Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy
Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy
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DOI：
10.1136/gutjnl-2013-306518
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发表时间：
2015-02-01
期刊：
影响因子：
24.5
通讯作者：
Salas, Azucena
中科院分区：
文献类型：
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作者：
Franco Leal, Raquel;Planell, Nuria;Salas, Azucena
背景抗肿瘤坏死因子α（TNF α）治疗可有效诱导和维持克罗恩病（CD）的缓解。高达40%的患者，但是，未能响应anti-TNF alpha.Objective要确定的机制，粘膜病变的持久性在患者谁没有响应anti-TNF alpha therapeutic.Design的基础上进行了观察性研究的基础上全基因组转录分析的肠活检标本CD接受（n=12）或不（n=10）抗TNF α治疗。在抗TNF α治疗后，将应答者的转录特征与无应答者的转录特征进行比较。使用患有非炎性肠病（非IBD）的对照（n=17）进行比较。通过实时RT-PCR在接受（n=17）或不接受（n=16）抗TNF α的CD患者和非IBD对照（n=7）的独立队列中验证感兴趣的基因。结果我们证实，对抗TNF α的应答伴随着大量基因的显著调节，包括IL 1B、S100 A8、CXCL 1，其与内窥镜活性相关。值得注意的是，对抗TNF α治疗无效的患者表现出混合的特征，维持IL 1B、IL 17 A和S100 A8的表达增加，同时表现出其他在活动性CD中通常上调的基因的显著调节，包括IL 6和IL 23 p19。结论我们的结果表明，即使在未能达到内镜缓解的患者中，抗TNF α治疗也显著下调了一部分炎症基因，这表明这些基因在无反应者中可能不是驱动炎症的主导基因。另一方面，我们确定了IL 1B和IL 17 A作为在无应答者中保持改变的基因，指出了在难治性患者中调节粘膜损伤的潜在更相关的靶点。
Background Anti-tumour necrosis factor alpha (TNF alpha) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNF alpha.Objective To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNF alpha therapy.Design An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNF alpha therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNF alpha therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNF alpha and non-IBD controls (n=7).Results We confirmed that response to anti-TNF alpha is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNF alpha showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19.Conclusions Our results show that anti-TNF alpha therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.