130 results on '"Festen, Eleonora A. M."'
Search Results
2. Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease
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Hu, Shixian, Bourgonje, Arno R., Gacesa, Ranko, Jansen, Bernadien H., Björk, Johannes R., Bangma, Amber, Hidding, Iwan J., van Dullemen, Hendrik M., Visschedijk, Marijn C., Faber, Klaas Nico, Dijkstra, Gerard, Harmsen, Hermie J. M., Festen, Eleonora A. M., Vich Vila, Arnau, Spekhorst, Lieke M., and Weersma, Rinse K.
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- 2024
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3. Proteomic analyses do not reveal subclinical inflammation in fatigued patients with clinically quiescent inflammatory bowel disease
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Bourgonje, Arno R., Wichers, Sietse J., Hu, Shixian, van Dullemen, Hendrik M., Visschedijk, Marijn C., Faber, Klaas Nico, Festen, Eleonora A. M., Dijkstra, Gerard, Samsom, Janneke N., Weersma, Rinse K., and Spekhorst, Lieke M.
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- 2022
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4. Gut mucosa dissociation protocols influence cell type proportions and single-cell gene expression levels
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Uniken Venema, Werna T. C., Ramírez-Sánchez, Aarón D., Bigaeva, Emilia, Withoff, Sebo, Jonkers, Iris, McIntyre, Rebecca E., Ghouraba, Mennatallah, Raine, Tim, Weersma, Rinse K., Franke, Lude, Festen, Eleonora A. M., and van der Wijst, Monique G. P.
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- 2022
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5. Hepcidin and Iron Status in Patients With Inflammatory Bowel Disease Undergoing Induction Therapy With Vedolizumab or Infliximab.
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Loveikyte, Roberta, Bourgonje, Arno R, Reijden, Johannes J van der, Bulthuis, Marian L C, Hawinkels, Lukas J A C, Visschedijk, Marijn C, Festen, Eleonora A M, Dullemen, Hendrik M van, Weersma, Rinse K, Goor, Harry van, Jong, Andrea E van der Meulen-de, and Dijkstra, Gerard
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- 2023
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6. Sex-Related Differences in Patients With Inflammatory Bowel Disease: Results of 2 Prospective Cohort Studies
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Severs, Mirjam, Spekhorst, Lieke M, Mangen, Marie-Josée J, Dijkstra, Gerard, Löwenberg, Mark, Hoentjen, Frank, van der Meulen-de Jong, Andrea E, Pierik, Marieke, Ponsioen, Cyriel Y, Bouma, Gerd, van der Woude, Janneke C, van der Valk, Mirthe E, Romberg-Camps, Marielle J L, Clemens, Cees H M, van de Meeberg, Paul, Mahmmod, Nofel, Jansen, Jeroen, Jharap, Bindia, Weersma, Rinse K, Oldenburg, Bas, Festen, Eleonora A M, and Fidder, Herma H
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- 2018
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7. Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease
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Imhann, Floris, Vich Vila, Arnau, Bonder, Marc Jan, Fu, Jingyuan, Gevers, Dirk, Visschedijk, Marijn C, Spekhorst, Lieke M, Alberts, Rudi, Franke, Lude, van Dullemen, Hendrik M, Ter Steege, Rinze W F, Huttenhower, Curtis, Dijkstra, Gerard, Xavier, Ramnik J, Festen, Eleonora A M, Wijmenga, Cisca, Zhernakova, Alexandra, and Weersma, Rinse K
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- 2018
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8. Type I collagen degradation fragments (C1M) and human neutrophil elastase-derived fragments of calprotectin (CPa9-HNE) reflect biochemical and endoscopic disease activity in patients with Inflammatory Bowel Disease
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Bourgonje, Arno R., Alexdóttir, Marta S., Loveikyte, Roberta, Pehrsson, Martin, Bay-Jensen, Anne-Christine, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Karsdal, Morten A., Faber, Klaas Nico, Mortensen, Joachim H., Dijkstra, Gerard, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
Background Crohn’s disease (CD) and ulcerative colitis (UC) are characterized by intestinal inflammation and increased extracellular matrix (ECM) remodeling, which are key pathophysiological mechanisms in patients with IBD and highly related to mucosal damage. Alterations in intestinal ECM turnover as well as macrophage and neutrophil activity may be reflected by secreted products that are released into the systemic circulation. In this study, we aimed to investigate associations between serum biomarkers of neutrophil activity (serum calprotectin) and collagen degradation (mucosal damage), and disease activity in patients with IBD. Methods Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C6), matrix metalloproteinase (MMP)-mediated collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) and intestinal inflammation (VICM [macrophage activity], human neutrophil elastase-derived fragment of calprotectin (CPa9-HNE [serum calprotectin, neutrophil activity]) were measured using Protein FingerPrint assay (PFA) technology in 100 patients with IBD (CD: n=44; UC: n=56). Biochemical disease activity was assessed using C-reactive protein (CRP) levels and available faecal calprotectin (FCal) levels. Endoscopic disease activity was determined using the Simple Endoscopic Score for CD (SES-CD) and Mayo endoscopic subscore for UC. Results C1M strongly associated with elevated CRP levels (defined as >5mg/L, P
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- 2022
9. Biomarkers of neutrophil activity and extracellular matrix turnover predict long-term response to vedolizumab in patients with Crohn's disease
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Alexdóttir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Bay-Jensen, Anne-Christine, Pehrsson, Martin, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Faber, Klaas Nico, Dijkstra, Gerard, Mortensen, Joachim H., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
Background Crohn‘s disease (CD) is a form of inflammatory bowel disease characterized by high infiltration of immune cells into the intestinal tissue, resulting in increased proteolytic mediated extracellular matrix (ECM) remodeling. Disease management has improved with the use of biologics such as vedolizumab (VEDO). However, considering the high rate of primary non-response to VEDO, there is an unmet need for predictive serum biomarkers capable of determining response to treatment prior to its initiation. This study investigated whether biomarkers of neutrophil activity, mucosal damage, and ECM remodeling could serve as non-invasive tools for predicting long-term response to VEDO in patients with CD. Methods Serum biomarkers of human neutrophil elastase (HNE)-derived fragment of calprotectin (CPa9-HNE [serum calprotectin]) and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n=32) before VEDO therapy initiation. The ratio C4M/C4G (myeloid/lymphoid mediated degradation) was computed. Long-term response was defined as the continuation of treatment beyond one year after the start of therapy. Baseline biomarker levels were compared between responders and non-responders using Mann-Whitney U-tests, and area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Biomarker levels were divided into tertiles and chi-square tests were used to investigate the relationship between tertiles and response proportions. Results Biomarkers CPa9-HNE, C1M, C3M, C4M, PRO-C3, C3M/PRO-C3, and C4M/C4G were significantly increased at baseline in non-responders compared with responders (all P
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- 2022
10. In-depth characterisation of the serum antibody epitope repertoire in Inflammatory Bowel Disease by high-throughput phage-displayed immunoprecipitation sequencing
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Bourgonje, Arno R., Andreu-Sánchez, Sergio, Vogl, Thomas, Hu, Shixian, Vich Vila, Arnau, Leviatan, Sigal, Kurilshchikov, Aleksandr, Klompus, Shelley, Kalka, Iris N., van Dullemen, Hendrik M., Weinberger, Adina, Visschedijk, Marijn C., Festen, Eleonora A. M., Faber, Klaas Nico, Wijmenga, Cisca, Dijkstra, Gerard, Segal, Eran, Fu, Jingyuan, Zhernakova, Alexandra, Weersma, Rinse K., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
Background Patients with IBD show distinct antibody responses, particularly against microbiota. However, a comprehensive overview of the antibody epitope repertoire in IBD is lacking. Here, we characterized serum antibody responses in patients with IBD and population controls using a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow and associated these to disease phenotypes and the faecal microbiome. Methods PhIP-seq was leveraged to characterise antibody responses against 344,000 rationally selected peptide antigens in 497 patients with IBD which were compared with 1,326 individuals from a population-based cohort (Fig. 1A-B). Antibody profiles were linked to 23 IBD-specific clinical features such as disease location and surgical history and to faecal microbiota composition (Fig. 1C). Results Patients with IBD demonstrated distinct antibody epitope repertoires compared with individuals from the general population, with 373 differentially abundant antibody-bound peptides (202 overrepresented, 171 underrepresented) belonging to bacterial flagellins (69), virulence factors (102), other antigens of both commensal and pathogenic bacteria (90) as well as viruses (67) and food proteins (24) (Figure 2). In particular, antibody responses against bacterial flagellins, many of which belong to Lachnospiraceae bacteria (e.g. Roseburia spp.), but also Eubacterium spp. and pathogens (e.g. Legionella, Clostridium, Burkholderia) dominated in patients with Crohn’s disease (CD), and were associated with ileal disease involvement and more complicated disease behaviour (e.g. fibrostenotic disease, surgical history) as well as anti-Saccharomyces cerevisiae antibody positivity. Furthermore, many other antigens were newly identified, e.g. decreased responses to E. coli virulence factors and genome polyproteins of enteroviruses, and increased responses to food antigens (wheat, barley) and autoantigens (particularly collagen type I and VI). Antibody epitope repertoires were able to accurately discriminate CD from population controls (area under the curve [AUC]=0.88, test set evaluation), showing very high discriminative performance (positive and negative predictive value of 72% and 93%, respectively, representing predicted classes in test set) (Fig. 3A-C), which was less accurate for ulcerative colitis (UC) (Fig. 3D-F). Conclusion This study demonstrates the size, diversity and complexity of systemic antibody epitope repertoires in patients with IBD compared to controls, showing that distinct clinical phenotypes of IBD are characterized by unique antibody signatures. PhIP-seq is a powerful tool for identifying systemic immune-based biomarkers and exposing novel immunological targets in immune-mediated inflammatory diseases like IBD.
