Publications by authors named "C Janneke van der Woude"

211 Publications

Increased risk of high-grade cervical neoplasia in women with inflammatory bowel disease: a case-controlled cohort study.

J Crohns Colitis 2021 Feb 20. Epub 2021 Feb 20.

Erasmus MC, University Medical Center, Gastroenterology and Hepatology, Rotterdam, the Netherlands.

Background And Aims: Women with inflammatory bowel disease (IBD) may be at higher risk for cervical intraepithelial neoplasia (CIN). However, data are conflicting. The aim of this study is to assess the risk of high-grade dysplasia and cancer (CIN2+) in IBD women and identify risk factors.

Methods: Clinical data from adult IBD women in a multicentre Dutch IBD prospective cohort (PSI) from 2007 onwards were linked to cervical cytology and histology records from the Dutch nationwide cytology and pathology database (PALGA) from 2000 to 2016. Patients were frequency matched 1:4 to a general population cohort. Standardized detection rates (SDR) were calculated for CIN2+. Longitudinal data were assessed to calculate CIN2+ risk during follow-up using incidence rate ratios (IRR) and risk factors were identified in multivariable analysis.

Results: Cervical records were available from 2,098 IBD women (77%) and 8,379 in the matched cohort; median follow-up 13 years. CIN2+ detection rate was higher in the IBD cohort than in the matched cohort (SDR 1.27, 95%CI 1.05-1.52). Women with IBD had an increased risk of CIN2+ (IRR 1.66, 95%CI 1.21-2.25), and persistent or recurrent CIN during follow-up (OR 1.89, 95%CI 1.06-3.38). Risk factors for CIN2+ in IBD women were smoking and disease location (ileocolonic (L3) or upper-GI (L4)). CIN2+ risk was not associated with exposure to immunosuppressants.

Conclusion: Women with IBD are at increased risk for CIN2+ lesions. These results underline the importance of HPV vaccination and adherence to cervical cancer screening guidelines in IBD women, regardless of exposure to immunosuppressants.
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http://dx.doi.org/10.1093/ecco-jcc/jjab036DOI Listing
February 2021

Fecal calprotectin is an early predictor of endoscopic response and histologic remission after the start of vedolizumab in inflammatory bowel disease.

Therap Adv Gastroenterol 2020 24;13:1756284820979765. Epub 2020 Dec 24.

Erasmus MC, Department of Gastroenterology and Hepatology, Rotterdam, The Netherlands, PO Box 2040, Rotterdam, 3000 CA, The Netherlands.

Background And Aims: Early prediction of the effect of vedolizumab (VDZ) in inflammatory bowel disease (IBD) is of paramount importance to guide clinical decisions. This study assessed whether early fecal calprotectin (FC) can predict endoscopic response and histologic remission after VDZ initiation.

Methods: This was a prospective study. Inclusion criteria were endoscopic inflammation and FC >100 µg/g. FC was determined at baseline and weeks 2, 4, 8 and 16. At week 16, endoscopies with ileal and colonic biopsies were performed. FC changes were assessed with Wilcoxon Rank Sum tests. ROC statistics were used to assess the diagnostic accuracy of FC.

Results: In total, 45 patients [27 Crohn's disease (CD), 16/2 ulcerative colitis (UC)/IBD-unclassified] [40% males, median age 39 (28-51) years] were included. Week 16 endoscopic response and histologic remission rates were 58% and 33%. A median 37% decline in FC at week 2 was observed only in endoscopic responders,  = 0.025. FC <250 µg/g at week 8 predicted endoscopic response in both UC and CD (positive predictive value 100%), whereas absence of FC decline at week 8 corresponded with absence of endoscopic response in CD [negative predictive value (NPV) 82%] and absence of histologic remission in both UC and CD (NPV 90%).

Conclusion: The onset of a decline in FC as early as week 2 is associated with endoscopic response to VDZ induction. FC <250 µg/g at week 8 is associated with endoscopic response, whereas absence of FC decline at week 8 is associated with absence of both endoscopic response and histologic remission. FC levels 8 weeks after the start of VDZ could be used to guide clinical decisions and might substitute for endoscopic response evaluation.
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http://dx.doi.org/10.1177/1756284820979765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768861PMC
December 2020

Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management.

Inflamm Bowel Dis 2021 Feb;27(3):e25

Department of Vascular Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1093/ibd/izaa295DOI Listing
February 2021

Genetic risk scores identify genetic aetiology of inflammatory bowel disease phenotypes.

J Crohns Colitis 2020 Nov 6. Epub 2020 Nov 6.

Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands.

Background And Aims: Inflammatory bowel disease (IBD) phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores (GRS) to disentangle the genetic contributions to IBD phenotypes.

Methods: Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts (cohort A, n=1,097; cohort B, n=2,156). Genetic risk scoring was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS-phenotype (FDR corrected P<.05) associations identified in cohort A were put forward for replication in cohort B.

