修回日期: 2015-07-03
接受日期: 2015-07-24
在线出版日期: 2015-11-08
我国炎症性肠病(inflammatory bowel disease, IBD)发病率逐年上升, 本文主要介绍IBD发病的免疫学机制, 并且对目前新出现的生物制剂之一-英夫利昔单抗(infliximab, IFX)在这类疾病中应用的理论学基础及疗效进行介绍, 讨论IFX血清浓度与临床持续应答和内镜下缓解的相关性, IFX血清浓度在溃疡性结肠炎(ulcerative colitis)和克罗恩病(Crohn's disease)中的差异, 术前IFX血清浓度对手术预后的影响, 重点讨论对于复发患者、有IFX抗体(anti-IFX antibodies, ATI)产生或对药物失去应答(lose a response, LOR)患者在用药选择上, IFX血清浓度检测有重要的指导价值.
核心提示: 本文在生物制剂英夫利昔单抗(infliximab, IFX)应用于炎症性肠病(inflammatory bowel disease)的机制及疗效基础上, 讨论IFX血清浓度与临床持续应答、内镜下缓解的相关性, 在溃疡性结肠炎(ulcerative colitis )和克罗恩病(Crohn's disease)中的差异, 术前IFX血清浓度对手术预后的影响以及对复发患者、有IFX抗体(anti-IFX antibodies)产生或对药物失去应答的患者在用药选择上, IFX血清浓度检测具有重要的指导价值.
引文著录: 施嫣红, 翁韵, 刘占举. 血清英夫利昔单抗浓度检测对炎症性肠病患者疗效的评估价值. 世界华人消化杂志 2015; 23(31): 4946-4953
Revised: July 3, 2015
Accepted: July 24, 2015
Published online: November 8, 2015
The incidence of inflammatory bowel disease (IBD) is increasingly rising. This paper mainly introduces the immunological pathogenesis of IBD, and clarifies the theoretical basis, clinical efficacy and applications of infliximab (IFX), which is one of the new biological agents. We also discuss the relationship between serum IFX level and clinical response as well as endoscopic improvement, the difference between ulcerative colitis (UC) and Crohn's disease (CD) in serum IFX concentration, and the effect of preoperative serum IFX concentration on postoperative prognosis, highlighting the value of serum IFX concentration detection in the treatment of patients with recurrence, anti-IFX antibodies (ATI) or loss of response.
- Citation: Shi YH, Weng Y, Liu ZJ. Detection of serum infliximab concentration for evaluation of treatment efficacy in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2015; 23(31): 4946-4953
- URL: https://www.wjgnet.com/1009-3079/full/v23/i31/4946.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i31.4946
炎症性肠病(inflammatory bowel disease, IBD)是一种累及肠道的慢性、复发性炎症疾病, 包括溃疡性结肠炎(ulcerative colitis, UC)和克罗恩病(Crohn's disease, CD). 其病因及发病机制目前尚不完全明确[1], 目前大多学者认为肠道持续感染、肠黏膜屏障缺损、肠黏膜免疫调节异常、遗传和环境等因素共同参与了疾病发生过程[2-5]. 其中, 免疫因素在IBD的发病机制中极为重要[6].
肠道内细菌及微生物抗原增高及肠道菌群失衡诱导IBD的发生, 伴随着肠上皮细胞间紧密连接蛋白表达下降, 肠黏膜屏障功能受损, 通透性增加, 导致大量微生物和食物抗原吸收增加, 诱导黏膜组织内中性粒细胞、巨噬细胞、T细胞、B细胞和树突状细胞激活, 产生大量促炎症细胞因子[7], 同时这些免疫细胞可激活细胞内一系列信号, 诱导细胞核因子-κB(nuclear factor-κB, NF-κB)激活, 促使细胞因子、黏附分子和趋化因子释放, 引起免疫应答[8,9].
研究[10-12]发现CD的炎症肠黏膜组织内CD4+ T细胞产生大量Th1/Th17效应相关的促炎症细胞因子如干扰素-γ(interferon γ, IFN-γ)、肿瘤坏死因子(tumor necrosis factor, TNF)、白介素-17A(interleukin-17A, IL-17A)、IL-12、IL-18、IL-21、IL-23; 而UC的炎症肠黏膜组织内CD4+ T和自然杀伤细胞(natural killer T cells, NKT)可分泌大量Th2效应相关的细胞因子(如IL-4、IL-13), 这些促炎因子加重肠黏膜炎症损伤.
