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Serological and faecal biomarkers in inflammatory bowel disease
Örebro University, School of Medical Sciences.
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are relapsing and remitting disorders characterised by chronic inflammation at various sites in the gastrointestinal tract, resulting in diarrhoea and abdominal pain. Neither the aetiology nor the pathophysiology is yet fully understood, and there is currently no cure.

The overall aim of this thesis was to add a piece of the puzzle to understanding the complex pathogenesis of IBD; to determine the role of genetic and environmental factors in the development of antibodies in IBD - which could provide insight to the aetiology of the diseases; and to find sensitive and specific faecal biomarkers to predict future flare in the diseases.

By conducting twin-studies, we found that some serological antibodies associated with Crohn's disease seemed to be genetically predisposed (anti-OmpC and anti-I2). Genetic predisposition do not play a predominant role in the generation of other antibodies, such as ASCA, anti-CBir1 or the autoantibody most commonly found in ulcerative colitis; pANCA. Exposure to environmental factors during childhood are suggested to be of importance in the development of ASCA and anti-CBir1 in CD. Active smoking seemed to have a protective effect against development of pANCA.

Faecal calprotectin is a known marker for intestinal inflammation. In our third study, three faecal calprotectin assays were compared, which revealed overall poor agreement. This implies that standardisation of the method is highly needed.

In our final study, we measured faecal eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in patients with IBD every third month over a two-year period. The results revealed that the risk of relapse in UC can be predicted by measuring EDN consecutively.

Place, publisher, year, edition, pages
Örebro: Örebro University , 2018. , p. 62
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 170
Keywords [en]
Crohn's disease, ulcerative colitis, inflammatory bowel disease, faecal calprotectin, antibodies, eosinophils, ECP, EDN
National Category
General Practice
Identifiers
URN: urn:nbn:se:oru:diva-62769ISBN: 978-91-7529-223-6 (print)OAI: oai:DiVA.org:oru-62769DiVA, id: diva2:1159348
Public defence
2018-02-02, Örebro universitet, Campus USÖ, hörsal C1, Södra Grev Rosengatan 32, Örebro, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2017-11-22 Created: 2017-11-22 Last updated: 2018-01-26Bibliographically approved
List of papers
1. Concordance in Anti-OmpC and Anti-I2 Indicate the Influence of Genetic Predisposition: Results of a European Study of Twins with Crohn's Disease
Open this publication in new window or tab >>Concordance in Anti-OmpC and Anti-I2 Indicate the Influence of Genetic Predisposition: Results of a European Study of Twins with Crohn's Disease
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2016 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 10, no 6, p. 695-702Article in journal (Refereed) Published
Abstract [en]

Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort.

Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Örebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay.

Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and -0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA.

Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.

Place, publisher, year, edition, pages
Oxford, United Kingdom: Oxford University Press, 2016
Keywords
Crohn’s disease, serology, genetics
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-50589 (URN)10.1093/ecco-jcc/jjw021 (DOI)000377920100010 ()26818662 (PubMedID)
Available from: 2016-06-08 Created: 2016-06-08 Last updated: 2018-07-13Bibliographically approved
2. Environmental and genetic factors in the development of perinuclear-antineutrophil cytoplasmic antibody (pANCA) positive ulcerative colitis: a European twin study
Open this publication in new window or tab >>Environmental and genetic factors in the development of perinuclear-antineutrophil cytoplasmic antibody (pANCA) positive ulcerative colitis: a European twin study
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(English)Manuscript (preprint) (Other academic)
National Category
General Practice
Identifiers
urn:nbn:se:oru:diva-64027 (URN)
Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-01-11Bibliographically approved
3. Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time
Open this publication in new window or tab >>Clinical implications of assay specific differences in f-calprotectin when monitoring inflammatory bowel disease activity over time
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2017 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 52, no 3, p. 344-350Article in journal (Refereed) Published
Abstract [en]

Objective: With several faecal calprotectin (FC) assays on the market, it has been difficult to define a uniform threshold for discriminating between remission and active disease in patients with inflammatory bowel disease (IBD). We aimed to compare the results of different FC-assays in IBD patients, followed over time.

Material and methods: IBD patients provided faecal samples and reported clinical activity every third month prospectively over a two year period. FC was measured with two ELISA - (Bühlmann and Immunodiagnostik) and one automated fluoroimmunoassay (Phadia).

Results: In total, 13 patients provided 91 faecal samples. The median (IQR) concentration of FC was higher at active disease than at remission for all assays: Bühlmann 845 (1061-226) μg/g versus 62 (224-39) μg/g, Phadia 369 (975-122) μg/g versus 11 (52-11) μg/g, and Immundiagnostik 135 (302-69) μg/g versus 8 (56-4) μg/g. The Bühlmann assay produced the largest absolute difference but the corresponding relative difference seemed to be more pronounced when analysed by the Phadia - (ratio of means 8.5; 95% CI 3.3-21.9) or the Immundiagnostik assay (ratio of means 7.4; 95% CI 3.1-17.6) than by the Bühlmann assay (ratio of means 5.3; 95% CI 2.7-10.6). Consequently, the specificity for discriminating active disease from remission varied between assays (34-75%) when the cut-off 50 μg/g was used, whereas the differences in sensitivity were less pronounced.

Conclusions: Cross-comparisons revealed overall poor agreement between the assays as well as differences in the dynamics of FC. These findings suggest that standardisation of the method is needed to implement FC as a disease monitoring tool at large-scale.

Place, publisher, year, edition, pages
Oxon, United Kingdom: Taylor & Francis, 2017
Keywords
Biomarker, Crohn's disease, faecal calprotectin, inflammatory bowel, disease, ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-53665 (URN)10.1080/00365521.2016.1256424 (DOI)000392488800015 ()27881032 (PubMedID)2-s2.0-84996799488 (Scopus ID)
Funder
Swedish Research Council, 521-2011-2764
Note

Funding Agencies:

Örebro University Hospital Research Foundation OLL-333321

Uppsala-Örebro Regional Research Foundation RFR-314671

Available from: 2016-11-28 Created: 2016-11-28 Last updated: 2018-07-23Bibliographically approved
4. Prognostic significance of eosinophile granule proteins in inflammatory bowel disease
Open this publication in new window or tab >>Prognostic significance of eosinophile granule proteins in inflammatory bowel disease
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(English)Manuscript (preprint) (Other academic)
National Category
General Practice
Identifiers
urn:nbn:se:oru:diva-64028 (URN)
Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2018-01-11Bibliographically approved

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