Results: Crohn's disease (CD) GRS were associated with fibrostenotic CD (R 2=7.4%, FDR=.02) and ileocaecal resection (R 2=4.1%, FDR=1.6E-03), and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis (UC) GRS (R 2=7.1%, FDR=.02) and primary sclerosing cholangitis (PSC) GRS (R 2=3.6%; FDR=.03) were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour (R 2=1.7%; FDR=.04).

Conclusions: Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, while colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa223DOI Listing
November 2020

Management of Pregnant Inflammatory Bowel Disease Patients During the COVID-19 Pandemic.

J Crohns Colitis 2020 Oct;14(Supplement_3):S807-S814

Erasmus University Medical Center, Department of Gastroenterology and Hepatology, the Netherlands.

The rapid emergence of the novel coronavirus [SARS-CoV2] and the coronavirus disease 2019 [COVID-19] has caused significant global morbidity and mortality. This is particularly concerning for vulnerable groups such as pregnant women with inflammatory bowel disease [IBD]. Care for pregnant IBD patients in itself is a complex issue because of the delicate balance between controlling maternal IBD as well as promoting the health of the unborn child. This often requires continued immunosuppressive maintenance medication or the introduction of new IBD medication during pregnancy. The current global COVID-19 pandemic creates an additional challenge in the management of pregnant IBD patients. In this paper we aimed to answer relevant questions that can be encountered in daily clinical practice when caring for pregnant women with IBD during the current COVID-19 pandemic.

Podcast: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665400PMC
October 2020

Health outcomes of 1000 children born to mothers with inflammatory bowel disease in their first 5 years of life.

Gut 2020 Oct 12. Epub 2020 Oct 12.

Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: The 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.

Design: We 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.

Results: We 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%) had intrauterine exposure to anti-tumour necrosis factor-α (anti-TNF-α) (60 with concomitant thiopurine) and 240 (24%) were exposed to thiopurine monotherapy. The 564 children (56%) not exposed to anti-TNF-α and/or thiopurine served as control group. There was no association between adverse long-term health outcomes and in utero exposure to IBD treatment. We did find an increased rate of intrahepatic cholestasis of pregnancy (ICP) in case thiopurine was used during the pregnancy without affecting birth outcomes and long-term health outcomes of children. All outcomes correspond with the general age-adjusted population.

Conclusion: In our study, we found no association between in utero exposure to anti-TNF-α and/or thiopurine and the long-term outcomes antibiotic-treated infections, severe infections needing hospital admission, adverse reactions to vaccinations, growth failure, autoimmune diseases and malignancies.
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http://dx.doi.org/10.1136/gutjnl-2019-319129DOI Listing
October 2020

Infliximab Trough Levels Are Not Predictive of Relapse in Patients with IBD in Endoscopic Remission: A Multicenter Cohort Study.

Dig Dis Sci 2020 Oct 10. Epub 2020 Oct 10.

Division of Gastroenterology, Harvard Medical School, Massachusetts General Hospital Crohn's and Colitis Center, 165 Cambridge Street, 9th Floor, Boston, MA, 02114, USA.

Background: Therapeutic drug monitoring (TDM) is important in optimizing use of biologics in inflammatory bowel diseases (IBD). However, the role of proactive TDM during remission remains uncertain.

Methods: This retrospective study included patients receiving infliximab (IFX) therapy at Massachusetts General Hospital or Erasmus University Medical Center. All eligible patients had completed induction phase of IFX and were in clinical and endoscopic remission. Our primary outcome was clinical relapse within 2 years after baseline. Multivariable regression models examined the association between infliximab trough levels during remission and relapse, need for IBD-related surgery or hospitalization.

Results: Our study cohort included 110 patients with IBD (72 CD, 38 UC) on IFX maintenance therapy. In total, 12 patients (10.9%) experienced relapse of disease over 2 years. The mean IFX trough level at baseline was 8.0 µg/mL (± 8.6) and did not differ between the institutions. 49.1% of patients had levels < 5 µg/mL and 2.7% had antibodies to infliximab at baseline. There was no difference in the mean IFX trough levels between patients who relapsed (7.5 µg/mL ± 3.7 µg/mL) over 24 months compared to those who did not (8.1 µg/mL ± 7.9 µg/mL, p = 0.815). On multivariable logistic regression analysis, IFX trough levels at baseline were not associated with relapse of disease over 24 months (OR 1.01, 95% CI 0.93-1.09, p = 0.856).

Conclusion: This retrospective multicenter study provides evidence that IFX trough levels during quiescent disease do not predict relapse over 2 years, suggestive that proactive TDM in this setting is not warranted.
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http://dx.doi.org/10.1007/s10620-020-06645-0DOI Listing
October 2020

High Immunogenicity to Influenza Vaccination in Crohn's Disease Patients Treated with Ustekinumab.

Vaccines (Basel) 2020 Aug 14;8(3). Epub 2020 Aug 14.

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands.