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- 2022
11. Serological biomarkers of type VI and XXII collagen formation predict and monitor infliximab treatment response in patients with Crohn's disease
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Alexdóttir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Bay-Jensen, Anne-Christine, Pehrsson, Martin, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Faber, Klaas Nico, Dijkstra, Gerard, Mortensen, Joachim H., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
Background Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal (GI) tract characterized by excessive protease activity and extracellular matrix (ECM) remodeling. Although biologics such as TNF-α antibodies have improved the management of disease, up to 30–50% of patients still experience non-response to treatment. Biomarkers may be useful to improve therapeutic decision-making and monitor treatment response, thereby optimizing biological therapy and decreasing the risk of surgical intervention. This study assessed whether serological biomarkers of ECM turnover could monitor or predict response to TNF-α-antagonists in patients with and without surgical history. Methods Using protein fingerprint technology, serum biomarkers of type VI (PRO-C6) and XXII (PRO-C22) collagen formation were measured in 63 patients with CD undergoing infliximab (IFX) induction therapy. Disease activity was defined by a composite of the Harvey-Bradshaw Index (HBI) and physician’s global assessments (PGA). Response to treatment was defined as steroid-free remission (HBI
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- 2022
12. Mucosal microbiota modulate host intestinal immune signatures in Inflammatory Bowel Disease
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Hu, Shixian, Bourgonje, Arno R., Gacesa, Ranko, Jansen, Bernadien H., Bangma, Amber, Hidding, Iwan, Festen, Eleonora A. M., van Dullemen, Hendrik M., Visschedijk, Marijn C., Dijkstra, Gerard, Harmsen, Hermie J. M., Vich Vila, Arnau, Spekhorst, Lieke M., Weersma, Rinse K., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Organ Transplantation (GIOT), Translational Immunology Groningen (TRIGR), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Microbes in Health and Disease (MHD)
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Background Host intestinal immune gene signatures and microbial dysregulations expose potential mechanisms in the pathogenesis of inflammatory bowel diseases (IBD). Profiling of mucosa-attached microbiota allows the understanding of locally present microbial communities and their immediate impact on the host. This study evaluated interactions between host mucosal gene expression and intestinal mucosa-attached microbiota in IBD. Methods Intestinal mucosal bulk RNA-sequencing data was combined with mucosal 16S rRNA gene sequencing data from 696 intestinal biopsies derived from 337 patients with IBD (181 with Crohn’s disease [CD] and 156 with ulcerative colitis [UC]) and 16 non-IBD controls. Hierarchical all-against-all associations testing (HAllA) was used to assess factors affecting host gene expressions and microbiota. Mucosal cell enrichments were predicted by deconvolution. Linear mixed interaction models were used to investigate host-microbiota interactions, adjusting for age, sex, BMI and batch effects. Variation explanation analysis was performed by Lasso regression. Results In total, 15,934 intestinal genes and 113 microbial taxa were identified and included in subsequent analyses. Host intestinal gene expressions were characterized by tissue- and inflammation-specificity, whereas intraindividual variability of the mucosal microbiota dominated over disease location and inflammation effects. We observed forty associations between the mucosal expression of genes and the abundance of specific microbes independent of dysbiosis (FDR
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- 2022
13. Proteomic analyses do not reveal subclinical inflammation in fatigued patients with quiescent Inflammatory Bowel Disease
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Bourgonje, Arno R., Wichers, Sietse J., Hu, Shixian, van Dullemen, Hendrik M., Visschedijk, Marijn C., Faber, Klaas Nico, Festen, Eleonora A. M., Dijkstra, Gerard, Samsom, Janneke N., Weersma, Rinse K., Spekhorst, Lieke M., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
Background Fatigue is a common and clinically challenging symptom in patients with inflammatory bowel diseases (IBD). While fatigue occurs most often in patients with active disease, up to 50% of patients with quiescent disease still report significant fatigue of unknown aetiology. Here, we aimed to investigate whether fatigue in patients with quiescent IBD is reflected by circulating inflammatory proteins, that in turn might reflect ongoing subclinical inflammation. Methods Ninety-two (92) different inflammation-related proteins were measured in plasma of 350 patients with quiescent IBD (188 Crohn’s disease [CD]; 162 ulcerative colitis [UC]). Quiescent IBD was defined as clinical (Harvey-Bradshaw Index [HBI]
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- 2022
14. Serological biomarkers of type III and IV collagen remodeling predict and monitor infliximab treatment response in patients with Inflammatory Bowel Disease
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Alexdóttir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Bay-Jensen, Anne-Christine, Faber, Klaas Nico, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Dijkstra, Gerard, Mortensen, Joachim H., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
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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
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- 2021
15. Type IV collagen formation/degradation ratio predicts response to infliximab induction therapy in patients with Ulcerative Colitis
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Bourgonje, Arno R., Alexdóttir, Marta S., Loveikyte, Roberta, Bay-Jensen, Anne-Christine, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Karsdal, Morten A., Faber, Klaas Nico, Mortensen, Joachim H., Dijkstra, Gerard, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
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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
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- 2021
16. Biomarkers reflecting extracellular matrix turnover and inflammation can be used to monitor disease activity and treatment response in patients with Crohn's disease undergoing infliximab induction therapy
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Alexdóttir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Bay-Jensen, Anne-Christine, Faber, Klaas Nico, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Dijkstra, Gerard, Mortensen, Joachim H., Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
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
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- 2021
17. Type I collagen degradation fragments and type IV collagen formation/degradation ratio are serological biomarkers for stricturing (Montreal B2) Crohn's disease
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Bourgonje, Arno R., Alexdóttir, Marta S., Loveikyte, Roberta, Bay-Jensen, Anne-Christine, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Karsdal, Morten A., Faber, Klaas Nico, Mortensen, Joachim H., Dijkstra, Gerard, Center for Liver, Digestive and Metabolic Diseases (CLDM), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
- Abstract
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
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- 2021
18. Serological biomarkers of type I, III and IV collagen turnover are associated with the presence and future progression of stricturing and penetrating Crohnʼs disease.
