P103 Degradation and formation of type III, IV and V collagen are associated with disease activity, disease severity and disease extension in patients with ulcerative colitis

Abstract Background ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease that causes inflammation and ulcers in the innermost layers of the large intestine (colon) and rectum. Assessment of intestinal inflammation in UC is crucial and still remains a difficult challenge for the clinician. Although endoscopic modalities with biopsy sampling seem to be the most reliable method for estimating disease severity, they are invasive and costly. Apart from endoscopic interventions, disease severity can be assessed using both laboratory studies and non-invasive imaging tests. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBCs), acid glycoprotein, platelet count and albumin are in common use but have only modest accuracy in reflecting UC disease activity. Therefore, adjunctive use of additional serum markers that will be more sensitive and specific for determination of disease activity and achieving diagnostic accuracy is strongly needed in daily clinical practice. Aim of the Work to investigate the diagnostic utility of beta 2 microglobulin (B2-M) levels and analyze this correlation with the activity of ulcerative colitis disease. Patients and Methods a case control study that was conducted at the Gastroenterology Clinic, Internal Medicine Department, Ain Shams University during the period of January to July 2018. 60 patients were recruited for the study. They were divided as follows; Group “A”: 40 patients newly diagnosed as ulcerative colitis based on colonoscopy and biopsy, subdivided as follows; 20 patients with active ulcerative colitis and 20 patients with inactive ulcerative colitis. Group “B”: 20 healthy individuals free from any systemic diseases serving as a control group. Results in this study, the serum levels of serum B2-microglobulins were highest in patients with active ulcerative colitis compared to those with inactive ulcerative colitis and the control groups. Also B2-microglobulins values become higher with higher number of presenting symptoms and endoscopic activity, which becomes higher in severe disease. Conclusion our results revealed that serum B2-microglobulin was simple and non-invasive marker that could be helpful for differentiating active UC from inactive disease. Moreover, it was more helpful when used together with serum laboratory inflammatory indices (ESR and CRP).

Download Full-text

P087 Biomarkers of elastin degradation differentiate between clinically inactive and active disease in ulcerative colitis patients

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.216 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S178-S179

Author(s):

M Pehrsson ◽

V Domislović ◽

M A Karsdal ◽

M Brinar ◽

A Barisic ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Disease Severity ◽

Matrix Protein ◽

Scoring Systems ◽

Cathepsin G ◽

Tissue Remodelling ◽

Montreal Classification ◽

Elastin Degradation ◽

Active Disease

Abstract Background In ulcerative colitis (UC), the state of chronic inflammation results in increased matrix metalloprotease (MMP) and serine protease activity, which effectively leads to a higher degree of intestinal tissue remodelling, including components of the extracellular matrix (ECM). One of these components is elastin a matrix protein of the interstitial matrix in the lamina propria and submucosa, providing tissue resilience and elasticity. As such, we investigated whether elastin degradation in UC patients was associated with disease activity and severity, potentially enabling patient differentiation based on elastin degradation. Methods Twenty-nine UC patients and 29 healthy donors were included in the study. Disease activity was determined according to the partial Mayo score (pMayo >1) and the Mayo Endoscopic Score (MES). Disease severity and extension was assessed using the Montreal classification. Disease severity was additionally assessed using the Trulove and Witt’s (TW) clinical score. The biomarkers of elastin degradation included: MMP-7 (ELM-7) cathepsin-G (EL-CG) and proteinase-3 (ELP-3), measured in serum by ELISA. One-way ANOVA (Kruskal–Wallis) correcting for the false discovery rate were applied for the statistical analysis. Results TW: ELP-3 levels in moderate-to-severe UC patients were significantly elevated in comparison with HD (p < 0.001). Partial Mayo: EL-CG levels in patients with active UC were significantly elevated in comparison with HD (p < 0.01), and UC patients in remission (p < 0.01). ELP-3 levels were likewise significantly elevated in active UC patients compared with HD (p < 0.001), and UC patients in remission (p < 0.01). Montreal classification: ELM-7 was significantly elevated in active UC compared with HD (p < 0.05), and UC patients in remission (p < 0.05). EL-CG were also significantly elevated in active UC compared with HD (p < 0.05), and UC patients in remission (p < 0.05). ELP-3 was significantly elevated in active UC compared with HD (p < 0.01). According to the MES score, ELP-3 levels in moderate-to-severe UC patients were significantly elevated in comparison to HD (p < 0.01). Conclusion The data presented in this study demonstrate an association between biomarkers of proteolytic elastin degradation and disease activity in UC patients especially the protease-3-derived biomarker, ELP-3, showed significant association with active UC in all the clinical scoring systems as well as the MES score. Utilising these minimally invasive elastin degradation biomarkers could serve as surrogate markers for monitoring of disease activity and potentially aid the differentiation of patients with an active disease from patients in remission or with a lower disease activity for UC.

