DIAGNOSTIC VALUE OF INTERLEUKIN-6 AND D-DIMER IN INFLAMMATORY BOWEL DISEASES

The article deals with the diagnostic value of changes in the content of interleukin-6 and D-dimer in patients with inflammatory bowel diseases (IBD) - Ulcerative Colitis (UC) and Crohn Disease (CD). Materials and methods: We have studied 34 patients with UC and 18 people with CD with continuously recurrent course. There are also analysed data of 15 patients with UC and 15 patients with CD in period of the remission. The control group included 30 healthy volunteers. Clinical, endoscopic examination, an immunoassay determination of the content of interleukin-6 (IL-6) and D-dimer, was carried out. CD activity was assessed using the Chron’s disease activity index. The localization of CD was established according to the Montreal classification. The clinical activity of the disease in patients with UC was determined using the classification according to Truelove-Witts. The value of the index consisted of the sum of points for each indicator, which allowed determining the activity of the inflammatory process. Statistical processing was performed using STATISTICA 10.0 (StatSoft. Inc., USA), at p<0.05, the discrepancies between the obtained data were considered statistically significant. Research results. According to the obtained data, mild activity was found in 7 patients with UC (20.6%) and 4 - with CD (22.3%), moderate severity - in 17 (50.0%) and 8 (44.4%) patients, severe - in 10 (29.4%) and 6 (33.3%) patients. In the remission stage, 15 patients with UC and 15 patients with CD were examined. According to the Montreal classification, lesions of the upper gastrointestinal tract (L4) were observed in 4 patients with CD (22.2%), terminal ileitis (L1) occurred in 10 patients (55.6%), 4 patients were diagnosed with ileocolitis (L3) - 22.2%. It has been established that patients with an active course of UC and CD had a higher level of proinflammatory markers and thrombosis markers (D-dimer and IL-6) compared with inactive course and control group (p<0.05). The D-dimer content in UC was 690±315 pg/l. It is confirmed the increase of the content of this marker in 2.55 times compared to control group and in 1.43 times than inactive course of the disease respectively. The level of IL-6 at active in course of UC was 3.36±1.78 pg/ml, increasing in 2.07 times against control and in 1.72 times compared with group of remission. In the active course of CD, the level of D-dimer reached 720±267 pg/ml, increasing in 2.67 times in relation to control and in 1.60 times with respect to patients under remission. The content of IL-6 in the active course of CD reached 4.07±2.17 pg/ml, increasing in 2.85 times in comparison to healthy individuals and in 2.83 times relatively patients with remission. While using the ROC-analysis, the most sensitive value as a “cut point” for the diagnosis of the active process in the course of IBD can be considered the content of the D-dimer in an amount of more than 650 pg/l. The calculated AUC in ROC-analysis for the IL-6 content was 73.7%±6.14% (61.7 - 85.7, p<0.001), indicating the prognostic value of the model. The values of the IL-6 content of more than 2.80 pg/ml are diagnostically significant to predict the active process in IBD.

P123 Type I collagen degradation fragments and type IV collagen formation/degradation ratio are serological biomarkers for stricturing (Montreal B2) Crohn’s disease

Background Crohn’s disease (CD) is characterized by increased extracellular matrix (ECM) remodeling, which is a key pathophysiological mechanism underlying intestinal stricture formation and other fibrotic disease complications. Alterations in intestinal ECM turnover may be reflected by products of collagen formation and degradation that are released into the systemic circulation. In this study, we aimed to investigate associations between serological biomarkers of collagen turnover and disease behavior subtypes according to the Montreal classification in patients with CD. Methods Serological biomarkers of collagen formation (PRO-C3, PRO-C4) and matrix metalloproteinase (MMP)-mediated collagen degradation (reC1M, C3M, C4M, C4G, C6Ma3) were measured using neo-epitope solid-phase competitive enzyme-linked immunosorbent assay (ELISA) technology in 101 patients with CD (Montreal B1: n=47; B2: n=28; B3: n=26) who were characterized according to the Montreal classification. Logistic regression modelling and receiver operating characteristics (ROC) statistics were used to assess discriminative power. Results Specific fragments of MMP-2,9,13-mediated degradation of type I collagen (reC1M) were significantly reduced in patients with stricturing (Montreal B2) disease compared to other disease phenotypes (B1 and B3) (P&lt;0.001). Ratios of type IV collagen formation and degradation (PRO-C4/C4M) were significantly elevated in Montreal B2 patients (P&lt;0.001). No differences in remaining serological biomarkers were observed between the different Montreal subtypes. Both reC1M and PRO-C4/C4M ratios demonstrated high discriminative power to distinguish inflammatory CD (B1) from stricturing (B2) CD, also after adjustment for confounding factors (area under the curve [AUC] 0.85 and 0.84, respectively). Conclusion Elevated degradation of type I collagen and excessive (relative) formation of type IV collagen strongly associate with stricturing CD (Montreal B2) and accurately discriminate it from inflammatory CD (Montreal B1). Therefore, reC1M and PRO-C4/C4M ratios could serve as serological biomarkers for stricturing CD. Our results should be validated in additional prospective, larger patient cohorts to corroborate these findings.

