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Abstract：
Infliximab is a monoclonal antibody that binds and neutralises tumour necrosis factor-alpha (TNF-α) which is present in high levels in the blood serum, mucosa and stool of patients with Crohn\'s disease.
To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn\'s disease.
On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP.
Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn\'s disease.
Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events.
Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse.
Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.
To determine the efficacy and safety of infliximab for maintaining remission in patients with Crohn\'s disease.
On 31 August, 2021 and 23 June, 2023, we searched CENTRAL, Embase, MEDLINE, ClinicalTrials.gov, and WHO ICTRP.
Randomised controlled trials (RCTs) in which infliximab was compared to placebo or another active comparator for maintenance, remission, or response in patients with Crohn\'s disease.
Pairs of review authors independently selected studies and conducted data extraction and risk of bias assessment. We expressed outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using GRADE. Our primary outcome was clinical relapse. Secondary outcomes were loss of clinical response, endoscopic relapse, and withdrawal due to serious and adverse events.
Nine RCTs with 1257 participants were included. They were conducted between 1999 and 2022; seven RCTs included biologically-naive patients, and the remaining two included a mix of naive/not naive patients. Three studies included patients in clinical remission, five included patients with a mix of activity scores, and one study included biologic responders with active disease at baseline. All studies allowed some form of concomitant medication during their duration. One study exclusively included patients with fistulating disease. The age of the participants ranged from 18 to 69 years old. All but one single-centre RCT were multicentre RCTs. Four studies were funded by pharmaceutical companies, two had a mix of commercial and public funding, and two had public funding. Infliximab is probably superior to placebo in preventing clinical relapse in patients who have mixed levels of clinical disease activity at baseline, and are not naive to biologics (56% vs 75%, RR 0.73, 95% CI 0.63 to 0.84, NNTB = 5, moderate-certainty evidence). We cannot draw any conclusions on loss of clinical response (RR 0.59, 95% CI 0.37 to 0.96), withdrawals due to adverse events (RR 0.66, 95% CI 0.37 to 1.19), or serious adverse events (RR 0.60, 95% CI 0.36 to 1.00) because the evidence is very low certainty. Infliximab combined with purine analogues is probably superior to purine analogues for clinical relapse (12% vs 59%, RR 0.20, 95% CI 0.10 to 0.42, NNTB = 2, moderate-certainty evidence), for patients in remission, and who are not naive to biologics. We cannot draw any conclusions on withdrawals due to adverse events (RR 0.47, 95% CI 0.15 to 1.49), and serious adverse events (RR 1.19, 95% CI 0.54 to 2.64) because the evidence is very low certainty. We cannot draw any conclusions about the effects of infliximab on serious adverse events compared to purine analogues (RR 0.79, 95% CI 0.37 to 1.68) for a population in remission at baseline because the evidence is very low certainty. There was no evidence available for the outcomes of clinical relapse, loss of clinical response, and withdrawal due to adverse events. Infliximab may be equivalent to biosimilar for clinical relapse (47% vs 40% RR 1.18, 95% CI 0.82 to 1.69), and it may be slightly less effective in averting loss of clinical response (49% vs 32%, RR 1.50, 95% CI 1.01 to 2.23, low-certainty evidence), for a population with mixed/low disease activity at baseline. Infliximab may be less effective than biosimilar in averting withdrawals due to adverse events (27% vs 0%, RR 20.73, 95% CI 2.86 to 150.33, low-certainty evidence). Infliximab may be equivalent to biosimilar for serious adverse events (10% vs 10%, RR 0.99, 95% CI 0.39 to 2.50, low-certainty evidence). We cannot draw any conclusions on the effects of subcutaneous biosimilar compared with intravenous biosimilar on clinical relapse (RR 1.01, 95% CI 0.65 to 1.57), loss of clinical response (RR 0.94, 95% CI 0.70 to 1.25), and withdrawals due to adverse events (RR 0.77, 95% CI 0.30 to 1.97) for an active disease population with clinical response at baseline because the evidence is of very low certainty. We cannot draw any conclusions on the effects of infliximab compared to adalimumab on loss of clinical response (RR 0.68, 95% CI 0.29 to 1.59), withdrawals due to adverse events (RR 0.10, 95% CI 0.01 to 0.72), serious adverse events (RR 0.09, 95% CI 0.01 to 1.54) for an active disease population with clinical response at baseline because the evidence is of very low certainty. There was no evidence available for the outcome of clinical relapse.
