17 results on '"de Krijger M"'
Search Results
2. Gut-liver interactions in primary sclerosing cholangitis and inflammatory bowel disease
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de Krijger, M., Ponsioen, C.Y., de Jonge, W.J., Wildenberg, Manon E., Verheij, J., Faculteit der Geneeskunde, Ponsioen, Cyriel I. J., de Jonge, Wouter J., Verheij, Joanne, Amsterdam Gastroenterology Endocrinology Metabolism, Tytgat Institute for Liver and Intestinal Research, and Graduate School
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digestive, oral, and skin physiology ,digestive system ,digestive system diseases - Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic inflammatory liver disease, with an unknown aetiology. The co-occurrence of PSC with inflammatory bowel disease (IBD) has raised the question whether these two disease entities share a common pathophysiological ground, promoting gut-liver interactions. Previous studies have shown that gut-specific T-cells expressing integrin α4β7 are also present in the peribiliary infiltrates in the livers of patients with PSC. In the first part of this thesis, we showed that hepatic expression of molecules contributing to this gut-homing pathway, differs between disease stages of PSC. Additionally, we showed the presence of integrin α4β7 expressing T-cells in the mucosa of patients with an ileal-anal pouch anastomosis. We also analyzed the methylation profile and immune cell composition in blood samples of patients with PSC and ulcerative colitis (PSC-UC). As therapies interfering with these gut-homing mechanisms are evolving, this research contributes to the search for treatment options in both disease entities. Quantification of fibrosis in liver biopsies of patients with PSC is strongly correlated with long-term clinical outcome in PSC. We validated these findings in a large multi-center cohort. We demonstrated that three staging systems were independent predictors of time to liver transplantation and liver cirrhosis-related events. Additionally, quantification of liver fibrosis using the collagen proportionate area (CPA) measurement correlated strongly-to-moderate with the histologic scoring systems. Possibly, these methods could aid in risk stratification, or serve as surrogate markers for disease progression in clinical trials. The risk of developing colorectal cancer (CRC) is 3-4-fold higher in patients with both PSC and IBD compared to IBD alone, but the underlying molecular basis for this aggravated risk is unknown. In the last part of this thesis, we performed an extensive screen on PSC-associated colorectal cancers and compared this with sporadic and IBD associated CRC. As we found only small differences, we argued that the excess risk of CRC in PSC-IBD was not explained by the investigated molecular changes, setting the stage for further investigation.
- Published
- 2022
3. P077 Different granulocyte subsets are involved in the pathogenesis in Crohn’s disease fistula
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Becker drs, M, primary, Koelink, P, additional, de Krijger, M, additional, Bemelman, W, additional, de Jonge, W, additional, Buskens, C, additional, and Wildenberg, M, additional
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- 2022
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4. DOP24 Crohn’s Disease fistula show skewed lymphoid/myeloid balance, altered myeloid cell profiles and high TNF-α expression
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Becker, M, primary, de Krijger, M, additional, Bemelman, W, additional, de Jonge, W, additional, Buskens, C, additional, and Wildenberg, M, additional
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- 2021
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5. International experience of vedolizumab in primary sclerosing cholangitis and inflammatory bowel disease
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Williamson, K, Lytvyak, E, De Krijger, M, Trivedi, P, Estes, D, Yu, L, Pratt, D, De Vries, A, Daretti, L, Liu, C, Bowlus, C, Marschall, H, Montano-Loza, A, Chapman, R, Van Der Woude, C, Marzioni, M, Keshav, S, Ponsioen, C, Hirschfield, G, and Levy, C
- Published
- 2019
6. International experience of vedolizumab in primary sclerosis cholangitis and inflammatory bowel disease
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Williamson, K., primary, Lytvyak, E., additional, Kremer, A.E., additional, de Krijger, M., additional, Trivedi, P., additional, Estes, D., additional, Yu, L., additional, Pratt, D., additional, de Vries, A., additional, Yimam, K.K., additional, Daretti, L., additional, Liu, C.H., additional, Bowlus, C., additional, Vetter, M., additional, Marschall, H.-U., additional, Montano-Loza, A., additional, Chapman, R.W.G., additional, Marzioni, M., additional, Keshav, S., additional, Ponsioen, C., additional, Hirschfield, G., additional, and Levy, C., additional
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- 2018
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7. P044 T cells expressing integrin α4β7 are abundant in fistula tracts of Crohn’s disease patients
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de Krijger, M, primary, Buskens, C J, additional, Wildenberg, M E, additional, Verseijden, C, additional, de Jonge, W J, additional, and Ponsioen, C Y, additional
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- 2018
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8. PS-134 - International experience of vedolizumab in primary sclerosis cholangitis and inflammatory bowel disease
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Williamson, K., Lytvyak, E., Kremer, A.E., de Krijger, M., Trivedi, P., Estes, D., Yu, L., Pratt, D., de Vries, A., Yimam, K.K., Daretti, L., Liu, C.H., Bowlus, C., Vetter, M., Marschall, H.-U., Montano-Loza, A., Chapman, R.W.G., Marzioni, M., Keshav, S., Ponsioen, C., Hirschfield, G., and Levy, C.