Download Full-text

P132 Performance of a severity score in risk stratification of patients with ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.261 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S203-S203

Author(s):

B Morão ◽

C Frias Gomes ◽

C Gouveia ◽

M P Costa Santos ◽

J Torres

Keyword(s):

Ulcerative Colitis ◽

Risk Stratification ◽

Hospital Admission ◽

Disease Severity ◽

Severity Score ◽

Disease Course ◽

Steroid Use ◽

Promising Tool ◽

Disease Extension ◽

Incident Cases

Abstract Background Patient stratification according to the risk of developing complications is an essential step to define the best treatment approach in patients with ulcerative colitis (UC). Recently, Siegel et al (Gut 2017) published a score that aims to access the disease severity, considering disease activity (both clinical and endoscopic factors) and complications during the disease course, ranging from 0 to 100 values (higher values indicating worse disease severity). Our goal was to evaluate the capacity of this score calculated at the time of diagnosis (dx) to predict disease course during follow-up (FU): steroid use, therapy escalation to immunomodulators or biologics, hospitalisation and/or abdominal surgery. Methods Retrospective cohort study including incident cases of UC in our centre between December 2012 and December 2018. We calculated the score at the time of dx and at the end of FU and collected data about disease course. Results Eighty-five patients (57% men with a mean age of 43 ± 17 years) with newly diagnosed UC were included. Disease extension according to Montreal was E1 in 30/85 patients, E2 in 37/85 patients and E3 in 18/85 patients. Median FU time was 40 months. Median risk score at the time of dx was 30 (IQR 3–91) and it was higher in patients with younger age (36 vs. 26, p = 0.08) and extensive colitis (64 vs. 26, p < 0.001). During FU, 19/85 and 17/85 patients needed steroid use and therapy escalation, respectively. Proximal disease extension occurred in one patient. Hospital admission for acute exacerbation and/or colectomy was required in 6/85. The score at dx was higher in patients who underwent hospital admission or colectomy (score: 70 vs. 26, p = 0.002), or that needed steroid (score: 57 vs. 26, p < 0.001) or therapy escalation (score: 57 vs. 26, p < 0.001) during FU. In a survival analysis, the time for steroid use (plogrank < 0.001) or therapy escalation (plogrank < 0.001) was lower in patients with a higher score at dx (61 vs. 88 months and 56 vs. 86 months, respectively). The median score at the end of FU was 3 (IQR 0–66); a second colonoscopy was not available in three patients, who were not included in this analysis. There was a score reduction in 77/82 patients (39/82 had a score of 0). Only one patient had a similar score and 4/85 patients had a higher score. Patients with a significant score reduction during FU (below the median) were more frequently patients with no need for steroid use (p < 0.001) or therapy escalation (p = 0.002). Conclusion This severity score seems to be a promising tool for risk stratification and prognosis determination in patients with UC, and its utility should be validated in prospective studies.

