Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease

 

Abstract

Background

The therapeutic role of 6-mercaptopurine and azathioprine remains controversial due to their perceived relatively slow-acting effect and adverse effects. A meta-analysis was performed to evaluate the efficacy of these agents for the maintenance of remission of quiescent Crohn's disease.

Objectives

To assess the efficacy of azathioprine and 6-mercaptopurine for maintenance of remission in quiescent Crohn's disease.

Search methods

Pertinent studies were selected using the MEDLINE data base (1966-May 1998), the Cochrane Controlled Trials Register, the Inflammatory Bowel Disease register, as well as abstracts from major gastrointestinal research meetings and references from published articles and review. This search strategy was updated (1998-May 2008) using the MEDLINE, EMBASE and International Pharmaceutical Abstracts databases, the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD group Specialized Trials Register.

Selection criteria

Randomized, double-blind, placebo-controlled trials of oral azathioprine or 6-mercaptopurine involving adult patients (> 18 years) with quiescent Crohn's disease.

Data collection and analysis

Data were extracted by three independent observers (EP, MC, LRS) based on the intention to treat principle. Peto odds ratios and 95% confidence intervals for maintenance of remission, steroid sparing, and withdrawals due to adverse effects were calculated. Numbers needed to treat or harm (NNT, NNH respectively) for the maintenance of remission, steroid sparing, and withdrawals due to adverse effects were also determined.

Main results

Seven trials of azathioprine therapy and one of 6-mercaptopurine were included in the review. Azathioprine and 6-mercaptopurine had a positive effect on maintaining remission. The Peto odds ratio (OR) for maintenance of remission with azathioprine was 2.32 (95% CI 1.55 to 3.49) with a NNT of 6. The Peto OR for maintenance of remission with 6-mercaptopurine was 3.32 (95% CI 1.40 to 7.87) with a of 4. Higher doses of azathioprine improved response. A steroid sparing effect with azathioprine was noted, with a Peto OR of 5.22 (95% CI 1.06 to 25.68) and NNT of 3 for quiescent disease. Withdrawals due to adverse events were more common in patients treated with azathioprine (Peto OR 3.74; 95% CI 1.48 to 9.45, NNH = 20) than with placebo.

Authors' conclusions

Azathioprine and 6-mercaptopurine are more effective than placebo for maintenance of remission in Crohn's disease. Higher response rates were obtained with azathioprine than 6-mercaptopurine. However, the one study evaluating 6-mercaptopurine used a relatively low dose of the drug. Future studies should look at the effect of higher doses of 6-mercaptopurine. There is weak evidence for a steroid sparing effect with azathioprine treatment.

 

Plain language summary

Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease

Azathioprine (1.0 to 2.5 mg/kg/day) used among patients with non-active Crohn's disease is effective for reducing the risk of disease recurrence over a 6 month to 2 year period. Higher doses of azathioprine (2.5 mg/kg/day) are more effective than lower doses (1.0 or 2.0 mg/kg/day) for preventing disease recurrence. There is also evidence that azathioprine may reduce the need for steroid treatment which could help reduce steroid related side effects. 6-Mercaptopurine may be effective for reducing the risk of disease recurrence over a 2 year period. Azathioprine appears to be more effective than 6-mercaptopurine but this may be due to the relatively low dose of 6-mercaptopurine (50 mg/day) used in the one study assessing this drug. Future studies should assess the effect of higher doses of 6-mercaptopurine. The long-term effectiveness of azathioprine and 6-mercaptopurine is unclear due to the short duration of the studies (6 months to 2 years). Azathioprine and 6-mercaptopurine appear to be slow acting drugs. They are associated with some uncommon but serious side effects. These include suppression of the body's ability to produce white blood cells (which fight infection) and platelets (which allow blood clotting to occur), inflammation of the pancreas and an increased risk of lymphoma. Patients who may benefit from this therapy include those whose Crohn's disease is chronically active or flares frequently. Azathioprine or 6-mercaptopurine may also benefit patients who are dependent on steroids but have experienced steroid side effects, or for whom steroids no longer work. The choice to use azathioprine or 6-mercaptopurine should be made after careful consideration of the risks and benefits of using these drugs.