TNF是一种能够诱导细胞繁殖和分化的促炎症细胞因子, Liu等[13]在三硝基苯磺酸诱导的IBD模型中发现, TNF-α是由巨噬细胞在炎症第一阶段释放, 是最重要的促炎症细胞因子之一. 过多的TNF-α诱导肠上皮间紧密连接分解及上皮细胞凋亡, 导致肠上皮屏障的破坏; 增加肠黏膜在固有免疫和获得性免疫中暴露于促炎因子的机会; 同时引发结肠上皮细胞趋化因子的分泌, 刺激细胞间黏附分子的表达, 增加白细胞在炎症部位的聚集和活化; 刺激促炎细胞因子生成, 放大炎症级联反应; 刺激成纤维细胞和巨噬细胞释放组织降解酶, 导致肠黏膜的损害[14,15].
目前临床上已经开展的生物靶向免疫治疗, 主要是通过阻断上述促炎症细胞因子(如TNF、IL-12/IL-23p40、IL-23p19)以有效抑制肠道炎症发生, 诱导活动期IBD患者病情缓解.
TNF与IBD发病关系密切, 且IBD患者病情与炎症肠黏膜中TNF的表达水平相关, 而抑制TNF的表达能明显缓解IBD病情[16]. 目前用于治疗IBD的抗TNF-α制剂主要包括英夫利昔单抗(infliximab, IFX)、阿达木单抗(adalimumab)和赛妥珠单抗(certolizumab pegol), 这些制剂通过与患者体内可溶性或跨膜性TNF-α特异性结合后, 抑制表达TNF的细胞功能, 并通过Fc段介导T细胞的补体结合作用诱导细胞凋亡, 产生抗体依赖的细胞毒作用, 从而达到抗炎效果[17,18].
研究[19]发现, IFX可有效修复活动期IBD患者破坏的肠黏膜屏障, 改善肠黏膜的损伤; 体外研究发现IFX可激活补体依赖的细胞溶解和抗体依赖的细胞介导的细胞毒作用; IFX能调节肠黏膜组织内T细胞促凋亡蛋白基因转录, 改变细胞内促凋亡蛋白和抗凋亡蛋白比例, 诱导黏膜内T细胞和单核-巨噬细胞凋亡; IFX能显著降低黏附分子和趋化因子生物活性, 阻止白细胞在肠黏膜组织内的浸润, 降低白细胞β7和CCR7表达[20]; 抑制炎症细胞肠黏膜组织内辅助信号分子表达, 降低白细胞激活; IFX可增强Treg效应, 有效上调其免疫抑制活性, 恢复Th的平衡, 起到免疫保护作用[21]; IFX不仅能抑制经典激活的巨噬细胞(classical activated macrophage, CAM)功能, 诱导肠黏膜炎症缓解, 参与组织修复, 还能诱导替代激活的巨噬细胞(alternative activated macrophage, AAM)增殖分化[22]; IFX能降低炎症肠黏膜组织内血管生成及血管内皮细胞增殖分化, 降低VEGF表达; 阻止肠黏膜组织内促炎症因子如IFN-γ、IL-1、IL-6等表达, 上调抑制炎症因子表达; 诱导肠黏膜组织内miRNA10a表达, 降低IL-12/IL-23p40、NOD2表达以及Th17细胞浸润[23].
IFX是首个被批准应用于临床治疗IBD的抗TNF-α生物制剂, 是一种由基因工程生产的人-鼠嵌合体IgG1单克隆抗体, 其分子系列中75%是人源性, 25%鼠源性. IFX主要适用于中度、重度活动性CD患者; 激素及免疫抑制剂治疗无效或激素依赖者; 不能耐受激素及免疫抑制剂治疗者; 与CD相关的瘘管形成者[24]. 目前认为, 具有年轻、狭窄型病变、病变范围广、伴有肛周病变等预后较差的危险因素的患者, 接受IFX治疗会明显受益[25]. 多项临床研究[26-28]证实IFX对活动性CD有效, 能促进内镜下黏膜修复、愈合瘘道、改善患者生活质量, 降低住院率及外科手术率. 目前IFX也被批准用于中度至重度的UC, 根据ACT1、ACT2试验拓展研究, 发现UC患者在使用IFX3年后仍有应答[29], 且对于重症难治性UC而言, IFX较环孢素效果更佳[30].
IFX治疗IBD具有确切的疗效, 可有效诱导并维持中、重度活动性CD的缓解; 诱导并维持CD瘘管的闭合; 对于难治性UC或中重度UC有较明显的疗效; 早期使用能有效促进黏膜愈合; 减少激素的使用; 降低住院率和结肠切除率[31-33].
