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Background Crohn’s disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by high protease activity and increased extracellular matrix (ECM) turnover. Although immunotherapeutic drugs such as anti-TNFα have shown great promise in the treatment of CD, still up to 20–40% of patients do not respond to therapy. Failure to establish effective treatment may lead to further disease progression and potential disease complications. The aim of this study was to investigate whether biomarkers of ECM turnover and intestinal inflammation could serve as non-invasive tools for monitoring treatment response to anti-TNFα in patients with CD. Methods Serum biomarkers of matrix metalloproteinase (MMP)-related type I collagen degradation (reC1M), intestinal inflammation (VICM [macrophage activity], CPa9-HNE [serum calprotectin, neutrophil activity]) and type III collagen formation (PRO-C3) were measured using competitive ELISA in patients with CD (n=54) undergoing infliximab (IFX) induction therapy. Disease activity was defined by composite assessment of the Harvey-Bradshaw Index (HBI) together with physician’s global assessments (PGA). Clinical remission (HBI Table 1. Differences in biomarker levels between baseline and week 14 in CD patients receiving IFX treatment stratified by response. Biomarker concentrations presented as median [IQR]. Results In patients responding to IFX treatment (n=50), serum levels of reC1M, VICM, and CPa9-HNE (all P Conclusion Serum biomarkers for type I collagen degradation (reC1M), intestinal inflammation (VICM, CPa9-HNE) and type III collagen formation (PRO-C3) are linked to the pathology of CD, reflecting treatment response. Together, these biomarkers could be used as surrogate markers for disease monitoring during IFX treatment in CD to further improve disease management.

Background Up to 50% of patients with ulcerative colitis (UC) do not respond to biological therapies, including TNF-α-antagonists (e.g., infliximab, IFX) and migration inhibitors (e.g., the α4β7-integrin inhibitor vedolizumab, VEDO). Therefore, serological biomarkers that predict therapy response are urgently needed. In this respect, biomarkers of extracellular matrix (ECM) remodeling, including basement membrane (BM) remodeling, and intestinal inflammation may hold promise as these processes play an important role in the pathophysiology of UC. In this study, we aimed to assess the predictive ability of serological biomarkers of ECM turnover and intestinal inflammation with regard to clinical response to IFX and VEDO therapy in patients with UC. Methods Serological biomarkers of collagen formation (PRO-C3, PRO-C4), matrix metalloproteinase (MMP)-mediated collagen degradation (reC1M, C3M, C4M, C4G, C6Ma3) and intestinal inflammation (macrophage activity marker [VICM] and calprotectin degradation fragments [CPa9-HNE]) were measured using neo-epitope solid-phase competitive enzyme-linked immunosorbent assay (ELISA) technology in 80 patients with UC who received either infliximab (IFX, n=26) or vedolizumab (VEDO, n=54) induction therapy. Clinical response to therapy was defined by composite assessment of available Simple Clinical Colitis Activity Index (SCCAI) scores and physician’s global assessments (PGA) derived from clinical records. Logistic regression modelling and receiver operating characteristics (ROC) statistics were used to assess discriminative capacity regarding response to IFX and VEDO. Results Only baseline ratios of type IV collagen formation and degradation (PRO-C4/C4M) were significantly elevated in patients with UC who clinically responded to IFX therapy (P Conclusion The baseline ratio of type IV collagen formation/degradation demonstrated high predictive accuracy with regard to response to IFX therapy in patients with UC, which may imply that patients with increased BM formation vs. degradation are more likely to respond. Furthermore, VICM may hold promise as a predictor for non-response to IFX therapy. Serological biomarkers of ECM turnover and intestinal inflammation may aid in predicting response to biological therapy and deserve validation in larger, prospective cohort studies.

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 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.

Background Immunotherapeutic drugs such as anti-TNFα antibodies have greatly improved the treatment of inflammatory bowel disease (IBD). However, up to 20-40% of patients still fail to respond to therapy as the pattern of disease is variable. Better patient profiling could increase treatment response and improve quality of life. The aim of this study was to assess whether serological biomarkers reflecting tissue formation and different forms of basement membrane (BM) degradation could monitor or predict treatment response to anti-TNFα in patients with Crohn’s disease (CD) and Ulcerative Colitis (UC). Methods Using competitive ELISA, serum biomarkers of matrix metalloproteinase (MMP)-mediated type IV collagen degradation (C4M), T-cell related collagen degradation (C4G) and type III and IV collagen formation (PRO-C3, PRO-C4) were measured in 89 patients (CD=63, UC=26) receiving infliximab (IFX) induction therapy. Disease activity was defined by composite assessment of the Harvey-Bradshaw Index (HBI) for CD and Simple Clinical Colitis Activity Index (SCCAI) for UC together with physician’s global assessments (PGA). Clinical remission (HBI Results In patients with CD, baseline ratios of C4M/C4G (P Figure 1: A) Serum levels at baseline or week 14 between non-responders and responders for CD and UC. B) ROC curves showing discriminative capacity of the biomarkers (ratios) between responders and non-responders. Conclusion Increased baseline ratios of type IV collagen remodeling (C4M/C4G, PRO-C4/C4G) in serum predict treatment response to IFX in patients with CD, whereas PRO-C3 may serve as a monitoring tool reflecting tissue restoration. The ratio between MMP- and granzyme B-mediated degradation of type IV collagen (C4M/C4G) in serum was elevated in non-responders compared to responders and may serve as non-invasive tool to monitor treatment response in patients with UC. Together, these biomarkers may help reveal different profiles of ECM turnover and inflammation and thus aid in better prediction and monitoring of response to anti-TNFα treatment.