Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Postdoctoral CAPES fellow, Brazil.
Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Bioinformatics Platform, CIBERehd, Barcelona, Spain.
Gut. 2015 Feb;64(2):233-42. doi: 10.1136/gutjnl-2013-306518. Epub 2014 Apr 3.
Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα.
To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy.
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-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα 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-TNFα and non-IBD controls (n=7).
We confirmed that response to anti-TNFα 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-TNFα 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.
Our results show that anti-TNFα 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.
抗肿瘤坏死因子 α（TNFα）治疗有效地诱导并维持克罗恩病（CD）的缓解。然而，高达 40%的患者对抗 TNFα 治疗无反应。
确定抗 TNFα 治疗无反应患者黏膜病变持续存在的机制。
对接受（n=12）或未接受（n=10）抗 TNFα 治疗的 CD 患者的肠活检标本进行基于全基因组转录分析的观察性研究。将应答者的转录特征与抗 TNFα 治疗后的非应答者进行比较。使用非炎症性肠病（非 IBD）对照（n=17）进行比较。通过实时 RT-PCR 在接受（n=17）或未接受（n=16）抗 TNFα 和非 IBD 对照（n=7）的 CD 患者的独立队列中验证感兴趣的基因。
我们证实，抗 TNFα 的反应伴随着大量基因的显著调节，包括 IL1B、S100A8、CXCL1，与内镜活动相关。值得注意的是，对抗 TNFα 无反应的患者表现出混合特征，维持 IL1B、IL17A 和 S100A8 的表达增加，同时表现出其他在活动 CD 中通常上调的基因的显著调节，包括 IL6 和 IL23p19。
我们的结果表明，抗 TNFα 治疗即使在未能达到内镜缓解的患者中也显著下调了一组炎症基因，这表明这些基因可能不是非应答者中驱动炎症的主要因素。另一方面，我们确定了 IL1B 和 IL17A 作为在非应答者中改变的基因，这指向了在难治性患者中调节黏膜损伤的潜在更相关靶点。