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- 2018
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9. Genetic Profiling of Colorectal Carcinomas of Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.
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de Krijger M, Carvalho B, Rausch C, Bolijn AS, Delis-van Diemen PM, Tijssen M, van Engeland M, Mostafavi N, Bogie RMM, Dekker E, Masclee AAM, Verheij J, Meijer GA, and Ponsioen CY
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- Genetic Profile, Humans, Microsatellite Instability, Cholangitis, Sclerosing complications, Cholangitis, Sclerosing genetics, Cholangitis, Sclerosing surgery, Colorectal Neoplasms complications, Colorectal Neoplasms genetics, Inflammatory Bowel Diseases complications, Inflammatory Bowel Diseases genetics
- Abstract
Background: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) run a 10-fold increased risk of developing colorectal cancer (CRC) compared to patients with IBD only. The aim of this study was to perform an extensive screen of known carcinogenic genomic alterations in patients with PSC-IBD, and to investigate whether such changes occur already in nondysplastic mucosa., Methods: Archival cancer tissue and nondysplastic mucosa from resection specimens of 19 patients with PSC-IBD-CRC were characterized, determining DNA copy-number variations, microsatellite instability (MSI), mutations on 48 cancer genes, and CpG island methylator phenotype (CIMP). Genetic profiles were compared with 2 published cohorts of IBD-associated CRC (IBD-CRC; n = 11) and sporadic CRC (s-CRC; n = 100)., Results: Patterns of chromosomal aberrations in PSC-IBD-CRC were similar to those observed in IBD-CRC and s-CRC, MSI occurred only once. Mutation frequencies were comparable between the groups, except for mutations in KRAS, which were less frequent in PSC-IBD-CRC (5%) versus IBD-CRC (38%) and s-CRC (31%; P = .034), and in APC, which were less frequent in PSC-IBD-CRC (5%) and IBD-CRC (0%) versus s-CRC (50%; P < .001). Cases of PSC-IBD-CRC were frequently CIMP positive (44%), at similar levels to cases of s-CRC (34%; P = .574) but less frequent than in cases with IBD-CRC (90%; P = .037). Similar copy number aberrations and mutations were present in matched cancers and adjacent mucosa in 5/15 and 7/11 patients, respectively., Conclusions: The excess risk of CRC in patients with PSC-IBD was not explained by copy number aberrations, mutations, MSI, nor CIMP status, in cancer tissue, nor in adjacent mucosa. These findings set the stage for further exome-wide and epigenetic studies., (© 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)
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- 2022
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10. Carboxylesterase-1 Assisted Targeting of HDAC Inhibitors to Mononuclear Myeloid Cells in Inflammatory Bowel Disease.