研究[34]发现, 25%-40%IBD患者在IFX维持治疗中出现对药物失去应答(lose a response, LOR), 每年因LOR而终止用药的患者接近10%, 其发病机制目前并不清楚, 可能与IFX药物浓度不足及抗体的出现有关. 低的IFX谷浓度与低的临床应答有更直接的关系, 超过了抗IFX抗体(anti-IFX antibodies, ATI)的出现[35]. 尽管抗体在较短的应答时间内起了一定作用, 但研究[36,37]提示, 相比ATI的存在而言, 可检测的IFX谷浓度可预测患者的临床应答和内镜下黏膜的愈合. 谷血清浓度是指在下次用药之前血清IFX药物浓度的最低点. 研究[38]发现, IFX治疗的IBD患者血清中, 可测得谷血清浓度的患者与无法测得谷血清浓度的患者临床缓解率分别为69%、15%, 内镜缓解率分别为76%、28%, 结肠切除风险分别为55%、7%.
谷血清浓度与临床持续应答、低的CRP水平和内镜下缓解正相关[38]. SONIC试验中发现, 无论在治疗的30 wk或46 wk, 高IFX血清浓度CD患者病情缓解更常见[39]. ACCENT试验中, 在谷血清浓度高(>10 μg/mL)的CD中64%的患者瘘管完全愈合, 而无法测得谷血清浓度的CD中仅有25%患者瘘管获得愈合[40]. 来自于ACT1和ACT2的UC研究发现, 治疗第1年中, IFX血清浓度的升高提高了UC患者的临床应答、缓解及黏膜愈合的可能性[41]. 无法测得IFX血清浓度的患者的结肠切除率明显提高[36].
Kunitake等[42]发现术前使用IFX并不增加CD及UC患者的术后的感染、死亡、肠梗阻、吻合口瘘、血栓形成等并发症. 但Lau等[43]在2013-05的佛罗里达州消化疾病周上报道, 可测得IFX血清浓度的患者与无法测得血清浓度的患者术后复发率分别为32%、18%, 感染发生率为22%、10%, 术后住院率16%、7%, 这个结果虽未达统计学意义, 但在IFX血清浓度低、中、高的亚群分析中IFX血清浓度>8 μg/mL的患者术后感染的并发症(26% vs 10%, P = 0.03)及术后住院率(20% vs 7%, P = 0.05)较低浓度的患者均增高, 故认为CD患者术前IFX血清浓度升高, 可能面临着更大的术后并发症的风险. 但在UC患者中, 术前IFX血清浓度对手术的预后无任何影响[44].
对IBD缓解后复发或停用IFX的患者, 再次使用IFX治疗, 结果还是令人满意的, 药物浓度的监测也能预测长期停用后再次运用IFX患者的临床应答. Baert等[44]发现, 在第1次重新使用IFX前检测药物浓度和抗体对临床无任何意义, 但在药物使用后常规检查浓度及抗体, 如果发现患者有ATI阳性, 且无法检测到IFX药物浓度, 那么IFX治疗应停止.
IFX血清浓度在UC和CD两个疾病中无区别, IFX谷血清浓度的个体差异主要与个体药物清除率不同有关, 涉及肌酐清除率、肝脏代谢、药物相互作用及血清白细胞基数. 另外, IFX药物浓度与血清白蛋白相关[45], 高的血清白蛋白可延长IFX的半衰期, 提高疗效.
IFX药物浓度过低无法足够抑制TNF-α活性, 在SONIC试验中, 计算出30 wk时缓解的CD患者IFX血清浓度阈值为3 μg/mL, 维持缓解时谷IFX血清浓度达3 μg/mL或更高是决定临床应答及26 wk时黏膜愈合的关键因素[46]; 而在大多数获得临床缓解的UC患者中30 wk时IFX浓度在2.4-6.8 μg/mL[41]. 另有报道[47]表明, UC患者中, IFX诱导缓解8 wk时血清浓度达41 μg/mL, 维持治疗时IFX血清浓度达3.7 μg/mL或以上被认为是UC患者取得最佳预后的血清浓度.
IFX使用中可产生抗体, 2010年的一项回顾性分析[48]显示, 测定155例患者的IFX血清浓度及IFX抗体, 在35例(23%)患者中检测到IFX抗体, 51例(33%)检测到治疗浓度的IFX. Master等[49]发现, 在可检测到IFX浓度的持续应答的患者中, 有ATI和无ATI对疗效无任何区别. ATI阳性与低的谷浓度有显著关系, 大多数出现在检测不到或极低的谷浓度时. 一项研究[41]发现, 77%的患者中IFX浓度在0.00-2.31 μg/mL能检测到ATI阳性, 相反谷浓度在14.98-39.59 μg/mL是检测不到ATI, 故一般认为ATI的阳性与IFX浓度低于3 μg/mL有关. 另外, ATI往往出现在25%的丢失应答、有药物不良反应及过敏的IBD患者中[50].
