Severine Vermeire

Academisch Medisch Centrum Universiteit van Amsterdam, Amsterdam, North Holland, Netherlands

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Publications (349)3158.67 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The role of Aeromonas species as an enteropathogen in patients with and without inflammatory bowel disease (IBD) is still debated. The aim was to explore the significance of positive Aeromonas stool cultures in IBD and patients without IBD. Observational retrospective study including all patients with a stool culture positive for Aeromonas between January 2011 and October 2013 at the Leuven University Hospitals. Demographics, clinical, and endoscopic outcomes and laboratory results were analyzed. A total of 77 patients (11 IBD) were identified. In 37 cases, Aeromonas caused a mild self-limited gastrointestinal infection. Among the 40 patients needing antibiotics, 22 presented a mild-to-moderate gastrointestinal infection; 4 suffered from extraintestinal complications; and 4 were coinfected by Campylobacter spp. A. veronii caused more frequently severe infection than the other species (25% versus 5%; P = 0.046). In 2 patients with ulcerative colitis, Aeromonas triggered a moderate-to-severe flare and 2 cases appeared in the context of de novo Crohn's disease. In contrast, in 1 patient with ulcerative colitis and 2 patients with Crohn's disease, Aeromonas caused a mild gastrointestinal infection not worsening the disease activity and in 4 patients with Crohn's disease, it presented in the context of active disease with no clear pathogenic role. Patients with IBD were treated more often with antibiotics (82 versus 41%, P = 0.012) and had more complications (46 versus 14%, P = 0.024). Aeromonas caused mostly mild infections but also moderate and severe infections. A. veronii was more prevalent in patients with IBD and was associated with worse clinical outcomes. Aeromonas caused milder infections in patients without IBD. Other risk factors for severe infection were not found.
    Inflammatory Bowel Diseases 01/2015; 21(1):71-78. · 5.12 Impact Factor
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    ABSTRACT: Determination of infliximab (IFX) serum concentrations has been used for treatment optimization of patients with inflammatory bowel disease (IBD). A wide range of ELISA assays exists to quantitate IFX. Most of these assays lack specificity and cross-react with other anti-tumor necrosis factor (TNF) agents. The ability of these IFX assays to detect IFX in complex with anti-drug antibodies is not known. The objective of our study was to develop an IFX-specific immunoassay to monitor IFX serum concentrations and to evaluate the impact of anti-drug antibodies on the assay performance. A panel of monoclonal antibodies towards IFX (MA-IFX) was generated by hybridoma technology and evaluated to replace the polyclonal antibody in a TNF-coated IFX assay. The selected monoclonal antibody-based (MA-based) IFX ELISA was benchmarked to a clinically validated, reference polyclonal antibody-based (pAb-based) IFX ELISA using 209 IBD serum samples. Fifty-five MA-IFX were generated and grouped into nine clusters. Out of 22 monoclonal antibodies tested, MA-IFX6B7 was selected in the IFX ELISA and the assay was further optimized. MA-IFX6B7 is a high affinity (KD= 1.40E-09 mol/L), non-inhibitory IgG1 antibody, that binds to the Fab fragment of IFX and exhibits no cross-reactivity with other anti-TNF drugs. The linearity of an IFX dose-response curve was demonstrated in the range of 1.2 ng/mL - 37.5 ng/mL (R= 0.988). The MA-based assay showed a good Pearson correlation (R = 0.986) and intraclass correlation coefficient (ICC = 0.985) with the pAb-based assay. The MA-based assay detects IFX in complex with non-neutralizing anti-IFX antibodies but not when complexed with neutralizing anti-IFX antibodies. In this study, a highly specific MA-IFX was developed as detection antibody in an ELISA to quantify IFX serum concentrations. The assay was benchmarked to the clinically validated reference pAb-based IFX ELISA.
    Therapeutic drug monitoring. 12/2014;
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    ABSTRACT: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma (EAC). Increased risk for BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. The Barrett's and esophageal adenocarcinoma consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma in CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify SNPs that increased risk for BE in a genome-wide association study (GWAS) and to validate previously-reported associations. We performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by the BEACON. We performed genotype analysis of 10,158 patients with BE and 21,062 controls. We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR], 1.14; 95% CI, 1.09-1.18; P=1.8×10(-11)) and rs2701108 (12q24.21; OR, 0.90; 95% CI, 0.86-0.93; P=7.5×10(-9)). The closest protein-coding genes were GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. We also identified 3 SNPS already identified by the BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, near ALDH1A2 (OR, 0.90; 95%, CI 0.87-0.93; P=3.72×10(-9)). We identified 2 loci associated with risk for BE and provide data to support a locus previously associated with risk in the BEACON. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 11/2014; · 12.82 Impact Factor
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    ABSTRACT: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD.
