Publications by authors named "Adriaan A van Bodegraven"

88 Publications

Rac1/pSTAT3 expression: A pharmacodynamic marker panel as a first step toward optimization of thiopurine therapy in inflammatory bowel disease patients.

Cytometry A 2021 Oct 1. Epub 2021 Oct 1.

Department of Clinical Chemistry and Haematology, Zuyderland Medical Centre Sittard-Geleen, Heerlen, The Netherlands.

Thiopurine derivatives, such as azathioprine and mercaptopurine, are standard conventional treatment options in inflammatory bowel disease (IBD). Unfortunately, approximately half of patients discontinue thiopurine therapy within 2 years. To improve the prediction of clinical effectiveness, thiopurine therapy is currently optimized using therapeutic drug monitoring. Ras-related C3 botulinum toxin substrate 1 (Rac1) has been suggested as a potential pharmacodynamic marker of the thiopurine effect in lymphocytes. The active thiopurine metabolite 6-thioguanine triphosphate (6-Thio-GTP) causes T cell apoptosis via Rac1 and the downstream transcription factor signal transducer and activator of transcription 3 (STAT3). The aim of this study was to develop and validate a functional pharmacodynamic multiparameter flow cytometric assay to determine Rac1/pSTAT3 expression in the various leukocyte subpopulations in peripheral blood in order to predict therapeutic response in IBD patients in the future. Peripheral blood samples of healthy subjects (no fever or clinical complaints of active disease, C-reactive protein < 10 mg/L) were used for immunocytochemical labeling, applying an optimized fixation and permeabilization strategy. A gating procedure was performed to separate all leukocyte subpopulations. Quantitative data were obtained by measuring presence and median fluorescent intensity. In vitro, Rac1 presence and expression were detectable in all leukocyte subpopulations. After IL-6 stimulation, used as proxy for inflammation, a distinct pSTAT3 signal could be detected in T lymphocytes of healthy subjects. In vivo, an upregulated pSTAT3 signal was detected in nearly all IBD patients with active disease and differed substantially from the signal found in IBD patients in remission on thiopurines and healthy subjects. We developed and validated a functional flow cytometric assay to assess Rac1 and pSTAT3 presence and expression. This opens a venue for a pharmacodynamic assay to predict thiopurine effectiveness in IBD patients.
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http://dx.doi.org/10.1002/cyto.a.24506DOI Listing
October 2021

Replacement of Nitrite in Meat Products by Natural Bioactive Compounds Results in Reduced Exposure to N-Nitroso Compounds: The PHYTOME Project.

Mol Nutr Food Res 2021 Aug 12:e2001214. Epub 2021 Aug 12.

Department of Toxicogenomics, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, the Netherlands.

Scope: It has been proposed that endogenously form N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as critical factor in the formation of NOCs, the impact of replacing the additive sodium nitrite (E250) by botanical extracts in the PHYTOME project is evaluated.

Method And Results: A human dietary intervention study is conducted in which healthy subjects consume 300 g of meat for 2 weeks, in subsequent order: conventional processed red meat, white meat, and processed red meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of red meat products enriched with phytochemicals leads to a significant reduction in the faecal excretion of NOCs, as compared to traditionally processed red meat products. Gene expression changes identify cell proliferation as main affects molecular mechanism. High nitrate levels in drinking water in combination with processed red meat intake further stimulates NOC formation, an effect that could be mitigated by replacement of E250 by natural plant extracts.

Conclusion: These findings suggest that addition of natural extracts to conventionally processed red meat products may help to reduce CRC risk, which is mechanistically support by gene expression analyses.
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http://dx.doi.org/10.1002/mnfr.202001214DOI Listing
August 2021

Bone loss in patients with inflammatory bowel disease: cause, detection and treatment.

Curr Opin Gastroenterol 2021 03;37(2):128-134

Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland MC, Sittard-Geleen-Heerlen; Department of Gastroenterology, Amsterdam UMC, Location Vrije Universiteit, the Netherlands.

Purpose Of Review: Inflammatory bowel disease (IBD) is associated with bone loss leading to osteoporosis and increased fracture risk. Bone loss is the result of changes in the balanced process of bone remodeling. Immune cells and cytokines play an important role in the process of bone remodeling and it is therefore not surprising that cytokines as observed in IBD are involved in bone pathology. This review discusses the role of cytokines in IBD-associated bone loss, including the consequences for treatment.

Recent Findings: Many studies have been conducted that showed the effect of a single cytokine on bone cells in vitro, including interleukin (IL)-1β, IL-6, IL-8, IL-12/IL-23, IL-17, IL-18, IL-32 and interferon-γ. Recently new members of the IL-1 family (IL-1F) have been related to IBD but the consequences for bone health remain uncertain.

Summary: Overall, patients have to deal with a cocktail of cytokines, present in their serum. The combination of cytokines can affect bone cells differently compared to the effects of a single cytokine. This implicates that treatment, focused on reducing the inflammation could work best for bone health as well. Vitamin D might also play a role in this.
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http://dx.doi.org/10.1097/MOG.0000000000000710DOI Listing
March 2021

COVID-19 in the IBD Population: The Need for Correct Nomenclature.