P196 Colon-involving versus non-colon-involving Crohn’s disease classification: is the Montreal classification outdated?

Background An appropriate disease classification is essential for the management of Crohn’s disease (CD) patients. Recently, a new classification of colon-involving versus non-colon-involving disease extension was considered to be more predictive of adverse outcomes than the Montreal classification (MRC). We aimed to investigate the association of a colon-based classification with clinically relevant outcomes in patients with CD compared with the MRC. Methods Retrospective cohort-study which consecutively included adult CD patients with at least 1 year of follow-up. Patients were categorized into colon-involving and non-colon-involving disease and according to the MRC. Patients’ demographic, clinical, biochemical, and imaging data were recorded and compared between the two classifications. The primary outcome was the need for treatment with steroids or biologics, hospitalization and major abdominal surgery. Results Of 327 patients, 52.3% were female with a mean age of 43.3±13.1 years. The most common disease location according to MRC was L1 (48.9%), followed by L3 (41.3%) and L2 (9.8%). Overall, 51.1% of patients had colon-involving disease. Although patients with colon-involvement at diagnosis had higher frequency of perianal lesions (27.5% vs 16.9%, P&lt;0.05) and serum inflammatory biomarkers (lower hemoglobin, and higher leucocyte and platelet counts, c-reactive protein and erythrocyte sedimentation rate), this classification was not predictive of relevant outcomes. Considering the two types of colon-involving disease (L2, L3), patients with L2 disease had higher extraintestinal manifestations (43.8% vs 20.7%, respectively, P&lt;0.05), higher B1 disease behavior (87.5% vs 58.5%, respectively, P&lt;0.05) and lower B2 disease behavior (6.25% vs 22.2%, respectively, P&lt;0.05). Disease location according to MRC was predictive of the need for treatment with biologics, hospitalization and major abdominal surgery in univariate analysis, but not in multivariate analysis. Conclusion Although simpler, defining Crohn’s disease extension by colon-involving versus non-colon-involving is not more predictive of adverse outcomes than the Montreal classification. Therefore, the use of Montreal Classification should still be considered essential in the adequate management of IBD patients.

Magnetic Resonance Enterography and Capsule Endoscopy in Patients Undergoing Patency Capsule for the Evaluation of Small Bowel Crohn’s Disease: A Korean Clinical Experience

Objective. Studies comparing magnetic resonance enterography (MRE) and capsule endoscopy (CE) for the assessment of small bowel (SB) Crohn’s disease (CD) are scarce in Korea. In addition, there is no Korean experience of patency capsule (PC) examination prior to CE. The primary aim of this study was to compare diagnostic yields of MRE and CE for the assessment of SB CD. Secondary objectives were to compare the detection rate of proximal SB lesions by each modality in the Montreal classification and evaluate the safety and feasibility of PC in Korean CD patients. Methods. MRE was performed as the first examination to assess SB CD. PC examination and CE were then performed. Diagnostic yields of active SB disease by MRE and CE were then analyzed. Results. Disintegration of the patency capsule was shown in 5 patients out of 26 patients, who did not undergo CE. These 5 patients were accounted as negative CE findings. Overall, MRE and CE detected 80.8% and 65.4% of active SB lesions of CD in 26 patients, respectively (P=0.212). MRE and CE detected 0% (0/26) and 19.2% (5/26) (P=0.051) of jejunal lesions, 30.8% (8/26) and 42.3% (11/26) (P=0.388) of proximal ileal lesions, and 80.8% (21/26) and 53.8% (14/26) (P=0.039) of terminal ileal lesions, respectively. According to the Montreal classification, MRE and CE independently detected proximal disease (L4) in 30.8% (8/26) and 53.8% (14/26) (P=0.092), respectively. Conclusions. The diagnostic yields of MRE and CE for the assessment of SB CD including proximal SB lesions were similar. MRE is a more objective tool for detecting clinically relevant stricture than PC although PC examination could be performed safely before CE to prove the patency of SB. This trial is registered with KCT0004305.