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Bourgonje, Arno R., Alexdottir, Marta S., Otten, Antonius T., Loveikyte, Roberta, Bay‐Jensen, Anne‐Christine, Pehrsson, Martin, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Karsdal, Morten A., Faber, Klaas Nico, Mortensen, Joachim H., and Dijkstra, Gerard
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COLLAGEN ,CROHN'S disease ,PEPTIDE mass fingerprinting ,INFLAMMATORY bowel diseases ,INTESTINAL fistula ,MATRIX metalloproteinases ,BIOMARKERS - Abstract
Summary: Background: Increased collagen remodelling is a key pathophysiological component underlying intestinal stricture and fistula development in Crohn's disease (CD). Aims: To investigate associations between serological biomarkers of collagen turnover and disease behaviour according to the Montreal classification in patients with CD. Methods: Serological biomarkers of type III/IV collagen formation (PRO‐C3, PRO‐C4) and matrix metalloproteinase (MMP) or granzyme‐B (GrzB)‐mediated type I, III, IV and VI collagen degradation (C1M, C3M, C4M, C4G, C6Ma3) were measured using neo‐epitope protein fingerprint assays in 101 patients with CD (Montreal B1: n = 37; B2: n = 27; B3: n = 37) and 96 controls. Patients were followed up until their last outpatient visit to monitor stricturing/penetrating disease progression and recurrence and the occurrence of surgical interventions. Results: C1M, C3M and C4M were significantly reduced in patients with stricturing disease (Montreal B2) and accurately differentiated them from patients with either non‐stricturing, non‐penetrating (B1) or penetrating (B3) disease (all p < 0.001, multivariable analysis). Similarly, the type IV collagen formation/degradation (PRO‐C4/C4M) ratio demonstrated high discriminative capacity (B1/B2: AUC = 0.90; B1/B3: AUC = 0.87, both p < 0.001, multivariable analysis). Prospectively, higher baseline levels of C1M and C4G were associated with an increased risk of penetrating disease progression (C4G: hazard ratio [HR] 1.71 [1.05–2.81], p < 0.05). Conclusions: Elevated degradation of type I, III and IV collagen and excessive (relative) formation of type IV collagen strongly associates with stricturing CD. Type I and IV collagen fragments show predictive potential for the risk of penetrating disease progression. These biomarkers may become valuable tools for detection and prediction of stricturing and penetrating CD. [ABSTRACT FROM AUTHOR]
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- 2022
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19. Serological Biomarkers of Extracellular Matrix Turnover and Neutrophil Activity Are Associated with Long-Term Use of Vedolizumab in Patients with Crohn's Disease.
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Alexdottir, Marta S., Bourgonje, Arno R., Karsdal, Morten A., Pehrsson, Martin, Loveikyte, Roberta, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Weersma, Rinse K., Faber, Klaas Nico, Dijkstra, Gerard, and Mortensen, Joachim H.
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EXTRACELLULAR matrix ,LEUCOCYTE elastase ,CROHN'S disease ,PEPTIDE mass fingerprinting ,VEDOLIZUMAB ,MATRIX metalloproteinases - Abstract
Crohn's disease (CD) is a relapsing-remitting inflammatory disease of the gastrointestinal (GI) tract characterized by increased extracellular matrix (ECM) remodeling. The introduction of the α4β7-integrin inhibitor vedolizumab (VEDO) has improved disease management, although there is a high rate of primary non-response in patients with CD. We studied whether ECM biomarkers of neutrophil activity and mucosal damage could predict long-term response to VEDO in patients with CD. Serum levels of human neutrophil elastase (HNE)-derived fragments of calprotectin (CPa9-HNE), and matrix metalloproteinase (MMP)-derived fragments of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen, type III collagen formation (PRO-C3), basement membrane turnover (PRO-C4) and T-cell activity (C4G), were measured using protein fingerprint assays in patients with CD (n = 32) before VEDO therapy. Long-term response was defined as VEDO treatment of at least 12 months. CPa9-HNE was significantly increased at baseline in non-responders compared with responders (p < 0.05). C1M, C3M, C4M, C6Ma3, and PRO-C4 were also significantly increased at baseline in non-responders compared with responders (all p < 0.05). All biomarkers were associated with response to VEDO (all p < 0.05). To conclude, baseline levels of serum biomarkers for neutrophil activity and mucosal damage are linked to the pathology of CD, and are associated with long-term use of VEDO in patients with CD. Therefore, these biomarkers warrant further validation and could aid in therapeutic decision-making concerning vedolizumab therapy. [ABSTRACT FROM AUTHOR]
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- 2022
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20. Use of Tumor Necrosis Factor-a Antagonists Is Associated With Attenuated IgG Antibody Response Against SARS-CoV-2 in Vaccinated Patients With Inflammatory Bowel Disease.
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Otten, Antonius T., Bourgonje, Arno R., Horinga, Petra P., van der Meulen, Hedwig H., Festen, Eleonora A. M., van Dullemen, Hendrik M., Weersma, Rinse K., van Leer-Buter, Coretta C., Dijkstra, Gerard, and Visschedijk, Marijn C.
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INFLAMMATORY bowel diseases ,ANTIBODY formation ,CROHN'S disease ,SARS-CoV-2 ,IMMUNOGLOBULIN G - Abstract
Introduction: Patients with Inflammatory Bowel Disease (IBD) frequently receive immunomodulating treatment, which may render them at increased risk of an attenuated immune response upon vaccination. In this study, we assessed the effects of different types of commonly prescribed immunosuppressive medications on the serological response after vaccination against SARS-CoV-2 in patients with IBD. Methods: In this prospective observational cohort study, IgG antibody titers against SARS-CoV-2 were measured 2-10 weeks after completion of standard vaccination regimens in patients with IBD. Clinical characteristics, previous history of SARS-CoV-2 infection, type of vaccine (mRNA- or vector-based) and medication use were recorded at the time of sampling. Subsequently, a chemiluminescent microparticle immunoassay was used for the quantitative determination of IgG antibodies against the receptor-binding domain (RBD) of the S1 subunit of the spike protein of SARS-CoV-2. Results: Three hundred and twelve (312) patients with IBD were included (172 Crohn's disease [CD] and 140 ulcerative colitis [UC]). Seroconversion (defined as titer of >50 AU/ ml) was achieved in 98.3% of patients. Antibody concentrations were significantly lower in patients treated with TNF-α-antagonists vs. non-users of TNF-α-antagonists (geometric mean [95% confidence interval]: 2204 [1655-2935] vs. 5002 [4089-6116] AU/ml, P<0.001). In multivariable models, use of TNF-α-antagonists (P<0.001), vector vaccines (P<0.001), age (>50 years) (P<0.01) and CD (P<0.05) were independently associated with lower anti-SARS-CoV-2 antibody titers. In patients who received mRNA vaccines, users of thiopurines (either prescribed as monotherapy or in combination with biologicals) demonstrated significantly lower antibody titers compared to thiopurine non-users (P<0.05). Conclusion: Despite reassuring findings that most patients with IBD have detectable antibodies after anti-SARS-CoV-2 vaccination, TNF-a-antagonists were found to be strongly associated with an attenuated IgG antibody response after vaccination against SARS-CoV-2, independent of vaccine type, the time elapsed after vaccination and blood sampling, prior SARS-CoV-2 infection and patient age. Patients treated with thiopurines and receiving mRNA-based vaccines demonstrated lower anti-SARS-CoV-2 antibody titers compared with non-users. [ABSTRACT FROM AUTHOR]
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- 2022
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21. Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease.
