Correlation between plasma P1-IgM levels and systemic markers of liver damage, inflammation, and ... more Correlation between plasma P1-IgM levels and systemic markers of liver damage, inflammation, and adipokines. Pearson R correlation between plasma IgM titers towards P1 and plasma ALT (A), AST (B), γ-GT (C), IL-1β (D), and IL-8 (E), respectively. (TIF 110 kb)
Single logistic regression model and odds ratio determination for P1-specific IgM levels in NAFLD... more Single logistic regression model and odds ratio determination for P1-specific IgM levels in NAFLD. Odds ratios for the predictive power of anti-P1 IgM titers (log2 scale) for fatty liver disease after adjustment for age, gender, waist circumference, and total IgM. (TIF 68Â kb)
Corticosteroids (CS), first-line therapeutics for Crohn’s disease (CD) with moderate or severe di... more Corticosteroids (CS), first-line therapeutics for Crohn’s disease (CD) with moderate or severe disease activity, were found to restore intestinal permeability in CD patients, whereas the underlying molecular events are still largely unknown. This study aimed to investigate the effect and mechanisms of CS prednisolone on epithelial barrier using CD patient-derived intestinal organoids. 3D intestinal organoids were generated from colon biopsies of inactive CD patients. To mimic the inflammatory microenvironment, a mixture of cytokines containing TNF-α, IFN-γ, and IL-1β were added to the organoid culture with or without pre-incubation of prednisolone or mifepristone. Epithelial permeability of the organoids was assessed by FITC-D4 flux from the basal to luminal compartment using confocal microscopy. Expression of junctional components were analyzed by qRT-PCR, immunofluorescence staining, and western blot. Activity of signaling pathways were analyzed using western blot. Exposure of the...
ObjectiveThe aim of this study was to describe the long-term health outcomes of children born to ... more ObjectiveThe aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes.DesignWe performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies.ResultsWe included 1000 children born to 626 mothers (381 (61%) Crohn’s disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) ...
Aims Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the c... more Aims Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn’s disease [CD]. Methods Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index≤ 4 points], biochemical remission (faecal calprotectin ≤ 200 μg/g and/or C-reactive protein ≤5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticostero...
Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to d... more Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to develop extra-intestinal malignancies. Immunosuppressed transplant patients show increased incidence of head and neck cancer with impaired survival. This study aims to identify risk factors for oral cavity (OCC) and pharyngeal carcinoma (PC) development in IBD, to compare clinical characteristics in IBD with the general population, and to assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all IBD patients with OCC and PC between 1993 and 2011. Two case-control studies were performed: We compared cases with the general IBD population to identify risk factors, and we compared cases with non-IBD cancer patients for outcome analyses. Results: We included 66 IBD patients and 2141 controls with OCC, 31 IBD patients and 1552 controls with PC, and 1800 IBD controls. Age at IBD diagnosis was a risk factor for OCC development, Crohn's disease (CD; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07), and ulcerative colitis (UC; OR, 1.03; 95% CI, 1.01-1.06). For PC, this applied to UC (OR, 1.05; 95% CI, 1.01-1.06). IBD OCC cases showed impaired survival (P = 0.018); in PC, survival was similar. There was no effect of immunosuppression on survival. Human papillomavirus (HPV) testing of IBD cases revealed 52.2% (12/23) HPV-positive oropharyngeal carcinomas (OPCs). Conclusion: This study shows that IBD is associated with impaired OCC survival. Higher age at IBD diagnosis is a risk factor for OCC development. We found no influence of immunosuppression on survival; 52.2% of OPC in IBD contained HPV.
The understanding of gender differences in inflammatory bowel disease (IBD) patients is an import... more The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC). Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data. In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (<16 years) was more frequently encountered in males than in females...
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of dise... more GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess... more To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. 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). 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 y...
Crohn's Disease (CD) is a chronic inflammatory disease with unpredictable behaviour. More tha... more Crohn's Disease (CD) is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. We performed a within-case analysis comparing "extreme phenotypes" using the Immunochip and replication of the top SNPs with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis (recurrent after surgery) and 619 cases with purely inflammatory CD. Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007, (P = 6.09 × 10-11), located on chromosome 16, in lncRNA RP11-679B19.1, a lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-β and downstream genes...
