P669 Effect of vedolizumab therapy on whole blood transcriptional profiles in patients with Inflammatory Bowel Disease
Haglund, S.(1,2,3);Söderman, J.(1,3);Almer, S.(2,4);
(1)Laboratory Medicine, Region Jönköping County, Jönköping, Sweden;(2)Department of Medicine, Karolinska Institutet- Solna, Stockholm, Sweden;(3)Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden;(4)IBD-unit- Division of Gastroenterology, Karolinska University Hospital, Stockholm, Sweden
Vedolizumab (VDZ) is one of many new biological drugs used in patients with inflammatory bowel disease who fail more conventional therapy. Despite proven efficacy, subgroups of patients show limited clinical benefit from VDZ. Here, we hypothesized that differences in clinical response to VDZ therapy might be reflected in changes in gene expression in whole blood which potentially could serve as easy accessible candidate biomarkers.
Transcriptional profiles of 20 patients (Crohn’s disease 13, ulcerative colitis 7) were established by sequencing of RNA isolated from stabilized whole blood collected at baseline (T0), and at follow-up at week 10-12 (T1) following three infusions of VDZ. Clinical response was defined as a decrease of > 3 in the simplified Harvey Bradshaw Index or in the Simple Clinical Colitis Activity Index at T1 compared with T0. Differently expressed genes were identified by using the R packages Rsubread, edgeR and limma with hg38 as reference genome. Pathway analyses were done by gene set enrichment analysis (GSEA, Broad Institute) using Reactome and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Routine laboratory parameters were obtained.
Overall, two genes were down-regulated (IGLV2-23 > 2-fold) and four genes were up-regulated (ADAMTS5 > 2-fold) at follow up (FDR < 0.05). This was attributed to regulation in responders (n=9), but not in non-responder (n=11). In responders, 55 genes were down-regulated (25 genes > 2-fold, e.g. IGHV3-74) and 146 genes were up-regulated (8 genes > 2-fold, e.g. OLFM1) at T1 vs. T0. However, at T0 there were no differences between responders and non-responders suitable as predictive biomarkers. Nevertheless, 89 KEGG pathways were differently enriched between study groups at baseline, and up to 44 pathways within the groups when studying the transcriptional profiles over time (FDR < 0.075). The plasma-concentration of VDZ was not associated with the clinical outcome, and was not correlated with the dose of VDZ (mg/kg bodyweight).
There is a strong need for reliable and predictive biomarkers in decision making for personalised medicine. Our study shows that VDZ affects the transcriptional profile in blood of patients responding to treatment, whereas no gene regulation was noticed in non-responders. It also suggests that whole blood is not optimal for identifying predictive pre-treatment biomarkers based on individual genes in patients with need for this integrin inhibitor. However, treatment outcome may depend on several interacting genes, illustrated by the identification of significant pathway differences between study groups, both at baseline (T0) as well as in response to treatment (T1). Further studies are needed to confirm our findings.