Influenza vaccination can be less effective in patients treated with immunosuppressive therapy. However, little is known about the effects of ustekinumab; an anti-IL-12/23 agent used to treat Crohn's disease (CD), on vaccination response. In this prospective study, we assessed immune responses to seasonal influenza vaccination in CD patients treated with ustekinumab compared to CD patients treated with anti-TNFα therapy (adalimumab) and healthy controls. Humoral responses were assessed with hemagglutinin inhibition (HI) assays. Influenza-specific total CD3, CD3CD4, and CD3CD8 T-cell responses were measured with flow cytometry. Fifteen patients treated with ustekinumab; 12 with adalimumab and 20 healthy controls were vaccinated for seasonal influenza in September 2018. Seroprotection rates against all vaccine strains in the ustekinumab group were high and comparable to healthy controls. Seroconversion rates were comparable, and for A/H3N2 highest in the ustekinumab group. HI titers were significantly higher in the ustekinumab group and healthy controls than in the adalimumab group for the B/Victoria strain. Post-vaccination T-cell responses in the ustekinumab group were similar to healthy controls. One-month post-vaccination proliferation of CD3CD8 T-cells was highest in the ustekinumab group. In conclusion, ustekinumab does not impair immune responses to inactivated influenza vaccination. Therefore, CD patients treated with ustekinumab can be effectively vaccinated for seasonal influenza.
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http://dx.doi.org/10.3390/vaccines8030455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565576PMC
August 2020

The Effect of Psychotherapy on Quality of Life in IBD Patients: A Systematic Review.

Inflamm Bowel Dis 2020 Aug 1. Epub 2020 Aug 1.

Department of Gastroenterology and Hepatology, The Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam University Medical Centre, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.

Background: Patients with inflammatory bowel disease (IBD) express a need for additional psychotherapy; however, psychological support is not incorporated in the routine care of persons with IBD. This systematic review aims to assess the effect of psychotherapy on quality of life (QoL).

Methods: A systematic search was conducted on October 7, 2019, using Embase, Medline (Ovid), PubMed, Cochrane, Web of Science, PsycInfo, and Google Scholar to collect all types of clinical trials with psychotherapeutic interventions that measured QoL in patients with IBD aged ≥18 years. Quality of evidence was systematically assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria.

Results: Out of 2560 articles, 31 studies (32 articles) were included with a total number of 2397 patients with active and inactive IBD. Of the 31 eligible studies, 11 reported a significant positive effect and 6 had ambiguous results regarding the impact of psychotherapeutic interventions on QoL. Treatment modalities differed in the reported studies and consisted of cognitive-behavioral therapy, psychodynamic therapy, acceptance and commitment therapy, stress management programs, mindfulness, hypnosis, or solution-focused therapy. All 4 studies focusing on patients with active disease reported a positive effect of psychotherapy. Trials applying cognitive-behavioral therapy reported the most consistent positive results.

Conclusions: Psychotherapeutic interventions can improve QoL in patients with IBD. More high-quality research is needed before psychological therapy may be implemented in daily IBD practice and to evaluate whether early psychological intervention after diagnosis will result in better coping strategies and QoL throughout life.
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http://dx.doi.org/10.1093/ibd/izaa144DOI Listing
August 2020

Inflammatory Bowel Disease Management During the COVID-19 Outbreak: The Ten Do's and Don'ts from the ECCO-COVID Taskforce.

J Crohns Colitis 2020 Oct;14(Supplement_3):S798-S806

Department of Gastroenterology, Nancy University Hospital, Vandoeuvre-Les-Nancy, France.

Our knowledge of COVID-19 is changing and evolving rapidly, with novel insights and recommendations, almost on a daily basis. It behooves the medical community to provide updated information on a regular basis, on best practice to facilitate optimal care of infected patients and on appropriate advice for the general population. This is particularly important in the case of patients with chronic conditions, such as inflammatory bowel disease [IBD]. In this review, we have compiled existing evidence on the impact of COVID-19 in IBD patients and provide guidance on the most appropriate care to adopt during the pandemic. Our review highlights that IBD, per se, is not a risk factor for COVID-19. However, all IBD patients with symptoms should be tested for SARS-CoV-2 and the procedures for disease management should be carefully adapted: [i] in SARS-CoV-2-positive IBD patients, medical treatments should be re-evaluated [with a particular focus on corticosteroids] always with the purpose of treating active disease and maintaining remission; [ii] non-urgent surgeries and endoscopic procedures should be postponed for all patients; [iii] online consultancy should be implemented; and [iv] hospitalization and surgery should be limited to life-threatening situations.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454472PMC
October 2020

Patient sex does not affect endoscopic outcomes of biologicals in inflammatory bowel disease but is associated with adverse events.

Int J Colorectal Dis 2020 Aug 26;35(8):1489-1500. Epub 2020 Jun 26.

Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands.

Purpose: Biological therapies are currently the mainstay in the treatment of patients with inflammatory bowel diseases (IBD). Several factors are known to influence the efficacy and tolerability of biologicals, such as CRP levels or previous biological use. Whether patient sex affects the efficacy or tolerability is unclear but would help with better risk and benefit stratification. This systematic review assesses patient sex on the efficacy and tolerability of biological therapies in IBD patients.