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Elfiky AMI, Ghiboub M, Li Yim AYF, Hageman IL, Verhoeff J, de Krijger M, van Hamersveld PHP, Welting O, Admiraal I, Rahman S, Garcia-Vallejo JJ, Wildenberg ME, Tomlinson L, Gregory R, Rioja I, Prinjha RK, Furze RC, Lewis HD, Mander PK, Heinsbroek SEM, Bell MJ, and de Jonge WJ
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- Animals, Humans, Intestinal Mucosa metabolism, Lipopolysaccharides, Mice, Monocytes, Myeloid Cells, Carboxylic Ester Hydrolases metabolism, Colitis chemically induced, Colitis drug therapy, Colitis metabolism, Crohn Disease drug therapy, Crohn Disease metabolism, Histone Deacetylase Inhibitors pharmacology, Inflammatory Bowel Diseases metabolism
- Abstract
Background and Aims: Histone deacetylase inhibitors [HDACi] exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif [ESM] technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 [CES1]. This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease [IBD]., Methods: CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells, and Crohn's disease [CD] colon mucosa, by mass cytometry, quantitative polymerase chain reaction [PCR], and immunofluorescence staining, respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in dextran sulphate sodium [DSS]-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promoter., Results: CES1 mRNA was highly expressed in human blood CD14+ monocytes, in vitro differentiated and lipopolysaccharide [LPS]-stimulated macrophages, and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1+ cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-α production 1000 times more potently than its control, HDAC800, in CES1high monocytes. In healthy donor peripheral blood, CES1 expression was significantly higher in CD14++CD16- monocytes compared with CD14+CD16++ monocytes. In CD-inflamed colon, a higher number of mucosal CD68+ macrophages expressed CES1 compared with non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, while having limited potential in ameliorating DSS-induced colitis., Conclusions: We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)
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- 2022
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11. Epigenetic Signatures Discriminate Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis From Patients With Ulcerative Colitis.
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de Krijger M, Hageman IL, Li Yim AYF, Verhoeff J, Garcia Vallejo JJ, van Hamersveld PHP, Levin E, Hakvoort TBM, Wildenberg ME, Henneman P, Ponsioen CY, and de Jonge WJ
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- Area Under Curve, Biomarkers, Cell Adhesion Molecules, Neuronal, Epigenesis, Genetic, Humans, Male, Cholangitis, Sclerosing genetics, Colitis, Ulcerative complications, Colitis, Ulcerative diagnosis, Colitis, Ulcerative genetics
- Abstract
Background: Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease affecting the intra- and extrahepatic bile ducts, and is strongly associated with ulcerative colitis (UC). In this study, we explored the peripheral blood DNA methylome and its immune cell composition in patients with PSC-UC, UC, and healthy controls (HC) with the aim to develop a predictive assay in distinguishing patients with PSC-UC from those with UC alone., Methods: The peripheral blood DNA methylome of male patients with PSC and concomitant UC, UC and HCs was profiled using the Illumina HumanMethylation Infinium EPIC BeadChip (850K) array. Differentially methylated CpG position (DMP) and region (DMR) analyses were performed alongside gradient boosting classification analyses to discern PSC-UC from UC patients. As observed differences in the DNA methylome could be the result of differences in cellular populations, we additionally employed mass cytometry (CyTOF) to characterize the immune cell compositions., Results: Genome wide methylation analysis did not reveal large differences between PSC-UC and UC patients nor HCs. Nonetheless, using gradient boosting we were capable of discerning PSC-UC from UC with an area under the receiver operator curve (AUROC) of 0.80. Four CpG sites annotated to the NINJ2 gene were found to strongly contribute to the predictive performance. While CyTOF analyses corroborated the largely similar blood cell composition among patients with PSC-UC, UC and HC, a higher abundance of myeloid cells was observed in UC compared to PSC-UC patients., Conclusion: DNA methylation enables discerning PSC-UC from UC patients, with a potential for biomarker development., Competing Interests: Author EL was employed by Horaizon BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 de Krijger, Hageman, Li Yim, Verhoeff, Garcia Vallejo, van Hamersveld, Levin, Hakvoort, Wildenberg, Henneman, Ponsioen and de Jonge.)
