Daniel Bergemalm

Long-term effectiveness of vedolizumab in inflammatory bowel disease : a national study based on the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG)

Abstract Objectives: Clinical trials have demonstrated the efficacy of vedolizumab in inflammatory bowel disease (IBD). However, these findings may not reflect the clinical practice. Therefore, we aimed to describe a vedolizumab-treated patient population and assess long-term effectiveness. Materials and methods: Patients initiating vedolizumab between 1 June 2014 and 30 May 2015 were identified through the Swedish National Quality Registry for IBD. Prospectively collected data on treatment and disease activity were extracted. Clinical remission was defined as Patient Harvey Bradshaw index <5 in Crohn’s disease (CD) and Patient Simple Clinical Colitis Activity index <3 in ulcerative colitis (UC). Results: Two-hundred forty-six patients (147 CD, 92 UC and 7 IBD-Unclassified) were included. On study entry, 86% had failed TNF-antagonist and 48% of the CD patients had undergone ≥1 surgical resection. After a median follow-up of 17 (IQR: 14–20) months, 142 (58%) patients remained on vedolizumab. In total, 54% of the CD- and 64% of the UC patients were in clinical remission at the end of follow-up, with the clinical activity decreasing (p < .0001 in both groups). Faecal-calprotectin decreased in CD (p < .0001) and in UC (p = .001), whereas CRP decreased in CD (p = .002) but not in UC (p = .11). Previous anti-TNF exposure (adjusted HR: 4.03; 95% CI: 0.96–16.75) and elevated CRP at baseline (adjusted HR: 2.22; 95% CI: 1.10–4.35) seemed to be associated with discontinuation because of lack of response. Female sex was associated with termination because of intolerance (adjusted HR: 2.75; 95% CI: 1.16–6.48). Conclusion: Vedolizumab-treated patients represent a treatment-refractory group. A long-term effect can be achieved, even beyond 1 year of treatment.

Subphenotypes of inflammatory bowel disease are characterized by specific serum protein profiles

Objective Genetic and immunological data indicate that inflammatory bowel disease (IBD) are characterized by specific inflammatory protein profiles. However, the serum proteome of IBD is still to be defined. We aimed to characterize the inflammatory serum protein profiles of Crohn’s disease (CD) and ulcerative colitis (UC), using the novel proximity extension assay. Methods A panel of 91 inflammatory proteins were quantified in a discovery cohort of CD (n = 54), UC patients (n = 54), and healthy controls (HCs; n = 54). We performed univariate analyses by t-test, with false discovery rate correction. A sparse partial least-squares (sPLS) approach was used to identify additional discriminative proteins. The results were validated in a replication cohort. Results By univariate analysis, 17 proteins were identified with significantly different abundances in CD and HCs, and 12 when comparing UC and HCs. Additionally, 64 and 45 discriminant candidate proteins, respectively, were identified with the multivariate approach. Correspondingly, significant cross-validation error rates of 0.12 and 0.19 were observed in the discovery cohort. Only FGF-19 was identified from univariate comparisons of CD and UC, but 37 additional discriminant candidates were identified using the multivariate approach. The observed cross-validation error rate for CD vs. UC remained significant when restricting the analyses to patients in clinical remission. Using univariate comparisons, 16 of 17 CD-associated proteins and 8 of 12 UC-associated proteins were validated in the replication cohort. The area under the curve for CD and UC was 0.96 and 0.92, respectively, when the sPLS model from the discovery cohort was applied to the replication cohort. Conclusions By using the novel PEA method and a panel of inflammatory proteins, we identified proteins with significantly different quantities in CD patients and UC patients compared to HCs. Our data highlight the potential of the serum IBD proteome as a source for identification of future diagnostic biomarkers.

Elevated fecal peptidase D at onset of colitis in Galphai2-/- mice, a mouse model of IBD

Background The identification of novel fecal biomarkers in inflammatory bowel disease (IBD) is hampered by the complexity of the human fecal proteome. On the other hand, in experimental mouse models there is probably less variation. We investigated the fecal protein content in mice to identify possible biomarkers and pathogenic mechanisms. Methods Fecal samples were collected at onset of inflammation in Galphai2-/- mice, a well-described spontaneous model of chronic colitis, and from healthy littermates. The fecal proteome was analyzed by two-dimensional electrophoresis and quantitative mass spectrometry and results were then validated in a new cohort of mice. Results As a potential top marker of disease, peptidase D was found at a higher ratio in Galphai2-/- mouse feces relative to controls (fold change 27; p = 0.019). Other proteins found to be enriched in Gαi2-/- mice were mainly pancreatic proteases, and proteins from plasma and blood cells. A tendency of increased calprotectin, subunit S100-A8, was also observed (fold change 21; p = 0.058). Proteases are potential activators of inflammation in the gastrointestinal tract through their interaction with the proteinase-activated receptor 2 (PAR2). Accordingly, the level of PAR2 was found to be elevated in both the colon and the pancreas of Galphai2-/- mice at different stages of disease. Conclusions These findings identify peptidase D, an ubiquitously expressed intracellular peptidase, as a potential novel marker of colitis. The elevated levels of fecal proteases may be involved in the pathogenesis of colitis and contribute to the clinical phenotype, possibly by activation of intestinal PAR2.