    Inflammatory Bowel Diseases 07/2014; · 5.12 Impact Factor
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    ABSTRACT: Inflammatory bowel diseases (IBD) are chronic, relapsing to continuously active inflammatory disorders of the gastrointestinal tract, of potentially destructive nature. So far, the excessive and/or unbalanced immune response has been the target of the majority of the IBD treatments. Despite the increasing use of immunosuppressants and anti-TNF-α inhibitors, about 30% of patients with Crohn's disease and about one-tenth of patients with ulcerative colitis still require major abdominal surgery at 5-10 years. As a result, new therapeutic approaches are urgently needed. The endothelium has a key role in the development of the inflammation, as it selectively governs the leukocyte trafficking and the influx of leukocytes into the intestinal mucosa. Drugs blocking such crossing, specifically at intestinal level, are going to be a new therapeutic option in IBD.
    Expert Review of Clinical Immunology 05/2014; · 2.89 Impact Factor
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    ABSTRACT: Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials. The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement. Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome. It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal.
    Gut 05/2014; · 10.73 Impact Factor
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    ABSTRACT: Although inflammatory bowel diseases (IBD) significantly impact the patient's quality of life, no European-level data exists on patients' perspectives. The primary objective of this survey was to obtain an international perspective of the impact of IBD on patients' lives. Secondary objectives included obtaining a better understanding of the quality of care, access to care, and differences between countries, age groups, and sub-groups of IBD. The survey questionnaire consisted of 52 questions in six categories. The survey was translated into ten languages, tested on volunteers, and promoted across 25 national IBD associations. Data was collected anonymously online, and participation was optional. 4670 patients completed the survey. Most respondents received a final diagnosis within a year from noticing first symptoms, but 67% had to visit emergency clinic at least once before diagnosis. 85% had been hospitalized in the last five years. 64% felt that gastroenterologists should ask more probing questions and 54% that they did not get to tell something potentially important to their physician. Most respondents experienced symptoms weekly also in remission. Most had been absent from work due to IBD and 24% had received unfair comments about their work performance. 45% felt that IBD had negatively affected their performance in educational settings. The results of this survey can be used in defining strategic priorities and planning projects and awareness raising activities. The unmet needs of IBD patients can be better demonstrated and communicated to the public, health service managers and politicians.
    Journal of Crohn s and Colitis 03/2014; · 3.39 Impact Factor
  • Journal of Crohn s and Colitis 02/2014; 8:S4–S5. · 3.39 Impact Factor
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    ABSTRACT: Serum infliximab trough levels correlate with efficacy; dose escalation is often beneficial in patients with Crohn's disease who stop responding to infliximab treatment. To carry out a post hoc analysis of A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I) to evaluate the association between serum infliximab trough levels and C-reactive protein (CRP) after 14 weeks of induction treatment with durable sustained long-term response (Crohn's Disease Activity Index decrease ≥70 points and reduction ≥25% from baseline). ACCENT I was a multicentre, randomised, placebo-controlled study. Week 14 trough levels and CRP percentage decrease from baseline to week 14 were compared between patients with and without durable sustained response through week 54. Sensitivity and specificity were determined to predict durable sustained response. Receiver operating characteristic (ROC) curves identified optimal cut-off points; logistic regression determined ORs. After induction with 5 mg/kg infliximab, 25% (37/147) and 33% (47/144) of patients sustained week 14 response to infliximab 5 or 10 mg/kg, respectively, administered every 8 weeks without dose escalation, through week 54. Median week 14 trough levels of patients with and without durable sustained response to infliximab 5 mg/kg were 4.0 and 1.9 μg/mL, respectively (p=0.0331). Optimal predictors of durable sustained response to maintenance infliximab 5 mg/kg were week 14 trough level ≥3.5 µg/mL and ≥60% CRP decrease (ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)), respectively, in patients with raised baseline CRP (>8.0 mg/L); area under the ROC curve was 0.75 for both predictors. A ≥3.5 µg/mL week 14 infliximab serum level did not predict durable sustained response to 10 mg/kg maintenance infliximab. Patients with durable sustained response to maintenance infliximab 5 mg/kg had higher postinduction trough levels than patients without durable sustained response. Serum infliximab trough levels ≥3.5 µg/mL and ≥60% CRP decrease were significantly associated with durable sustained response.