Download Full-text

P047 Differences in extra cellular matrix remodelling in highly active Crohn’s disease and ulcerative colitis

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.176 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S156-S157

Author(s):

V Domislović ◽

J H Mortensen ◽

M A Karsdal ◽

M Brinar ◽

T Manon-Jensen ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Type Iv Collagen ◽

Collagen Degradation ◽

Type Iii Collagen ◽

Collagen Turnover ◽

Collagen Formation ◽

Type Iii ◽

Highly Active ◽

Type Iv

Abstract Background Ulcerative colitis (UC) and Crohn’s disease (CD) require continuous evaluation of disease activity and response to therapy. Current gold standard is endoscopy; therefore it is important to investigate biomarkers associated with endoscopic disease activity. Extra cellular matrix (ECM) consists of basement membrane (BM) and interstitial matrix (IM). BM consists mainly of type IV collagen, while IM of types I, III and V collagen. Pathological environment leads to impaired remodelling, structure, quality and function of the ECM. We investigated biomarkers of collagen degradation and formation and their association with endoscopic disease activity and in patients with CD and UC. Methods In this cross-sectional study, we measured six biomarkers of ECM remodelling in 94 IBD patients (60 with CD and 34 UC). Biomarkers of type III collagen degradation (C3M) and formation (PRO-C3), type IV collagen degradation (C4M), formation (PRO-C4), type V collagen formation (PRO-C5) and PROC23 were measured in serum by ELISA. Inflammatory activity was measured using endoscopic scores; SES-CD for CD, MES and modified MES (mMES) for UC. Patients were divided in remission and mild activity group vs. moderate-to-severe activity (SES-CD < 3 vs. ≥3 and MES < 2 vs. ≥2) Student t-test and correlation analysis were applied in statistical analysis. Results CD patients with moderate and severe disease had lower levels of PRO-C3 (14.7 ± 10.5 vs. 9.9 ± 4.6, p = 0.04), and higher levels of C4M (26.54 ± 10.5 vs. 37.8 ± 20, p = 0.009) compared with patients in remission and mild disease. Biomarker of type III collagen turnover (C3M/PROC3) showed higher levels in moderate and severe active disease in CD (1 ± 0.5 vs. 1.8 ± 1.1, p = 0.006). UC patients with moderate to severe activity showed higher levels of type III collagen turnover biomarker (C3M/PROC3) (1.1 ± 0.4 vs. 1.97 ± 1, p = 0.049). C4M correlated positively (r = 0.28, p = 0.03) and PRO-C3 correlated negatively (r = −0.29, p = 0.03) to SES-CD and combined in a multivariate regression model (r = 0.39, p = 0.009). C3M (r = 0.60, p = 0.004) and C4M (r = 0.36, p = 0.039) correlated positively with mMES. Conclusion In highly active CD, there is increased type IV collagen degradation and reduced type III collagen formation. Both biomarkers significantly correlate with SES-CD, with increased correlation when combined together. Type III collagen turnover is increased in highly active CD and UC. Biomarkers of types III and IV collagen degradation correlate significantly with mMES. Biomarkers of types III and IV collagen could be used to differentiate highly active CD from UC. Our findings suggest that biomarkers of basement membrane and interstitial matrix remodelling may be used as surrogate markers for monitoring of disease activity for UC and CD.

Download Full-text

OP31 Meta–omics reveals microbiome-driven proteolysis as a contributing factor to the severity of ulcerative colitis disease activity

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.030 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S030-S031

Author(s):

R Mills ◽

P Dulai ◽

Y Vázquez-Baeza ◽

Q Zhu ◽

G Humphrey ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Disease Severity ◽

