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P111 Clinical validation of a blood-based prognostic biomarker in Inflammatory bowel disease; towards personalised medicine in IBD

P. Lyons*1

1University of Cambridge, Department of Medicine, Cambridge, UK

Background

The inherent patient to patient variability in disease course observed in inflammatory bowel disease (IBD incorporating both Crohn’s disease and ulcerative colitis) has a direct impact on disease management; patients with aggressive disease are undertreated by conventional ‘step-up’ therapy, whilst 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 previously described, a transcriptional signature detectable within peripheral blood CD8+ T cells of IBD patients at diagnosis, which correlates with subsequent disease course (McKinney et al. Nat Med 2010). We have now developed a whole blood, qPCR-based biomarker test that can re-capitulate the CD8+ subgroups without the need for cell separation, and overcomes the technical challenges of separating cell populations, which would not be possible in a routine clinical setting. Here we describe the development and validation of this biomarker and its use in the first biomarker-stratified clinical trial for Crohn’s disease. Successful completion of the trial should provide the first step towards personalised medicine in IBD.

Methods

We simultaneously obtained a whole blood PAXgene RNA tube and peripheral blood CD8+ T-cell sample from a training cohort of 69 newly diagnosed IBD patients, Gene expression in both samples was measured by microarray and machine learning used to identify a transcriptional classifier in whole blood gene expression data that would re-capitulate the CD8+ transcriptional subgroups and correlated with prognosis. The classifier was initially trained using leave-one-out cross-validation, and the genes identified were subsequently tested by qPCR and an optimised qPCR assay developed. Independent validation of the biomarker was established using a second, independent validation cohort of 84 newly diagnosed patients with IBD from 4 sites around the UK.

Results

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 extended this data set and embarked on the PROFILE trial: PRedicting Outcomes For Crohn’s dIsease using a moLecular biomarker.

Conclusion

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.