Dr Nuru Noor, Clinical Lecturer in Gastroenterology University of Cambridge
Background
The course of IBD varies substantially between individuals, but currently there are limited reliable prognostic markers to guide clinical practice. Previously, we have described a transcriptional signature detectable within peripheral blood CD8 T-cells at diagnosis, identifying two subgroups of patients, correlating with prognosis. We sought to translate this biomarker to re-capitulate the prognostic CD8 subgroups and to assess whether this can be used to improve clinical outcomes by appropriately matching therapy to disease course.
Methods
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. Statistical modelling was then used to identify a transcriptional classifier in whole-blood gene expression data re-capitulating the CD8 findings and optimised into a multi-gene qPCR assay with independent validation in a second, independent cohort of 123 newly-diagnosed patients. The PROFILE trial has incorporated this classifier to compare relative efficacy of 'top-down' and 'accelerated step-up' therapy between biomarker-defined subgroups in 386 patients with newly-diagnosed Crohn’s disease.
Results
Using a 17-gene qPCR assay, 123 patients from the validation cohort could be classified into two distinct genomic subgroups, IBDhi and IBDlo. The IBDhi patients experienced significantly more aggressive disease than IBDlo, with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)). This biomarker is being used to stratify therapy in the PROFILE trial, where 386 participants have been randomized with very early Crohn’s disease (median disease duration 12 days), and follow-up is ongoing.
Conclusions
We have developed, optimized and validated a whole-blood qPCR classifier that predicts disease course from diagnosis in patients with IBD. This classifier is currently being assessed to see whether it can select which patients with newly-diagnosed Crohn’s disease would benefit most from “top-down” or “accelerated step-up” treatment strategies. The findings from PROFILE will therefore answer two key clinical questions and it is envisaged will have direct implications for clinical practice around the world.