调整IFX用药可作为缓解LOR发生的方法之一, 提高IFX剂量至10 mg/kg, 或缩短给药间隔(4或6 wk)是一种有效方法. 研究[47]发现, 在静脉滴注IFX剂量低于12 mg/mL时, 剂量增加能使29例CD患者中25例产生临床应答, 比更换另一种药物更有效. 据研究[41,51]显示, 缩短IFX给药间隔或提高药物剂量这两种方式对恢复药物应答无明显差异, 然而, 能达到治疗的血清浓度不是很清楚, 来自于不同试验的532例CD患者提示: >3 μg/mL的谷血清浓度能对抗炎症活动, 可降低治疗失败的风险. Steenholdt等[52]表明, 防止失去应答的谷血清浓度为≥0.5 μg/mL, Hibi等[53]发现取得强的临床应答的谷血清浓度为1 μg/mL, 但黏膜愈合需要4 μg/mL的谷血清浓度[54].
用药剂量的调整在低IFX血清浓度的患者中是一种可行的办法, 而如果是抗体的出现是引起应答失败的原因, 那么只有调换其他药物[55].
临床上影响IFX的疗效除ATI的出现外, 还与是否同时使用免疫抑制剂有关. 免疫抑制剂、高剂量的激素, 可能减少IFX免疫原性的产生. 有报道[46]称, 单一使用IFX组30 wk时谷IFX浓度为1.6 μg/mL, 而在IFX联合硫唑嘌呤组可达3.5 μg/mL, 联合治疗可以提高IFX浓度, 而单一治疗需要更高剂量IFX的输入才能达到相同的IFX浓度和临床缓解. 有研究[43]显示, IFX联合硫唑嘌呤治疗CD患者, 在中断硫唑嘌呤后与继续联合使用硫唑嘌呤进行比较, 发现中断硫唑嘌呤后IFX的谷血清浓度逐渐下降, 可能是免疫抑制剂影响了IFX的细胞膜受体Fc段的表达, 干扰IFX与受体Fc段的结合, 影响了临床疗效. 同时使用免疫抑制剂治疗对低IFX浓度的患者有长期影响临床应答的作用, 但对高浓度IFX的患者无任何影响.
IFX的血清浓度监测在临床上发挥了重要的作用, 血清浓度监测比经验性增加药物剂量或换用二线或三线抗TNF-α治疗药物更合理, 能更有效的制定个体化用药. 如果IBD患者ATI阳性, 同时具有有效的IFX血清药物浓度, 而且临床应答良好, 那么继续使用IFX治疗的同时还应密切监测药物浓度; 如果ATI阳性, IFX血药浓度低或检测不到, 那么须选择不同的药物.
近年来国内炎症性肠病(inflammatory bowel disease, IBD)患者逐年增多, 随着对IBD发病机制的深入认识, 生物制剂英夫利昔单抗(infliximab, IFX)的应用也越来越多, 虽IFX治疗IBD具有确切的疗效, 但仍有部分IBD患者在IFX维持治疗中失去应答, IFX血清药物浓度的检测可预测临床应答, 在IFX的临床应用中起着尤其重要的指导作用.
宋军, 副教授, 华中科技大学同济医学院附属协和医院消化内科; 毛高平, 教授, 中国人民解放军空军总医院
IFX治疗IBD是临床研究热点, IFX可诱导、维持中重度活动性克罗恩病(Crohn's disease, CD)的缓解及瘘管的闭合, 对难治性溃疡性结肠炎(ulcerative colitis, UC)或中重度UC有较明显的疗效, 且早期使用能有效促进黏膜愈合, 但对IFX失去应答及后续的治疗国内研究较少, 本文对IBD临床的治疗提供一定的参考.
近年来, 随着生物制剂广泛的应用于治疗IBD, 欧美一些国家对IFX治疗IBD发表了相关的共识意见和指南, 对中国医生有一定的参考价值.
本文在IFX治疗IBD的理论基础上, 详细分析了IFX治疗IBD过程中失去应答的可能原因, 提出了IBD失去应答患者的治疗方案, 对IBD的临床治疗有重要的指导意义.
本文提出了IFX的血清浓度监测在临床上发挥了重要的作用, 指导临床医师进行药物及剂量的调整, 能更有效的为患者制定个体化用药.
谷血清浓度: 指在下次用药之前血清IFX药物浓度的最低点.
文章思路清晰、科学规范, 可读性较强, 反映了血清英夫利昔单抗浓度检测在IBD临床治疗中的指导意义, 具有重要的临床实用性和应用价值.
编辑: 郭鹏 电编: 都珍珍
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