J Crohns Colitis 2021 May;15(5):872-873

Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine [Co-MIK], Zuyderland Medical Centre, Sittard-Geleen, The Netherlands.

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http://dx.doi.org/10.1093/ecco-jcc/jjaa222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665394PMC
May 2021

Clinical Outcomes of Covid-19 in Patients With Inflammatory Bowel Disease: A Nationwide Cohort Study.

J Crohns Colitis 2021 Apr;15(4):529-539

Department of Gastroenterology and Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Background And Aims: The COVID-19 risk and disease course in inflammatory bowel disease [IBD] patients remains uncertain. Therefore, we aimed to assess the clinical presentation, disease course, and outcomes of COVID-19 in IBD patients. Second, we determined COVID-19 incidences in IBD patients and compared this with the general population.

Methods: We conducted a multicentre, nationwide IBD cohort study in The Netherlands and identified patients with COVID-19. First, we assessed the COVID-19 disease course and outcomes. Second, we compared COVID-19 incidences between our IBD study cohort and the general Dutch population.

Results: We established an IBD cohort of 34 763 patients. COVID-19 was diagnosed in 100/34 763 patients [0.29%]; 20/100 of these patients [20%] had severe COVID-19 defined as admission to the intensive care unit, mechanical ventilation, and/or death. Hospitalisation occurred in 59/100 [59.0%] patients and 13/100 [13.0%] died. All patients who died had comorbidities and all but one were ≥65 years old. In line, we identified ≥1 comorbidity as an independent risk factor for hospitalisation (odds ratio [OR] 4.20, 95% confidence interval [CI] 1.58-11.17,; p = 0.004). Incidences of COVID-19 between the IBD study cohort and the general population were comparable (287.6 [95% CI 236.6-349.7] versus 333.0 [95% CI 329.3-336.7] per 100000 patients, respectively; p = 0.15).

Conclusions: Of 100 cases with IBD and COVID-19, 20% developed severe COVID-19, 59% were hospitalised and 13% died. A comparable COVID-19 risk was found between the IBD cohort [100/34 763 = 0.29%] and the general Dutch population. The presence of ≥1 comorbidities was an independent risk factor for hospitalisation due to COVID-19.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665430PMC
April 2021

Editorial: the most commonly used IBD indices still fail to represent real life and subjective patient experience.

Aliment Pharmacol Ther 2020 06;51(11):1202-1203

Zuyderland Medical Centre, Sittard-Geleen, The Netherlands.

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http://dx.doi.org/10.1111/apt.15720DOI Listing
June 2020

Tofacitinib for ulcerative colitis: results of the prospective Dutch Initiative on Crohn and Colitis (ICC) registry.

Aliment Pharmacol Ther 2020 05 1;51(9):880-888. Epub 2020 Apr 1.

Department of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: Tofacitinib is a Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC).

Aim: To evaluate effectiveness, safety and use of tofacitinib in daily practice.

Methods: UC patients initiating tofacitinib were prospectively enrolled in 15 hospitals in the Netherlands. Corticosteroid-free clinical remission (short clinical colitis activity index [SCCAI] ≤2), biochemical remission (faecal calprotectin level ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, predictors of remission, safety outcomes, treatment dose and effect on lipids were determined at weeks 12 and 24. Endoscopic outcomes were evaluated in centres with routine endoscopic evaluation.

Results: In total, 123 UC patients (95% anti-TNF, 62% vedolizumab and 3% ustekinumab experienced) were followed for a median duration of 24 weeks (interquartile range 12-26). The proportion of patients in corticosteroid-free clinical, biochemical, and combined corticosteroid-free clinical and biochemical remission rate at week 24 was 29% (n: 22/77), 25% (n: 14/57), and 19% (n: 11/57) respectively. Endoscopic remission (Mayo = 0) was achieved in 21% of patients at week 12 (n: 7/33). Prior vedolizumab exposure was associated with reduced clinical remission (odds ratio 0.33, 95% confidence interval [CI] 0.11-0.94). At week 24, 33% (n: 14/42) of patients still on tofacitinib treatment used 10 mg twice daily. In total, 33 tofacitinib-related adverse events (89 per 100 patient years) occurred, 7 (6% of total cohort) resulted in discontinuation. Cholesterol, HDL and LDL levels increased during induction treatment by 18% (95% CI 9-26), 18% (95% CI 8-28) and 21% (95% CI 14-39) respectively.

Conclusion: Tofacitinib is an effective treatment for UC after anti-TNF and vedolizumab failure. However, a relatively high rate of adverse events was observed resulting in discontinuation in 6% of patients.
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http://dx.doi.org/10.1111/apt.15689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187329PMC
May 2020

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Scand J Gastroenterol 2019 Jun 16;54(6):753-760. Epub 2019 Jun 16.

Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam , the Netherlands.

Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies,  = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.
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http://dx.doi.org/10.1080/00365521.2019.1629006DOI Listing
June 2019

Sustained effectiveness, safety and therapeutic drug monitoring of tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies.

Aliment Pharmacol Ther 2019 07 16;50(1):54-65. Epub 2019 May 16.

Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy.

Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged tioguanine maintenance therapy.

Methods: In this nationwide, multicentre study, medical records of tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC).

Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×10 RBC (P < 0.05).

Conclusions: Long-term tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×10 RBC is proposed as target level with higher odds for clinical effectiveness.
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http://dx.doi.org/10.1111/apt.15280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618772PMC
July 2019

Key insights from therapeutic drug monitoring in Crohn's disease patients.

Expert Opin Drug Metab Toxicol 2019 May 21;15(5):399-406. Epub 2019 Apr 21.

a Department of Gastroenterology and Hepatology, Amsterdam UMC , Vrije Universiteit Amsterdam , Amsterdam , The Netherlands.

Introduction: The incidence and prevalence of Crohn's disease are increasing causing a significant disease burden. Therapeutic drug monitoring (TDM) is advocated as a promising tool for personalized or individual-tailored therapy strategies and has been welcomed as a new means to improve current therapy strategies. Nevertheless, pharmacokinetic-based TDM has limitations, and straightforward target concentrations for most therapies are lacking. Areas covered: In the following concise review of literature, key insights of TDM in thiopurine, methotrexate, anti-TNF, vedolizumab and ustekinumab therapy for Crohn's disease are being described. Expert opinion: Therapeutic drug monitoring may, up till now, be helpful to adjust thiopurine and infliximab therapy, primarily in a reactive setting, in case of inefficacy and of occurrence of adverse event. With this restricted application, the goal of individualized therapy based on TDM has not yet been achieved.
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http://dx.doi.org/10.1080/17425255.2019.1597054DOI Listing
May 2019

The effect of surgical fecal stream diversion of the healthy colon on the colonic microbiota.

Eur J Gastroenterol Hepatol 2019 04;31(4):451-457

Department of Medical Microbiology and Infection Control.

Objectives: The intestinal microbiota plays an important role in intestinal health. After colonic diversion from the fecal stream, luminal nutrients for bacteria are expected to be depleted, inducing changes in microbial composition. In this study, we describe microbial changes in the healthy colon following surgical fecal stream diversion, studied in the surgically constructed sigmoid-derived neovagina.

Methods: At various postoperative times after sigmoid vaginoplasty, rectal, neovaginal, and skin microbial swabs were obtained for microbial analysis by interspacer profiling, a PCR-based bacterial profiling technique. Differences in bacterial profiles, in terms of bacterial abundance and phylum diversity, were assessed. Microbial dissimilarities between anatomical locations were analyzed with principal coordinate analysis and partial least squares discriminant analysis.

Results: Bacterial samples were obtained from 28 patients who underwent sigmoid vaginoplasty. By principal coordinate analysis, microbial profiles of samples from the sigmoid-derived neovagina were distinctively different from rectal samples. Partial least squares discriminant analysis showed that the most discriminative species derived from the phylum Bacteroidetes. The abundance and diversity of Bacteroidetes species were reduced following fecal stream diversion compared with rectal samples (median Shannon diversity index of 2.76 vs. 2.18, P<0.01). Similar abundance of Phyla Firmicutes, Actinobacteria, Fusobacteria, Verrucomicrobia, and Proteobacteria was observed.

Conclusion: By analyzing the microbiome of sigmoid-derived neovaginas, we studied the effects of fecal diversion on the microbial composition of the healthy intestine. Most changes were observed in the phylum Bacteroidetes, indicating that these bacteria are likely part of the diet-dependent (butyrate-producing) colonic microbiome. Bacteria of other phyla are likely to be part of the diet-independent microbiome.
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http://dx.doi.org/10.1097/MEG.0000000000001330DOI Listing
April 2019

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.

Inflamm Bowel Dis 2018 11;24(12):2606-2612

Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype.

Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients.

Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients.

Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.
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http://dx.doi.org/10.1093/ibd/izy163DOI Listing
November 2018

High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients.

Nucleosides Nucleotides Nucleic Acids 2018 3;37(6):317-323. Epub 2018 May 3.

a Department of Gastroenterology and Hepatology , VU University Medical Center , Amsterdam.

Objectives: Thiopurines play an essential role in the management of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Over the past decade, several strategies to optimize treatment with thiopurines have been evaluated, including co-administration of allopurinol, a xanthine-oxidoreductase (XO) inhibitor, to low-dose thiopurine therapy. We aimed to assess the inter-individual variability of XO-activity between IBD-patients.

Methods: We assessed XO activity in serum of IBD-patients of two medical centers in The Netherlands using the Amplex® Red Xanthine/Xanthine Oxidase Assay Kit, which measures the superoxide formation in a coupled reaction to the red-fluorescent oxidation product, resofurine.

