Papers by A A van Bodegraven
Journal of Crohn's and Colitis
Background Treatment goals for Crohn’s disease (CD) tend to shift from clinical towards endoscopi... more Background Treatment goals for Crohn’s disease (CD) tend to shift from clinical towards endoscopic remission as a potential means to reduce intestinal damage. Additionally, sustained corticosteroid (CS) free remission is warranted to prevent drug related side effects. In clinical trials, long-term efficacy of treatment is assessed by a range of outcome measures at variable time points. Besides clinical activity, it is recommended by the EMA to measure biochemical and endoscopic activity, given the poor correlation between commonly applied clinical activity indices and mucosal inflammation. Finally, STRIDE advices to add a PROM given the frequent perception gap in disease control between patient and health care professionals. Moreover, the relapsing-remitting nature of CD challenges timing of efficacy evaluations. Use of cross-sectional outcomes only on predetermined moments disregards the health status in between these measurements. In this systematic review, we provide an overview ...
Journal of Crohn's and Colitis, 2014
Background and aims: A drug interaction between infliximab and azathioprine has previously been r... more Background and aims: A drug interaction between infliximab and azathioprine has previously been reported in Crohn's disease patients: the concentration of the main active thiopurine metabolites, the 6-thioguanine nucleotides (6-TGN), increased 1-3 weeks after the first infliximab infusion by 50% compared to baseline. The aim of this prospective study was to determine the effect of adalimumab on thiopurine metabolism in Crohn's disease patients, evaluated by 6-TGN and 6-methylmercaptopurine ribonucleotides (6-MMPR) concentration measurement.
Gastroenterology, 2016
Background: Very early onset IBD (VEO-IBD) is frequently considered to be a different disease pro... more Background: Very early onset IBD (VEO-IBD) is frequently considered to be a different disease process than older onset IBD. The aggressive phenotype and young age suggest a greater genetic contribution to the disease. We have demonstrated an enrichment of variants in primary immunodeficiency genes in patients with VEO-IBD using whole exome sequencing (WES). Understanding the relevance of the identified variants, however, remains a challenge. The function of mutations in many of these genes and their downstream effects remain largely unknown. Our primary aim is to identify dysregulations in gene expression through whole transcriptome sequencing (RNA-Seq) of samples from VEO-IBD patients where WES identified candidate causal variants, in order to delineate their role in disease pathogenesis. Methods: IBD patients with onset at <5 years and parents were recruited. Exome capture was performed by Agilent SureSelect V4, and sequencing was accomplished using the Illumina HiSeq. Variants likely to alter protein function, including missense and loss of function mutations, were retained for subsequent analysis. RNA was isolated from whole blood. Libraries were constructed using the Illumina TruSeq Stranded Total RNA Sample Preparation Kit with RiboZero and sequencing was performed using Illumina NextSeq 500. RNAseq reads were aligned to the reference human genome using Tophat2. Transcriptome assembly and quantification (normalized FPKM) were performed using Cufflinks. An outlier analysis approach was used to determine differential expression (p<0.05). Results: Among the candidate variants identified by WES, a homozygous mutation in DAPK1 (p.Ile662Met) was detected in a male diagnosed with onset of severe VEO-IBD at 4 months of age, unresponsive to medical therapy, who underwent a diverting ileostomy. DAPK1, which has not been previously implicated in VEO-IBD, is a multifunctional gene with a dual role in inhibiting and promoting inflammation, in part via mediation of TNF a. DAPK1 negatively regulates inflammation through the inhibition of NF-kB, thus inhibiting IL-6 expression and STAT3 activation. Upstream regulator analysis of transcriptome expression data in this patient revealed that NF-kB complex (p=3.53x10-9), STAT3 (p=6.58x10-12) and IL-6 (p= 3.58x10-2) were significantly activated, consistent with DAPK1 deactivation. Conclusions: Integration of WES and transcriptome data is a powerful approach to determine the effect of candidate causal variants. Currently there is a paucity of data utilizing this strategy in patients with VEO-IBD. This case illustrates the ability to detect downstream effects of suspected causal variants. This systems biology-based approach may provide further understanding of the pathways responsible for disease in a subset of VEO-IBD patients and potentially lead to new avenues for successful therapy of VEO-IBD.
