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P122 Rectal bleeding accurately reflects mucosal inflammation in patients with Ulcerative Colitis

M. Keir*1, C. Cabanski2, R. Zhao2, J.-F. Colombel3, J. Panes4, T. Lu5, W. Faubion6, J. Fletcher7, B. Feagan8, P. Kulkarni2, P. Higgins9, G. de Hertogh10, G. van Assche11, J. Mansfield12, W. Sandborn13, P. Rutgeerts14, S. Vermeire14, S. O'Byrne2

1Genentech Research & Early Development, ITGR Diagnostic Discovery, South San Francisco, United States, 2Genentech, Research and Early Development, South San Francisco, United States, 3Icahn School of Medicine at Mount Sinai, Department of Gastroenterology, New York, United States, 4Hospital Clinic de Barcelona, IDIBAPS and CIBERehd, Gastroenterology Unit, Barcelona, Spain, 5Genentech, Early Clinical Development, South San Francisco, United States, 6Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, United States, 7Mayo Clinic, Radiology, Rochester, MN, United States, 8Robarts Clinical Trials Inc., Robarts Research Institute, University of Western Ontario, London, Ontario, Canada, 9University of Michigan, Internal Medicine - Gastroenterology, Ann Arbor, MI, United States, 10University Hospitals Leuven, Department of Pathology, Leuven, Belgium, 11University Hospital Leuven, Gastroenterology, Leuven, Belgium, 12Newcastle University, Department of Gastroenterology, Newcastle Upon Tyne, United Kingdom, 13University of California San Diego, Division of Gastroenterology, La Jolla, United States, 14KU Leuven, Division of Gastroenterology, Leuven, Belgium

Background

Evaluation of disease activity in ulcerative colitis (UC) clinical trials currently relies upon a symptoms-based scoring system; however, UC patients may have symptoms in the absence of active mucosal inflammation. Therefore, symptoms scores may not accurately distinguish between different levels of mucosal inflammation or healing. These symptoms scores are used for patient enrollment and efficacy in clinical trials, and an imperfect tool can dilute the treatment effect considerably.

Methods

Symptom scores from UC patients were used to compare the relationship between symptoms and mucosal inflammation. Specifically, rectal bleeding (RB) and stool frequency (SF) scores, individually and in combination, were compared to endoscopy scores for patients in two independent studies [1], [2], n=103 and 118, respectively. Mucosal inflammation was assessed by the Mayo endoscopy subscore using an active disease cut-off of 2 or greater. The symptom scores of RB and SF were individually classified as high if the score was 1 or greater. The two symptom scores were also combined using the sum of RB and SF scores with a cutoff of 1 or greater. In addition, histologic disease activity, measured by the Geboes score [3] using a cutoff of 2 or greater, was compared to symptom scores in a single study [2], n=101.

Results

RB and SF scores, both individually and in combination, are highly accurate at identifying UC patients with active disease as measured by endoscopy (sensitivity of 81% and 85% for RB; 95% and 94% for SF; 95% and 97% for the combination in the two independent studies, respectively). Additionally, the symptom scores are effective at identifying patients with active disease based on histology (sensitivity of 84% for RB, 95% for SF, and 98% for the combination). However, RB scores are superior to SF scores and the combination when identifying UC patients with low disease activity as measured by endoscopy (specificity of 77% and 81% for RB; 62% and 42% for SF; 54% and 39% for the combination in the two independent studies, respectively) and histological healing (specificity of 54% for RB, 33% for SF, and 28% for the combination).

Conclusion

Both RB scores, SF scores, and their combination identify most UC patients with active mucosal inflammation, as measured by endoscopy or histology. However, when identifying UC patients with inactive disease, RB scores are superior to SF scores and the combination of RB and SF. Thus, rectal bleeding is the most reliable symptom score for identifying the level of mucosal inflammation in UC patients taking part in clinical trials.

References:

[1] Faubion et al., (2013), EMerging BiomARKers in Inflammatory Bowel Disease (EMBARK) Study Identifies Fecal Calprotectin, Serum MMP9, and Serum IL-22 as a Novel Combination of Biomarkers for Crohn's Disease Activity: Role of Cross-Sectional Imaging, Am J Gastroenterol, 1891-1900

[2] Vermeire et al., (2014), Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial, The Lancet, 309-318

[3] Geboes et al.,, (2000), A reproducible grading scale for histological assessment of inflammation in ulcerative colitis, Gut, 404-409