Results: We observed a high inter-individual variability of XO-activity in 119 patients, with a median activity of 16 µU/ml/hour (range 1-85 µU/ml/hour). The XO-activity was influenced by gender (male 19.5 vs. female 14.0 µU/ml/hour, p < 0.01), patient's age (Pearson's correlation r = 0.21, p = 0.02) and duration of IBD (r = 0.23, p = 0.01). The XO activity was not affected by the type of IBD, smoking status, body mass index or (type of) thiopurine use (p > 0.05).

Conclusions: There is a high inter-individual variability of XO-activity in IBD-patients; XO-activity is positively associated with male gender and patient's age.
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http://dx.doi.org/10.1080/15257770.2018.1460477DOI Listing
May 2019

Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long-standing colitis: results of a 15-year multicentre, multinational cohort study.

Gut 2019 04 2;68(4):615-622. Epub 2018 May 2.

Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.

Objectives: Surveillance colonoscopy is thought to prevent colorectal cancer (CRC) in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk.

Design: A multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia or CRC.

Results: Of 775 patients with long-standing IBD colitis, 44% (n=340) had 1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No aCRN occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having 1 positive colonoscopy on follow-up of 6.1 (P25-P75: 4.6-8.2) years after the index procedure.

Conclusion: Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of aCRN occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe.
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http://dx.doi.org/10.1136/gutjnl-2017-315440DOI Listing
April 2019

Cancer-Associated Chemotherapy Induces Less IBD Exacerbations and a Reduction of IBD Medication Afterwards.

Inflamm Bowel Dis 2018 06;24(7):1606-1611

Department of Gastroenterology and Hepatology, Zuyderland Medical Centre, Sittard-Geleen-Heerlen, the Netherlands.

Background: The prevalence of inflammatory bowel disease (IBD) is increasing and, consequently, more IBD patients will develop cancer with need for cancer-associated chemotherapy. Physicians are therefore confronted with whether they should continue, stop, or restart IBD medication in relation with chemotherapy. The current strategy in our hospital is to discontinue immunomodulating IBD medication, comprising corticosteroids, anti-tumour necrosis factor (anti-TNF), and other immunosuppressives, before starting chemotherapy.

Methods: Out of 1826 patients with IBD, we analyzed 41 IBD patients who received chemotherapy between January 2006-2017. The primary endpoint was the effect of chemotherapy on IBD course, assessed by number of exacerbations and use of IBD medication. The paired-samples t-test and Wilcoxon Signed-Rank test were performed.

Results: The mean number of IBD exacerbations of 0.3 (0.0-0.6) per 5 years after chemotherapy was lower compared to 1.4 (0.8-1.9) exacerbations per 5 years before chemotherapy exposure (P < 0.01). In terms of IBD medication, there was a decrease in the number of patients using mesalazine (47% vs 71%, P < 0.01) or corticosteroids (9% vs 32%, P = 0.02) in a time span of 5 years after compared to 5 years before chemotherapy. There was also a trend of less use of immunosuppressives (anti-TNF 0% vs 15%, P = 0.25; thiopurines 12% vs 34%, P = 0.13).

Conclusions: Cancer-associated chemotherapy is associated with a more benign course of IBD that may contribute to the decision to discontinue anti-TNF or other immunosuppressives in relation to cancer-associated treatment both before the start of chemotherapy, as well as reinitiating aggressive immunosuppressives for IBD afterwards.
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http://dx.doi.org/10.1093/ibd/izy053DOI Listing
June 2018

Methotrexate and Thioguanine Rescue Therapy for Conventional Thiopurine Failing Ulcerative Colitis Patients: A Multi-center Database Study on Tolerability and Effectiveness.

Inflamm Bowel Dis 2018 06;24(7):1558-1565

Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam.

Background: Patients with active ulcerative colitis (UC) failing conventional therapies are in need of rescue strategies. Due to the fact that accepted step-up therapy with biologicals is expensive and sometimes unavailable, alternative therapies are warranted. Methotrexate (MTX) and thioguanine (TG) have both been suggested as alternative maintenance strategies in conventional thiopurine failing UC patients. In this multicenter database study, we compared safety and effectiveness (drug-survival) of MTX and TG in UC patients.

Methods: We collected data from the Parelsnoer database, a prospective Dutch national database consisting of inflammatory bowel disease patients from all university hospitals in The Netherlands. Additional data were collected from detailed chart review.

Results: In total, 99 UC patients were included, of which 48 used TG, 43 used MTX, and 8 patients had a history of both TG and MTX use. In 12% of the patients, biological therapy had failed. Roughly 70% of the patients in both groups were able to continue therapy for over 1 year. Adverse events were noted in 33% of all the patients and were mainly elevated liver enzymes or gastrointestinal complaints. Twenty-eight patients (28%) continued therapy (15 TG, 13 MTX) without the need of escalation therapy (eg, corticosteroids, biologicals, or surgery). Drug survival curves of both drugs were comparable, just as the number of patients with sustained clinical benefit of therapy (P > 0.05).