Classifying Crohn’s disease into colon-involving versus non-colon-involving groups is a better predictor of clinical outcomes than the Montreal classification

Background: A suitable disease classification is essential for individualized therapy in patients with Crohn’s disease (CD). Although a potential mechanistic classification of colon-involving and non-colon-involving disease was suggested by recent genetic and microbiota studies, the clinical implication has seldom been investigated. We aimed to explore the association of this colonic-based classification with clinical outcomes in patients with CD compared with the Montreal classification. Methods: This was a retrospective study of CD patients from a tertiary referral center. Patients were categorized into colon-involving and non-colon-involving disease, and according to the Montreal classification. Clinico-demographic data, medications, and surgeries were compared between the two classifications. The primary outcome was the need for major abdominal surgery. Results: Of 934 patients, those with colonic involvement had an earlier median (interquartile range) age of onset [23.0 (17.0–30.0) versus 26.0 (19.0–35.0) years, p = 0.001], higher frequency of perianal lesions (31.2% versus 14.5%, p < 0.001) and extraintestinal manifestations (21.8% versus 14.5%, p = 0.010), but lower frequency of stricture (B2) (16.3% versus 24.0%, p = 0.005), than those with non-colon-involving disease. Colon-involving disease was a protective factor against major abdominal surgery [hazard ratio, 0.689; 95% confidence interval (CI), 0.481–0.985; p = 0.041]. However, patients with colon-involving CD were more prone to steroids [odds ratio (OR), 1.793; 95% CI, 1.206–2.666; p = 0.004] and azathioprine/6-mercaptopurine (AZA/6-MP) treatment (OR, 1.732; 95% CI, 1.103–2.719; p = 0.017) than were patients with non-colon-involving disease. The Montreal classification was not predictive of surgery or steroids and AZA/6-MP treatment. Conclusion: This study supports the rationale for disease classification based on the involvement of colon. This new classification of CD is a better predictor of clinical outcomes than the Montreal classification.

P204 Re-established CRP cut-off in UC; it may be a better predictor of mucosal remission

Background Although faecal calprotectin can predict mucosal remission in ulcerative colitis, the CRP level in this context is insufficient and frequently stay under the current cut off level. While some patients with active mucosal disease have normal CRP levels most patients in mucosal remission have much lower CRP levels. The aim of this study is to define CRP cut off levels in the prediction of mucosal remission, considering both extensiveness and severity, in ulcerative colitis. Methods We retrospectively reviewed colonoscopy reports of ulcerative colitis patients (who are not on any steroid treatment at that time) which were performed between December 2016 and March 2019 and also their CRP levels which were obtained at the same week of the colonoscopy examination. We excluded the data of patients with any other possible cause of inflammation or infection at the time of laboratory assessment. Degree of mucosal disease at colonoscopy was evaluated according to endoscopic Mayo score. Mucosal remission was defined as endoscopic Mayo score 0 or 1. The extent of mucosal inflammation was classified according to Montreal classification. The CRP level with optimal sensitivity and specificity for mucosal remission prediction was assessed by ROC curve analysis and positive and negative predictive values were also calculated. Results A total of 331 colonoscopy reports of 260 patients (122 m, 138 f) were involved in this study. There were no significant differences between ages of patients when compared with ex, and Montreal classification and we did not find any correlation between age and CRP levels. Sensitivity, specificity, positive predictive value and negative predictive values for 5 mg/l, 3 mg /l and 2 mg/l are summarised in Table 1. CRP levels which predict Mayo 0 disease, mucosal remission (Mayo 0–1) and Mayo 3 disease are shown in Table 2. At the ROC curve analysis, we found that CRP level of approximately 2.9 mg/l can predict mucosal remission with a 77% sensitivity and % 80 specificity in all examinations without grouping into a separate segmental disease. For subgroups with Montreal E1, E2 and E3 ROC curve analysis suggested 1,8 mg/l (sn. 84%, sp. 90%), 2,7 mg/l (sn. 75%, sp. 75%) and 3 mg/l (sn. 80%, sp. 80%) CRP levels can be used for prediction of mucosal remission respectively (Table 3). It is important to emphasise that 30% of all patients with Mayo 3 colonoscopy and further 23% of patients with Montreal E3–Mayo 3 activity have CRP levels below the regular cut-off value of 5 mg/l. Conclusion CRP cut-off level of approximately 2.9 mg/l can predict mucosal remission in ulcerative colitis better than standard cut-off of 5 mg/l which has a low positive predictive value and specificity even at extended and active mucosal disease.