P866 Faecal microbiota in newly diagnosed Crohn’s disease and its relation to treatment escalation

Faecal microbiota in newly diagnosed Crohns disease and its relation to treatment escalation

OP022 Proximity extension assay based proteins show immune cell specificity and can diagnose and predict outcomes in inflammatory bowel diseases: IBD Character study

Proximity extension assay based proteins show immune cell specificity and can diagnose and predict outcomes in inflammatory bowel diseases : IBD Character study

P788 Microbiota related disease activity and distribution in subgroups of inflammatory bowel disease

Microbiota related disease activity and distribution in subgroups of inflammatory bowel disease

Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease - IBD Character

Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease - IBD Character

Proximity Extension Assay based Proteins Show Immune Cell Specificity and can Diagnose and Predict Outcomes in Inflammatory Bowel Diseases: IBD Character Study

Introduction Proximity extension assays (PEA) allows multiprotein profiling and utilises the specificity of antibody proximity and the sensitivity of polymerase chain reaction to detect proteins of interests. As part of IBD Character, we performed high-throughput prospective case-control serum profiling to identify proteins that can predict Inflammatory Bowel Disease (IBD) and its disease course. Method Serum profiling was performed in newly diagnosed IBD and Non-IBD cases using PEA panels (Olink Proteomics) from 6 centres in Europe. Phenotypic data were obtained for all patients and follow up outcome data were captured for the Edinburgh and Oslo IBD cohorts. Treatment escalation was defined as the need for surgery and/or biologic therapies after initial induction of remission. Statistical analysis was performed using R. Results Protein profiles were available in 635 patients (152 CD, 159 UC, 26 IBD-U, 298 non-IBD). 61 protein markers were significantly associated with IBD including MMP12 (Holm-adjusted p=4.1×10–26). Mapping top markers to cell-specific FANTOM 5 [1], several differentially expressed proteins originate from innate and adaptive immune cells such as dendritic cells. 5 proteins differentiate UC from CD including MMP-12 (p=4.6×10–4) Follow up data were available for 206 patients of which 49 patients required treatment escalation. The data were randomly split into a testing (n=130) and a validation cohort (n=76). Using multivariable analyses with age, sex and follow up time as covariates, 9 proteins survived Holm adjustment and 8 of these proteins remained signficant in the validation cohort. 1000 iterations of unsupervised linear discriminant consensus clustering were performed using 7 randomly selected top proteins and identified 2 patients groups that had significantly different disease courses(Image):logrank p=2.2×10–10, HR 5.6 (2.0–15.6); outperforming conventional biomarkers in predicting treatment escalation (hsCRP >4 mg/L, HR 3.2 (1.7–5.8), p=0.0003 and Alb Conclusion We have identified immune cell-specific PEA-based serum proteins that can diagnose IBD and predict disease course. These data demonstrate the translational potential of a PEA based technology in IBD Reference . FANTOM Consortium(2014), A promoter level mammalian expression atlas, Nature2014, 507:462–70 Disclosure of Interest R. Kalla: None Declared, A Adams Conflict with: EC FP7, S Vatn: None Declared, D Bergemalm: None Declared, P Ricanek: None Declared, J Lindstrom: None Declared, A Ocklind Conflict with: Olink is an SME within IBD Character, N Nordberg Conflict with: Olink is an SME within IBD Character, N Kennedy: None Declared, N Ventham: None Declared, M Vatn: None Declared, J Soderholm: None Declared, M Pierik: None Declared, L Torkvist: None Declared, F Gomollon: None Declared, J Jahnsen: None Declared, J Halfvarson: None Declared, J Satsangi: None Declared

EPIGENETIC ALTERATIONS AT DIAGNOSIS PREDICT SUSCEPTIBILITY, PROGNOSIS AND TREATMENT ESCALATION IN INFLAMMATORY BOWEL DISEASE AND IBD CHARACTER

Epigenetic alterations at diagnosis predict susceptibility, prognosis and treatment escalation in inflammatory bowel disease - IBD Character