Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia; Department of Medicine (Austin Health), University of Melbourne, Melbourne, VIC, Australia.
Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia.
Lancet Gastroenterol Hepatol. 2024 Nov;9(11):981-996. doi: 10.1016/S2468-1253(24)00200-0. Epub 2024 Sep 2.
The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC.
In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed.
Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study.
Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3.
Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.
对于激素难治性急性重度溃疡性结肠炎（ASUC），英夫利昔单抗的最佳给药策略尚不清楚。我们比较了强化和标准剂量英夫利昔单抗解救策略，并探讨了 ASUC 中英夫利昔单抗诱导后的维持治疗。
在这项开放标签、多中心、随机对照试验中，来自澳大利亚 13 家三级医院的年龄在 18 岁及以上、接受静脉注射激素难治性 ASUC 的患者按 1:2 的比例随机分配（1:2）接受首剂 10 mg/kg 英夫利昔单抗或 5 mg/kg 英夫利昔单抗（随机分组 1）。采用区组随机化和既往硫嘌呤暴露史和研究地点分层，通过计算机生成的随机化方案保持分配隐藏。10 mg/kg 组（强化诱导策略[IIS]）的患者在无反应时第 7 天或更早时接受第二剂；5 mg/kg 组的所有患者在第 3 天至第 7 天之间（1:1；随机分组 2）重新随机分配至标准诱导策略（SIS）或加速诱导策略（AIS），从而产生三个诱导组。SIS 组患者在第 0、2 和 6 周接受 5 mg/kg 英夫利昔单抗治疗，如果第 3 天至第 7 天无反应，则额外给予 5 mg/kg 剂量。AIS 组患者在第 0、1 和 3 周接受 5 mg/kg 英夫利昔单抗治疗，如果第 3 天至第 7 天无反应，则增加第 1 周剂量至 10 mg/kg。主要结局为第 7 天的临床反应（Lichtiger 评分降至<10，与基线相比下降≥3 分，直肠出血改善，粪便频率降至每天≤4 次）。次要终点评估第 7 天和探索性终点的结局，并比较诱导方案至第 3 个月。从第 3 个月开始，根据治疗经验选择维持治疗，使用硫嘌呤单药治疗、英夫利昔单抗联合硫嘌呤或英夫利昔单抗单药治疗，并作为队列研究进行随访至第 12 个月。分析采用意向治疗。这项试验在 ClinicalTrials.gov 注册，NCT02770040，已经完成。
2016 年 7 月 20 日至 2021 年 9 月 24 日期间，共纳入 138 例患者（46 例女性[46%]，92 例男性[54%]）；46 例患者接受首剂 10 mg/kg 英夫利昔单抗，92 例患者接受 5 mg/kg 英夫利昔单抗。随机分组 1 后，我们观察到 10 mg/kg 组和 5 mg/kg 组第 7 天临床反应的患者比例之间无显著差异（30 例[65%]vs 56 例[61%]，校正硫嘌呤治疗史的风险比为 1.06[95%CI 0.94-1.20]，p=0.32）。我们未发现次要终点包括临床反应时间或第 7 天 Lichtiger 评分与基线的变化有显著差异。2 例接受 10 mg/kg 英夫利昔单抗治疗的患者在第 7 天内接受了结肠切除术，而 5 mg/kg 组无患者接受该治疗（p=0.21）。10 mg/kg 组和 5 mg/kg 组各有 3 例患者发生 3 例严重不良事件。随机分组 2 后，第 14 天的临床反应率（IIS 组 46 例中的 34 例[74%]，AIS 组 48 例中的 35 例[73%]，SIS 组 44 例中的 30 例[68%]，p=0.81）、第 3 个月的临床缓解率（23 例[50%]、25 例[52%]、21 例[48%]，p=0.92）、第 3 个月的激素无缓解率（19 例[41%]、20 例[42%]、18 例[41%]，p=1.0）、第 3 个月的内镜缓解率（21 例[46%]、22 例[46%]、21 例[48%]，p=0.98）和第 3 个月的结肠切除术率（IIS 组 45 例中的 3 例[7%]，AIS 组 47 例中的 9 例[19%]，SIS 组 43 例中的 5 例[12%]，p=0.20）在各组之间无显著差异。第 8 天至第 3 个月之间，IIS 组有 2 例（4%）、AIS 组有 8 例（17%）、SIS 组有 8 例（18%）患者至少有一次可能与英夫利昔单抗相关的感染性不良事件（p=0.082）。该研究中无死亡事件发生。
英夫利昔单抗是 ASUC 的一种安全有效的解救治疗方法。在激素难治性 ASUC 中，首剂 10 mg/kg 英夫利昔单抗在第 7 天的临床反应方面并不优于 5 mg/kg 英夫利昔单抗。强化、加速和标准诱导方案在第 14 天的临床反应率或第 3 个月的缓解率或结肠切除术率方面没有显著差异。
澳大利亚国家卫生和医学研究委员会、澳大利亚胃肠病学会、Gandel 慈善基金会、澳大利亚研究生奖学金、杨森制药公司。