Methods: A systematic literature review was performed using Embase (including MEDLINE), MEDLINE OvidSP, Cochrane Central Register of Controlled Trials, Web of Science and PubMed. The primary outcome was the influence of patient sex on endoscopic outcomes in IBD patients treated with biologicals. The secondary outcome was the influence of patient sex on adverse events. Studies were included in the assessment regardless of study type or setting.

Results: The search yielded 19,461 citations; after review, 55 studies were included in the study, involving 28,465 patients treated with adalimumab, certolizumab pegol, infliximab, or vedolizumab. There was no significant association between patient sex and endoscopic efficacy in 41 relevant studies. Increased adverse events were associated with female sex in 7 out of 14 relevant studies.

Conclusions: There is no evidence for a sex difference in endoscopically measured response to biological therapies in IBD patients. However, there is an influence of sex on the occurrence of adverse events.
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http://dx.doi.org/10.1007/s00384-020-03663-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340671PMC
August 2020

Ozanimod in Crohn's disease: a promising new player.

Lancet Gastroenterol Hepatol 2020 09 15;5(9):791-792. Epub 2020 Jun 15.

Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015GD Rotterdam, Netherlands. Electronic address:

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http://dx.doi.org/10.1016/S2468-1253(20)30189-8DOI Listing
September 2020

Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

BMJ Open 2020 05 26;10(5):e035326. Epub 2020 May 26.

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands

Introduction: Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW).

Methods And Analysis: The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness.

Ethics And Dissemination: The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences.

Trial Registration Numbers: EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).
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http://dx.doi.org/10.1136/bmjopen-2019-035326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259868PMC
May 2020

Ustekinumab is associated with superior effectiveness outcomes compared to vedolizumab in Crohn's disease patients with prior failure to anti-TNF treatment.

Aliment Pharmacol Ther 2020 07 22;52(1):123-134. Epub 2020 May 22.

Maastricht, the Netherlands.

Background: Both vedolizumab and ustekinumab can be considered for the treatment of Crohn's disease (CD) when anti-TNF treatment fails. However, head-to-head trials are currently not available or planned.

Aim: To compare vedolizumab and ustekinumab in Crohn´s disease patients in a prospective registry specifically developed for comparative studies with correction for confounders.

Methods: Crohn´s disease patients, who failed anti-TNF treatment and started vedolizumab or ustekinumab in standard care as second-line biological, were identified in the observational prospective Dutch Initiative on Crohn and Colitis Registry. Corticosteroid-free clinical remission (Harvey Bradshaw Index ≤4), biochemical remission (C-reactive protein ≤5 mg/L and fecal calprotectin ≤250 µg/g), combined corticosteroid-free clinical and biochemical remission, and safety outcomes were compared after 52 weeks of treatment. To adjust for confounding and selection bias, we used multiple logistic regression and propensity score matching.

Results: In total, 128 vedolizumab- and 85 ustekinumab-treated patients fulfilled the inclusion criteria. After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014), while safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups. The propensity score matched cohort with sensitivity analyses showed comparable results.

Conclusions: Ustekinumab was associated with superior effectiveness outcomes when compared to vedolizumab, while safety outcomes were comparable after 52 weeks of treatment in CD patients who have failed anti-TNF treatment.
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http://dx.doi.org/10.1111/apt.15745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318204PMC
July 2020

Autologous Platelet-Rich Stroma in Complex Perianal Fistulas.

Dis Colon Rectum 2020 06;63(6):860-861

Department of Surgery, IJsselland Hospital, Capelle aan den IJssel, The Netherlands.

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http://dx.doi.org/10.1097/DCR.0000000000001546DOI Listing
June 2020

Preface: Pregnancy in GI-disorders.

Best Pract Res Clin Gastroenterol 2020 Feb - Apr;44-45:101672

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.bpg.2020.101672DOI Listing
May 2020

Effect of biologicals and JAK inhibitors during pregnancy on health-related outcomes in children of women with inflammatory bowel disease.

Best Pract Res Clin Gastroenterol 2020 Feb - Apr;44-45:101665. Epub 2019 Dec 28.

Department of Gastroenterology, Erasmus MC University Medical Center, 's Gravendijkwal 230, 3015, CE, Rotterdam, the Netherlands. Electronic address:

Current guidelines advise to maintain immunomodulators and biologicals in pregnant patients because relapse of inflammatory bowel is associated with unfavourable pregnancy outcome. With the exception of Methotrexate, IBD therapy seems not to be related to an increase of congenital malformations or infections requiring hospitalisation of the babies, although the effect the on the developing immune system of the exposed infants remains unknown. In this review we will focus on the effect of IBD drugs on health-related outcomes in children taking into account possible long-term effects of biologicals and immunomodulators, which are transferred across the placenta.
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http://dx.doi.org/10.1016/j.bpg.2019.101665DOI Listing
July 2020

Limited added value of laboratory monitoring in thiopurine maintenance monotherapy in inflammatory bowel disease patients.

