Rismo Renathe, Olsen Trine, Cui Guanglin, Paulssen Eyvind J, Christiansen Ingrid, Johnsen Knut, Florholmen Jon, Goll Rasmus
Institute of Clinical Medicine, University of Tromsø, Research Group of Gastroenterology and Nutrition, Tromsø, Norway.
Scand J Gastroenterol. 2013 Mar;48(3):311-9. doi: 10.3109/00365521.2012.758773. Epub 2013 Jan 10.
To investigate mucosal cytokine gene expression levels in healed mucosa after anti-tumor necrosis factor (TNF) therapy in patients with Crohn's disease (CD) as possible risk factors for relapse after discontinuation of therapy.
Thirty-seven CD patients treated with anti-TNF agents until complete mucosal healing, documented by endoscopy, discontinued anti-TNF treatment and entered a follow-up study. Levels of mRNA expression of interleukin (IL)17A (IL17A), IL23, interferon-gamma (IFNG), TNF-alpha (TNF), IL10 and Forkhead Box P3 (FOXP3) were measured in biopsies from healed mucosa and analyzed as possible risk factors of relapse. Mucosal cytokine transcript levels from patients without CD served as controls.
Patients were followed after therapy withdrawal until relapse. Median time to relapse was 20 and 68 weeks for patients with elevated and normalized IL17A and TNF expression levels, respectively (p = 0.02 for IL17A and p = 0.003 for TNF, log-rank). Expression levels of TNF, IL17A and FOXP3 were significantly higher in patients who relapsed before 26 weeks than in those who did not relapse, and also higher in patients with relapse before week 52 versus non-relapsers. Elevated expression levels of TNF and IL17A in healed mucosa significantly increased the risk of relapse (HR = 3.4, p = 0.03, sensitivity 80%, specificity 38% and HR = 4.1, p = 0.008, sensitivity 81%, specificity 61%, respectively).
Normalization of mucosal gene expression of cytokines after anti-TNF therapy does not occur in all patients with healed mucosa as judged by endoscopy. Normalization of TNF and/or IL17A expression predicts long-term remission.
研究克罗恩病（CD）患者接受抗肿瘤坏死因子（TNF）治疗后愈合黏膜中细胞因子基因表达水平，作为治疗中断后复发的潜在危险因素。
37例接受抗TNF药物治疗直至内镜证实黏膜完全愈合的CD患者，停止抗TNF治疗并进入随访研究。检测愈合黏膜活检组织中白细胞介素（IL）17A（IL17A）、IL23、干扰素-γ（IFNG）、TNF-α（TNF）、IL10和叉头框蛋白P3（FOXP3）的mRNA表达水平，并分析其作为复发潜在危险因素的可能性。无CD患者的黏膜细胞因子转录水平作为对照。
治疗停药后对患者进行随访直至复发。IL17A和TNF表达水平升高和正常的患者复发的中位时间分别为20周和68周（IL17A的p = 0.02，TNF的p = 0.003，对数秩检验）。在26周前复发的患者中，TNF、IL17A和FOXP3的表达水平显著高于未复发患者，在52周前复发的患者中也高于未复发患者。愈合黏膜中TNF和IL17A表达水平升高显著增加复发风险（HR = 3.4，p = 0.03，敏感性80%，特异性38%；HR = 4.1，p = 0.008，敏感性81%，特异性61%）。
根据内镜判断，并非所有黏膜愈合的患者在抗TNF治疗后细胞因子的黏膜基因表达均能恢复正常。TNF和/或IL17A表达恢复正常预示着长期缓解。
