Timmer Antje, Patton Petrease H, Chande Nilesh, McDonald John W D, MacDonald John K
Department of Health Services Research, Carl von Ossietzky University of Oldenburg, Oldenburg, Germany, 26111.
Cochrane Database Syst Rev. 2016 May 18;2016(5):CD000478. doi: 10.1002/14651858.CD000478.pub4.
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.
To assess the effectiveness and safety of azathioprine and 6-mercaptopurine for maintaining remission of ulcerative colitis.
The MEDLINE, EMBASE and Cochrane Library databases were searched from inception to 30 July 2015. Both full randomized controlled trials and associated abstracts were included.
Randomized controlled trials of at least 12 months duration that compared azathioprine or 6-mercaptopurine with placebo or standard maintenance therapy (e.g. mesalazine) were included.
Two authors independently extracted data using standard forms. Disagreements were solved by consensus including a third author. Study quality was assessed using the Cochrane risk of bias tool. The primary outcome was failure to maintain clinical or endoscopic remission. Secondary outcomes included adverse events and withdrawal due to adverse events. Analyses were performed separately by type of control (placebo, or active comparator). Pooled risk ratios were calculated based on the fixed-effect model unless heterogeneity was shown. The GRADE approach was used to assess the overall quality of evidence for pooled outcomes.
Seven studies including 302 patients with ulcerative colitis were included in the review. The risk of bias was high in three of the studies due to lack of blinding. Azathioprine was shown to be significantly superior to placebo for maintenance of remission. Fourty-four per cent (51/115) of azathioprine patients failed to maintain remission compared to 65% (76/117) of placebo patients (4 studies, 232 patients; RR 0.68, 95% CI 0.54 to 0.86). A GRADE analysis rated the overall quality of the evidence for this outcome as low due to risk of bias and imprecision (sparse data). Two trials that compared 6-mercaptopurine to mesalazine, or azathioprine to sulfasalazine showed significant heterogeneity and thus were not pooled. Fifty per cent (7/14) of 6-mercaptopurine patients failed to maintain remission compared to 100% (8/8) of mesalazine patients (1 study, 22 patients; RR 0.53, 95% CI 0.31 to 0.90). Fifty-eight per cent (7/12) of azathioprine patients failed to maintain remission compared to 38% (5/13) of sulfasalazine patients (1 study, 25 patients; RR 1.52, 95% CI 0.66 to 3.50). One small study found that 6-mercaptopurine was superior to methotrexate for maintenance of remission. In the study, 50% (7/14) of 6-mercaptopurine patients and 92% (11/12) of methotrexate patients failed to maintain remission (1 study, 26 patients; RR 0.55, 95% CI 0.31 to 0.95). One very small study compared azathioprine with cyclosporin and found that there was no significant difference between patients failing remission on azathioprine (50%, 4/8) or cyclosporin (62.5%, 5/8) (1 study, 16 patients, RR 0.80 95% CI 0.33 to 1.92). When placebo-controlled studies were pooled with aminosalicylate-comparator studies to assess adverse events, there was no statistically significant difference between azathioprine and control in the incidence of adverse events. Nine per cent (11/127) of azathioprine patients experienced at least one adverse event compared to 2% (3/130) of placebo patients (5 studies, 257 patients; RR 2.82, 95% CI 0.99 to 8.01). Patients receiving azathioprine were at significantly increased risk of withdrawing due to adverse events. Eight per cent (8/101) of azathioprine patients withdrew due to adverse events compared to 0% (0/98) of control patients (5 studies, 199 patients; RR 5.43, 95% CI 1.02 to 28.75). Adverse events related to study medication included acute pancreatitis (3 cases, plus 1 case on cyclosporin) and significant bone marrow suppression (5 cases). Deaths, opportunistic infection or neoplasia were not reported.
AUTHORS' CONCLUSIONS: Azathioprine therapy appears to be more effective than placebo for maintenance of remission in ulcerative colitis. Azathioprine or 6-mercaptopurine may be effective as 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. This review updates the existing review of azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis which was published in the Cochrane Library (September 2012).