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Bourgonje, Arno R., Bolte, Laura A., Vranckx, Lianne L. C., Spekhorst, Lieke M., Gacesa, Ranko, Hu, Shixian, van Dullemen, Hendrik M., Visschedijk, Marijn C., Festen, Eleonora A. M., Samsom, Janneke N., Dijkstra, Gerard, Weersma, Rinse K., and Campmans-Kuijpers, Marjo J. E.
- Abstract
Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn's disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) < 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR < 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR < 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet–inflammation relationship. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease.
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Bourgonje, Arno R, Hu, Shixian, Spekhorst, Lieke M, Zhernakova, Daria V, Vila, Arnau Vich, Li, Yanni, Voskuil, Michiel D, Berkel, Lisette A van, Folly, Brenda Bley, Charrout, Mohammed, Mahfouz, Ahmed, Reinders, Marcel J T, Heck, Julia I P van, Joosten, Leo A B, Visschedijk, Marijn C, Dullemen, Hendrik M van, Faber, Klaas Nico, Samsom, Janneke N, Festen, Eleonora A M, and Dijkstra, Gerard
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- 2022
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23. Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease.
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Karmi, Naomi, Bangma, Amber, Spekhorst, Lieke M., van Dullemen, Hendrik M., Visschedijk, Marijn C., Dijkstra, Gerard, Weersma, Rinse K., Voskuil, Michiel D., and Festen, Eleonora A. M.
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INFLAMMATORY bowel diseases ,CROHN'S disease ,ULCERATIVE colitis - Abstract
Background: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. Materials and methods: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. Results: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. Conclusions: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Dietary Intake Pattern is Associated with Occurrence of Flares in IBD Patients.
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Peters, Vera, Spooren, Corinne E G M, Pierik, Marie J, Weersma, Rinse K, Dullemen, Hendrik M van, Festen, Eleonora A M, Visschedijk, Marijn C, Masclee, Adriaan A M, Hendrix, Evelien M B, Almeida, Rui Jorge, Perenboom, Corine W M, Feskens, Edith J M, Dijkstra, Gerard, Campmans-Kuijpers, Marjo J E, and Jonkers, Daisy M A E
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- 2021
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25. Isotype-specific Antibody Responses to Mycobacterium avium paratuberculosis Antigens Are Associated With the Use of Biologic Therapy in Inflammatory Bowel Disease.
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Sloot, Kimberley W J van der, Voskuil, Michiel D, Blokzijl, Tjasso, Dinkla, Annemieke, Ravesloot, Lars, Visschedijk, Marijn C, Dullemen, Hendrik M van, Festen, Eleonora A M, Alizadeh, Behrooz Z, Leer-Buter, Coretta van, Weersma, Rinse K, Goor, Harry van, Koets, Ad P, and Dijkstra, Gerard
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- 2021
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26. A Combined Set of Four Serum Inflammatory Biomarkers Reliably Predicts Endoscopic Disease Activity in Inflammatory Bowel Disease
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Bourgonje, Arno R., von Martels, Julius Z. H., Gabriëls, Ruben Y., Blokzijl, Tjasso, Buist-Homan, Manon, Heegsma, Janette, Jansen, Bernadien H., van Dullemen, Hendrik M., Festen, Eleonora A. M., Visschedijk, Marijn C., Weersma, Rinse K., de Vos, Paul, Faber, Klaas Nico, Dijkstra, Gerard, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Man, Biomaterials and Microbes (MBM), Center for Liver, Digestive and Metabolic Diseases (CLDM), and Groningen Institute for Organ Transplantation (GIOT)
- Abstract
Background Mucosal healing is the ultimate treatment goal in inflammatory bowel disease (IBD). Endoscopic examination is the gold standard to determine disease activity in IBD, as routine activity measures, such as C-reactive protein (CRP), faecal calprotectin and clinical disease indices are inconsistent in representing luminal disease activity. Therefore, there is a great need for non-invasive biomarkers to assess mucosal inflammation. The aim of this study was to build an accurate prediction model of endoscopic disease activity in patients with quiescent and active IBD, based on a combination of serum inflammatory biomarkers. Methods Serum concentrations of 10 inflammatory biomarkers were analysed in 118 IBD patients (64 Crohn’s disease (CD), 54 ulcerative colitis (UC)) prior to biological treatment and 20 healthy controls. In 71 IBD patients, endoscopic disease activity was assessed by the Simple Endoscopic Score for CD (SES-CD) and Mayo endoscopic subscore for UC. Nonparametric ROC estimation with bootstrap inference was used to establish the best combination of inflammatory biomarkers predicting endoscopic disease activity. Results Six (6) inflammatory biomarkers (serum amyloid A (SAA), Eotaxin-1, IL-6, IL-8, IL-17A and TNF-α) all individually showed better prediction of IBD disease activity compared with routine measures (CRP, faecal calprotectin and HBI/SCCAI scores). The best combination of predictive inflammatory biomarkers consisted of serum SAA, IL-6, IL-8 and Eotaxin-1, showing an optimism-adjusted area under the ROC curve of 0.84 (95% CI: 0.73–0.94, P < 0.0001), which predicted significantly better (P = 0.002) than serum CRP levels with an AuROC of 0.57 (95% CI: 0.43–0.72, P = 0.32). The resulting combined calculated probability had a maximum sensitivity of 90.7% and specificity of 68.4% in correctly classifying IBD patients into the low and high endoscopic disease activity category (Youden’s J statistic = 0.58). Conclusions The combination of SAA, IL-6, IL-8 and Eotaxin-1 is superior over routine measures in predicting endoscopic disease activity in IBD. Serum inflammatory biomarkers are valuable tools for monitoring intestinal inflammation and guiding therapeutic decisions.
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- 2019
27. Exome sequencing in patient‐parent trios suggests new candidate genes for early‐onset primary sclerosing cholangitis.
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Haisma, Sjoukje‐Marije, Weersma, Rinse K., Joosse, Maria E., Koning, Barbara A. E., Meij, Tim, Koot, Bart G. P., Wolters, Victorien, Norbruis, Obbe, Daly, Mark J., Stevens, Christine, Xavier, Ramnik J., Koskela, Jukka, Rivas, Manuel A., Visschedijk, Marijn C., Verkade, Henkjan J., Barbieri, Ruggero, Jansen, Dianne B. H., Festen, Eleonora A. M., Rheenen, Patrick F., and Diemen, Cleo C.
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CHOLANGITIS ,GENES ,INFLAMMATORY bowel diseases ,RECESSIVE genes ,BILE ducts ,GENE expression ,GENE frequency - Abstract
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a rare bile duct disease strongly associated with inflammatory bowel disease (IBD). Whole‐exome sequencing (WES) has contributed to understanding the molecular basis of very early‐onset IBD, but rare protein‐altering genetic variants have not been identified for early‐onset PSC. We performed WES in patients diagnosed with PSC ≤ 12 years to investigate the contribution of rare genetic variants to early‐onset PSC. METHODS: In this multicentre study, WES was performed on 87 DNA samples from 29 patient‐parent trios with early‐onset PSC. We selected rare (minor allele frequency < 2%) coding and splice‐site variants that matched recessive (homozygous and compound heterozygous variants) and dominant (de novo) inheritance in the index patients. Variant pathogenicity was predicted by an in‐house developed algorithm (GAVIN), and PSC‐relevant variants were selected using gene expression data and gene function. RESULTS: In 22 of 29 trios we identified at least 1 possibly pathogenic variant. We prioritized 36 genes, harbouring a total of 54 variants with predicted pathogenic effects. In 18 genes, we identified 36 compound heterozygous variants, whereas in the other 18 genes we identified 18 de novo variants. Twelve of 36 candidate risk genes are known to play a role in transmembrane transport, adaptive and innate immunity, and epithelial barrier function. CONCLUSIONS: The 36 candidate genes for early‐onset PSC need further verification in other patient cohorts and evaluation of gene function before a causal role can be attributed to its variants. [ABSTRACT FROM AUTHOR]
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- 2021
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28. Treatment of severe acute ulcerative colitis in SARS-CoV-2 infected patients: report of three cases and discussion of treatment options.