 

摘要

背景

使用Azathioprine和 6Mercaptopurine(6MP)維持克隆氏症的緩解效果

Azathioprine和 6Mercaptopurine因為相對效果起始慢及不良反應，所以在臨床應用上仍有爭議。所以藉由統合分析來評估這些藥劑對於維持緩解無症狀克隆氏症的效果。

目標

評估Azathioprine和 6Mercaptopurine對於維持緩解無症狀克隆氏症效果。

搜尋策略

利用MEDLINE資料庫 (1966年至1998年5月) 、Cochrane Controlled Trials Register、Inflammatory Bowel Disease register，並從主要的腸胃研究會議的摘要，以及從已發表的文章與回顧文獻的參考文獻挑選出相關研究。本搜尋策略利用MEDLINE、EMBASE及and International Pharmaceutical Abstracts databases, the Cochrane Central Register of Controlled Trials及the Cochrane IBD/FBD group Specialized Trials Register進行更新(1998年−2008年5月)。

選擇標準

納入針對克隆氏症無症狀成人(18歲以上)患者，並接受口服azathioprine或6mercaptopurine 的隨機性、雙盲、安慰劑對照試驗

資料收集與分析

由三個獨立觀察者(EP, MC, LRS)根據意圖治療 (intention to treat)原則擷取數據。計算維持緩解的Peto勝算比和95%信賴區間、類固醇的減量和因為停藥所引發的不良事件。另外也分別確定維持緩解、類固醇的減量和因為停藥造成的不良反應所需要被治療的病人數(NNT)或是達到被傷害需要的病人數目(NNH)、。

主要結論

本回顧納入7個azathioprine治療和1個6mercaptopurine治療的研究。Azathioprine和6mercaptopurine 對於維持緩解都具有正面效果，使用Azathioprine維持緩解的Peto勝算比為2.32(95%信賴區間1.55至3.49)，而需要治療的患者人數為6，而使用6mercaptopurine維持緩解的peto勝算比為3.32(95%信賴區間1.40至7.87)，而需要治療的患者人數為4，更高劑量的Azathioprine會增加效果。使用Azathioprine可減少類固醇劑量，Peto勝算比為5.22(95%信賴區間 1.06至25.68)，需要被治療的人數為3。使用Azathioprine會比使用安慰劑更常因不良事件停藥 (Peto勝算比為3.74；95%信賴區間1.48至9.45，不良事件停藥需要的患者數為20)。

作者結論

Azathioprine和6mercaptopurine這兩種藥物都比安慰劑更能夠維持克隆氏症緩解。Azathioprine比6mercaptopurine 有更高的反應率。但這個研究中6mercaptopurine 所使用的劑量較低。應進一步試驗了解較高劑量6mercaptopurine 的效果。有較薄弱的證據顯示Azathioprine治療可減少類固醇需要量。

翻譯人

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

總結

無症狀克隆氏症的患者每天使用1.0至2.5毫克Azathioprine可有效降低疾病的復發率半年至兩年。較高劑量的Azathioprine(每天2.5毫克)比較低劑量的Azathioprine (每天1.0毫克)更能預防疾病復發。也有些證據指出使用Azathioprine可能可以減少類固醇需求量，進而降低與類固醇有關的副作用發生率。6Mercaptopurine可能可以降低疾病復發的風險至少兩年，Azathioprine療效似乎比6Mercaptopurine好，但這可能比較這兩種藥的試驗中使用的6Mercaptopurine劑量較低所致(每天50毫克)。應進一步試驗了解較高劑量6mercaptopurine 的效果。因為研究為期較短(6個月至2年)，所以長期使用Azathioprine和6Mercaptopurine的效果仍未確定。Azathioprine和6Mercaptopurine似乎是作用緩慢的藥物。並合併一些不常見但嚴重的副作用，包括抑制身體製造對抗感染的白血球和使血液凝固的血小板、胰臟發炎和增加引發淋巴癌的風險。這個治療有助於長期有症狀或是經常發作的克隆氏症患者。Azathioprine或6Mercaptopurine可能也有助於依賴類固醇但有類固醇造成副作用的患者，或類固醇也沒效的患者。選擇使用Azathioprine或6Mercaptopurine應審慎評估使用藥物的風險和益處再決定。