Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

 

Abstract

Background

Maintenance of remission is a major issue in inflammatory bowel disease. In ulcerative colitis, the evidence for the effectiveness of azathioprine and 6-mercaptopurine for the maintenance of remission is still controversial.

Objectives

To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.

Search methods

The MEDLINE database was used to search literature from 1966 to 2006. A manual search was also performed using references from these articles as well as review articles, proceedings from major gastrointestinal meetings and data available from the Cochrane Collaboration database. Authors of maintenance trials were asked about unpublished studies.

Selection criteria

Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (mesalamine) were included.

Data collection and analysis

Data were extracted by two raters using standard forms. Disagreements were solved by informal consent, including a third rater. Jadad scores were applied to assess study quality. Analyses were performed separately by type of control (placebo, or active comparator). Pooled odds ratios were calculated based on the fixed effects model unless heterogeneity was shown.

Main results

Six studies were identified including 286 patients with ulcerative colitis. The study quality was mostly poor. Azathioprine was shown to be superior for the maintenance of remission as compared to placebo based on four trials (failure to maintain remission: OR 0.41; 95% CI 0.24 to 0.70). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity. Both studies using active comparators were open label. Adverse effects occurred in 11 of 127 patients receiving azathioprine, including acute pancreatitis (3 cases) and significant bone marrow suppression (5 cases).

Authors' conclusions

Azathioprine may be an effective maintenance therapy for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids. More research is needed to evaluate superiority over standard maintenance therapy, especially in the light of a potential for adverse events from azathioprine.

 

Plain language summary

Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis

Studies of azathioprine and 6-mercaptopurine for maintenance treatment of ulcerative colitis.
Six studies were reviewed and provide the best evidence we have. Study quality was mostly poor. The studies tested 286 people over the age of eighteen who had ulcerative colitis. The subjects received oral azathioprine or 6-mercaptopurine, placebo (fake pills) or standard maintenance treatment (mesalazine or sulfasalazine). The studies lasted for at least 12 months.

What is ulcerative colitis and could azathioprine and 6-mercaptopurine work?
Ulcerative colitis is a chronic inflammatory disorder of the colon. The most common symptoms of ulcerative colitis are bloody diarrhea and abdominal pain. Azathioprine and 6-mercaptopurine are thought to reduce inflammation by blocking the immune system.

What did the studies show?
The studies showed that azathioprine was better than placebo for maintenance treatment (i.e. preventing the disease from coming back once the patient has responded to treatment). Fifty-six per cent of patients treated with azathioprine were disease free after one year of treatment compared to 35% of patients who received placebo.

How safe are azathioprine and 6-mercaptopurine?
The drugs were generally well tolerated and side effects occurred infrequently. However serious side effects such as acute pancreatitis (an inflammation of the pancreas that causes severe abdominal pain - a 2% risk) and bone marrow suppression (failure to make normal blood cells - a 4% risk) can occur. Patients taking these drugs should be regularly monitored for evidence of effectiveness and side effects.

What is the bottom line?
Given the established effectiveness and safety of aminosalicylates (i.e. mesalazine or sulfasalazine) for the maintenance of remission in ulcerative colitis, azathioprine and 6-mercaptopurine cannot be recommended as first line treatment to prevent the disease from coming back. However, azathioprine may be an effective maintenance treatment for patients who have failed or cannot tolerate mesalazine or sulfasalazine and for patients who require repeated courses of steroids.

 

摘要

背景

使用Azathioprine和6Mercaptopurine(6MP)維持緩解潰瘍性大腸炎

對於炎症性腸疾病來說，維持緩解是個重要的議題。目前對使用硫唑嘌呤和6硫醇嘌呤的維持緩解效果仍存在有爭議。

目標

評估使用Azathioprine和6Mercaptopurine維持緩解潰瘍性大腸炎的效果。

搜尋策略

搜尋1966年至2006年MEDLINE資料庫文獻。並且以人工的方式蒐集這些文章及回顧性文獻的參考文獻、主要的胃腸科會議記錄以及Cochrane Collaboration資料庫資料。並聯絡維持治療試驗的作者取得未發表的研究的資料。

選擇標準

針對比較azathioprine或6mercaptopurine與安慰劑或標準維持療法(mesalamine)至少12個月的隨機性對照試驗。

資料收集與分析

由兩名評估者以標準格式擷取資料。不一致的部分由非正式的同意來解決，包括由第三位評估者。以Jadad量表來評量研究品質。依不同型態的對照組(安慰劑組或是對照藥組)分別進行分析。除非有異質性，否則以固定效應模式計算彙整勝算比。

主要結論

納入包括有286名潰瘍性大腸炎患者的6個研究。大部分試驗品質不好。在4個與安慰劑的試驗， Azathioprine維持緩解的效果比較好 (無法維持緩解的勝算比 0.41，95%信賴區間 0.24至0.70)。有2個試驗比較6mercaptopurine 和mesalazine或比較azathioprine和Sulfasalazine有顯著地異質性。這兩個試驗對照藥都是公開標示。在127名服用 azathioprine 患者有11名出現不良反應，包括急性胰臟炎(3名)和明顯的骨髓抑制(5名)。

作者結論

對mesalazine或sulfasalazine無效或無法忍受的患者及需要一再類固醇治療的患者， Azathioprine可能可以有效的維持效果。仍需要進行更多的試驗評估優於標準維持治療的程度，特別是顯示Azathioprine有潛在引發的不良反應跡象。

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

Azathioprine 對某些潰瘍性大腸炎的患者來說可能可提供維持的功效。 Azathioprine與6mercaptopurine潰瘍性大腸炎維持治療的試驗:六個被評讀的試驗提供了最好的證據。大部分的試驗品質不佳。參加研究對象是286名年齡大於18歲的潰瘍性大腸炎患者。這些受試者都接受口服 azathioprine 或6mercaptopurine 、安慰劑(假藥片)或標準維持治療(mesalazine或 sulfasalazine)。所有研究都持續至少12個月。 甚麼是潰瘍性大腸炎? azathioprine 和6mercaptopurine 是否有效?潰瘍性大腸炎是一種結腸的慢性發炎現象。其最常出現的症狀是腹瀉帶血和腹痛。 azathioprine 和6mercaptopurine 被認為可以阻擋免疫系統減少發炎反應。這些試驗提供那些資訊?這些試驗呈現 azathioprine 比安慰劑更有維持治療的效果(即患者治療有效後可以預防再復發)。56%的患者在接受 azathioprine 治療後一年沒有再發病，而接受安慰劑治療患者只有35%。 使用 azathioprine 和6mercaptopurine 安全嗎?一般這兩種藥耐受度都很好，也不常有副作用。然而有可能發生像急性胰臟炎(一種會引起嚴重腹痛的胰臟發炎現象，發生風險2%)和骨髓抑制現象(無法產生正常的血球細胞，發生風險4%)的嚴重副作用。病患服用這些藥物時應定期監控藥效與副作用的徵兆。 底線是甚麼?已確定aminosalicylates類藥物(如 mesalazine或sulfasalazine)在維持潰瘍性大腸炎的緩解功效和安全性下，目前並不建議將 azathioprine 和6mercaptopurine 做為預防復發的第一線用藥。然而對mesalazine或sulfasalazine無效或無法忍受的患者及需要一再類固醇治療的患者， Azathioprine可能可以有效的維持效果。