英孚立昔肠黏膜丢失与克罗恩病初治失反应关联研究

Loss of infliximab into feces is associated with lack of response to therapy in patients with Crohn′s disease

目的部分克罗恩病(Crohn′s disease,CD)患者对抗肿瘤坏死因子a(TNF-α)药物治疗无效,并且其机制未明,如英夫利昔单抗(Infliximab,IFX)。探讨抗TNF-α单抗(英孚利昔单抗)是否因肠道黏膜损伤而经肠粘膜丢失,从而降低了英孚利昔的血药浓度,从而影响CD患者的治疗疗效。方法收集32例初次接受英夫利昔单抗治疗的中度至重度活动期回结肠型CD患者(CDAI>220)的2周内的粪便样本。采用酶联免疫吸附试验测定粪便中英夫利昔单抗浓度,同时测定患者第2周的血清英孚利昔单抗浓度。并分别于英夫利昔单抗治疗后2周、8周和3个月评估临床和内镜治疗反应。结果收集的179份粪便样本中135份检出英夫利昔单抗(75.4%),最高浓度出现在第一次用药后的第一天。在第2周,临床无反应的患者,其第一天粪便英夫利昔单抗浓度显著高于有临床反应的患者[(7.01±0.71)mg/mL vs.(1.04±0.58)mg/mL,P=0.031],而粪便中英夫利昔单抗浓度和血清中英夫利昔单抗浓度无相关性。结论英夫利昔单抗经过肠道丢失到CD患者的粪便中。治疗后第一天粪便中英夫利昔单抗的高浓度与初治无反应相关。需要进一步的研究来确定抗体是如何通过肠粘膜丢失的,以及这一过程又是如何影响治疗的反应。

Objective It is not clear that some patients with crohn′s disease do not respond to treatment with anti-tumor necrosis factor(anti-TNF)agents,such as infliximab.We investigated whether loss of anti-TNF agents through intestinal mucosa reduces the efficacy of infliximab in patients with CD.Methods We collected fecal samples from 32 consecutive patients with moderate to severely active CD during the first 2 weeks of infliximab therapy.Infliximab concentrations were measured in serum and supernatants of fecal samples using an ELISA.Clinical and endoscopic responses were assessed 2 and 8 weeks and 3 months after treatment began.Results Infliximab was detected in 135 of 179 fecal samples(75.4%).The highest concentrations were measured in the first days after the first infusion.Patients that were clinical non-responses at week 2 had significantly higher fecal concentrations of infliximab after the first day of treatment than patients with clinical responses(median concentration,7.01±0.71 mg/mL in nonresponders vs.1.04±0.58 mg/mL in responders,P=0.031).We did not observe a correlation between fecal and serum concentrations of infliximab.Conclusions Infliximab is lost into stools of patients with CD.High fecal concentrations of infliximab in the first days after therapy begins are associated with primary nonresponse.