Aliment Pharmacol Ther 2020 06 28;51(12):1353-1364. Epub 2020 Apr 28.

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: To timely detect myelotoxicity and hepatotoxicity, laboratory monitoring at 3-month intervals is advised throughout thiopurine maintenance treatment for IBD. However, reported incidence rates of myelotoxicity and hepatotoxicity in maintenance treatment are low.

Aim: To assess incidence rates and clinical consequences of myelotoxicity and hepatotoxicity in thiopurine maintenance therapy after at least 1 year of thiopurine treatment.

Methods: Retrospective analysis of therapy adjustment for laboratory toxicity in adult IBD patients after 12 consecutive months of azathioprine (AZA) or mercaptopurine monotherapy (ie baseline) between 2000 and 2016. Incidence rates of laboratory toxicity (ie myelotoxicity [leucocyte count <4.0 × 10e9/L, and/or platelet count <150 × 10e9/L] and/or hepatotoxicity (gamma-glutamyltransferase [GGT], alkaline phosphatase [AP], ALT and/or AST above ULN, excluding isolated increased AST/AP]) and associated diagnostic procedures and complications were assessed.

Results: In total, 12,391 laboratory assessments were performed on 1132 patients (56% female, AZA 74%) during 3.3 years of median follow-up. Median monitoring frequency was 3.1 assessments/treatment year. Only 83/12,391 (0.7%) assessments resulted in therapy adjustment, dose reduction in 46 patients, cessation in 28 and allopurinol initiation in nine; risk of therapy adjustment was 1.9% per treatment year. Incidence rates of myelotoxicity were 7.1% (5.1% mild/1.8% moderate/0.1% severe) and hepatotoxicity 5.1% (3.8% mild/1.1% moderate/0.2% severe) per treatment year. Treatment-related complications with concurrent laboratory toxicity occurred in 12 patients (1.1%) and would not have been prevented by monitoring.

Conclusion: Severe laboratory toxicity is uncommon after 1 year of thiopurine monotherapy at 4-month monitoring intervals. Therapy adjustments are rare after detection of laboratory toxicity. After 1 year of thiopurine monotherapy, laboratory monitoring may be lowered to less than a 4-month interval.
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http://dx.doi.org/10.1111/apt.15734DOI Listing
June 2020

Fecal calprotectin is a reliable marker of endoscopic response to vedolizumab therapy: A simple algorithm for clinical practice.

J Gastroenterol Hepatol 2020 Nov 4;35(11):1893-1901. Epub 2020 May 4.

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

Background And Aim: The association of fecal calprotectin (FC) and endoscopic response in inflammatory bowel disease patients during vedolizumab (VDZ) treatment is largely unknown. The aim of this study is to assess the diagnostic value of FC to predict endoscopic response.

Methods: Patients with active endoscopic disease at baseline were included. Endoscopies and FC tests were performed at baseline and week 16. Patients with a confirmed endoscopic response at week 16 continued VDZ maintenance therapy, and endoscopy and FC tests were performed at week 52. Endoscopic response was defined as endoscopic Mayo score reduction of ≥ 1, SES-CD of ≥ 50%, or Rutgeerts' score of ≥ 1. Correlations were assessed using Spearman and receiver operating characteristic statistics.

Results: A total of 114 patients, 46 ulcerative colitis and 68 Crohn's disease patients (44 men, median age 40 years), were included after the start of VDZ; 85% was anti-tumor necrosis factor alpha refractory. Endoscopic response was observed in 60 (53%) patients at week 16; the response sustained in 73% at week 52. FC decreased significantly from 819 at baseline to 154 μg/g at week 16. FC at weeks 16 and 52 were significantly correlated to (sustained) endoscopic response (r = -0.62 / r = -0.67, P < 0.001). FC < 200 μg/g indicates endoscopic response (area under the curve = 0.89, positive predictive value = 94%), whereas FC > 450 μg/g indicates endoscopic non-response after induction (negative predictive value = 83%). An increase in FC level of > 400 μg/g after induction indicates endoscopic loss of response (area under the curve = 0.97, negative predictive value = 96%).

Conclusion: This prospective study demonstrates a significant correlation between FC and endoscopic response to VDZ. FC < 200 μg/g prognosticate endoscopic response, and FC > 450 μg/g endoscopic non-response. An increase in FC of > 400 μg/g after induction indicates endoscopic loss of response. This simple FC algorithm may guide clinical decisions on the continuation and optimization of VDZ in inflammatory bowel disease patients.
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http://dx.doi.org/10.1111/jgh.15063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687080PMC
November 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

Systematic Review and External Validation of Prediction Models Based on Symptoms and Biomarkers for Identifying Endoscopic Activity in Crohn's Disease.

Clin Gastroenterol Hepatol 2020 Jul 24;18(8):1704-1718. Epub 2019 Dec 24.

Department of Gastroenterology and Hepatology, Utrecht, The Netherlands. Electronic address:

Background & Aims: Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy.

