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P048 Exploring mucosal function as a clinical endpoint in ulcerative colitis

S. Kjaergaard*1,2, M. M. B. Damm1, J. Chang3, L. B. Riis4, R. Hytting-Andreasen5, S. Krug6, J. D. Schulzke6, N. Bindslev2, M. B. Hansen1

1Bispebjerg Hospital, Digestive Disease Center, Copenhagen, Denmark, 2Faculty of Health and Medical Sciences, Department of Biomedical Sciences, Copenhagen, Denmark, 3University of Manchester, Wellcome Trust Centre for Cell-Matrix Research, Manchester, UK, 4Herlev Hospital, Department of Pathology, Copenhagen, Denmark, 5NNF Center of Basic Metabolic Research, University of Copenhagen, Department of Biomedical Sciences, Copenhagen, Denmark, 6Institute of Clinical Physiology, Charité, Berlin, Germany

Background

The standard for assessing disease activity, clinical remission and response to therapy in ulcerative colitis (UC) includes evaluation of symptoms (eg, stool frequency and rectal bleeding) and endoscopic mucosal status. The ultimate goal is reversal of inflammation and normalisation of the gut including mucosal function (ie, barrier integrity). During active disease, the composition of the tight junction (TJ) complex is altered compromising barrier integrity. We hypothesise that mucosal integrity does not correlate with mucosal healing as assessed by endoscopy and histology. In this exploratory study, we studied mucosal barrier integrity (ie, TJ proteins) and correlated it to endoscopic and histological findings in quiescent UC.

Methods

We obtained sigmoid biopsies during endoscopy from 33 UC patients (mean age 39, 23–75 years., 18 females) in clinical and endoscopic remission and 17 gut-healthy controls (mean age 46, 20–68 years., 9 females). The median remission and disease duration prior to inclusion were 8 months (1–61) and 96 months (3–420). Histology was assessed using Geboes score. Mucosal barrier integrity was assessed by examining levels of protein and mRNA for TJ proteins claudin-2, claudin-4, occludin, and tricellulin. All levels were examined by western blot (WB) with densitometric analysis and quantitative polymerase chain reaction (qPCR). All evaluations were blinded and performed by central reading.

Results

The majority of UC patients, 24 (73%), had a Mayo endoscopic sub-score of 0 and the remaining, 9 (27%), scored 1. Histologically, 22 (67%), had signs of mild-to-moderate chronic inflammation, while only 11 (33%) had no signs of inflammation assessed by Geboes score. All controls were with normal endoscopic and histological findings. On protein level, only claudin-4 was reduced (55%, p = 0.012) in UC remission patients compared with controls. mRNA levels were significantly up-regulated for both claudin-2 (5-fold, p = 0.034) and claudin-4 (2-fold, p = 0.031), while occludin was down-regulated (3-fold, p < 0.0001). Tricellulin was unaltered. Furthermore, the correlation between barrier integrity and histology appears weak.

Conclusion

Compared with healthy controls, some UC patients in clinical and endoscopic remission demonstrate an altered expression of TJ proteins. No apparent correlation was found between these changes and histology. It is unresolved whether these abnormalities carry an increased risk for early and/or increased severity at relapse. We propose to further evaluate mucosal functional remission as a potential target-to-treat endpoint.