Conclusion: Both MTX and TG may be used and maintained as rescue therapy with sustained clinical benefit in one-third of the UC patients failing conventional therapies.
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http://dx.doi.org/10.1093/ibd/izy047DOI Listing
June 2018

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Inflammatory Bowel Disease.

Clin Pharmacokinet 2018 09;57(9):1075-1106

Department of Gastroenterology, Zuyderland Medical Center, Sittard-Geleen, The Netherlands.

According to recent clinical consensus, pharmacotherapy of inflammatory bowel disease (IBD) is, or should be, personalized medicine. IBD treatment is complex, with highly different treatment classes and relatively few data on treatment strategy. Although thorough evidence-based international IBD guidelines currently exist, appropriate drug and dose choice remains challenging as many disease (disease type, location of disease, disease activity and course, extraintestinal manifestations, complications) and patient characteristics [(pharmaco-)genetic predisposition, response to previous medications, side-effect profile, necessary onset of response, convenience, concurrent therapy, adherence to (maintenance) therapy] are involved. Detailed pharmacological knowledge of the IBD drug arsenal is essential for choosing the right drug, in the right dose, in the right administration form, at the right time, for each individual patient. In this in-depth review, clinical pharmacodynamic and pharmacokinetic considerations are provided for tailoring treatment with the most common IBD drugs. Development (with consequent prospective validation) of easy-to-use treatment algorithms based on these considerations and new pharmacological data may facilitate optimal and effective IBD treatment, preferably corroborated by effectiveness and safety registries.
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http://dx.doi.org/10.1007/s40262-018-0639-4DOI Listing
September 2018

Genomic and Expression Analyses Identify a Disease-Modifying Variant for Fibrostenotic Crohn's Disease.

J Crohns Colitis 2018 04;12(5):582-588

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.

Background And Aims: 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.

Methods: We performed a within-case analysis comparing 'extreme phenotypes' using the Immunochip and replication of the top single nucleotide polymorphisms [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.

Results: Combined meta-analysis resulted in a genome-wide significant signal for SNP rs11861007 [p = 6.0910-11], located on chromosome 16, in lncRNA RP11-679B19.1, an 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 in ileocecal resection material from ten patients with and without the WWOX risk allele. Patients carrying the risk allele [A] showed enhanced colonic expression of TGF-β compared to patients homozygous for the wild-type [G] allele [p = 0.0079].

Conclusion: We have identified a variant in WWOX and in lncRNA RP11-679B19.1 as a disease-modifying genetic variant associated with recurrent fibrostenotic CD and replicated this association in an independent cohort. WWOX can potentially play a crucial role in fibrostenosis in CD, being positioned at the crossroads of inflammation and fibrosis.
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http://dx.doi.org/10.1093/ecco-jcc/jjy001DOI Listing
April 2018

Thiopurines in Inflammatory Bowel Disease: New Findings and Perspectives.

J Crohns Colitis 2018 Apr;12(5):610-620

Department of Gastroenterology, Pneumology and Endocrinology, Universitätsklinikum Erlangen, University of Erlangen-Nürnberg, Germany.

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
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http://dx.doi.org/10.1093/ecco-jcc/jjx181DOI Listing
April 2018

Analytical Pitfalls of Therapeutic Drug Monitoring of Thiopurines in Patients With Inflammatory Bowel Disease.

Ther Drug Monit 2017 12;39(6):584-588

*Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam; and †Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen-Sittard-Geleen, the Netherlands.

The use of thiopurines in the treatment of inflammatory bowel disease (IBD) can be optimized by the application of therapeutic drug monitoring. In this procedure, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) metabolites are monitored and related to therapeutic response and adverse events, respectively. Therapeutic drug monitoring of thiopurines, however, is hampered by several analytical limitations resulting in an impaired translation of metabolite levels to clinical outcome in IBD. Thiopurine metabolism is cell specific and requires nucleated cells and particular enzymes for 6-TGN formation. In the current therapeutic drug monitoring, metabolite levels are assessed in erythrocytes, whereas leukocytes are considered the main target cells of these drugs. Furthermore, currently used methods do not distinguish between active nucleotides and their unwanted residual products. Last, there is a lack of a standardized laboratorial procedure for metabolite assessment regarding the substantial instability of erythrocyte 6-TGN. To improve thiopurine therapy in patients with IBD, it is necessary to understand these limitations and recognize the general misconceptions in this procedure.
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http://dx.doi.org/10.1097/FTD.0000000000000455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690305PMC
December 2017

Finding hidden treasures in old drugs: the challenges and importance of licensing generics.

Drug Discov Today 2018 01 1;23(1):17-21. Epub 2017 Sep 1.

Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.

Identifying new indications for existing drugs creates new therapeutic options while bypassing much of the costs and time involved with bringing a new drug to market. The rediscovery of a generic drug, however, is a challenging pursuit because there is no formal regulatory approach and a lack of economic interest by pharmaceutical companies. This played a part in the re-registration of thioguanine as a rescue drug for the treatment of patients with inflammatory bowel disease in The Netherlands. In this article, we aim to underline the importance of drug rediscovery, the difficulties of this procedure in Europe and we attempt to suggest conceivable solutions.
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http://dx.doi.org/10.1016/j.drudis.2017.08.008DOI Listing
January 2018

Validation of Risk Factors for Fecal Incontinence in Patients With Crohn's Disease.