- Published
- 2022
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12. Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis.
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Saffioti F, Hall A, de Krijger M, Verheij J, Hübscher SG, Maurice J, Luong TV, Pinzani M, Ponsioen CY, and Thorburn D
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- Collagen, Humans, Liver pathology, Liver Cirrhosis pathology, Prospective Studies, Retrospective Studies, Cholangitis, Sclerosing pathology
- Abstract
Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC., Methods: Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations., Results: CPA correlated strongly with histological stage determined by each scoring system (P < .001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P = .011, P = .034 and P = .001, respectively)., Conclusion: Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2021
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13. Expression of MAdCAM-1 and Gut-homing T Cells in Inflamed Pouch Mucosa.
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de Krijger M, Wildenberg ME, Mookhoek A, Verheul S, de Jonge WJ, and Ponsioen CY
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- Adult, Antigens, CD metabolism, Case-Control Studies, Cohort Studies, Female, Humans, Integrin alpha Chains metabolism, Male, Middle Aged, Pouchitis etiology, Receptors, CCR metabolism, T-Lymphocyte Subsets metabolism, Cell Adhesion Molecules metabolism, Colitis, Ulcerative metabolism, Colitis, Ulcerative surgery, Integrins metabolism, Mucoproteins metabolism, Pouchitis metabolism, Proctocolectomy, Restorative adverse effects
- Abstract
Background and Aims: Pouchitis is a common complication following formation of an ileal pouch-anal anastomosis [IPAA] after proctocolectomy for ulcerative colitis [UC]. Gut-specific lymphocyte trafficking mechanisms have been identified as players in the pathogenesis of UC. In the present study, we aimed to characterise the presence of lymphocyte subsets expressing gut-homing molecules in pouches and peripheral blood of UC patients with and without pouchitis., Methods: Biopsy samples and peripheral blood were collected from 29 patients with an IPAA [seven with active inflammation, 22 without inflammation]. Expression of adhesion molecule MAdCAM-1 was assessed using immunohistochemistry, and flow cytometry was used to characterise expression of integrin α4β7, C-chemokine receptor 9 [CCR9], and CD103 on T cell subsets., Results: MAdCAM-1 expression was significantly increased in case of active inflammation in the pouch. T cells expressing integrin α4β7 were abundant in the pouch mucosa, but the frequency of integrin α4β7-expressing T cells was decreased on CD4+ lymphocytes during inflammation. Co-expression of gut-homing markers CCR9 and α4β7 was more pronounced in biopsies compared with peripheral blood, but was not enhanced upon active inflammation., Conclusions: Gut-homing T cells are abundant in pouch mucosa, but the classic hypothesis that the chronic inflammatory state is maintained by an accumulation of α4β7-expressing effector T cells is not supported by our data., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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14. Characterization of gut-homing molecules in non-endstage livers of patients with primary sclerosing cholangitis and inflammatory bowel disease.