Methods: We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP).

Results: We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing.

Conclusions: In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.
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http://dx.doi.org/10.1016/j.cgh.2019.12.014DOI Listing
July 2020

Diagnosis and Outcome of Oesophageal Crohn's Disease.

J Crohns Colitis 2020 Jun;14(5):624-629

Department of Gastroenterology, Venizeleio General Hospital, Heraklion, Greece.

Background And Aims: Crohn's disease [CD] can involve any part of the gastrointestinal tract. We aimed to characterize the clinical, endoscopic and histological features and treatment outcomes of CD patients with oesophageal involvement.

Methods: We collected cases through a retrospective multicentre European Crohn's and Colitis Organisation CONFER [COllaborative Network For Exceptionally Rare case reports] project. Clinical data were recorded in a standardized case report form.

Results: A total of 40 patients were reported (22 males, mean [±SD, range] age at oesophageal CD diagnosis: 25 [±13.3, 10-71] years and mean time of follow-up: 67 [±68.1, 3-240] months). Oesophageal involvement was established at CD diagnosis in 26 patients [65%] and during follow-up in 14. CD was exclusively located in the oesophagus in two patients. Thirteen patients [32.2%] were asymptomatic at oesophageal disease diagnosis. Oesophageal strictures were present in five patients and fistulizing oesophageal disease in one. Eight patients exhibited granulomas on biopsies. Proton-pump inhibitors [PPIs] were administered in 37 patients [92.5%]. Three patients underwent endoscopic dilatation for symptomatic strictures but none underwent oesophageal-related surgery. Diagnosis in pre-established CD resulted in treatment modifications in 9/14 patients. Clinical remission of oesophageal disease was seen in 33/40 patients [82.5%] after a mean time of 7 [±5.6, 1-18] months. Follow-up endoscopy was performed in 29/40 patients and 26/29 [89.7%] achieved mucosal healing.

Conclusion: In this case series the endoscopic and histological characteristics of isolated oesophageal CD were similar to those reported in other sites of involvement. Treatment was primarily conservative, with PPIs administered in the majority of patients and modifications in pre-existing inflammatory bowel disease-related therapy occurring in two-thirds of them. Clinical and endoscopic remission was achieved in more than 80% of the patients.
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http://dx.doi.org/10.1093/ecco-jcc/jjz201DOI Listing
June 2020

Pregnancy outcomes in inflammatory bowel disease patients treated with vedolizumab, anti-TNF or conventional therapy: results of the European CONCEIVE study.

Aliment Pharmacol Ther 2020 01 6;51(1):129-138. Epub 2019 Nov 6.

Leuven, Belgium.

Background: Women with inflammatory bowel diseases (IBD) often receive biologicals during pregnancy to maintain disease remission. Data on outcome of vedolizumab-exposed pregnancies (VDZE) are sparse.

Aims: To assess pregnancy and child outcomes of VDZE pregnancies and to compare these results to anti-TNF exposed (TNFE) or both immunomodulatory and biologic unexposed (CON IBD) pregnancies.

Methods: A retrospective multicentre case-control observational study was performed.

Results: VDZE group included 79 pregnancies in 73 IBD women. The TNFE and CON IBD group included 186 pregnancies (162 live births) in 164 IBD women and 184 pregnancies (163 live births) in 155 IBD women, respectively. At conception, cases more often had active disease ([VDZE: 36% vs TNFE: 17%, P = .002] and [VDZE: 36% vs CON IBD: 24%, P = .063]). No significant difference in miscarriage rates were found between groups (VDZE and TNFE: 16% vs 13%, P = .567; VDZE and CON IBD: 16% vs 10%, P = .216). In live-born infants, median gestational age and birthweight were similar between groups. Median Apgar score at birth was numerically equal. Prematurity was similar in the VDZE group compared to the control groups, even when correcting for disease activity during pregnancy. The frequency of congenital anomalies was comparable between groups as were the percentages of breastfed babies. During the first year of life, no malignancies were reported and infants' infection risk did not significantly differ between groups.

Conclusion: No new safety signal was detected in VDZE pregnancies although larger, prospective studies are required for confirmation.
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http://dx.doi.org/10.1111/apt.15539DOI Listing
January 2020

Health-related quality of life in the first 5 years of the children born to mothers with IBD does not differ from children born to healthy mothers.

J Psychosom Res 2019 12 25;127:109840. Epub 2019 Oct 25.

Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.

Objective: Inflammatory bowel disease (IBD) is often diagnosed in women in their reproductive years of life and therefore children are born to mothers with IBD. Health outcomes of children born to mothers with IBD seem favorable. However, little is known about the quality of life related to their health compared to children born to healthy mothers. Therefore, our first objective was to investigate the effect of having IBD during pregnancy on the health-related quality of life (HRQoL) of children born to mothers with IBD in the first 5 years of age compared to children born to healthy mothers. Secondly, we studied the effect of the different IBD related factors on the HRQoL.