Dis Colon Rectum 2017 Aug;60(8):845-851

1 Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands 2 Department of Gastroenterology, Geriatrics, Internal Medicine and Intensive Care Medicine, Zuyderland Medical Center, Heerlen-Geleen-Sittard, the Netherlands.

Background: Fecal incontinence has a great impact on daily life, and many patients are reluctant to report it.

Objective: The purpose of this study was to estimate the prevalence of fecal incontinence in patients with Crohn's disease, validate risk factors, and relate outcome with quality of life.

Design: The design was cross-sectional.

Settings: The study was conducted at an academic tertiary center.

Patients: Consecutive patients with Crohn's disease treated between 2003 and 2013 were included in this study.

Main Outcome Measures: A questionnaire was sent out in October 2013 to evaluate perianal disease, current symptoms of fecal incontinence, and its impact on quality of life (Fecal Incontinence Quality of Life questionnaire). Risk factors were validated with univariate and multivariate analyses.

Results: The questionnaire was responded by 325 (62%) of 528 patients. Median age was 42 years (range, 18-91 y), 215 (66%) were women, and a diagnosis of Crohn's disease was established for a median period of 12 years (interquartile range, 6-21 y). Fecal incontinence was reported by 65 patients (20%). Fecal incontinence was associated with liquid stools (p = 0.0001), previous IBD-related bowel resections (p = 0.001), stricturing behavior of disease (p = 0.02), and perianal disease (p = 0.03). Quality of life (lifestyle, coping, depression, and embarrassment) was poor in patients with fecal incontinence, particularly in patients with more frequent episodes of incontinence.

Limitations: There was no correction for disease activity in the multivariate regression analysis.

Conclusions: The prevalence of fecal incontinence in a tertiary population with Crohn's disease is substantially higher than in the community-dwelling population. Considering the reduced quality of life in incontinent patients, active questioning to identify fecal incontinence is recommended in those with liquid stools, perianal disease, or previous (intestinal or perianal) surgery. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.
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http://dx.doi.org/10.1097/DCR.0000000000000812DOI Listing
August 2017

Optimizing Thiopurine Therapy in Inflammatory Bowel Disease Among 2 Real-life Intercept Cohorts: Effect of Allopurinol Comedication?

Inflamm Bowel Dis 2017 11;23(11):2011-2017

*Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; and †Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen-Sittard-Geleen, the Netherlands.

Background: Thiopurines (azathioprine and mercaptopurine) are frequently used immunosuppressive drugs to maintain remission in patients with inflammatory bowel disease. Half of the conventional thiopurine-derivative users have to discontinue treatment within 5 years, mainly because of intolerable adverse events. Over recent years, different strategies to optimize thiopurine treatment were suggested, yet, studies describing the clinical effectiveness of these strategies remain scarce. The aims of this study were to compare tolerability and sustained clinical benefit of conventional thiopurine derivatives therapy among two 5-year real-life intercept cohorts and to assess the clinical value of specifically allopurinol cotherapy.

Methods: In this retrospective single-center cohort study, we analyzed data from patients in whom weight-based thiopurine monotherapy was initiated between 2005 and 2009 (cohort 1) or between 2010 and 2014 (cohort 2). The initiation of the second cohort was synchronic to the start of allopurinol-based optimization in our center. Optimization strategies were extracted from patient charts.

Results: In total, 105 patients were included (60 in cohort 1, and 45 in cohort 2). Metabolite measurement was performed in 37% versus 84% of the patients (P < 0.001). Subsequent optimization strategies were applied in 33% versus 58% of the patients because of inadequate metabolite concentrations, intolerance, or ineffectiveness (P = 0.01). Allopurinol was coadministered to therapy in 18 patients (40%) in the second cohort. Therapy was switched to thioguanine in 11 versus 6 patients (P > 0.05). Overall, total duration was longer in the second cohort (10.8 versus 34.1 months, P < 0.001). The number of ongoing thiopurine users (20% versus 49%) and sustained clinical benefit (13% versus 38%) were higher in the second cohort (both P < 0.05). This was mainly because of a decrease in hepatotoxicity after optimization (P < 0.01).

Conclusions: Optimization of thiopurine therapy by the use of therapeutic drug monitoring with subsequent administration of allopurinol cotherapy successfully enhanced sustained clinical benefit and tolerability in patients with inflammatory bowel disease.
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http://dx.doi.org/10.1097/MIB.0000000000001168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647119PMC
November 2017

Pharmacology of Thiopurine Therapy in Inflammatory Bowel Disease and Complete Blood Cell Count Outcomes: A 5-Year Database Study.

Ther Drug Monit 2017 08;39(4):399-405

Departments of *Gastroenterology and Hepatology and †Clinical Pharmacy, VU University Medical Center, Amsterdam; and ‡Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen-Sittard-Geleen, the Netherlands.

