Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel.
Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel.
Aliment Pharmacol Ther. 2018 Jan;47(2):212-218. doi: 10.1111/apt.14410. Epub 2017 Nov 9.
Primary nonresponse, defined as lack of clinical benefit during the induction phase, occurs in up to 30% of IBD patients treated with infliximab. The mechanisms underlying primary nonresponse have not yet been clearly defined.
To evaluate the association of early (week 2 and week 6) induction infliximab and anti-infliximab antibody levels with primary nonresponse.
A retrospective observational case-control study of inflammatory bowel disease patients treated with infliximab and followed at Sheba Medical Center between 2009 and 2016 was performed. Pre-infusion infliximab and antibodies to infliximab (ATI) levels were measured by our previously described drug-tolerant ELISA assay.
Thirty-five primary nonresponders have been identified and matched with 105 primary responders (1:3 ratios). Both week 2 and week 6 infliximab levels were significantly lower among primary nonresponders compared to responders (week 2, 6: median level 7.2, 2.2 μg/mL vs 13.5, 9.5 μg/mL, P = .0019, P < .0001 respectively). Antibodies to infliximab appeared more frequently (either week 2 or 6, 68% vs 28% prevalence, P = .0004) and at higher levels in nonresponders compared to responders (week 2, 6: median ATI 7.3, 10.8 μg/mL-eq vs 3.8, 4.4 μg/mL-eq, P = .005, P = .008 respectively). Moreover, week 2 infliximab levels <6.8 μg/mL (AUC = 0.68, P = .002, sensitivity 50%, specificity 86%) and antibodies to infliximab levels >4.3 μg/mL-eq (AUC = 0.78, P = .0004, sensitivity 77%, specificity 71%) were predictive of primary nonresponse. Among the other clinical and demographic variables, higher baseline ulcerative colitis clinical score, infliximab monotherapy, prior adalimumab therapy and previous Crohn's disease-related surgeries were also associated with an increased risk of primary nonresponse.
Infliximab levels below 6.8 μg/mL and antibodies to infliximab levels above 4.3 μg/mL-eq before the second infusion are associated with primary nonresponse, especially among Crohn's disease patients.
原发性无应答，定义为诱导期内缺乏临床获益，在接受英夫利昔单抗治疗的 IBD 患者中高达 30%。原发性无应答的机制尚未明确。
评估早期（第 2 周和第 6 周）诱导英夫利昔单抗和抗英夫利昔单抗抗体水平与原发性无应答的关系。
对 2009 年至 2016 年在谢巴医疗中心接受英夫利昔单抗治疗并接受随访的炎症性肠病患者进行回顾性观察性病例对照研究。通过我们之前描述的药物耐受 ELISA 测定法检测预输注英夫利昔单抗和抗英夫利昔单抗抗体（ATI）水平。
确定了 35 名原发性无应答者，并与 105 名原发性应答者（1:3 比例）相匹配。与应答者相比，原发性无应答者的第 2 周和第 6 周英夫利昔单抗水平显著降低（第 2 周，中位数水平 7.2、2.2μg/mL 与 13.5、9.5μg/mL，P=0.0019，P<0.0001）。抗英夫利昔单抗抗体出现的频率更高（第 2 周或第 6 周，分别为 68%和 28%，P=0.0004），且在无应答者中的水平更高（第 2 周，中位数 ATI 7.3、10.8μg/mL-等价物与 3.8、4.4μg/mL-等价物，P=0.005，P=0.008）。此外，第 2 周英夫利昔单抗水平<6.8μg/mL（AUC=0.68，P=0.002，敏感性 50%，特异性 86%）和抗英夫利昔单抗水平>4.3μg/mL-等价物（AUC=0.78，P=0.0004，敏感性 77%，特异性 71%）可预测原发性无应答。在其他临床和人口统计学变量中，更高的基线溃疡性结肠炎临床评分、英夫利昔单抗单药治疗、先前阿达木单抗治疗和先前克罗恩病相关手术也与原发性无应答的风险增加相关。
第二次输注前英夫利昔单抗水平<6.8μg/mL 和抗英夫利昔单抗水平>4.3μg/mL-等价物与原发性无应答相关，尤其是在克罗恩病患者中。