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Bourgonje, Arno R., van Linschoten, Reinier C. A., West, Rachel L., van Dijk, Maarten A., van Leer-Buter, Coretta C., Kats-Ugurlu, Gursah, Pierik, Marieke J., Festen, Eleonora A. M., Weersma, Rinse K., and Dijkstra, Gerard
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SARS-CoV-2 ,ULCERATIVE colitis ,COVID-19 ,INFLAMMATORY bowel diseases ,COVID-19 treatment - Abstract
In the wake of the coronavirus disease 2019 (COVID-19) pandemic, it is unclear how asymptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients who present with acute severe ulcerative colitis (UC) can be treated effectively and safely. Standard treatment regimens consist of steroids, immunomodulatory drugs, and biological therapies, but therapeutic decision-making becomes challenging as there are uncertainties about how to deal with these drugs in patients with COVID-19 and active UC. Importantly, guidelines for this particular group of patients with UC are still lacking. To inform therapeutic decision-making, we describe three consecutive cases of patients with active UC and COVID-19 and discuss their treatments based on theoretical knowledge, currently available evidence and clinical observations. Three patients were identified through our national inflammatory bowel disease network [Initiative on Crohn's and Colitis (ICC)] for whom diagnosis of SARS-CoV-2-infection was established by reverse transcription–polymerase chain reaction (RT-PCR) testing in nasopharynx, stools, and/or biopsies. Acute severe UC was diagnosed by clinical parameters, endoscopy, and histopathology. Clinical guidelines for SARS-CoV-2-negative patients advocate the use of steroids, calcineurin inhibitors, or tumor necrosis factor alpha (TNF-α)-antagonists as induction therapy, and experiences from the current three cases show that steroids and TNF-α-antagonists could also be used in patients with COVID-19. This could potentially be followed by TNF-α-antagonists, vedolizumab, or ustekinumab as maintenance therapy in these patients. Future research is warranted to investigate if, and which, immunomodulatory drugs should be used for COVID-19 patients that present with active UC. To answer this question, it is of utmost importance that future cases of patients with UC and COVID-19 are documented carefully in international registries, such as the SECURE-IBD registry. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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29. Environmental factors associated with biological use and surgery in inflammatory bowel disease.
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Sloot, Kimberley W J, Geertsema, Paul, Rijkmans, Hanneke C, Voskuil, Michiel D, Dullemen, Hendrik M, Visschedijk, Marijn C, Festen, Eleonora A M, Weersma, Rinse K, Alizadeh, Behrooz Z, and Dijkstra, Gerard
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INFLAMMATORY bowel diseases ,CROHN'S disease ,SMOKING cessation ,APPENDECTOMY ,ULCERATIVE colitis ,DISEASE progression - Abstract
Background and Aim: While major efforts were made studying the complex etiology of inflammatory bowel disease (IBD) including environmental factors, less is known about underlying causes leading to the heterogeneous and highly variable course of disease. As cigarette smoking cessation is the best‐known environmental factor with beneficial effect in Crohn's disease (CD), more exposome factors are likely involved. Further insights into the role of the exposome in heterogeneity of disease might not only further knowledge of underlying pathways, but also allow for better risk stratification. Methods: Seven hundred twenty‐eight IBD patients completed the validated Groningen IBD Environmental Questionnaire, collecting exposome data for 93 exposome factors. Associations with disease course, that is, for need for surgery or biological therapy, were evaluated using univariate and multivariate‐adjusted logistic regression modeling. Results: No significant associations were seen after Bonferroni correction. However, 11 novel exposome factors were identified with P < 0.05. Two factors were associated with course of CD and ulcerative colitis (UC): beer (CD OR0.3/UC OR0.3) and cannabis (0.5/2.2). While in CD, carpet flooring (0.5) was associated with biological use, and four factors were associated with surgery: working shifts (1.8), appendectomy (2.4), frequent tooth brushing (2.8), and large household size (0.1). For UC, migrants more often required biologicals (10.2). Childhood underweight (3.4), amphetamine use (6.2), and cocaine use (4.8) were associated with surgery. Five factors were replicated. Conclusions: We identified 16 environmental factors nominally associated with biological use and surgery in established IBD. These new insights form an important stepping stone to guide research on biological pathways involved, risk stratification, tailor‐made interventions, and preventive strategies in IBD. [ABSTRACT FROM AUTHOR]
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- 2021
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30. Prevalence of- and risk factors for work disability in Dutch patients with inflammatory bowel disease
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Spekhorst, Lieke M, Oldenburg, Bas, Van Bodegraven, Ad A., de Jong, Dirk J, Imhann, Floris, Van der Meulen-de Jong, Andrea E, Pierik, Marieke J., van der Woude, C Janneke, Dijkstra, Gerard, D'Haens, Geert R., Löwenberg, Mark, Weersma, Rinse K., Festen, Eleonora A M, and Parelsnoer Institute and the Dutch Initiative on Crohn and Colitis
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Crohn's disease ,Work disability ,Ulcerative Colitis ,Health Care Costs ,Inflammatory bowel disease - Abstract
AIM: To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. METHODS: For this retrospective cohort study, we retrieved clinical data from the Dutch IBD Biobank on July 2014, containing electronic patient records of 3388 IBD patients treated in the eight University Medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 IBD patients and compared with the general Dutch population. Multivariate analyses were performed for work disability (sick leave, partial and full disability) and long-term full work disability (> 80% work disability for > 2 years). RESULTS: Prevalence of work disability was higher in Crohn's disease (CD) (29%) and ulcerative colitis (UC) (19%) patients compared to the general Dutch population (7%). In all IBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. In CD patients, an age > 40 years at diagnosis, disease duration > 15 years, smoking, surgical interventions, and anti-TNFα use were associated with work disability. In UC patients, an age > 55 years, and immunomodulator use were associated with work disability. In CD patients, a lower education level (OR = 1.62, 95%CI: 1.02-2.58), and in UC patients, disease complications (OR = 3.39, 95%CI: 1.09-10.58) were associated with long-term full work disability. CONCLUSION: The prevalence of work disability in IBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among IBD patients.
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- 2017
31. Understanding human gut diseases at single-cell resolution.
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Bigaeva, Emilia, Venema, Werna T C Uniken, Weersma, Rinse K, and Festen, Eleonora A M
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- 2020
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32. Latent cytomegalovirus infection does not influence long-term disease outcomes in inflammatory bowel disease, but is associated with later onset of disease.