Background: Thiopurines are the prerequisite for immunomodulation in inflammatory bowel disease (IBD) therapy. When administered in high (oncological) dose, thiopurine metabolites act as purine antagonists, causing DNA-strand breakage and myelotoxicity. In lower IBD dosages, the mode of action is primarily restricted to anti-inflammatory effects. Then, myelosuppression and hepatotoxicity are the most common adverse events of thiopurines. The aim of this study was to assess the effect of thiopurine metabolites on hematologic and hepatic parameters and to determine which patient characteristics are related to generation of thiopurine metabolites.

Methods: The authors scrutinized the therapeutic drug monitoring database of the VU University medical center and subsequently merged this database with the Clinical Laboratory database of our hospital covering the same time period (2010-2015).

Results: The authors included 940 laboratory findings of 424 unique patients in this study. Concentrations of 6-thioguanine nucleotides (6-TGN) correlated negatively with red blood cell count, white blood cell count, and neutrophil count in both azathioprine (AZA) and mercaptopurine users. There was a positive correlation with mean corpuscular volume. In patients using 6-thioguanine, 6-TGN concentrations correlated positively with white blood cell count. Furthermore, there was an inverse correlation between patient's age and 6-TGN concentrations in patients using AZA or 6-thioguanine, and we observed an inverse correlation between body mass index and 6-TGN concentrations in patients using AZA or mercaptopurine. No relations were observed with liver test abnormalities.

Conclusions: Thiopurine derivative therapy influenced bone marrow production and the size of red blood cells. Age and body mass index were important pharmacokinetic factors in the generation of 6-TGN.
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http://dx.doi.org/10.1097/FTD.0000000000000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538301PMC
August 2017

Clinical experience and diagnostic algorithm of vulval Crohn's disease.

Eur J Gastroenterol Hepatol 2017 Jul;29(7):838-843

Departments of aGastroenterology and Hepatology bGynaecology cPediatric Gastroenterology, VU University Medical Center dDepartment of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam eDepartment of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen fDepartment of Gastroenterology and Hepatology, University Medical Center, Utrecht gDepartment of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine, Zuyderland Medical Center, Heerlen-Sittard-Geleen, The Netherlands.

Background And Aim: Vulval Crohn's disease (VCD) is a rare extraintestinal cutaneous manifestation of Crohn's disease. No consensus on the diagnostic workup and therapeutic management of this condition has been provided in the current literature.

Patients And Methods: Retrospective, multicentre descriptive case series of female patients diagnosed and treated with VCD. By chart review, data on initial symptoms, clinical courses, histologic findings and therapeutic management were collected.

Results: Fifteen female patients with a median age of 28 years (interquartile range: 28-44 years) suffering from Crohn's disease of the ileum (27%), colon (33%) and ileocolon (40%) were included. VCD manifested most frequently with vulval swelling (93%), pain (80%) and erythema (73%). Histologic analysis demonstrated granulomatous inflammation in 78% and a mixed inflammatory cell infiltrate in 67% of cases. In eight (53%) cases, topical therapy resulted in temporary reduction of vulval symptoms. Combotreatment with immunosuppressive agents and tumour necrosis factor α inhibitors was the most effective second-line therapy: five (33%) patients achieved sustained clinical remission with this therapeutic strategy.

Conclusion: The diagnostic workup of VCD is challenging and should be approached in a multidisciplinary manner. Histopathologic analysis of the vulva supports the diagnosis. Topical therapy and systemic treatment with immunosuppressive agents and tumour necrosis factor α inhibitors are advised to treat this condition.
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http://dx.doi.org/10.1097/MEG.0000000000000879DOI Listing
July 2017

Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy.

Inflamm Bowel Dis 2017 03;23(3):448-452

*Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands; †Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia; ‡Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands; and §Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland Medical Center, Heerlen, Sittard-Geleen, the Netherlands.

Background: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination.

Methods: An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist.

Results: Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670).

Conclusions: The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.
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http://dx.doi.org/10.1097/MIB.0000000000001036DOI Listing
March 2017

How I treat my inflammatory bowel disease-patients with thiopurines?

World J Gastrointest Pharmacol Ther 2016 Nov;7(4):524-530

Berrie Meijer, Chris JJ Mulder, Nanne KH de Boer, Department of Gastroenterology and Hepatology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.

Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease (IBD). Thiopurines used in IBD are azathioprine (2.0-2.5 mg/kg), mercaptopurine (1.0-1.5 mg/kg) and thioguanine (0.2-0.3 mg/kg). However, mainly due to numerous adverse events associated with thiopurine use, almost 50% of the patients have to discontinue conventional thiopurine treatment. Extensive monitoring and the application of several treatment strategies, such as split-dose administration, co-administration with allopurinol or dose reduction/increase, may increase the chance of successful therapy. With this review, we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands. We provide clinical information concerning safety issues, indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.
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http://dx.doi.org/10.4292/wjgpt.v7.i4.524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095571PMC
November 2016

6-methylmercaptopurine-induced leukocytopenia during thiopurine therapy in inflammatory bowel disease patients.