Methods: We prospectively followed 264 women with IBD, who visited the preconception outpatient clinic at our tertiary health center in the Netherlands from April 2013 through November 2016. Women of children aged 1-5 years were approached to fill in a 43-item validated TNO-AZL Preschool Children Quality of Life questionnaire (TAPQOL) to assess HRQoL (Fekkes et al., 2000; Bunge et al., 2005 [1,2]). Outcomes were compared to children of mothers without IBD.

Results: One-hundred-eighty-two women completed the TAPQOL questionnaire. In total 182 children of mothers with IBD were included [median age 3.0 years (IQR 2-4)]. From 70 healthy mothers, 70 children were included as controls. There was no significant difference in the HRQoL between children who were and were not born to mothers with IBD (P = .18). Also, no effect of the different IBD related factors was found.

Conclusion: In this study, we found no effect of having IBD during pregnancy on the health-related quality of life of children in the first 5 years of life.
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http://dx.doi.org/10.1016/j.jpsychores.2019.109840DOI Listing
December 2019

Vedolizumab for Inflammatory Bowel Disease: Two-Year Results of the Initiative on Crohn and Colitis (ICC) Registry, A Nationwide Prospective Observational Cohort Study: ICC Registry - Vedolizumab.

Clin Pharmacol Ther 2020 05 11;107(5):1189-1199. Epub 2019 Dec 11.

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

Prospective data of vedolizumab treatment for patients with inflammatory bowel disease (IBD) beyond 1 year of treatment is scarce but needed for clinical decision making. We prospectively enrolled 310 patients with IBD (191 with Crohn's disease (CD) and 119 patients with ulcerative colitis (UC)) with a follow-up period of 104 weeks (interquartile range: 103-104) in a nationwide registry. The corticosteroid-free clinical remission rate (Harvey Bradshaw Index ≤ 4, Short Clinical Colitis Activity index ≤ 2) at weeks 52 and 104 were 28% and 19% for CD and 27% and 28% for UC, respectively. Fifty-nine percent maintained corticosteroid-free clinical remission between weeks 52 and 104. Vedolizumab with concomitant immunosuppression showed comparable effectiveness outcomes compared with vedolizumab monotherapy (week 104: 21% vs. 23%; P = 0.77), whereas 8 of 13 severe infections occurred in patients treated with concomitant immunosuppression. To conclude, the clinical effect was 19% for CD and 28% for UC after 2 years of follow-up regardless of concomitant immunosuppression.
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http://dx.doi.org/10.1002/cpt.1712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232860PMC
May 2020

The pre- and post-authorisation data published by the European medicines agency on the use of biologics during pregnancy and lactation.

Br J Clin Pharmacol 2020 03 23;86(3):580-590. Epub 2020 Jan 23.

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

Aims: The effects of biologics on reproduction/lactation are mostly unknown although many patients that receive biologics are women of reproductive age. The first objective of this study was to investigate the publicly available data on pregnancy/lactation before and after marketing authorization in Europe of biologics for the indications of rheumatologic inflammatory autoimmune diseases and inflammatory bowel disease. Secondary objectives included the assessment of the clinical relevance of the provided data and comparison of initial and post-authorization data.

Methods: Initial and post-authorization data were extracted from the European Public Assessment Reports and the latest versions of Summary of Product Characteristics using publicly available documents on the European Medicines Agency's website. Four sections were categorized regarding pregnancy outcomes: pre-clinical/animal studies, human female fertility, pregnancy-related outcomes and congenital malformations in the human fetus. Three sections were categorized regarding lactation outcomes: pre-clinical/animal studies, excretion in human breast milk and absorption in children through breastfeeding. The clinical applicability of each category was scored by specified criteria, based on scientific literature, and further as defined by the authors.

Results: For the 16 included biologics, post-authorization data were delivered only for adalimumab, certolizumab pegol, etanercept and infliximab. For the 12 remaining biologics limited data on pregnancy and lactation during the post-marketing period of 2-21 years were available.

Conclusions: In this article several suggestions are provided for improving a multidisciplinary approach to these issues. The initiation of suitable registries by marketing authorization holders and data transparency for clinicians and academics are highly endorsed.
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http://dx.doi.org/10.1111/bcp.14145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080638PMC
March 2020

Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease.

PLoS One 2019 3;14(10):e0221924. Epub 2019 Oct 3.

Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.

Background: The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best.

Methods: We stimulate a total of 106 colonic biopsies from 19 Crohn's disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organoids and various cell culture models (either proficient or genetically deficient with respect to PXR) in vitro with the PXR ligand rifampicin or vehicle. Effects on NF-κB activity are assessed by measuring interleukin-8 (IL-8) and interleukin-1ß (IL-1ß) mRNA levels by qPCR and in cell culture models by NF-κB reporter-driven luciferase activity and Western blot for signal transduction elements.