Infliximab is probably more effective in preventing clinical relapse than placebo (moderate-certainty evidence). Infliximab in combination with purine analogues is probably more effective in preventing clinical and endoscopic relapse than purine analogues alone (moderate-certainty evidence). No conclusions can be drawn regarding prevention of loss of clinical response, occurrence of withdrawals due to adverse events, or total adverse events due to very low-certainty evidence for both of these comparisons. There may be little or no difference in prevention of clinical relapse, withdrawal due to adverse events or total adverse events between infliximab and a biosimilar (low-certainty evidence). Infliximab may lead to more loss of clinical response than a biosimilar (low-certainty evidence). We were unable to draw meaningful conclusions about other comparisons and outcomes related to missing data or very low-certainty evidence due to serious concerns about imprecision and risk of bias. Further research should focus on comparisons with other active therapies for maintaining remission, as well as ensuring adequate power calculations and reporting of methods.
摘要：
背景：英夫利昔单抗是一种单克隆抗体，可结合并中和血清中高水平的肿瘤坏死因子-α（TNF-α）。克罗恩病患者的粘膜和粪便。
目的：确定英夫利昔单抗维持克罗恩病患者缓解的有效性和安全性。
方法：8月31日，2021年6月23日，2023年，我们搜索了中部，Embase,MEDLINE,ClinicalTrials.gov,世卫组织ICTRP。
方法：将英夫利昔单抗与安慰剂或另一种用于维持的活性对照物进行比较的随机对照试验（RCT）。缓解,或克罗恩病患者的反应。
方法：成对的综述作者独立选择研究，进行数据提取和偏倚风险评估。我们用95%置信区间将结果表示为风险比和平均差异。我们使用GRADE评估证据的确定性。我们的主要结果是临床复发。次要结果是临床反应丧失，内镜下复发,以及由于严重和不良事件而退出。