Large Scale ◽

In Vitro Experiments ◽

Protease Inhibition ◽

Faecal Calprotectin ◽

High Severity

Abstract Background Ulcerative colitis (UC) is characterised by an aberrant immune response directed towards the gut microbiota. It remains poorly understood which mechanisms govern pathogenic roles of the microbiome in UC. Methods A prospective cohort of 40 UC patients were phenotyped with clinical (partial Mayo), biochemical (faecal calprotectin), endoscopic (Mayo endoscopic sub-score and ulcerative colitis Endoscopic Index of Severity) and histologic (Geboes) disease activity indices. Individual patient-matched faecal samples collected within 24 h prior to the lower endoscopy underwent 16S, shotgut metagenomic, metabolomic, metaproteomic, and metapeptidomic sequencing in addition to proteomic sequencing of paired serum samples. Sequencing datasets were integrated and analysed for microbial determinants of UC disease severity. Confirmatory in-vivo and in-vitro experiments were performed in Caco-2 epithelial monolayers and IL10 knockout mice. Results All meta-omics displayed large-scale shifts related to disease severity, with the metabolome and metaproteome best predicting disease severity and the metapeptidome demonstrating an increase of peptide fragments in UC patients with high severity. Broad-scale analyses and taxonomic inferences identified Bacteroides proteases as a distinguishing feature of disease severity, with the Bacteroides association being driven by changes in protease protein expression. Using a Caco-2 model we confirmed that epithelial disruption by Bacteroides vulgatus was prevented by protease inhibition, without influencing growth rates. Guided by the metagenome and metaproteome we transplanted a high-severity UC faecal sample with an increased abundance of proteases related to Bacteroides vulgatus into an IL10−/− gnotobiotic mouse model, and observed that colitis induced by transplant of faeces was attenuated by oral administration of protease inhibitors. Conclusion Through an integrated multi-omics data analysis we demonstrate that certain members of the microbiome, such as Bacteroides vulgatus, may contribute to exacerbating disease activity in UC through protease activity. In-vivo and in-vitro experiments provide evidence that bacterial protease inhibition may be a novel therapeutic approach in UC.

Download Full-text

P208 Correlation between physician and patient disease assessments in ulcerative colitis: 2-year UK data from the ICONIC study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.337 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S242-S244

Author(s):

N Bhala ◽

A Hart ◽

D Watts ◽

S Lewis ◽

S Ghosh ◽

...

Keyword(s):

Ulcerative Colitis ◽

Disease Activity ◽

Disease Severity ◽

Disease Burden ◽

Activity Index ◽

Routine Care ◽

Pictorial Representation ◽

Strongly Correlated ◽

Patient Health ◽

Life Impact

Abstract Background ICONIC is the largest prospective multi-country (n = 33) observational study assessing burden in adult ulcerative colitis (UC) patients under routine care. Both patient and physician assessments of disease severity, activity and life impact were captured 6 monthly up to 2 years. This local subanalysis evaluates baseline (BL) characteristics and the extent of agreement between patients and physicians in measures of disease activity in UK patients. Methods Adults with early UC (diagnosed ≤36 months) were enrolled irrespective of disease severity or treatment. Patient self-assessments include disease severity, Pictorial Representation of Illness and Self-Measure (PRISM, a tool assessing perception of disease-associated suffering; lower scores indicate greater disease burden), Patient Health Questionnaire-9 (PHQ-9), Short inflammatory bowel disease Questionnaire (SIBDQ) and patient-modified Simple Clinical Colitis Activity Index (P-SCCAI). Physician assessments include clinical parameters, PRISM, SCCAI. Correlation between PRISM and SIBDQ, PHQ-9 and SCCAI were evaluated by Spearman correlation. BL characteristics are based on observed data. Results BL characteristics of 63 UK patients in ICONIC are shown in Table 1. From BL to 2-years, patient/physician PRISM was moderately/strongly correlated with SIBDQ, PHQ-9, P-SCCAI or SCCAI (Table 2). For 62 patients with self and physician assessments, the level of agreement on disease severity at BL (concordant pairs) was: mild 66.7%, moderate 27.8%, severe 45.5%, in remission 50.0%. The mean ± SD P-SCCAI and physician SCCAI values at 2 years were 2.6 ± 2.6 and 1.5 ± 1.5, respectively; the measures were strongly correlated (Table 2). For patient/physician PRISM assessments at 2 years, scores were 5.2 ± 2.6 and 5.2 ± 2.1, respectively, and were moderately/strongly correlated (Table 2). Conclusion Results from this subanalysis of ICONIC demonstrate persistently high UC disease burden over 2-years, despite treatment. EIMs were common and therefore awareness of potential EIM impact is essential. PRISM, used for the first time in UC, was moderately correlated with disease-specific measures (SIBDQ/SCCAI) and a general depression assessment (PHQ-9). Alignment between patients and physicians on disease activity/severity varied according to the instrument used but was greatest for SCCAI.

Download Full-text