    Gut 01/2014; · 10.73 Impact Factor
  • Tim Vanuytsel, Séverine Vermeire, Isabelle Cleynen
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    ABSTRACT: Crohn's disease (CD) and ulcerative colitis (UC), collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut. Their precise etiology is unknown, although an increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD. The intestinal epithelium provides the largest interface between the external environment and the host, and is thus a crucial regulation site of innate and adaptive immunity. Zonulin is one of the few known physiological mediators of paracellular intestinal permeability. It was found upregulated in different immune diseases like Celiac disease and Type 1 Diabetes (T1D). Recently, human zonulin was identified as prehaptoglobin-2 (pre-HP2) which before only had been regarded as the inactive precursor for HP2. Haptoglobin (HP) is a hemoglobin-binding protein with immunomodulatory properties. Its gene harbors a common polymorphism with 2 different alleles: HP1 and HP2. Allele HP2 and genotype HP22 has been shown to be overrepresented in different immune diseases like Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and T1D, and has also been found to be more frequent in patients with IBD (UC and CD) than in healthy controls. In order to get some clues about the mechanism of action of HP(2) in IBD pathogenesis, we here review the current state of knowledge about zonulin and haptoglobin structure and function, and their plausible role in immune mediated diseases with an emphasis on IBD.
    Tissue barriers. 12/2013; 1(5):e27321.
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    ABSTRACT: We present two patients with inflammatory bowel disease who, despite negative tuberculosis screening, developed a de novo tuberculosis infection after the start of anti tumor necrosis factor alpha treatment. We discuss current screening methods and their limitations, the approach after positive screening and the timing to resume anti-TNFα treatment after TB infection. We shortly mention the immune reconstitution inflammatory syndrome (IRIS), described in a few cases after the stop of anti-TNFalpha while treating the tuberculosis infection. We conclude with some remaining questions concerning tuberculosis in IBD patients.
    Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
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    ABSTRACT: ABO encodes a glycosyltranferase which determines the major human histo-blood group. The FUT2 fucosyltransferase allows expression of ABO antigens on the gastrointestinal mucosa and in bodily secretions (secretor phenotype). A nonsense allele in FUT2 represents a susceptibility variant for Crohn's disease, and both the secretor and ABO blood group status affect the composition of the gut microbiota. Thus, we evaluated if variants in ABO might represent good candidates as Crohn's disease susceptibility loci. We recruited two case-control cohorts, from Italy (n=1301) and Belgium (n=2331). Subjects were genotyped for one SNP in FUT2 and two variants in ABO. No effect on Crohn's disease risk was detected for ABO variants, whereas an association was observed between the FUT2 polymorphism and Crohn's disease susceptibility in the Belgian sample, but not in the Italian cohort. The effect of histo-blood groups was evaluated using group O as the reference. Most non-O groups had odds ratios (ORs) higher than 1 in both cohorts, and combined analysis of the two samples indicated a predisposing effect for the A and B groups (OR=1.17, 95% CI: 1.02-1.32 and OR=1.33, 95% CI: 1.09-1.58, respectively). In Crohn's disease patients, the non-O blood group and the non-secretor status were associated with higher risk of developing a stricturing or penetrating disease. ABO histo-blood group might confer susceptibility to Crohn's disease and modulate disease severity.
    Journal of Crohn s and Colitis 11/2013; · 3.39 Impact Factor
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    ABSTRACT: Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
    Gut 11/2013; · 10.73 Impact Factor
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    ABSTRACT: Genome-wide association studies have identified several genes implicated in autophagy (ATG16L1, IRGM, ULK1, LRRK2, and MTMR3), intracellular bacterial sensing (NOD2), and endoplasmic reticulum (ER) stress (XBP1 and ORMDL3) to be associated with Crohn disease (CD). We studied the known CD-associated variants in these genes in a large cohort of 3451 individuals (1744 CD patients, 793 ulcerative colitis (UC) patients and 914 healthy controls). We also investigated the functional phenotype linked to these genetic variants. Association with CD was confirmed for NOD2, ATG16L1, IRGM, MTMR3, and ORMDL3. The risk for developing CD increased with an increasing number of risk alleles for these genes (P<0.001, OR 1.26 [1.20 to 1.32]). Three times as many (34.8%) CD patients carried a risk allele in all three pathways, in contrast to 13.3% of the controls (P<0.0001, OR = 3.46 [2.77 to 4.32]). For UC, no significant association for one single nucleotide polymorphism (SNP) was found, but the risk for development of UC increased with an increasing total number of risk alleles (P = 0.001, OR = 1.10 [1.04 to 1.17]). We found a genetic interaction between reference SNP (rs)2241880 (ATG16L1) and rs10065172 (IRGM) in CD. Functional experiments hinted toward an association between an increased genetic risk and an augmented inflammatory status, highlighting the relevance of the genetic findings.