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de Krijger M, Visseren T, Wildenberg ME, Hooijer GKJ, Verstegen MMA, van der Laan LJW, de Jonge WJ, Verheij J, and Ponsioen CY
- Abstract
Introduction: The co-occurrence of inflammatory bowel disease (IBD) in up to 80% of patients with primary sclerosing cholangitis (PSC) suggests a relation between the gut and the liver in patients with both PSC and IBD. One hypothesis suggests that aberrantly expressed homing molecules in the liver drive infiltration of gut-homing memory T-cells that are originally primed in intestinal environment. One of the main findings supporting this hypothesis is the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in PSC livers. Expression of homing molecules in early PSC remains unclear. The aim of this study was to investigate expression patterns of homing chemokines and adhesion molecules in PSC-IBD colons and livers, and to study whether changes are already present in early stages of PSC., Methods: Needle biopsies from livers of 20 PSC patients with short-term PSC (PSC-IBD
ST ) as well as explant liver biopsies of 8 patients with long-term PSC (PSC-IBDLT ) were collected (median disease duration 0 and 22 years, respectively). Only patients with concomitant IBD were included (89% ulcerative colitis and 11% Crohn's disease). Expression and distribution of MAdCAM-1, VAP-1, integrin β7, CCL25, CCL28, CXCL12, αE (CD103) and E-cadherin were assessed in both liver and colon tissue. Liver tissue collected from obstructive cholangitis in resection specimens for Klatskin tumors or resection specimens from hepatic metastasis, liver tissue of patients with hepatitis C virus (HCV) and of patients with primary biliary cholangitis (PBC) served as controls., Results: MAdCAM-1 expression in livers of PSC-IBDLT patients was increased compared to controls. The proportion of CD3+ T-cells expressing integrin β7 did not differ between PSC-IBDST and control groups, but was higher in liver tissue of PSC-IBDLT patients. There was no difference in αE+ T-cells between PSC-IBDLT and control groups. The chemokine CCL28 was highly expressed in biliary epithelial cells. This intense staining pattern was more pronounced in PSC-IBDST , but overall did not significantly differ from controls., Conclusions: We confirm that aberrant gut lymphocyte homing to the liver exists in PSC, linking gut and liver disease pathology in PSC-IBD. Our data suggests that this phenomenon increases over time in later stages of the disease, worsening ongoing inflammation., Competing Interests: C.Y. Ponsioen received research grants form Takeda, speaker’s fees from Takeda, Tillotts, and Abbvie, and consultancy fees from Takeda and Pliant. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)- Published
- 2020
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15. Effects of Vedolizumab in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.
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Lynch KD, Chapman RW, Keshav S, Montano-Loza AJ, Mason AL, Kremer AE, Vetter M, de Krijger M, Ponsioen CY, Trivedi P, Hirschfield G, Schramm C, Liu CH, Bowlus CL, Estes DJ, Pratt D, Hedin C, Bergquist A, de Vries AC, van der Woude CJ, Yu L, Assis DN, Boyer J, Ytting H, Hallibasic E, Trauner M, Marschall HU, Daretti LM, Marzioni M, Yimam KK, Perin N, Floreani A, Beretta-Piccoli BT, Rogers JK, and Levy C
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- Adolescent, Adult, Aged, Aged, 80 and over, Child, Cholangitis, Sclerosing blood, Cholangitis, Sclerosing complications, Cholangitis, Sclerosing immunology, Humans, Inflammatory Bowel Diseases blood, Inflammatory Bowel Diseases complications, Inflammatory Bowel Diseases immunology, Integrins immunology, Liver Function Tests, Middle Aged, Retrospective Studies, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Cholangitis, Sclerosing drug therapy, Gastrointestinal Agents therapeutic use, Inflammatory Bowel Diseases drug therapy, Integrins antagonists & inhibitors
- Abstract
Background & Aims: Gut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD., Methods: We collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n = 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes., Results: In the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P = .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P = .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation., Conclusions: In an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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- 2020
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16. Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis.
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de Krijger M, Wildenberg ME, de Jonge WJ, and Ponsioen CY
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- Antibodies, Monoclonal, Humanized therapeutic use, Cell Movement immunology, Cholangitis, Sclerosing drug therapy, Gastrointestinal Agents therapeutic use, Gastrointestinal Tract immunology, Humans, Immunologic Factors therapeutic use, Inflammatory Bowel Diseases drug therapy, Liver immunology, Cholangitis, Sclerosing complications, Cholangitis, Sclerosing immunology, Inflammatory Bowel Diseases complications, Inflammatory Bowel Diseases immunology, T-Lymphocytes immunology
- Abstract
Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree, characterised by stricturing bile duct disease and progression to liver fibrosis. The pathophysiology of PSC is still unknown. The concurrence with inflammatory bowel disease (IBD) in about 70% of cases has led to the hypothesis that gut-homing lymphocytes aberrantly traffic to the liver, contributing to disease pathogenesis in patients with both PSC and IBD (PSC-IBD). The discovery of mutual trafficking pathways of lymphocytes to target tissues, and expression of gut-specific adhesion molecules and chemokines in the liver has pointed in this direction. There is now increasing interest in using drugs that intervene with these trafficking pathways (e.g. vedolizumab, etrolizumab) for the treatment of PSC-IBD. In this review we discuss what is currently known about the immunological interactions between the gut and the liver in concomitant PSC and IBD, as well as potential therapeutic options for intervening in these mechanisms., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
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17. Validation of the prognostic value of histologic scoring systems in primary sclerosing cholangitis: An international cohort study.