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van der Sloot, Kimberley W. J., Voskuil, Michiel D., Visschedijk, Marijn C., Festen, Eleonora A. M., van Dullemen, Hendrik M., Weersma, Rinse K., Alizadeh, Behrooz Z., van Leer-Buter, Coretta, and Dijkstra, Gerard
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INFLAMMATORY bowel diseases ,CYTOMEGALOVIRUS diseases ,INFECTION ,CROHN'S disease ,DISEASE duration ,RHEUMATIC heart disease - Abstract
Cytomegalovirus (CMV) infection is common in the general population. CMV infection negatively affects disease course in transplant recipients and HIV patients. Whereas primary CMV infections may occur sporadically in seronegative patients, all seropositive patients with inflammatory bowel syndrome (IBD) are at risk for CMV reactivation due to the inflammatory mucosal and use of immunosuppressive medication. It is unclear whether latent CMV infection, and risk of reactivations, influences long-term disease outcomes. In this study, we aim to explore whether CMV infection affects disease outcomes in IBD patients. We performed a cross-sectional cohort study with 1404 patients with IBD from a single center. Clinical characteristics and disease outcomes were prospectively collected. We scrutinized CMV serology test results and performed additional CMV serology testing if serum was available. Out of 699 IBD patients with CMV serology, 303 (43.3%) were seropositive, comparable to the general Dutch population. CMV seropositivity was associated with older age, longer IBD disease duration, non-Western origin, birth outside the Netherlands and a lower educational level (p-values ≤.004). CMV seropositivity was not associated with more complicated long-term disease outcomes of IBD (p-values >.05). Seropositive patients presented with symptoms and were diagnosed at an older age compared to seronegative patients (p-values <.01). CMV seropositivity does not influence disease outcomes of IBD patients and seems to be associated with a delay in IBD onset. Guidelines regarding CMV screening in patients with IBD are currently based on a low level of evidence. These data support the recommendation that routine CMV serology measurement is not necessary in the clinical care of IBD. [ABSTRACT FROM AUTHOR]
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- 2020
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33. Predicted efficacy of a pharmacogenetic passport for inflammatory bowel disease.
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Bangma, Amber, Voskuil, Michiel D., Uniken Venema, Werna T. C., Brugge, Harm, Hu, Shixian, Lanting, Pauline, Franke, Lude, Dijkstra, Gerard, Festen, Eleonora A. M., and Weersma, Rinse K.
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PHARMACOGENOMICS ,INFLAMMATORY bowel diseases ,PASSPORTS - Abstract
Summary: Background: High inter‐individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine‐induced myelosuppression, thiopurine‐induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre‐treatment pharmacogenetic testing into clinical guidelines has been slow. Aim: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. Methods: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole‐exome sequencing and the Illumina Global Screening Array. An in‐house‐developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic‐guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. Results: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine‐induced myelosuppression, thiopurine‐induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. Conclusions: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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34. Riboflavin Supplementation in Patients with Crohn's Disease [the RISE-UP study].
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Martels, Julius Z H von, Bourgonje, Arno R, Klaassen, Marjolein A Y, Alkhalifah, Hassan A A, Sadabad, Mehdi Sadaghian, Vila, Arnau Vich, Gacesa, Ranko, Gabriëls, Ruben Y, Steinert, Robert E, Jansen, Bernadien H, Bulthuis, Marian L C, Dullemen, Hendrik M van, Visschedijk, Marijn C, Festen, Eleonora A M, Weersma, Rinse K, Vos, Paul de, Goor, Harry van, Faber, Klaas Nico, Harmsen, Hermie J M, and Dijkstra, Gerard
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- 2020
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35. Anti-inflammatory Gut Microbial Pathways Are Decreased During Crohn's Disease Exacerbations.
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Klaassen, Marjolein A Y, Imhann, Floris, Collij, Valerie, Fu, Jingyuan, Wijmenga, Cisca, Zhernakova, Alexandra, Dijkstra, Gerard, Festen, Eleonora A M, Gacesa, Ranko, Vila, Arnau Vich, and Weersma, Rinse K
- Published
- 2019
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36. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.
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Walker, Gareth J., Harrison, James W., Heap, Graham A., Voskuil, Michiel D., Andersen, Vibeke, Anderson, Carl A., Ananthakrishnan, Ashwin N., Barrett, Jeffrey C., Beaugerie, Laurent, Bewshea, Claire M., Cole, Andy T., Cummings, Fraser R., Daly, Mark J., Ellul, Pierre, Fedorak, Richard N., Festen, Eleonora A. M., Florin, Timothy H., Gaya, Daniel R., Halfvarson, Jonas, and Hart, Ailsa L.
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CROHN'S disease ,GENETIC polymorphisms ,GENOMES ,HYDROLASES ,RESEARCH funding ,TRANSFERASES ,ULCERATIVE colitis ,WHITE people ,CASE-control method ,HAPLOTYPES ,LEUKOCYTE count ,SEQUENCE analysis ,THERAPEUTICS - Abstract
Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.Exposures: Genetic variants associated with TIM.Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P = .03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 × 10-7) of TIM, independent of TPMT genotype and thiopurine dose.Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required. [ABSTRACT FROM AUTHOR]- Published
- 2019
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37. SLC39A8 missense variant is associated with Crohn's disease but does not have a major impact on gut microbiome composition in healthy subjects.
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Collij, Valerie, Imhann, Floris, Vich Vila, Arnau, Fu, Jingyuan, Dijkstra, Gerard, Festen, Eleonora A. M., Voskuil, Michiel D., Daly, Mark J., Xavier, Ramnik J., Wijmenga, Cisca, Zhernakova, Alexandra, and Weersma, Rinse K.
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CROHN'S disease ,INFLAMMATORY bowel diseases ,ULCERATIVE colitis ,GUT microbiome ,RIBOSOMAL RNA - Abstract
Background: Gene-microbiome interactions are important in aetiology and pathogenesis of inflammatory bowel disease, a chronic inflammatory disorder of the gastrointestinal tract consisting of Crohn’s disease and ulcerative colitis. Scarce studies on gene-microbiome interactions show very little overlap in their results. Therefore, it is of utmost importance that gene-microbiome studies are repeated. We aimed to replicate the association between the SLC39A8 [Thr]391 risk allele and gut microbiome composition in patients with inflammatory bowel disease and healthy controls. Methods: We collected faecal samples, peripheral blood and extensive phenotype data from 291 patients with inflammatory bowel disease and 476 healthy controls. Carrier status information was obtained from whole exome sequencing data, generated using the Illumina HiSeq. The gut microbiome composition was determined by tag-sequencing the 16S rRNA gene. Associations between carrier status and disease were tested using the Wilcoxon-Mann-Whitney test. Associations between carriers and gut microbiome composition were determined using principal coordinate analyses, variance explained, alpha diversity and additive general linear models in inflammatory bowel disease, healthy controls and all groups combined. Results: Crohn’s disease patients were more often carriers of the missense variant (21/171, 12.3%) than controls (30/476, 6.3%) (OR = 2.1, P = 0.01). We could not identify associations between carrier status and overall gut microbiome composition and microbial richness in all tested groups after correcting for potential confounding factors. We did identify 37 different operational taxonomical units to be associated with carrier status among the tested groups. Two of these 37 were identified before in the discovery study. Conclusions: We could confirm the genetic association of the SLC39A8 [Thr]391 risk allele with Crohn’s disease but we could only limited replicate the association in gut microbiome composition. Independent replication of gene-microbiome studies is warranted to identify true biological mechanisms. [ABSTRACT FROM AUTHOR]
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- 2019
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38. Cohort profile: design and first results of the Dutch IBD Biobank: a prospective, nationwide biobank of patients with inflammatory bowel disease.
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Spekhorst, Lieke M., Imhann, Floris, Festen, Eleonora A. M., van Bodegraven, Ad A., de Boer, Nanne K. H., Bouma, Gerd, Fidder, Herma H., D'Haens, Geert, Hoentjen, Frank, Hommes, Daan W., de Jong, Dirk J., Löwenberg, Mark, Maljaars, P. W. Jeroen, van der Meulen-de Jong, Andrea E., Oldenburg, Bas, Pierik, Marieke J., Ponsioen, Cyriel Y., Stokkers, Pieter C., Verspaget, Hein W., and Visschedijk, Marijn C.
