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PWE-084 Whole Blood MRNA Expression Profiling of Crohn’S Disease in the Certifi Ustekinumab Study Discriminates Clinical Subtypes
  1. K Li1,
  2. C Brodmerkel1,
  3. S Telesco1,
  4. K Ma1,
  5. C Gasink1
  1. 1Janssen. R&D LLC, Spring House, United States

Abstract

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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