A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn'... more A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab con...
Journal of gastrointestinal and liver diseases : JGLD, 2016
Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in ... more Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in inflammatory bowel disease (IBD). Previous literature suggests that especially Crohn's disease patients are at an increased risk for developing gastric cancer (GC). This study aimed to identify risk factors for GC development in IBD and to compare the clinical characteristics of GC in IBD to those in the general population. We retrospectively searched the Dutch Pathology Database to identify all Dutch IBD patients with GC between January 2004 and December 2008. Two case-control studies were performed. I: to identify risk factors for GC in IBD, with controls from the IBD South Limburg (IBDSL) population-based cohort; and II: to compare GC disease course in IBD patients with the general population. General population data were obtained from the Eindhoven Cancer Registry (ECR). We included 59 patients with IBD and GC (cases). Cases were significantly older at IBD diagnosis than IBDSL co...
Monitoring mucosal inflammation is crucial to prevent complications and disease progression in Cr... more Monitoring mucosal inflammation is crucial to prevent complications and disease progression in Crohn’s disease (CD). Endoscopy is the current standard, but is invasive. Clinical activity scores and non-invasive biochemical markers do not correlate well with mucosal inflammation. Microbial perturbations have been associated with disease activity in CD. Therefore, we aimed to investigate its potential use to differentiate CD patients in remission from those with an exacerbation. From 71 CD patients repeated fecal samples were collected, resulting in 97 active disease and 97 remission samples based on a combination of biochemical and clinical parameters. The microbiota composition was assessed by pyrosequencing of the 16S rRNA V1-V3 region. Random Forest analysis was used to find the most discriminatory panel of operational taxonomic units (OTUs) between active and remission samples. An independent internal validation set was used to validate the model. A combination of 50 OTUs was abl...
Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated dise... more Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a hi...
Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific e... more Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific antibodies and represent danger-associated molecular patterns that are generated during chronic inflammatory processes. In a murine model for hepatic inflammation during non-alcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found to be protective. Here, our aim was to determine an association between OSE-specific antibody titers and NAFLD in humans. IgM and IgG levels with specificity for various OSE were assessed in the plasma of patients with NAFLD (n = 71) and healthy controls (n = 68). Antibody titers were comprehensively analyzed in patients with NAFLD after classification by histological evaluation of liver biopsies. Statistical analysis was performed to determine significant correlations and odds ratios. To study the specificity for NAFLD, plasma antibody titers were measured in patients wit...
Background Healing rates after surgical closure for high perianal fistula in patients with Crohn'... more Background Healing rates after surgical closure for high perianal fistula in patients with Crohn's disease are even more disappointing than in patients with cryptoglandular fistulas. The objective was to improve healing rates by combining the well-known mucosal advancement flap with platelet-rich plasma. Methods A prospective pilot study was conducted in one tertiary referral centre. Consecutive patients with primary or recurrent Crohn's disease-related high perianal fistulas, defined as involving the middle and/or upper third parts of the anal sphincter complex, were included. A staged procedure was performed with non-cutting seton treatment for 3 months first, followed by a mucosal advancement flap with injection of platelet-rich plasma into the fistula tract. Results Ten consecutive patients were operated on between 2009 and 2014. Half (50 %) of the patients had undergone previous fistula surgery. Mean follow-up was 23.3 months (SD 13.0). Healing of the fistula was 70 % (95 % confidence interval, 33-89 %) at 1 year. One (10 %) patient had a recurrence, and in two (20 %) patients, the fistula was persistent after treatment. An abscess occurred in one (10 %) patient. The median post-operative Vaizey score was 8.0 (range 0-21), indicating a moderate to severe continence impairment. Conclusions The results of combining the mucosal advancement flap with platelet-rich plasma in patients with Crohn's disease-related high perianal fistulas are moderate with a healing rate of 70 %. Further investigation is needed to determine the benefits and risks on continence status for this technique in this patient population.
Background: Currently there is no guideline for the treatment of patients with Crohn's disease an... more Background: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. Methods/Design: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. Discussion: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. Trial registration: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).
