Authors
B. VERSTOCKT (1), S. VERSTOCKT (2), J. DEHAIRS (3), V. BALLET (4), H. BLEVI (5), W. WOLLANTS (5), C. BREYNAERT (6), G. VAN ASSCHE (5), S. VERMEIRE (5), M. FERRANTE (5) / [1] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, Department of Chronic Diseases, metabolism and ageing, [2] Laboratory for Complex Genetics, KU Leuven, , Belgium, Department of Human Genetics, [3] Laboratory of Lipid Metabolism and Cancer, KU Leuven, , Belgium, Department of Oncology, [4] University Hospitals Leuven, Leuven, Belgium, Department of Gastroenterology and Hepatology, [5] Translational Research Center for Gastrointestinal Disorders (TARGID), KULeuven, Leuven, Belgium, Department of Chronic Diseases, Metabolism and Ageing, [6] Laboratory of Clinical Immunology, KU Leuven, , Belgium, Department of Microbiology and Immunology
Introduction
With the expanding therapeutic armamentarium for inflammatory bowel diseases (IBD), biomarkers predicting efficacy are urgently needed.
Aim
To predict outcome to anti-TNF therapy, 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 these agents.
Methods
We prospectively included 35 (discovery) and 19 (validation) consecutive IBD patients with active disease (both Crohn's disease and ulcerative colitis) initiating anti-TNF therapy, as well as 22 patients initiating ustekinumab and 51 patients initiating vedolizumab. Whole blood expression levels of OSM, TNF, TNFR2 and TREM1 (total and all individual transcripts separately) were measured prior to start of therapy using qPCR, and mucosal gene expression in inflamed biopsies using RNA-sequencing. Endoscopic remission was defined as an SES-CD≤2 at week 24 for Crohn's disease and a Mayo endoscopic sub-score≤1 at week 8-14 for ulcerative colitis.
Results
Baseline whole blood TREM1 expression was significantly downregulated in future anti-TNF healers (p<0.001, both discovery and validation cohort). Receiver operator characteristic statistics showed an area under the curve (AUC) of 0.78 (p=0.001), resulting in post-test probabilities of 77.1% and 90.0% for endoscopic remission and non-remission, respectively. A similar accuracy could be observed in mucosal TREM1 expression (AUC 0.77, p=0.003), which outperformed the accuracy of serum TREM1 at the protein level (AUC 0.58, p=0.31). Whole blood TREM1 expression did not significantly correlate with CRP (spearman = -0.08, p=0.38), faecal calprotectin (spearman = -0.06, p=0.64) or serum TNF (spearman = - 0.15, p=0.63). OSM, TNF and TNFR2 were not differentially expressed in whole blood (p=0.09, p=0.13, p=0.24 respectively), whereas they were at the mucosal level (p=0.007, p=0.02, p=0.008 respectively). The whole blood TREM1 predictive signal was anti-TNF specific, as no changes in expression were seen in ustekinumab and vedolizumab treated patients, neither in whole blood (p=0.82, p=0.53 respectively), nor in tissue (p=0.24, p=0.10, respectively).
Conclusions
We identified and validated low TREM-1 as a specific biomarker for anti-TNF induced endoscopic remission. These results can aid in the selection of therapy in biological-naïve patients, but should be confirmed in a randomized trial prior to translation into daily clinical practice.
