University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium; KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.
KU Leuven Department of Human Genetics, Laboratory for Complex Genetics, Leuven, Belgium.
EBioMedicine. 2019 Feb;40:733-742. doi: 10.1016/j.ebiom.2019.01.027. Epub 2019 Jan 24.
With the changed therapeutic armamentarium for Crohn's disease (CD) and ulcerative colitis (UC), biomarkers predicting treatment response are urgently needed. We studied whole blood and mucosal expression of genes previously reported to predict outcome to anti-TNF therapy, and investigated if the signature was specific for anti-TNF agents.
We prospectively included 54 active IBD patients (24CD, 30UC) initiating anti-TNF therapy, as well as 22 CD patients initiating ustekinumab and 51 patients initiating vedolizumab (25CD, 26UC). Whole blood expression of OSM, TREM1, TNF and TNFR2 was measured prior to start of therapy using qPCR, and mucosal gene expression in inflamed biopsies using RNA-sequencing. Response was defined as endoscopic remission (SES-CD ≤ 2 at week 24 for CD and Mayo endoscopic sub-score ≤ 1 at week 10 for UC).
Baseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FC = 0.53, p = .001) and CD (FC = 0.66, p = .007), as well as in the complete cohort (FC = 0.67, p < .001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (p = .001). A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, p = .003), which outperformed the accuracy of serum TREM1 (AUC 0.58, p = .31). Although differentially expressed in tissue, OSM, TNF and TNFR2 were not differentially expressed in whole blood. The TREM1 predictive signal was anti-TNF specific, as no changes were seen in ustekinumab and vedolizumab treated patients.
We identified low TREM-1 as a specific biomarker for anti-TNF induced endoscopic remission. These results can aid in the selection of therapy in biologic-naïve patients.
随着克罗恩病（CD）和溃疡性结肠炎（UC）治疗手段的改变，迫切需要预测治疗反应的生物标志物。我们研究了先前报道的可预测抗 TNF 治疗结果的全血和黏膜基因表达，并研究了该特征是否对抗 TNF 药物具有特异性。
我们前瞻性纳入了 54 例开始接受抗 TNF 治疗的活动性 IBD 患者（24 例 CD，30 例 UC），以及 22 例开始接受乌司奴单抗治疗的 CD 患者和 51 例开始接受维得利珠单抗治疗的患者（25 例 CD，26 例 UC）。在开始治疗前，使用 qPCR 测量全血中 OSM、TREM1、TNF 和 TNFR2 的表达，使用 RNA 测序测量炎症活检组织中的基因表达。以内镜缓解为治疗应答定义（CD 患者第 24 周 SES-CD≤2，UC 患者第 10 周 Mayo 内镜下评分≤1）。
在 UC（FC=0.53，p=0.001）和 CD（FC=0.66，p=0.007）患者中，以及在整个队列中（FC=0.67，p<0.001），未来抗 TNF 应答者的全血 TREM1 表达下调。接受者操作特征统计显示曲线下面积（AUC）为 0.78（p=0.001）。黏膜 TREM1 可达到相似的准确性（AUC 0.77，p=0.003），优于血清 TREM1 的准确性（AUC 0.58，p=0.31）。尽管在组织中差异表达，但 OSM、TNF 和 TNFR2 在全血中无差异表达。TREM1 预测信号是抗 TNF 特异性的，因为在接受乌司奴单抗和维得利珠单抗治疗的患者中没有观察到变化。
我们发现低 TREM-1 是抗 TNF 诱导的内镜缓解的特异性生物标志物。这些结果可以帮助生物制剂初治患者选择治疗方案。