结果：纳入了9个RCT，1257名参与者。他们在1999年至2022年之间进行；七个RCT包括未接受生物学治疗的患者，其余两名患者包括幼稚/非幼稚患者。三项研究包括临床缓解的患者，五名患者包括混合活动评分，一项研究包括基线时患有活动性疾病的生物反应者。所有研究都允许在其持续时间内进行某种形式的伴随药物治疗。一项研究仅包括患有瘘管疾病的患者。参与者的年龄从18岁到69岁不等。除一个单中心RCT外，所有RCT均为多中心RCT。四项研究由制药公司资助，两个有商业和公共资金的混合，两个有公共资金。英夫利昔单抗在预防基线时具有混合水平临床疾病活动的患者的临床复发方面可能优于安慰剂。对生物制剂并不幼稚(56%对75%，RR0.73，95%CI0.63至0.84，NNTB=5，中等确定性证据)。我们无法得出任何关于临床反应丧失的结论（RR0.59，95%CI0.37至0.96），因不良事件而退出(RR0.66，95%CI0.37至1.19)，或严重不良事件（RR0.60，95％CI0.36至1.00），因为证据的确定性非常低。英夫利昔单抗联合嘌呤类似物的临床复发可能优于嘌呤类似物（12％vs59％，RR0.20，95%CI0.10至0.42，NNTB=2，中等确定性证据)，对于缓解期的患者，对生物制品并不幼稚。我们无法就不良事件导致的提款得出任何结论（RR0.47，95%CI0.15至1.49），和严重不良事件（RR1.19，95％CI0.54至2.64），因为证据的确定性非常低。对于基线缓解的人群，我们无法得出关于英夫利昔单抗对严重不良事件的影响的任何结论（RR0.79，95％CI0.37至1.68），因为证据的确定性非常低。没有证据表明临床复发的结果，临床反应丧失，和因不良事件而退出。英夫利昔单抗可能相当于临床复发的生物仿制药（47%vs40%RR1.18，95%CI0.82至1.69），在避免临床反应丧失方面可能效果稍差(49%vs32%，RR1.50，95%CI1.01至2.23，低确定性证据)，对于基线时疾病活动性混合/低的人群。英夫利昔单抗在避免因不良事件而退出药物方面可能不如生物仿制药有效(27%vs0%,RR20.73，95%CI2.86至150.33，低确定性证据）。英夫利昔单抗可能相当于生物仿制药的严重不良事件（10％vs10％，RR0.99，95%CI0.39至2.50，低确定性证据)。我们无法得出皮下生物仿制药与静脉生物仿制药相比对临床复发的影响的任何结论（RR1.01,95%CI0.65至1.57），临床反应丧失(RR0.94，95%CI0.70至1.25)，对于基线时具有临床反应的活动性疾病人群,以及由于不良事件(RR0.77,95%CI0.30~1.97)而退出治疗,因为证据的确定性非常低.我们无法得出英夫利昔单抗与阿达木单抗相比对临床反应丧失的影响的任何结论（RR0.68，95％CI0.29至1.59），因不良事件而退出（RR0.10，95%CI0.01至0.72），对于基线时出现临床缓解的活动性疾病人群,严重不良事件(RR0.09,95%CI0.01~1.54),因为证据的确定性非常低.没有证据表明临床复发的结果。
结论：英夫利昔单抗在预防临床复发方面可能比安慰剂更有效（中度确定性证据）。英夫利昔单抗联合嘌呤类似物可能比单独使用嘌呤类似物更有效地预防临床和内镜下复发（中度确定性证据）。没有关于预防临床反应丧失的结论，由于不良事件而发生的提款，或由于这两种比较的确定性证据非常低而导致的总不良事件。在预防临床复发方面可能有很小或没有区别，因英夫利昔单抗和生物仿制药之间的不良事件或总不良事件而停药(低确定性证据).英夫利昔单抗可能导致比生物仿制药更多的临床反应丧失（低确定性证据）。由于对不精确和偏倚风险的严重担忧，我们无法就与缺失数据或极低确定性证据相关的其他比较和结果得出有意义的结论。进一步的研究应该集中在与其他积极疗法的比较，以维持缓解，以及确保足够的功率计算和方法报告。
目的：确定英夫利昔单抗维持克罗恩病患者缓解的有效性和安全性。
方法：8月31日，2021年6月23日，2023年，我们搜索了中部，Embase,MEDLINE,ClinicalTrials.gov,世卫组织ICTRP。
方法：将英夫利昔单抗与安慰剂或另一种用于维持的活性对照物进行比较的随机对照试验（RCT）。缓解,或克罗恩病患者的反应。
方法：成对的综述作者独立选择研究，进行数据提取和偏倚风险评估。我们用95%置信区间将结果表示为风险比和平均差异。我们使用GRADE评估证据的确定性。我们的主要结果是临床复发。次要结果是临床反应丧失，内镜下复发,以及由于严重和不良事件而退出。