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

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 &gt;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 &lt; 0.001). Partial Mayo: EL-CG levels in patients with active UC were significantly elevated in comparison with HD (p &lt; 0.01), and UC patients in remission (p &lt; 0.01). ELP-3 levels were likewise significantly elevated in active UC patients compared with HD (p &lt; 0.001), and UC patients in remission (p &lt; 0.01). Montreal classification: ELM-7 was significantly elevated in active UC compared with HD (p &lt; 0.05), and UC patients in remission (p &lt; 0.05). EL-CG were also significantly elevated in active UC compared with HD (p &lt; 0.05), and UC patients in remission (p &lt; 0.05). ELP-3 was significantly elevated in active UC compared with HD (p &lt; 0.01). According to the MES score, ELP-3 levels in moderate-to-severe UC patients were significantly elevated in comparison to HD (p &lt; 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.

P779 Intestinal cancer associated with Crohn’s disease: difference between those with short duration and those with long duration

Background Patients with Crohn’s disease (CD) have increased risk of developing intestinal cancer (IC). In patients with ulcerative colitis, cancer risk is thought to increase around 10 years after the onset of colitis. However, in patients with CD, significant proportion of those was with shorter CD duration, and little has been known about the clinical management. The aim of this study was to clarify the clinicopathological characteristics of IC associated with Crohn’s disease with short duration. Methods We searched for IC cases associated with CD from a Japanese medical database (Ichushi). We picked up 272 cases, where we selected the two groups: those with short duration (5 years or less; S-group; n = 51) and those with long duration (15 years or more; L-group; n = 135). The median durations of the two groups were 0 year and 20 years, respectively. Results The age at cancer diagnosis was 51 years (interquartile (40–62)) and 45 (39–56) in S-group and L-group, respectively (p = 0.028). Patients in S-group were significantly older at the time of cancer diagnosis (p &lt; 0.0001). The age at CD diagnosis was older in S-group than that in L-group (51 (38.5–62) years vs. 22 (9–68) years) with statistically significance (p &lt; 0.0001). Relating to disease location of CD according to the Montreal classification, the proportion of L1 and L2 were significantly more in S-group than L-group (31% vs. 18%, and 49% vs. 10%, respectively; p &lt; 0.0001). Penetrating type were significantly less in S group than that in L-group (28% vs. 59%; p = 0.003) in terms of disease behaviour according to the Montreal classification. In Japan, we found that majority of the colorectal cancer associated with CD is located at anorectum. However, in S-group, the proportion of anorectal cancer was only 26%, whereas that in L-group was 69%, and the difference reached statistical significance (p &lt; 0.0001). Well to moderately differentiated adenocarcinoma accounts for 81% in S-group, while the ratio was 44% in L-group, and the difference was significant (p &lt; 0.0001). Mucinous carcinoma was predominant in L-group (39%), and the proportion was significantly lower in S-group (12%; p = 0.0022). Clinical stage was similar in both groups, and the median was stage 2 (interquartile 1–3; p = 0.071). Median survivals were 21 and 26 months, and overall survival was also similar between the two groups (p = 0.51). Conclusion Some features were different between S-group and L-group, while the prognosis was not satisfactory in both groups despite relatively early clinical cancer stage. Older patients with short CD duration should be included as candidates of surveillance for neoplasia.