Background

Anti-tumour necrosis factor (TNF) agents are the mainstay of long-term treatment for refractory ulcerative colitis. However, long-term use of anti-TNF therapy might lead to an increased risk of malignancy or infection. To date, no randomised controlled trial has evaluated whether anti-TNF agents can be safely discontinued in patients with ulcerative colitis in remission. We therefore aimed to compare outcomes in these patients who continued infliximab with those who discontinued infliximab.

Methods

We did a multicentre, open-label randomised controlled trial at 24 specialist centres in Japan. We enrolled patients with ulcerative colitis who were in remission, had been treated with intravenous infliximab (5 mg/kg) every 8 weeks, and had started infliximab at least 14 weeks before study enrolment. No restrictions regarding age and comorbidities were used to exclude participation. Patients who were confirmed to be in remission for more than 6 months, to be corticosteroid-free, and to have a Mayo Endoscopic Subscore (MES) of 0 or 1 were centrally randomised. An independent organisation randomly assigned patients (1:1) into either the infliximab-continued group or infliximab-discontinued group, using a computer-generated stratified randomisation procedure. The stratified factors were the use of immunomodulators (yes or no) and MES (0 or 1). Neither patients nor health-care providers were masked to the randomisation. The primary endpoint was the remission rate at week 48 in the full analysis set, which was based on the intention-to-treat principle and excluded participants with no efficacy data after randomisation. This study was registered with the University Hospital Medical Information Network Center Trials registry, UMIN000012092.

Findings

Between June 16, 2014, and July 28, 2017, 122 patients were eligible for screening and a total of 95 patients were randomly assigned to the infliximab-continued group (n=48) or the infliximab-discontinued group (n=47). 92 patients (n=46 for both groups) were included in the full analysis set. 37 (80·4% [95% CI 66·1–90·6]) of 46 patients in the infliximab-continued group and 25 (54·3% [39·0–69·1]) of 46 patients in the infliximab-discontinued group were in remission at week 48. The between-group difference was 26·1% (95% CI 7·7–44·5; p=0·0076) before adjustment and 27·3% (95% CI 8·0–44·1; p=0·0059) after adjustment for stratification factors. Eight (17%) of 48 patients in the infliximab-continued group and six (13%) of 47 in the infliximab-discontinued group developed adverse events (between-group difference 3·9% [95% CI −10·3 to 18·1]; p=0·59). In the infliximab-continued group, one patient had an infusion reaction and two patients had psoriatic skin lesions. Eight (66·7%, 95% CI 34·9–90·1) of the 12 patients in the infliximab-discontinuation group who were re-treated with infliximab after relapsing were in remission within 8 weeks of re-treatment; none had infusion reactions.

Interpretation

Maintenance of remission was significantly more common in patients who continued infliximab than in those who discontinued. Discontinuing infliximab should therefore be discussed with caution, taking both risk of relapse and efficacy of re-treatment into account.

Funding

Mitsubishi Tanabe Pharma Corporation and the Intractable Disease Project of the Ministry of Health, Labour and Welfare of Japan.

Translation

For the Japanese translation of the abstract see Supplementary Materials section.

中文翻译：

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溃疡性结肠炎缓解期（HAYABUSA）患者停用英夫利昔单抗：一项多中心、开放标签、随机对照试验

背景

抗肿瘤坏死因子 (TNF) 药物是难治性溃疡性结肠炎长期治疗的中流砥柱。然而，长期使用抗 TNF 治疗可能会导致恶性肿瘤或感染的风险增加。迄今为止，还没有随机对照试验评估溃疡性结肠炎缓解期患者是否可以安全停用抗 TNF 药物。因此，我们旨在比较这些继续使用英夫利昔单抗的患者与停用英夫利昔单抗的患者的结局。

方法

我们在日本的 24 个专科中心进行了一项多中心、开放标签的随机对照试验。我们招募了处于缓解期的溃疡性结肠炎患者，每 8 周接受一次静脉注射英夫利昔单抗 (5 mg/kg) 治疗，并且在纳入研究前至少 14 周开始使用英夫利昔单抗。没有使用关于年龄和合并症的限制来排除参与。确认缓解超过 6 个月、不使用皮质类固醇并且梅奥内窥镜评分 (MES) 为 0 或 1 的患者被集中随机分组。一个独立组织使用计算机生成的分层随机化程序将患者 (1:1) 随机分配到英夫利昔单抗继续治疗组或英夫利昔单抗停用组。分层因素是使用免疫调节剂（是或否）和 MES（0 或 1）。患者和医疗保健提供者都没有被随机化掩盖。主要终点是全分析集中第 48 周的缓解率，该数据基于意向治疗原则，并排除了随机化后没有疗效数据的参与者。本研究已在大学医院医学信息网络中心试验注册处注册，UMIN000012092。

调查结果

2014 年 6 月 16 日至 2017 年 7 月 28 日期间，122 名患者符合筛查条件，总共 95 名患者被随机分配到英夫利昔单抗继续组（n=48）或英夫利昔单抗停药组（n=47）。92 名患者（两组 n = 46）包括在完整分析集中。英夫利昔单抗继续治疗组 46 名患者中有 37 名（80·4% [95% CI 66·1–90·6]），46 名患者中有 25 名（54·3% [39·0-69·1]）英夫利昔单抗停用组在第 48 周时缓解。调整前的组间差异为 26·1%（95% CI 7·7–44·5；p=0·0076）和 27·3%（95% CI 8·0–44·1；p=0·0059）调整分层因素后。英夫利昔单抗继续治疗组 48 名患者中有 8 名 (17%) 和英夫利昔单抗停药组 47 名患者中有 6 名 (13%) 发生不良事件（组间差异 3·9% [95% CI -10·3 至 18 ·1]；p=0·59)。在英夫利昔单抗继续治疗组中，1 名患者出现输液反应，2 名患者出现银屑病皮损。英夫利昔单抗停药组 12 例复发后再次接受英夫利昔单抗治疗的患者中有 8 例（66·7%，95% CI 34·9–90·1）在再治疗的 8 周内缓解；没有人有输液反应。

口译

在继续使用英夫利昔单抗的患者中，维持缓解的情况明显多于停药的患者。因此，应谨慎讨论停用英夫利昔单抗，同时考虑复发风险和再治疗效果。

资金

Mitsubishi Tanabe Pharma Corporation 和日本厚生劳动省疑难杂症项目。

翻译

有关摘要的日语翻译，请参阅补充材料部分。