBASE (1980 to December 2006). 手動搜尋了期刊和參考資料清單上的相關文章,包括藥物的益處和副作用.監管機構提供了更多副作用的相關訊息.

選擇標準

收集所有針對多發性硬化症的病人身上使用azathioprine至少一年和對照組的比較性且平行分組的隨機對照試驗研究。世代研究、病例對照研究、病例系列、和病例報告也被用來評估藥物的副作用。

資料收集與分析

潛在相關的參考資料被評估,而且由兩位獨立的作者提取所有的資料.

主要結論

有5個試驗符合標準,包括698個隨機的病人:其中499 (71.5%)個病人的資料可以用來分析一年的復發率,488 (70%)個病人可以用來分析第二年的復發率,415 (59.5%)個病人可以用來分析第三年的復發率. azathioprine可以減少復發的病人數,在第一年的相對風險減少率[RRR]是20%;(95% CI = 5% to 33), 第二年RRR = 23%; (95% CI = 12% to 33%),而第三年RRR = 18%;(95% CI = 7% to 27%).這些結果在敏感度分析是一致的.在研究中並沒有異質性.從只有3個小型的試驗,共有87個病人可以用來計算從前兩年到第三年有疾病進展的病人數.在第三年的追蹤,使用azathioprine有統計上顯著的好處(RRR = 42%; 95% CI = 7% to 64%).這個結果在敏感度分析後是更具顯著效力的,而且在這些試驗中沒有出現異質性。胃腸道障礙,骨髓抑制和肝毒性在azathioprine這一組比在安慰劑組還要多;這結果是可以預期的,並且透過監測和劑量調整很容易被處理。很少因為副作用而停用azathioprine,大多發生在使用azathioprine的第一年,主要是由於無法忍受胃腸道的不適(5%)。從這些試驗和世代研究和個案研究的數據中,並沒有顯示出azathioprine會增加致癌的風險。當azathioprine使用超過十年和累積劑量超過600克時與可能致癌的長期風險有關。

作者結論

azathioprine對於多發性硬化症長期復發和需要類固醇的病人是適合的維持治療方式。累積劑量不應該超過600克,因和可能增加致癌的風險有關。考慮好處和壞處的衡量,azathioprine是用來代替beta 干擾素治療多發性硬化症好的選擇。下一步合理的試驗是直接比較azathioprine和beta 干擾素。事實上,直接比較這兩種治療在多發性硬化症上目前還沒有被研究過。]

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

Azathioprine是用於治療多發性硬化症最被廣泛使用的免疫抑制劑,在使用interferons或glatiramer acetate之前, athazioprine是可能替代interferons beta治療多發性硬化症的選擇.它的安全性已經被考慮,主要是因為可能增加致癌的風險,這篇回顧的作者試圖去評估AZA治療多發性硬化症的好處和壞處.在相關的醫學文獻研究中,只有5個符合方法學上品質的標準可以將其列入這次的審查,其中包括共698人,分別在第一,二,三年進行追蹤.考慮到失能的進展和復發的次數,研究人員發現AZA組減少了復發的病人數,不管是在第一年的治療,或在兩三年後的追蹤都是如此。AZA治療也減少了在前二至三年有病程進展的病人數. 副作用,如胃腸道障礙,骨髓抑制和肝毒性頻繁地發生,但它們是已知和可預期的,因此很容易被處理,因為副作用而撤除AZA的很少,主要是由於胃腸不適.兩個研究已有死亡的報告,其中有4人是對照組,8人是AZA組。這些小數目沒辦法做統計的分析.關於在8篇論文中被發表,長期AZA治療多發性硬化症有致癌風險的衝突性結論沒有被考慮到目前的審查中,因為他們來於自其他的臨床試驗.病人出現癌症(三個在AZA組和1個在安慰劑組)在這篇審查中的五個研究中的二個被報告出來。有很多研究AZA治療非多發性硬化症患者的報告可以被找到.所有數據沒有顯示AZA會增加致癌的風險。可能的長期風險,可能與十年以上的療程和累積劑量超過600克以上有關.

Plain language summary

The effects of the immunosuppressive drug azathioprine (AZA) widely used in multiple sclerosis (MS) before the treatments with interferons or glatiramer acetate

AZA is a possible alternative to interferon beta for treating MS. As concerns have been raised about its safety, mainly due to possible increased risk of cancer, the authors of this review tried to assess the balance between benefits and harms of AZA treatment in MS.
Among the pertinent medical literature only five studies met the methodological quality criteria necessary for their inclusion in this review, comprising a total of 698 participants, with follow-up at one, two and three years.
Taking into account the disability progression and the number of relapses, the authors found evidence that AZA reduced the number of patients who had relapses during the first year of treatment , and at two and three years' follow-up as well. AZA treatment also reduced the number of patients who progressed during the first two to three years of therapy.
Adverse effects such as gastrointestinal disturbances, bone marrow suppression and hepatic toxicity occurred frequently; but they were known and anticipated, thus quite easily managed: withdrawals due to adverse events were few, and mainly due to gastrointestinal intolerance.
Two studies had deaths reported, comprising of four persons in the control group, and eight in the AZA group. These small numbers do not allow a statistical analysis.
Conflicting conclusions on potential risk of cancer in MS patients with long-term AZA treatment have been reported in eight published papers, not considered in the present review because they came from sources other than clinical trials. The presence of patients who developed cancer ( three in the AZA and 1 the placebo group) was reported in two out of five studies considered in this review. Numerous studies of AZA treated patient populations other than MS patients are also available. The whole data, however, does not show an increase in risk of malignancy from AZA. Possible long-term risks may be related to a treatment duration above ten years and cumulative doses above 600 g.

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