J Gastroenterol Hepatol 2017 Jun;32(6):1183-1190

Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands.

Background And Aim: Thiopurines have a favorable benefit-risk ratio in the treatment of inflammatory bowel disease. A feared adverse event of thiopurine therapy is myelotoxicity, mostly occurring due to toxic concentrations of the pharmacologically active metabolites 6-thioguaninenucleotides. In oncology, myelosuppression has also been associated with elevated 6-methylmercaptopurine (6-MMP). In this case series, we provide a detailed overview of 6-MMP-induced myelotoxicity in inflammatory bowel disease patients.

Methods: We retrospectively scrutinized pharmacological laboratory databases of five participating centers over a 5-year period. Patients with leukocytopenia at time of elevated 6-MMP levels (>5700 pmol/8 × 10 red blood cells) were included for detailed chart review.

Results: In this case series, we describe demographic, clinical, and pharmacological aspects of 24 cases of 6-MMP-induced myelotoxicity on weight-based thiopurine therapy with a median steady-state 6-MMP level of 14 500 pmol/8 × 10 red blood cells (range 6600-48 000). All patients developed leukocytopenia (white blood cell count 2.7 ± 0.9 × 10 /L) after a median period of 11 weeks after initiation of thiopurine therapy (interquartile range 6-46 weeks). Eighteen patients (75%) developed concurrent anemia (median hemoglobin concentration 6.9 × 10 /L), and four patients developed concurrent thrombocytopenia (median platelet count 104 × 10 /L). Leukocytopenia resolved in 20 patients (83%) within 4 weeks upon altered thiopurine treatment regimen, and white blood cell count was increasing, but not yet normalized, in the remaining four patients.

Conclusion: We observed that thiopurine-induced myelotoxicity also occurs because of (extremely) high 6-MMP concentrations in patients with a skewed thiopurine metabolism. Continued treatment with adapted thiopurine therapy was successful in almost all patients.
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http://dx.doi.org/10.1111/jgh.13656DOI Listing
June 2017

Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review.

World J Gastroenterol 2016 Oct;22(40):9012-9021

Berrie Meijer, Chris JJ Mulder, Adriaan A van Bodegraven and Nanne KH de Boer, Department of Gastroenterology and Hepatology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands.

Aim: To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease (IBD) patients, irrespective of the (hepato-) toxicity profile.

Methods: A systematic literature search of the MEDLINE database using PubMed was performed using the keywords "thioguanine", "6-TG", "thioguanine", "inflammatory bowel disease", "IBD", "Crohn's disease", "Ulcerative colitis" and "effectiveness" in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were cross-checked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed.

Results: A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospective manner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients (225 patients with Crohn's disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance ( = 321) or thioguanine administration ( = 32) were included for analysis, of which 228 (65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years (median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg (range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients (20%).

Conclusion: The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.
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http://dx.doi.org/10.3748/wjg.v22.i40.9012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083806PMC
October 2016

Characterization of Microbiota in Children with Chronic Functional Constipation.

PLoS One 2016 19;11(10):e0164731. Epub 2016 Oct 19.

Department of Medical Microbiology & Infection Control, VU University Medical Center, Amsterdam, The Netherlands.

Objectives: Disruption of the intestinal microbiota is considered an etiological factor in pediatric functional constipation. Scientifically based selection of potential beneficial probiotic strains in functional constipation therapy is not feasible due to insufficient knowledge of microbiota composition in affected subjects. The aim of this study was to describe microbial composition and diversity in children with functional constipation, compared to healthy controls.

Study Design: Fecal samples from 76 children diagnosed with functional constipation according to the Rome III criteria (median age 8.0 years; range 4.2-17.8) were analyzed by IS-pro, a PCR-based microbiota profiling method. Outcome was compared with intestinal microbiota profiles of 61 healthy children (median 8.6 years; range 4.1-17.9). Microbiota dissimilarity was depicted by principal coordinate analysis (PCoA), diversity was calculated by Shannon diversity index. To determine the most discriminative species, cross validated logistic ridge regression was performed.

Results: Applying total microbiota profiles (all phyla together) or per phylum analysis, no disease-specific separation was observed by PCoA and by calculation of diversity indices. By ridge regression, however, functional constipation and controls could be discriminated with 82% accuracy. Most discriminative species were Bacteroides fragilis, Bacteroides ovatus, Bifidobacterium longum, Parabacteroides species (increased in functional constipation) and Alistipes finegoldii (decreased in functional constipation).

Conclusions: None of the commonly used unsupervised statistical methods allowed for microbiota-based discrimination of children with functional constipation and controls. By ridge regression, however, both groups could be discriminated with 82% accuracy. Optimization of microbiota-based interventions in constipated children warrants further characterization of microbial signatures linked to clinical subgroups of functional constipation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164731PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070844PMC
May 2017
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