P028 A BLOOD-BASED PROGNOSTIC BIOMARKER IN INFLAMMATORY BOWEL DISEASE; TOWARDS PERSONALISED MEDICINE IN IBD.

Abstract

The course of Inflammatory Bowel Disease (IBD incorporating both Crohn’s Disease and ulcerative colitis) varies substantially between affected individuals, but reliable prognostic markers are not available in clinical practice. This hinders disease management because patients with aggressive disease will be undertreated by conventional “step-up” therapy, while those with indolent disease would be exposed to the risks and side-effects of unnecessary immunosuppression if a “top-down” approach was indiscriminately used. We have described, initially in ANCA-associated vasculitis and SLE (McKinney et al. Nat Med 2010) and then in IBD (Lee et al. JCL 2011), a transcriptional signature detectable within peripheral blood CD8+ T cells at diagnosis which correlates with subsequent disease course. To overcome the technical challenges of separating cell populations, which would not be possible in a routine clinical setting, we sought to develop a whole blood qPCR-based biomarker that can re-capitulate the CD8+ subgroups without the need for cell separation. Here we describe the development and validation of this biomarker and a biomarker-stratified trial that will test whether it can deliver personalised medicine in IBD. From a training cohort of 69 newly diagnosed IBD patients, we simultaneously obtained a whole blood PAXgene RNA tube and peripheral blood CD8+ T cell sample. Gene expression in both samples was measured by microarray. After confirming that the CD8+ transcriptional signature was detectable and correlated with prognosis, we used machine learning to identify a transcriptional classifier in whole blood gene expression data that would re-capitulate the CD8+ transcriptional subgroups. This was initially trained using leave-one-out cross-validation, and the genes identified were subsequently tested by qPCR and an optimized qPCR assay developed. Independent validation of this biomarker was established using a second, independent cohort of 84 newly diagnosed patients with IBD from 4 sites around the United Kingdom. This validated the biomarker and confirmed that the subgroups it identified had significantly different disease courses (analogous to those observed with the CD8+ T cell subgroups). We have now embarked on the PROFILE trial: PRedicting Outcomes For Crohn’s dIsease using a moLecular biomarkEr; the first ever biomarker-stratified trial in any inflammatory disease, to determine whether this biomarker can deliver personalised medicine in CD. We have developed, optimised and validated a whole blood qPCR classifier that is able to predict disease course from diagnosis in IBD patients. This represents a major step towards personalised therapy in IBD, and is currently being used investigate whether this could make personalised medicine a reality in CD.