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de Vries EM, de Krijger M, Färkkilä M, Arola J, Schirmacher P, Gotthardt D, Goeppert B, Trivedi PJ, Hirschfield GM, Ytting H, Vainer B, Buuren HR, Biermann K, Harms MH, Chazouilleres O, Wendum D, Kemgang AD, Chapman RW, Wang LM, Williamson KD, Gouw AS, Paradis V, Sempoux C, Beuers U, Hübscher SG, Verheij J, and Ponsioen CY
- Subjects
- Adult, Biopsy, Needle, Cholangitis, Sclerosing surgery, Cohort Studies, Female, Humans, Immunohistochemistry, Internationality, Kaplan-Meier Estimate, Liver Transplantation methods, Male, Middle Aged, Multivariate Analysis, Observer Variation, Prognosis, Proportional Hazards Models, Risk Assessment, Severity of Illness Index, Survival Rate, Treatment Outcome, Cholangitis, Sclerosing mortality, Cholangitis, Sclerosing pathology, Liver Transplantation mortality
- Abstract
Histologic scoring systems specific for primary sclerosing cholangitis (PSC) are not validated. We recently determined the applicability and prognostic value of three histological scoring systems in a single PSC cohort. The aim of this study was to validate their prognostic use and reproducibility across a multicenter PSC cohort. Liver biopsies from PSC patients were collected from seven European institutions. Histologic scoring was performed using the Nakanuma, Ishak, and Ludwig scoring systems. Biopsies were independently scored by six liver pathologists for interobserver agreement. The prognostic value of clinical, biochemical, and all three histologic scoring systems on predicting composite endpoints 1 (PSC-related death and liver transplantation), 2 (liver transplantation), and 3 (liver-related events), was assessed using univariable and multivariable Cox proportional hazards modeling. A total of 119 PSC patients were identified, and the median follow-up was 142 months. During follow-up, 31 patients died (20 PSC-related deaths), 31 patients underwent liver transplantation, and 35 patients experienced one or more liver-related events. All three staging systems were independent predictors of endpoints 2 and 3 (Nakanuma system: hazard ratio [HR], 3.16 [95% confidence interval (CI), 1.49-6.68] for endpoint 2 and HR, 2.05 [95% CI, 1.17-3.57] for endpoint 3; Ishak system: HR, 1.55 [95% CI, 1.10-2.18] for endpoint 2 and HR, 1.43 [95% CI, 1.10-1.85] for endpoint 3; Ludwig system: HR, 2.62 [95% CI, 1.19-5.80] for endpoint 2 and HR, 2.06 [95% CI, 1.09-3.89] for endpoint 3). Only the Nakanuma staging system was independently associated with endpoint 1: HR, 2.14 (95% CI, 1.22-3.77). Interobserver agreement was moderate for Nakanuma stage (κ = 0.56) and substantial for Nakanuma component fibrosis (κ = 0.67), Ishak stage (κ = 0.64), and Ludwig stage (κ = 0.62)., Conclusion: We confirm the independent prognostic value and demonstrate for the first time the reproducibility of staging disease progression in PSC using the Nakanuma, Ishak, and Ludwig staging systems. The Nakanuma staging system-incorporating features of chronic biliary disease-again showed the strongest predictive value. (Hepatology 2017;65:907-919)., (© 2016 by the American Association for the Study of Liver Diseases.)
- Published
- 2017
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