Study Finds Low TREM1 Expression in Blood Predicts Anti-TNF Response in IBD

Researchers say they validated whole blood expression of a gene involved in inflammatory response as an accurate biomarker predicting response to anti—tumor necrosis factor (TNF) for endoscopic remission in patients with Crohn disease (CD) and ulcerative colitis (UC), both types of inflammatory bowel disease (IBD) in a finding that could assist in deciding whether biologic-naïve patients should receive anti-TNF therapy.

The gene, triggering receptor expressed on myeloid cells 1 (TREM1), has been suggested previously as a potential biomarker for response to anti-TNF agents.

The study, published in EBioMedicine, notes that biologics have revolutionized treatment for patients with inflammatory bowel disease (IBD), but up to one-third never respond to a particular anti-TNF therapy. This is the first prospective study examining the predictive value of whole blood messenger RNA (mRNA) transcripts from genes previously identified in tissue as key to predicting patient response.

The study examined whole blood samples from 54 patients with active IBD (24 with CD, 30 with UC) starting anti-TNF therapy with infliximab or adalimumab, as well as 22 patients with CD beginning ustekinumab and 51 patients initiating vedolizumab (25 with CD, 26 with UC).

Whole blood expression of oncostatin M (OSM), TREM1, TNF and TNFR2 was measured prior to the start of therapy using quantitative real-time polymerase chain reaction and mucosal gene expression in inflamed biopsies using RNA-sequencing.

Response was defined based on endoscopic findings. In patients with CD, endoscopic remission was assessed after 6  months and defined as a Simple Endoscopic Disease (SES-CD) score of 2 or lower; for UC, remission was defined as a Mayo endoscopic subscore of 1 or lower at week 10.

The results showed that baseline whole blood TREM1 was downregulated in future anti-TNF responders, both in UC (FC&#8239; = &#8239;0.53, P &#8239;=&#8239;.001) and CD (FC &#8239;= &#8239;0.66, P &#8239;=&#8239;.007), as well as in the complete cohort (FC &#8239;= &#8239;0.67, P&#8239; <.001). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (P &#8239;=&#8239;.001).

A similar accuracy could be achieved with mucosal TREM1 (AUC 0.77, P &#8239;=&#8239;.003), which outperformed the accuracy of serum TREM1 (AUC 0.58, P &#8239;=&#8239;.31). Although differentially expressed in tissue, OSM, TNF, and TNFR2 expression was not significantly different between future responders and non-responders (FC &#8239;= &#8239;0.61, P =.09; FC =&#8239; 0.74, P =.13; FC = 0.94, P =.24), respectively.

The TREM1 predictive signal was anti-TNF specific, as no changes were seen in patients treated with ustekinumab (which targets interleukin 12 and 23) and vedolizumab (an anti-integrin agent).

Based on the results, the researchers note that remission rates may be improved by prioritizing anti-TNF therapy to those patients with low TREM1 expression.

In addition, a simple blood sample to predict who will respond to therapy is less invasive than colonoscopy and easier to implement in clinical practice, the authors note.

These findings could be improved by using an unbiased, genome-wide approach through RNA-sequencing of whole blood in an effort to detect other novel, predictive biomarkers, the authors say. In any case, they write, the study is another way to create personalized medicine for patients, although larger, randomized studies are needed.

Reference

Verstockt B, Verstockt S, Dehairs J, et al. Low TREM1 expression in whole blood predicts anti-TNF response in inflammatory bowel disease [published online January 23, 2019]. EBioMedicine. doi: 10.1016/j.ebiom.2019.01.027.