Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease

Abstract

BackgroundWith 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.MethodsWe 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).FindingsBaseline 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.InterpretationWe 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.

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

“…In humans, TREM-1 + Mfs are increased in IBD patients and its engagement enhanced pro-inflammatory cytokine secretion while a TREM-1 antagonist dampened it (254,255). Finally, Verstockt et al have shown that low TREM-1 expression in both whole blood and intestinal mucosa can predict anti-TNF therapy responders (353,354). Thus, TREM-1 could be a potential biomarker for predicting the effect of anti-TNF therapy and, secondly, blocking TREM-1 could be an attractive target for IBD treatment.…”

Epithelial cell biomarkers are predictive of response to biologic agents in Crohn’s disease

“…Several mucosal biomarkers have been reported to be associated with response to anti-TNF agents in CD: oncostatin M, 15 TNFR2 and IL13RA2, 16,17 and TREM1. 18,19 For example, high pretreatment levels of transmembrane TNF positive cells were observed to be positively associated with response to adalimumab, 22 whereas high pre-treatment levels of oncostatin M were found to be negatively associated with response to infliximab and goliumumab. 19 With respect to predicting response to anti-integrin therapy, high mucosal gene expressions of α E 23 and granzyme A 24 were demonstrated to be associated with improved response to etrolizumab in patients with UC.…”

“…Mucosal and blood biomarkers that can predict responses to anti-TNFs using the multi-omics approach include oncostatin M, 15 TNFR2 and IL13RA2, 16,17 and TREM1. 18,19 However, integrating them into routine clinical care has not yet occurred.…”

Editorial: better outcomes for Crohn's disease—more than just the drugs?

“…The cost reductions, now being seen with the availability of biosimilars, will further improve the cost‐effectiveness of this class . Finally, the identification of predictive biomarkers may lead to a more personalised approach to the use of these agents …”

“…9 Finally, the identification of predictive biomarkers may lead to a more personalised approach to the use of these agents. 10 Improvements in IBD outcomes over a decade may have many causes. It is essential that we continue to look to improve outcomes not only through the use of new pharmaceutical agents but also through improving the services we provide to our patients.…”