In the last decades, treatment options and strategies for ulcerative colitis (UC) have radically ... more In the last decades, treatment options and strategies for ulcerative colitis (UC) have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the last two decades in the South-Limburg area of the Netherlands. In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 (cohort A), cohort 1998-2005 (cohort B), and cohort 2006-2010 (cohort C). The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios (HR) for early colectomy (within six months after diagnosis), late colectomy (beyond six months after diagnosis), and hospitalisation were calculated using Cox regression models. In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators (8.1% to 22.8% to 21.7%, p<0.01) and biol...
Correlation between plasma P1-IgM levels and systemic markers of liver damage, inflammation, and ... more Correlation between plasma P1-IgM levels and systemic markers of liver damage, inflammation, and adipokines. Pearson R correlation between plasma IgM titers towards P1 and plasma ALT (A), AST (B), γ-GT (C), IL-1β (D), and IL-8 (E), respectively. (TIF 110 kb)
Single logistic regression model and odds ratio determination for P1-specific IgM levels in NAFLD... more Single logistic regression model and odds ratio determination for P1-specific IgM levels in NAFLD. Odds ratios for the predictive power of anti-P1 IgM titers (log2 scale) for fatty liver disease after adjustment for age, gender, waist circumference, and total IgM. (TIF 68Â kb)
Corticosteroids (CS), first-line therapeutics for Crohn’s disease (CD) with moderate or severe di... more Corticosteroids (CS), first-line therapeutics for Crohn’s disease (CD) with moderate or severe disease activity, were found to restore intestinal permeability in CD patients, whereas the underlying molecular events are still largely unknown. This study aimed to investigate the effect and mechanisms of CS prednisolone on epithelial barrier using CD patient-derived intestinal organoids. 3D intestinal organoids were generated from colon biopsies of inactive CD patients. To mimic the inflammatory microenvironment, a mixture of cytokines containing TNF-α, IFN-γ, and IL-1β were added to the organoid culture with or without pre-incubation of prednisolone or mifepristone. Epithelial permeability of the organoids was assessed by FITC-D4 flux from the basal to luminal compartment using confocal microscopy. Expression of junctional components were analyzed by qRT-PCR, immunofluorescence staining, and western blot. Activity of signaling pathways were analyzed using western blot. Exposure of the...
ObjectiveThe aim of this study was to describe the long-term health outcomes of children born to ... more ObjectiveThe aim of this study was to describe the long-term health outcomes of children born to mothers with inflammatory bowel disease (IBD) and to assess the impact of maternal IBD medication use on these outcomes.DesignWe performed a multicentre retrospective study in The Netherlands. Women with IBD who gave birth between 1999 and 2018 were enrolled from 20 participating hospitals. Information regarding disease characteristics, medication use, lifestyle, pregnancy outcomes and long-term health outcomes of children was retrieved from mothers and medical charts. After consent of both parents, outcomes until 5 years were also collected from general practitioners. Our primary aim was to assess infection rate and our secondary aims were to assess adverse reactions to vaccinations, growth, autoimmune diseases and malignancies.ResultsWe included 1000 children born to 626 mothers (381 (61%) Crohn’s disease, 225 (36%) ulcerative colitis and 20 (3%) IBD unclassified). In total, 196 (20%) ...
Aims Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the c... more Aims Ustekinumab is a monoclonal antibody that selectively targets p40, a shared subunit of the cytokines interleukin [IL]-12 and IL-23. It is registered for the treatment of inflammatory bowel diseases. We assessed the 2-year effectiveness and safety of ustekinumab in a real world, prospective cohort of patients with Crohn’s disease [CD]. Methods Patients who started ustekinumab were prospectively enrolled in the nationwide Initiative on Crohn and Colitis [ICC] Registry. At weeks 0, 12, 24, 52 and 104, clinical remission Harvey Bradshaw Index≤ 4 points], biochemical remission (faecal calprotectin ≤ 200 μg/g and/or C-reactive protein ≤5 mg/L], perianal fistula remission, extra-intestinal manifestations, ustekinumab dosage and safety outcomes were determined. The primary outcome was corticosteroid-free clinical remission at week 104. Results In total, 252 CD patients with at least 2 years of follow-up were included. Of all included patients, the proportion of patients in corticostero...
Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to d... more Background: Immunosuppressed inflammatory bowel disease (IBD) patients are at increased risk to develop extra-intestinal malignancies. Immunosuppressed transplant patients show increased incidence of head and neck cancer with impaired survival. This study aims to identify risk factors for oral cavity (OCC) and pharyngeal carcinoma (PC) development in IBD, to compare clinical characteristics in IBD with the general population, and to assess the influence of immunosuppressive medication on survival. Methods: We retrospectively searched the Dutch Pathology Database to identify all IBD patients with OCC and PC between 1993 and 2011. Two case-control studies were performed: We compared cases with the general IBD population to identify risk factors, and we compared cases with non-IBD cancer patients for outcome analyses. Results: We included 66 IBD patients and 2141 controls with OCC, 31 IBD patients and 1552 controls with PC, and 1800 IBD controls. Age at IBD diagnosis was a risk factor for OCC development, Crohn's disease (CD; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02-1.07), and ulcerative colitis (UC; OR, 1.03; 95% CI, 1.01-1.06). For PC, this applied to UC (OR, 1.05; 95% CI, 1.01-1.06). IBD OCC cases showed impaired survival (P = 0.018); in PC, survival was similar. There was no effect of immunosuppression on survival. Human papillomavirus (HPV) testing of IBD cases revealed 52.2% (12/23) HPV-positive oropharyngeal carcinomas (OPCs). Conclusion: This study shows that IBD is associated with impaired OCC survival. Higher age at IBD diagnosis is a risk factor for OCC development. We found no influence of immunosuppression on survival; 52.2% of OPC in IBD contained HPV.
The understanding of gender differences in inflammatory bowel disease (IBD) patients is an import... more The understanding of gender differences in inflammatory bowel disease (IBD) patients is an important step towards tailored treatment for the individual patient. The aim of this study was to compare disease phenotype, clinical manifestations, disease activity, and healthcare utilization between men and women with Crohn's disease (CD) and ulcerative colitis (UC). Two multicenter observational cohort studies with a prospective design were used to explore the differences between men and women regarding demographic and phenotypic characteristics and healthcare utilization. Detailed data on IBD-phenotype was mainly available from the Dutch IBD Biobank, while the COIN cohort provided healthcare utilization data. In the Dutch IBD Biobank study, 2118 CD patients and 1269 UC patients were analyzed. Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early onset CD (<16 years) was more frequently encountered in males than in females...
GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of dise... more GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess... more To determine the prevalence of work disability in inflammatory bowel disease (IBD), and to assess risk factors associated with work disability. 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). 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 y...
Crohn's Disease (CD) is a chronic inflammatory disease with unpredictable behaviour. More tha... more Crohn's Disease (CD) is a chronic inflammatory disease with unpredictable behaviour. More than half of CD patients eventually develop complications such as stenosis, for which they then require endoscopic dilatation or surgery, as no anti-fibrotic drugs are currently available. We aim to identify disease-modifying genes associated with fibrostenotic CD. We performed a within-case analysis comparing "extreme phenotypes" using the Immunochip and replication of the top SNPs with Agena Bioscience in two independent case-control cohorts totalling 322 cases with fibrostenotis (recurrent after surgery) and 619 cases with purely inflammatory CD. Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007, (P = 6.09 × 10-11), located on chromosome 16, in lncRNA RP11-679B19.1, a lncRNA of unknown function, and close to exon 9 of the WWOX gene, which codes for WW domain-containing oxidoreductase. We analysed mRNA expression of TGF-β and downstream genes...
A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn'... more A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 μg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab con...
Journal of gastrointestinal and liver diseases : JGLD, 2016
Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in ... more Both chronic inflammation and reduced immunosurveillance contribute to malignancy development in inflammatory bowel disease (IBD). Previous literature suggests that especially Crohn's disease patients are at an increased risk for developing gastric cancer (GC). This study aimed to identify risk factors for GC development in IBD and to compare the clinical characteristics of GC in IBD to those in the general population. We retrospectively searched the Dutch Pathology Database to identify all Dutch IBD patients with GC between January 2004 and December 2008. Two case-control studies were performed. I: to identify risk factors for GC in IBD, with controls from the IBD South Limburg (IBDSL) population-based cohort; and II: to compare GC disease course in IBD patients with the general population. General population data were obtained from the Eindhoven Cancer Registry (ECR). We included 59 patients with IBD and GC (cases). Cases were significantly older at IBD diagnosis than IBDSL co...