Journal of Crohn's and Colitis, 2018
Background: Crohn's disease (CD) is associated with substantial direct healthcare costs. Over tim... more Background: Crohn's disease (CD) is associated with substantial direct healthcare costs. Over time, a shift in costs has been observed, from hospitalisation to medication as major cost driver. However, this observation is based on comparisons of different patient cohorts. Therefore, in this study we aimed to assess shifts in direct costs of CD over the past two decades within the population-based IBD South Limburg (IBDSL) cohort. Methods: All CD patients in the IBDSL cohort with ≥1 year of follow-up were included. Three eras were distinguished based on year of diagnosis : 1991-1998, 1999-1905 and 2006-2011. Patients were followed up to 5 years from diagnosis, till loss-to-follow-up or end of data collection (2014). Data on resource utilisation (i.e. hospitalisation, surgery, diagnostics and medication) were assessed by scrutinising patient files and medical reports. Costs were calculated by multiplying resource use by Dutch reference prices for the corresponding era. If appropriate, prices were corrected for inflation using Dutch consumer price indices. Proportions between eras were compared using Chi-square tests. Results: In total, 1108 CD patients were included. Mean cumulative total costs and breakdown in the major contributing cost elements after 1 and 5 years from diagnosis are presented in Figure 1 for each Abstract DOP034 -Figure 1: Mean total costs and breakdown of costs per era in the first year and 5 years after diagnosis. Abstract DOP034 -Figure 2. Breakdown of medication costs per era.
Journal of Crohn's and Colitis, 2022
Conventional thiopurines such as azathioprine (AZA) and mercaptopurine (MP) remain drugs of choic... more Conventional thiopurines such as azathioprine (AZA) and mercaptopurine (MP) remain drugs of choice in maintaining remission and corticosteroid sparing in inflammatory bowel disease (IBD). Early discontinuation of thiopurine therapy occurs frequently, due to slow onset of effect and a relatively high frequency of early adverse drug reactions (ADR). Some ADR such as hepatotoxicity and gastro-intestinal complaints are associated with the thiopurine metabolite concentrations 6-thioguanine nucleotides (6-TGN) or 6-methylmercaptopurine ribonucleotides (6-MMPR), in particular elevated 6-MMPR concentrations or unfavorable 6-MMPR/6-TGN ratios. Early measurement of thiopurine metabolites may help to optimize thiopurine therapy in IBD. The aim of this study was to assess the predictive value of thiopurine metabolite measurement one week after thiopurine therapy initiation on discontinuation during the first three months of therapy. This was a multicenter prospective observational study in the ...
Journal of Crohn's and Colitis, 2022
The thiopurines, azathioprine (AZA) and mercaptopurine (MP), are effective and remain standard tr... more The thiopurines, azathioprine (AZA) and mercaptopurine (MP), are effective and remain standard treatment options in steroid sparing and maintaining remission in patients with inflammatory bowel disease (IBD). Approximately 25% of patients discontinue within three months after treatment initiation due to adverse events, of which about half due to hepatotoxicity. We hypothesise that identification of patients with an increased risk of adverse events and timely treatment optimisation (e.g. dose adjustment, adjuvant allopurinol) can prevent treatment failure due to adverse events. The primary objective of this prospective observational multicentre study was to optimise and validate a proposed hepatotoxicity predictive algorithm in IBD patients starting AZA or MP therapy. We adapted an algorithm from a previous study to predict the risk of developing hepatotoxicity in thiopurine drug treatment using multivariable logistic regression and a receiver operating characteristic curve. The dete...
Journal of Crohn's and Colitis, 2012
Gut, 2012
Objective The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact heal... more Objective The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. Design Crohn's disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3month costs per patients with a 95% CI obtained using non-parametric bootstrapping. Results A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. Conclusions We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.