结果：纳入了9个RCT，1257名参与者。他们在1999年至2022年之间进行；七个RCT包括未接受生物学治疗的患者，其余两名患者包括幼稚/非幼稚患者。三项研究包括临床缓解的患者，五名患者包括混合活动评分，一项研究包括基线时患有活动性疾病的生物反应者。所有研究都允许在其持续时间内进行某种形式的伴随药物治疗。一项研究仅包括患有瘘管疾病的患者。参与者的年龄从18岁到69岁不等。除一个单中心RCT外，所有RCT均为多中心RCT。四项研究由制药公司资助，两个有商业和公共资金的混合，两个有公共资金。英夫利昔单抗在预防基线时具有混合水平临床疾病活动的患者的临床复发方面可能优于安慰剂。对生物制剂并不幼稚(56%对75%，RR0.73，95%CI0.63至0.84，NNTB=5，中等确定性证据)。我们无法得出任何关于临床反应丧失的结论（RR0.59，95%CI0.37至0.96），因不良事件而退出(RR0.66，95%CI0.37至1.19)，或严重不良事件（RR0.60，95％CI0.36至1.00），因为证据的确定性非常低。英夫利昔单抗联合嘌呤类似物的临床复发可能优于嘌呤类似物（12％vs59％，RR0.20，95%CI0.10至0.42，NNTB=2，中等确定性证据)，对于缓解期的患者，对生物制品并不幼稚。我们无法就不良事件导致的提款得出任何结论（RR0.47，95%CI0.15至1.49），和严重不良事件（RR1.19，95％CI0.54至2.64），因为证据的确定性非常低。对于基线缓解的人群，我们无法得出关于英夫利昔单抗对严重不良事件的影响的任何结论（RR0.79，95％CI0.37至1.68），因为证据的确定性非常低。没有证据表明临床复发的结果，临床反应丧失，和因不良事件而退出。英夫利昔单抗可能相当于临床复发的生物仿制药（47%vs40%RR1.18，95%CI0.82至1.69），在避免临床反应丧失方面可能效果稍差(49%vs32%，RR1.50，95%CI1.01至2.23，低确定性证据)，对于基线时疾病活动性混合/低的人群。英夫利昔单抗在避免因不良事件而退出药物方面可能不如生物仿制药有效(27%vs0%,RR20.73，95%CI2.86至150.33，低确定性证据）。英夫利昔单抗可能相当于生物仿制药的严重不良事件（10％vs10％，RR0.99，95%CI0.39至2.50，低确定性证据)。我们无法得出皮下生物仿制药与静脉生物仿制药相比对临床复发的影响的任何结论（RR1.01,95%CI0.65至1.57），临床反应丧失(RR0.94，95%CI0.70至1.25)，对于基线时具有临床反应的活动性疾病人群,以及由于不良事件(RR0.77,95%CI0.30~1.97)而退出治疗,因为证据的确定性非常低.我们无法得出英夫利昔单抗与阿达木单抗相比对临床反应丧失的影响的任何结论（RR0.68，95％CI0.29至1.59），因不良事件而退出（RR0.10，95%CI0.01至0.72），对于基线时出现临床缓解的活动性疾病人群,严重不良事件(RR0.09,95%CI0.01~1.54),因为证据的确定性非常低.没有证据表明临床复发的结果。
结论：英夫利昔单抗在预防临床复发方面可能比安慰剂更有效（中度确定性证据）。英夫利昔单抗联合嘌呤类似物可能比单独使用嘌呤类似物更有效地预防临床和内镜下复发（中度确定性证据）。没有关于预防临床反应丧失的结论，由于不良事件而发生的提款，或由于这两种比较的确定性证据非常低而导致的总不良事件。在预防临床复发方面可能有很小或没有区别，因英夫利昔单抗和生物仿制药之间的不良事件或总不良事件而停药(低确定性证据).英夫利昔单抗可能导致比生物仿制药更多的临床反应丧失（低确定性证据）。由于对不精确和偏倚风险的严重担忧，我们无法就与缺失数据或极低确定性证据相关的其他比较和结果得出有意义的结论。进一步的研究应该集中在与其他积极疗法的比较，以维持缓解，以及确保足够的功率计算和方法报告。