Results: We observe a strict inverse correlation between colonic epithelial PXR levels and NF-κB target gene expression in colonic biopsies from Crohn's disease patients. PXR, activated by rifampicin, is rate-limiting for mucosal NF-κB activation in IBD. The correlation between colonic epithelial PXR levels and NF-κB target gene expression was also observed in intestinal organoids system. Furthermore, in preclinical in vitro models of intestinal inflammation, including intestinal organoids, genetic inactivation of PXR unleashes NF-κB-dependent signal transduction whereas conversely NF-κB signaling reduces levels of PXR expression.

Conclusions: Our data indicate that the PXR is a major and clinically relevant antagonist of NF-κB activity in the intestinal epithelial compartment during inflammatory bowel disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221924PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776398PMC
March 2020

Isolated ileal blind loop inflammation after intestinal resection with ileocolonic anastomosis in Crohn's disease: an often neglected endoscopic finding with an unfavorable outcome.

Eur J Gastroenterol Hepatol 2019 Nov;31(11):1370-1375

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam.

Objective: Postoperative endoscopic recurrence in patients with Crohn's disease (CD) is commonly classified using the Rutgeerts score. Ulcerations in the ileal blind loop are not taken into account in the Rutgeerts score, and the clinical relevance of these lesions is unknown. This study aimed to assess the outcome of isolated ileal blind loop inflammation (IBLI) in postoperative CD patients.

Methods: Adult CD patients who underwent intestinal surgery with ileocolonic anastomosis between 1997 and 2017 were included and postoperative endoscopy reports were retrospectively reviewed. IBLI was defined as isolated inflammation of the ileal blind loop with or without ulcera confined to the anastomosis. Outcome was assessed using endoscopic recurrence (Rutgeerts >i2) and surgical recurrence (re-resection).

Results: A total of 341 CD patients were included. In 125 out of 341 (37%) patients, the ileal blind loop was described in the endoscopy reports. IBLI was reported in 43 of 341 (13%) patients. Start or step-up drug therapy was initiated in 10 of 32 (31%) IBLI patients with abdominal symptoms within a median of 0.9 months [interquartile range (IQR) 0.7-1.4] after ileocolonoscopy. Endoscopic recurrence occurred in 4 out of 38 (11%) IBLI patients without re-resection, within a median of 12.4 months (IQR 6.8-13.3). Intestinal re-resection was performed in 5 out of 43 (16%) IBLI patients within a median of 3.7 months (IQR 3.5-10.8).

Conclusion: IBLI is associated with symptoms and an unfavorable outcome, with a high risk of endoscopic recurrence in the neoterminal ileum and intestinal re-resection during short-term follow-up. Therefore, the blind ileal loop needs to be assessed during endoscopy in postoperative CD patients.
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http://dx.doi.org/10.1097/MEG.0000000000001551DOI Listing
November 2019

Intestinal resection rates in Crohn's disease decline across two different epidemiological areas: a consistent observation not merely due to introduction of anti-TNFα.

Gut 2020 Sep 14;69(9). Epub 2019 Aug 14.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

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http://dx.doi.org/10.1136/gutjnl-2019-319321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456730PMC
September 2020

Real-life study of safety of thiopurine-allopurinol combination therapy in inflammatory bowel disease: myelotoxicity and hepatotoxicity rarely affect maintenance treatment.

Aliment Pharmacol Ther 2019 08;50(4):407-415

Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Background: Low-dose thiopurine-allopurinol (LDTA) combination therapy is a commonly applied optimisation strategy in IBD patients with a skewed thiopurine metabolism.

Aim: To assess continued LDTA maintenance treatment at annual intervals and explore risk factors for treatment cessation METHODS: Adult IBD patients treated with LDTA between 2009 and 2016 were retrospectively included. Data on the incidence of clinical and laboratory adverse events (AEs), including hepatotoxicity and myelotoxicity resulting in imposing LDTA therapy cessation and associated risk factors were collected.

Results: In total, 221 IBD patients (46% male, median age 42 years) were included. Maintenance LDTA treatment was continued in 78% of patients at 1 year (n = 145), 66% at 2 years (n = 83), 57% at 3 years (n = 52) and 52% at 4 years (n = 33). Treatment in patients receiving LDTA therapy for AEs during thiopurine monotherapy was more often continued than in patients initiating LDTA for other indications (eg, ineffectiveness of thiopurine monotherapy, routinely discovered skewed metabolism) (P = 0.016). Myelotoxicity during thiopurine monotherapy resolved in 87% and hepatotoxicity in 86% after median of 1.2 and 1.4 months after LDTA initiation. Cumulative incidence of AEs during LDTA resulting in therapy cessation within total follow-up of 449 treatment-years was 7% for clinical AEs, 4% for myelotoxicity and 1% for hepatotoxicity.

Conclusion: LDTA therapy is a safe and beneficial optimisation strategy in IBD patients. Continued maintenance LDTA treatment is 52% after 4 years of treatment and most commonly affected by ineffectiveness of LDTA rather than LDTA-attributed toxicity. LDTA optimisation strategy is most advantageous in patients failing thiopurine monotherapy due to AEs.
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http://dx.doi.org/10.1111/apt.15402DOI Listing
August 2019