Journal of Crohn's and Colitis, Jan 16, 2018
twice per year. We compared COPD patients with non-COPD controls matched by age and sex with a ra... more twice per year. We compared COPD patients with non-COPD controls matched by age and sex with a ratio of 1:5. Cases with newly diagnosed IBD that met both of ICD-10 codes (K50 for Crohn's disease and K51 for ulcerative colitis) and V code for rare intractable disease (V130 for Crohn's disease and V131 for ulcerative colitis) were identified in the study population, respectively. The Kaplan-Meier method was used to estimate the cumulative incidence of IBD. Results: During the mean follow-up duration of 3.9 years, COPD patients experienced IBD more frequently than non-COPD controls (10.8 per 1000 person-years vs. 7.7 per 1000 person-years, p < 0.001). The incidence of Crohn's disease was 2.58 per 1000 person-years in patients with COPD, but 1.61 per 1000 person-years in non-COPD control group (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.35-1.90; p < 0.001). In addition, the incidence of ulcerative colitis was 8.0 per 1000 person-years in patients with COPD, compared with 6.1 per 1000 person-years in non-COPD controls (HR, 1.31; 95% CI, 1.19-1.44; p < 0.001). Analysing the risk of IBD according to severity of COPD, the incidence rate of IBD was higher with increasing severity of COPD. Conclusions: The risk of IBD increased in the patients with COPD of South Korea. These results suggest an association between COPD and IBD. The possibility of IBD can be considered carefully when elderly smokers complained severe gastrointestinal symptoms based on the results.
Journal of Crohn's and Colitis
Background There is an increased focus on patient reported outcomes and patient reported experien... more Background There is an increased focus on patient reported outcomes and patient reported experiences as means to optimize provided care. Both are considered essential in improving quality and service. Zuyderland Medical Centre (ZMC) is transforming its inflammatory bowel disease (IBD) care into a patient oriented IBD Centre (PGC IBD) as a way to provide modern patient centred care. The project ‘Patient aan zet’ is an initiative of Crohn & Colitis NL (CCNL) and takes place in several hospitals. The aim of the project is to optimize quality of care for adult patients with IBD by ensuring that the patient is properly and unambiguously informed and the patients involvement increases in treatment. Methods A cross-sectional survey using a questionnaire was performed to map out expectations and experiences of patients with the IBD outpatient clinic of ZMC. This questionnaire (part of the project ‘Patient aan zet’) was developed by CCNL as an online self-completion instrument. The results o...
European Journal of Gastroenterology & Hepatology, 2005
Journal of Crohn's and Colitis
Background Since the gut microbiota is altered in patients with Inflammatory Bowel Disease (IBD),... more Background Since the gut microbiota is altered in patients with Inflammatory Bowel Disease (IBD), microbiome-based biomarkers may be useful for diagnosing and monitoring of IBD. Currently, endoscopy is the gold standard for diagnosis and monitoring disease activity, which can be a high burden for patients. This study aimed to compare intestinal microbiota profiles between three different sampling methods faecal samples, rectal swabs and colonic mucosal biopsies. This could provide more insight into the microbiota composition in different sample types and might contribute to the development of a less invasive biomarker for diagnosing and monitoring IBD. Methods Patients with IBD (Crohn’s Disease or Ulcerative Colitis) who were scheduled for endoscopy were asked to participate. Prior to bowel preparation, a fecal sample and rectal swab were collected. During colonoscopy, mucosal biopsies were derived 20 cm ab ano. Microbiota composition was analyzed by IS-pro, a PCR technique based on...
Two female patients aged 88 and 82 who were being treated for constipation with lactulose, develo... more Two female patients aged 88 and 82 who were being treated for constipation with lactulose, developed life-threatening dilatation of the bowel. Both underwent surgery. One of them was found to have cancer of the bowel; she had an uneventful postoperative recovery. No mechanical abnormalities were found in the second patient but she died due to respiratory insufficiency following aspiration. Lactulose is one of the most frequently prescribed laxatives. In the colon it is metabolized by bacteria into short-chain fatty acids, hydrogen and carbon dioxide. The resulting production of gas in the colon can contribute to a non-toxic megacolon, particularly in patients with delayed intestinal passage.
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Journal of Crohn's and Colitis Supplements, 2008
Poster Presentations cal and endoscopic response at week 52. A significant concordance was found ... more Poster Presentations cal and endoscopic response at week 52. A significant concordance was found between clinical and endoscopic findings (p<0,01). Response to IFX therapy was not influenced by age, gender, smoking habits, presence of extraintestinal manifestations of the disease and type of colitis. However, response to IFX therapy tends to be better in patients receiving concomitant azathioprine (p=0,065). Conclusions: Infliximab therapy is effective for inducing clinical remission and mucosal healing in patients with steroid-dependent UC. Concomitant immunosuppressive therapy may be helpful for improving the efficacy of IFX in this specific setting.
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Papers by A A van Bodegraven