Introduction Objective markers of Crohn’s Disease (CD) activity have been sought as diagnostic, phenotypic, prognostic and disease activity markers. Complications such as stricture and fistula and characteristics such as TNF-antagonist responsiveness have been suggested as discreet mechanistic CD subtypes. This study explored the ability of genome wide expression profiling in whole blood to differentiate CD sub-populations.
Methods In the previously reported Phase 2b ustekinumab CERTIFI study of patients with moderate to severely active CD who had failed or were intolerant to TNF-antagonists, whole blood samples were collected from a subset for mRNA expression profiling using Affymetrix HG-U133+ PM arrays. Baseline expression profiles were compared between patient sub-groups characterised by defined baseline disease attributes; and compared with those from samples obtained independently from healthy subjects. Expression modulations of > +/-1.5x and false discovery rate (FDR) p-value < 0.05 were considered significant.
Results Patients (n = 204) with moderate to severe CD had significant expression modulations in 1725 transcripts in the whole blood compared with healthy subjects (n = 49), including genes involved in inflammatory response and connective tissue disorders. A panel of 20 transcripts (including GAB2 and IL18R1) discriminated patients with only colonic (n = 49) vs. strictly ileal (n = 60) disease involvement. Significantly different expression modulations of 169, 321, and 151 transcripts, respectively, were identified in patients with high baseline CRP (>10 mg/dL, n = 97), faecal calprotectin (>850 mg/g, n = 80) or lactoferrin (>100 mg/g, n = 89) compared with patients with low baseline CRP (<3 mg/dL, n = 45), faecal calprotectin (<250 mg/g, n = 58), or lactoferrin (< 100 mg/g, n = 107). As expected, patients with high baseline CRP, faecal calprotectin, or lactoferrin had elevated gene expressions in inflammatory pathways such as IL-6 and acute phase response signalling. In contrast, gene expression profiles did not differentiate between patients with different durations of disease (long [>15 yrs] vs. short [<5yrs]); prior treatment response (Primary responder vs. non-responder) and treatment history (number of TNFs failed); and the presence or absence of complications (stricture/stenosis, fistula).
Conclusion Genome-wide expression profiling of peripheral blood samples provides the understanding of CD at the molecular level in circulation. This is a new, non-invasive method that can be used to identify systemic markers of local pathological alterations in CD and to discriminate clinically between different CD sub-types.
Disclosure of Interest K. Li Employee of: Janssen R&D, LLC, C. Brodmerkel Employee of: Janssen R&D, LLC, S. Telesco Employee of: Janssen R&D, LLC, K. Ma Employee of: Janssen R&D, LLC, C. Gasink Employee of: Janssen R&D, LLC
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