- Abstract
Purpose The Dutch IBD Biobank aims to facilitate the discovery of predictors for individual disease course and treatment response in patients with inflammatory bowel disease (IBD). In this paper, we aim to describe the establishment of the Dutch IBD Biobank, including the facilitators and barriers to establishment. Moreover, we aim to provide a complete overview of the content of the Dutch IBD Biobank. Participants Since 2007, every patient with IBD treated in one of the eight Dutch university medical centres is asked to participate in the Dutch IBD Biobank in which 225 standardised IBD-related data items and biomaterials, such as serum, DNA, biopsies and a stool sample, are collected. Findings to date As of June 2014, the Dutch IBD Biobank had enrolled 3388 patients with IBD: 2118 Crohn's disease (62.5%), 1190 ulcerative colitis (35.1%), 74 IBDunclassified (2.2%) and 6 IBD-indeterminate (0.2%). The inclusion of patients with IBD is ongoing. The quality of the biomaterials is good and serum, DNA and biopsies have been used in newly published studies. Future plans The genotyping (750 000 genetic variants) of all participants of the Dutch IBD Biobank is currently ongoing, enabling more genetic research. In addition, all participants will start reporting disease activity and outcome measures using an online platform and mobile app. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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39. Drug Repositioning in Inflammatory Bowel Disease Based on Genetic Information.
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Collij, Valerie, Festen, Eleonora A. M., Alberts, Rudi, and Weersma, Rinse K.
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- 2016
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40. MOLGENIS research: advanced bioinformatics data software for non-bioinformaticians.
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Velde, K Joeri van der, Imhann, Floris, Charbon, Bart, Pang, Chao, Enckevort, David van, Slofstra, Mariska, Barbieri, Ruggero, Alberts, Rudi, Hendriksen, Dennis, Kelpin, Fleur, Haan, Mark de, Boer, Tommy de, Haakma, Sido, Stroomberg, Connor, Scholtens, Salome, van de Geijn, Gert-Jan, Festen, Eleonora A M, Weersma, Rinse K, and Swertz, Morris A
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BIOINFORMATICS ,NUCLEOTIDE sequencing ,CLOUD computing ,GENOMICS ,MEDICAL care - Abstract
Motivation The volume and complexity of biological data increases rapidly. Many clinical professionals and biomedical researchers without a bioinformatics background are generating big '-omics' data, but do not always have the tools to manage, process or publicly share these data. Results Here we present MOLGENIS Research, an open-source web-application to collect, manage, analyze, visualize and share large and complex biomedical datasets, without the need for advanced bioinformatics skills. Availability and implementation MOLGENIS Research is freely available (open source software). It can be installed from source code (see http://github.com/molgenis), downloaded as a precompiled WAR file (for your own server), setup inside a Docker container (see http://molgenis.github.io), or requested as a Software-as-a-Service subscription. For a public demo instance and complete installation instructions see http://molgenis.org/research. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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41. Large-scale genetic analyses in an understudied disease: haemorrhoidal disease.
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Festen, Eleonora A. M. and Weersma, Rinse K.
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DIVERTICULOSIS ,SCIENTIFIC knowledge ,GENETIC variation ,INFLAMMATORY bowel diseases ,IRRITABLE colon ,CARDIOVASCULAR system ,ETIOLOGY of diseases - Published
- 2021
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42. A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease.
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Festen, Eleonora A. M., Goyette, Philippe, Green, Todd, Boucher, Gabrielle, Beauchamp, Claudine, Trynka, Gosia, Dubois, Patrick C., Lagacé, Caroline, Stokkers, Pieter C. F., Hommes, Daan W., Barisani, Donatella, Palmieri, Orazio, Annese, Vito, van Heel, David A., Weersma, Rinse K., Daly, Mark J., Wijmenga, Cisca, and Rioux, John D.
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- *
META-analysis , *GENOMES , *LOCUS (Genetics) , *CROHN'S disease , *CELIAC disease , *GENETIC regulation - Published
- 2011
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43. Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk.
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Festen, Eleonora A. M., Stokkers, Pieter C. F., van Diemen, Cleo C., van Bodegraven, Adriaan A., Boezen, H. Marieke, Crusius, Bart J. A., Hommes, Daniel W., van der Woude, Janneke C., Balschun, Tobias, Verspaget, Hein W., Schreiber, Stephan, de Jong, Dirk J., Franke, Andre, Dijkstra, Gerard, Wijmenga, Cisca, and Weersma, Rinse K.
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- *
GENETIC polymorphisms , *COLON diseases , *ULCERATIVE colitis , *INFLAMMATORY bowel diseases , *CONFIDENCE intervals , *LOCUS (Genetics) - Abstract
OBJECTIVES:Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.METHODS:The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the study's replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample. We genotyped eight SNPs identified in two more studies, in these individuals, and replicated all significantly associated SNPs in an additional 894 UC cases and 1,174 controls from our Dutch UC study sample. A combined analysis for all patients (n=1,455) and controls (n=1,902) was performed. Dose–response models were constructed with the associated risk alleles.RESULTS:We found 12 SNPs tagging ten loci, including HLA-DRA, IL10, IL23R, JAK2, S100Z, ARPC2, and ECM1, to be associated with UC. We identified 10q26, flagged by the UC-GWAS but not confirmed in its replication phase, as a UC locus and found a trend toward association for GAS7. No association with disease localization or severity was found. The dose–response models show that individuals carrying 11 or more risk alleles have an odds ratio of 8.2 (confidence interval 3.0–22.8) for UC susceptibility.CONCLUSIONS:We confirmed the association of multiple loci with UC in the Dutch population and found evidence for association of 10q26 and a trend suggesting association for GAS7. Genetic models show that multiple risk loci in an individual increase the risk for developing UC. [ABSTRACT FROM AUTHOR]
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- 2010
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44. Gut microbiota composition and functional changes in inflammatory bowel disease and irritable bowel syndrome.
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Vich Vila, Arnau, Imhann, Floris, Collij, Valerie, Jankipersadsing, Soesma A., Gurry, Thomas, Mujagic, Zlatan, Kurilshikov, Alexander, Bonder, Marc Jan, Jiang, Xiaofang, Tigchelaar, Ettje F., Dekens, Jackie, Peters, Vera, Voskuil, Michiel D., Visschedijk, Marijn C., van Dullemen, Hendrik M., Keszthelyi, Daniel, Swertz, Morris A., Franke, Lude, Alberts, Rudi, and Festen, Eleonora A. M.
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GUT microbiome ,INFLAMMATORY bowel diseases ,IRRITABLE colon ,METAGENOMICS ,GASTROINTESTINAL diseases ,BACTERIA classification - Abstract
Differences in gut microbiota composition and function were observed between patients with inflammatory bowel disease or irritable bowel syndrome. Distinguishing two similar gut disorders: Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are two of the most common diseases of the gastrointestinal tract. In new work, Vich Vila and colleagues have characterized the gut microbiota composition of both disorders using shotgun metagenomic sequencing of stool samples from 1792 individuals. Analyses involving bacterial taxonomy, metabolic functions, antibiotic resistance genes, virulence factors, and bacterial growth rates showed key differences between these two gut disorders. On the basis of gut microbiota composition differences, patients with IBD could be distinguished from those with IBS. Changes in the gut microbiota have been associated with two of the most common gastrointestinal diseases, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Here, we performed a case-control analysis using shotgun metagenomic sequencing of stool samples from 1792 individuals with IBD and IBS compared with control individuals in the general population. Despite substantial overlap between the gut microbiome of patients with IBD and IBS compared with control individuals, we were able to use gut microbiota composition differences to distinguish patients with IBD from those with IBS. By combining species-level profiles and strain-level profiles with bacterial growth rates, metabolic functions, antibiotic resistance, and virulence factor analyses, we identified key bacterial species that may be involved in two common gastrointestinal diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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45. Corrigendum: Genetic Analysis in A Dutch Study Sample Identifies More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk.