维持缓解是炎症性肠病的一个主要问题。在溃疡性结肠炎中，硫唑嘌呤和6-巯基嘌呤维持缓解有效性的证据仍存在争议。
评估硫唑嘌呤和6-巯基嘌呤维持溃疡性结肠炎缓解的有效性和安全性。
检索MEDLINE、EMBASE和Cochrane图书馆数据库，检索时间从建库至2015年7月30日。纳入全部随机对照试验及相关摘要。
纳入至少持续12个月的随机对照试验，这些试验比较了硫唑嘌呤或6-巯基嘌呤与安慰剂或标准维持治疗（如美沙拉嗪）。
两名作者使用标准表格独立提取数据。分歧通过包括第三位作者在内的共识解决。使用Cochrane偏倚风险工具评估研究质量。主要结局是未能维持临床或内镜缓解。次要结局包括不良事件和因不良事件而退出研究。根据对照类型（安慰剂或活性对照）分别进行分析。除非显示存在异质性，否则基于固定效应模型计算合并风险比。采用GRADE方法评估合并结局的总体证据质量。
本综述纳入了7项研究，共302例溃疡性结肠炎患者。由于缺乏盲法，其中3项研究的偏倚风险较高。硫唑嘌呤在维持缓解方面显著优于安慰剂。44%（51/115）的硫唑嘌呤患者未能维持缓解，而安慰剂组为65%（76/117）（4项研究，232例患者；RR 0.68，95%CI 0.54至0.86）。由于存在偏倚风险和数据不精确（数据稀少），GRADE分析将该结局的总体证据质量评为低质量。两项比较6-巯基嘌呤与美沙拉嗪或硫唑嘌呤与柳氮磺胺吡啶的试验显示出显著异质性，因此未进行合并分析。6-巯基嘌呤组50%（7/14）的患者未能维持缓解，而美沙拉嗪组为100%（8/8）（1项研究，22例患者；RR 0.53，95%CI 0.31至0.90）。硫唑嘌呤组58%（7/12）的患者未能维持缓解，而柳氮磺胺吡啶组为38%（5/13）（1项研究，25例患者；RR 1.52，95%CI 0.66至3.50）。一项小型研究发现，6-巯基嘌呤在维持缓解方面优于甲氨蝶呤。在该研究中，6-巯基嘌呤组50%（7/14）的患者和甲氨蝶呤组92%（11/12）的患者未能维持缓解（1项研究，26例患者；RR 0.55，95%CI 0.31至0.95）。一项非常小型的研究比较了硫唑嘌呤与环孢素，发现硫唑嘌呤组（50%，4/8）和环孢素组（62.5%，5/8）未能缓解的患者之间无显著差异（1项研究，16例患者，RR 0.80，95%CI 0.33至1.92）。当将安慰剂对照研究与氨基水杨酸类对照研究合并以评估不良事件时，硫唑嘌呤组和对照组在不良事件发生率上无统计学显著差异。硫唑嘌呤组9%（11/127）的患者至少经历了一次不良事件，而安慰剂组为2%（3/130）（5项研究，257例患者；RR 2.82，95%CI 0.99至8.01）。接受硫唑嘌呤治疗的患者因不良事件退出的风险显著增加。硫唑嘌呤组8%（8/101）的患者因不良事件退出，而对照组为0%（0/98）（5项研究，199例患者；RR 5.43，95%CI 1.02至28.75）。与研究药物相关的不良事件包括急性胰腺炎（3例，环孢素组另有1例）和严重骨髓抑制（5例）。未报告死亡、机会性感染或肿瘤。
在溃疡性结肠炎中，硫唑嘌呤治疗在维持缓解方面似乎比安慰剂更有效。硫唑嘌呤或6-巯基嘌呤对于美沙拉嗪或柳氮磺胺吡啶治疗失败或不耐受的患者以及需要反复使用类固醇治疗的患者可能是有效的维持治疗药物。需要更多研究来评估其相对于标准维持治疗的优越性，特别是考虑到硫唑嘌呤存在不良事件的可能性。本综述更新了Cochrane图书馆（2012年9月）发表的关于硫唑嘌呤和6-巯基嘌呤维持溃疡性结肠炎缓解的现有综述。