Monitoring mucosal inflammation is crucial to prevent complications and disease progression in Cr... more Monitoring mucosal inflammation is crucial to prevent complications and disease progression in Crohn’s disease (CD). Endoscopy is the current standard, but is invasive. Clinical activity scores and non-invasive biochemical markers do not correlate well with mucosal inflammation. Microbial perturbations have been associated with disease activity in CD. Therefore, we aimed to investigate its potential use to differentiate CD patients in remission from those with an exacerbation. From 71 CD patients repeated fecal samples were collected, resulting in 97 active disease and 97 remission samples based on a combination of biochemical and clinical parameters. The microbiota composition was assessed by pyrosequencing of the 16S rRNA V1-V3 region. Random Forest analysis was used to find the most discriminatory panel of operational taxonomic units (OTUs) between active and remission samples. An independent internal validation set was used to validate the model. A combination of 50 OTUs was abl...
Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated dise... more Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a hi...
Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific e... more Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific antibodies and represent danger-associated molecular patterns that are generated during chronic inflammatory processes. In a murine model for hepatic inflammation during non-alcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found to be protective. Here, our aim was to determine an association between OSE-specific antibody titers and NAFLD in humans. IgM and IgG levels with specificity for various OSE were assessed in the plasma of patients with NAFLD (n = 71) and healthy controls (n = 68). Antibody titers were comprehensively analyzed in patients with NAFLD after classification by histological evaluation of liver biopsies. Statistical analysis was performed to determine significant correlations and odds ratios. To study the specificity for NAFLD, plasma antibody titers were measured in patients wit...
Background Healing rates after surgical closure for high perianal fistula in patients with Crohn'... more Background Healing rates after surgical closure for high perianal fistula in patients with Crohn's disease are even more disappointing than in patients with cryptoglandular fistulas. The objective was to improve healing rates by combining the well-known mucosal advancement flap with platelet-rich plasma. Methods A prospective pilot study was conducted in one tertiary referral centre. Consecutive patients with primary or recurrent Crohn's disease-related high perianal fistulas, defined as involving the middle and/or upper third parts of the anal sphincter complex, were included. A staged procedure was performed with non-cutting seton treatment for 3 months first, followed by a mucosal advancement flap with injection of platelet-rich plasma into the fistula tract. Results Ten consecutive patients were operated on between 2009 and 2014. Half (50 %) of the patients had undergone previous fistula surgery. Mean follow-up was 23.3 months (SD 13.0). Healing of the fistula was 70 % (95 % confidence interval, 33-89 %) at 1 year. One (10 %) patient had a recurrence, and in two (20 %) patients, the fistula was persistent after treatment. An abscess occurred in one (10 %) patient. The median post-operative Vaizey score was 8.0 (range 0-21), indicating a moderate to severe continence impairment. Conclusions The results of combining the mucosal advancement flap with platelet-rich plasma in patients with Crohn's disease-related high perianal fistulas are moderate with a healing rate of 70 %. Further investigation is needed to determine the benefits and risks on continence status for this technique in this patient population.
Background: Currently there is no guideline for the treatment of patients with Crohn's disease an... more Background: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. Methods/Design: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. Discussion: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. Trial registration: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).
In the last decades, treatment options and strategies for ulcerative colitis (UC) have radically ... more In the last decades, treatment options and strategies for ulcerative colitis (UC) have radically changed. Whether these developments have altered the disease outcome at population level is yet unknown. Therefore, we evaluated the disease outcome of UC over the last two decades in the South-Limburg area of the Netherlands. In the Dutch population-based IBDSL cohort, three time cohorts were defined: cohort 1991-1997 (cohort A), cohort 1998-2005 (cohort B), and cohort 2006-2010 (cohort C). The colectomy and hospitalisation rates were compared between cohorts by Kaplan-Meier survival analyses. Hazard ratios (HR) for early colectomy (within six months after diagnosis), late colectomy (beyond six months after diagnosis), and hospitalisation were calculated using Cox regression models. In total, 476 UC patients were included in cohort A, 587 patients in cohort B, and 598 patients in cohort C. Over time, an increase in the use of immunomodulators (8.1% to 22.8% to 21.7%, p<0.01) and biol...
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Papers by Marieke Pierik