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Festen, Eleonora A. M., Stokkers, Pieter C. F., van Diemen, Cleo C., van Bodegraven, Adriaan A., Boezen, H. Marieke, Crusius, Bart J. A., Hommes, Daniel W., van der Woude, Janneke C., Balschun, Tobias, Verspaget, Hein W., Schreiber, Stephan, de Jong, Dirk J., Franke, Andre, Dijkstra, Gerard, Wijmenga, Cisca, and Weersma, Rinse K.
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- *
INFLAMMATORY bowel diseases , *DISEASE risk factors - Abstract
A correction to the article "Genetic Analysis in A Dutch Study Sample Identifi es More Ulcerative Colitis Susceptibility Loci and Shows Their Additive Role in Disease Risk" that was published in the previous issue is presented.
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- 2010
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46. Treatment strategies and biomarkers in Crohn's disease: the PROFILE trial.
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Bourgonje AR, Visschedijk MC, Festen EAM, Weersma RK, and Dijkstra G
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- Humans, Treatment Outcome, Infliximab therapeutic use, Crohn Disease drug therapy, Crohn Disease diagnosis, Biomarkers blood
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- 2024
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47. Biologicals in the prevention and treatment of intestinal graft rejection: The state of the art: Biologicals in Intestinal Transplantation.
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Karmi N, Uniken Venema WTC, van der Heide F, Festen EAM, and Dijkstra G
- Abstract
Intestinal transplantation is the standard treatment for patients with intestinal failure with severe complications due to parenteral nutrition; however, rejection leads to graft failure in approximately half of both adult and pediatric recipients within 5 years of transplantation. Although intensive immunosuppressive therapy is used in an attempt to reduce this risk, commonly used treatment strategies are generally practice- and/or expert-based, as head-to-head comparisons are lacking. In this ever-developing field, biologicals designed to prevent or treat rejection are used increasingly, with both infliximab and vedolizumab showing potential in the treatment of acute cellular rejection in individual cases and in relatively small patient cohorts. To help advance progress in clinical care, we review the current use of biologicals in intestinal transplantation, and we provide future perspectives to guide this progress., Competing Interests: Declaration of competing interest E.A.M.F. and W.T.C.U.V. were sponsored by an unrelated research grant from Takeda Pharmaceuticals. E.A.M.F. is supported by a ZonMW Clinical Fellowship grant (project number 90719075). G.D. received speakers fees from Janssen-Cilag, Abbvie, Takeda and Pfizer. Received unrelated research grants from Royal DSM and Janssen-Cilag. N.K. and F.H. declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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48. Exploring the Predictive Value of Gut Microbiome Signatures for Therapy Intensification in Patients With Inflammatory Bowel Disease: A 10-Year Follow-up Study.
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Al Radi ZMA, Prins FM, Collij V, Vich Vila A, Festen EAM, Dijkstra G, Weersma RK, Klaassen MAY, and Gacesa R
- Abstract
Background: Inflammatory bowel diseases (IBDs) pose a significant challenge due to their diverse, often debilitating, and unpredictable clinical manifestations. The absence of prognostic tools to anticipate the future complications that require therapy intensification presents a substantial burden to patient private life and health. We aimed to explore whether the gut microbiome is a potential biomarker for future therapy intensification in a cohort of 90 IBD patients., Methods: We conducted whole-genome metagenomics sequencing on fecal samples from these patients, allowing us to profile the taxonomic and functional composition of their gut microbiomes. Additionally, we conducted a retrospective analysis of patients' electronic records over a period of 10 years following the sample collection and classified patients into (1) those requiring and (2) not requiring therapy intensification. Therapy intensification included medication escalation, intestinal resections, or a loss of response to a biological treatment. We applied gut microbiome diversity analysis, dissimilarity assessment, differential abundance analysis, and random forest modeling to establish associations between baseline microbiome profiles and future therapy intensification., Results: We identified 12 microbial species (eg, Roseburia hominis and Dialister invisus) and 16 functional pathways (eg, biosynthesis of L-citrulline and L-threonine) with significant correlations to future therapy intensifications. Random forest models using microbial species and pathways achieved areas under the curve of 0.75 and 0.72 for predicting therapy intensification., Conclusions: The gut microbiome is a potential biomarker for therapy intensification in IBD patients and personalized management strategies. Further research should validate our findings in other cohorts to enhance the generalizability of these results., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)
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- 2024
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49. Fluorescently labelled vedolizumab to visualise drug distribution and mucosal target cells in inflammatory bowel disease.
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Gabriëls RY, van der Waaij AM, Linssen MD, Dobosz M, Volkmer P, Jalal S, Robinson D, Hermoso MA, Lub-de Hooge MN, Festen EAM, Kats-Ugurlu G, Dijkstra G, and Nagengast WB
- Abstract
Objective: Improving patient selection and development of biological therapies such as vedolizumab in IBD requires a thorough understanding of the mechanism of action and target binding, thereby providing individualised treatment strategies. We aimed to visualise the macroscopic and microscopic distribution of intravenous injected fluorescently labelled vedolizumab, vedo-800CW, and identify its target cells using fluorescence molecular imaging (FMI)., Design: Forty three FMI procedures were performed, which consisted of macroscopic in vivo assessment during endoscopy, followed by macroscopic and microscopic ex vivo imaging. In phase A, patients received an intravenous dose of 4.5 mg, 15 mg vedo-800CW or no tracer prior to endoscopy. In phase B, patients received 15 mg vedo-800CW preceded by an unlabelled (sub)therapeutic dose of vedolizumab., Results: FMI quantification showed a dose-dependent increase in vedo-800CW fluorescence intensity in inflamed tissues, with 15 mg (153.7 au (132.3-163.7)) as the most suitable tracer dose compared with 4.5 mg (55.3 au (33.6-78.2)) (p=0.0002). Moreover, the fluorescence signal decreased by 61% when vedo-800CW was administered after a therapeutic dose of unlabelled vedolizumab, suggesting target saturation in the inflamed tissue. Fluorescence microscopy and immunostaining showed that vedolizumab penetrated the inflamed mucosa and was associated with several immune cell types, most prominently with plasma cells., Conclusion: These results indicate the potential of FMI to determine the local distribution of drugs in the inflamed target tissue and identify drug target cells, providing new insights into targeted agents for their use in IBD., Trial Registration Number: NCT04112212., Competing Interests: Competing interests: GD received research grants from Royal DSM, Takeda and Janssen Pharmaceuticals and speaker fees from AbbVie, Pfizer, Takeda and Janssen Pharmaceuticals. EAMF is supported by a ZonMW Clinical Fellowship grant (project number 90719075) and has received an unrestricted research grant from Takeda. MD and SJ are employees and shareholders of Regeneron Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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50. Gut microbial metabolism of 5-aminosalicylic acid in inflammatory bowel disease.
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Karmi N, Sun S, Festen EAM, Vich Vila A, Gacesa R, and Weersma RK
- Abstract
Competing Interests: Competing interests: NK, SS and AVV declare no conflicts of interest. EAMF has received a research grant from Takeda Pharmaceuticals and is supported by a ZonMW Clinical Fellowship grant (project number 90719075). RG received funding by Janssen Pharmaceuticals (for unrelated research projects), received consulting funding from Esox Biologics (for unrelated research projects). RKW has received unrestricted Research Grants from Takeda, Johnson & Johnson, Ferring and Tramedico and speakers fees from Abbvie, MSD and Boston Scientific and has acted as a consultant for Takeda Pharmaceuticals.
- Published
- 2024
- Full Text
- View/download PDF
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