    Autophagy 11/2013; 9(12). · 12.04 Impact Factor
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    ABSTRACT: Introduction: The advent of tumor necrosis factor (TNF) antagonists represented a radical change in the management of inflammatory bowel disease (IBD). Both in short- and long-term, anti-TNF therapy has been shown to reduce symptoms, heal mucosal ulcers, reduce hospitalizations and surgeries and spare corticosteroids. Areas covered: A literature search to August 2013 was performed to identify the most relevant reports on the use of TNF antagonists in IBD. First, the authors focused on the mechanism of action of TNF antagonists. Second, they evaluated different indications, contraindications, the optimal time to start and the role of combining TNF antagonists with immunomodulators. Third, they explored the importance of mucosal healing, followed by the controversial topic on when TNF antagonists should be stopped. This is followed by the subjects of treatment failure, immunogenicity and therapeutic drug monitoring. Last, they analyzed safety issues including exposure to TNF antagonists during pregnancy. Expert opinion: TNF antagonists have become indispensable in the management of IBD. Efforts to focus on treatment of inflammatory signs only and on optimization of treatment with therapeutic drug monitoring are underway. The advent of several new compounds and "biosimilars" will further challenge the position of TNF antagonists in the treatment algorithm of IBD.
    Expert opinion on biological therapy 11/2013; · 3.22 Impact Factor
  • Marc Ferrante, Séverine Vermeire, Paul J Rutgeerts
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    ABSTRACT: Introduction: The introduction of antibodies directed against tumor necrosis factor (anti-TNF) has dramatically changed our concept of treating both patients with Crohn's disease (CD) and patients with rheumatoid arthritis (RA). Subcutaneous injections with certolizumab pegol (CZP) have been shown efficacious for both CD and RA. In this review, the authors focus on the safety of CZP among other anti-TNF agents. Areas covered: A literature search till June 2013 was performed to identify all trials studying CZP in patients with CD and RA. In addition, abstracts of major congresses were assessed. The authors first focused on the mechanism of action of CZP, and evaluated the efficacy of this drug in both CD and RA. Next, they explored the available safety data on CZP, including infection and malignancy risk, injection site reactions, the development of antibodies against CZP, as well as its use during pregnancy. Expert opinion: Based on the provided literature, CZP seems to have a similar safety profile to other anti-TNF agents. However, in young females considering pregnancy, CZP may be advocated over other anti-TNF agents as it does not actively cross the placenta.
    Expert Opinion on Drug Safety 10/2013; · 2.74 Impact Factor
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    ABSTRACT: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up. We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis. Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (pFDR=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly. Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors.
    Gut 10/2013; · 10.73 Impact Factor
  • Séverine Vermeire, Marc Ferrante, Paul Rutgeerts
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    ABSTRACT: Several aspects of the management of Crohn's disease (CD) are shared between patients. The goal of all therapies should be to achieve clinical and endoscopic remission in a timely manner to avoid disease progression and abdominal resections. The way this goal is achieved may differ and predicting how the disease will evolve, what the most appropriate therapy with the highest chance of success will be, how long a therapy needs to be continued, and what the intensity of follow-up should be are more difficult questions and require an individualised approach. Clinical parameters have been suggested to aid in the therapeutic decision process but lack specificity. Although much promise has been put in molecular markers, these have not yet found their way to the clinic. More recently, clinicians have started to gain interest in drug level monitoring to adapt doses of immunomodulators and/or anti-tumour necrosis factor antibodies in an individualised manner. An increasing number of studies show that therapeutic drug monitoring can help physicians to improve and personalise the management of their patients. What is needed now are pharmaco-economic studies showing that personalised management of CD is cost effective.
    Gut 10/2013; 62(10):1511-5. · 10.73 Impact Factor
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    ABSTRACT: The complex genetic aetiology underlying irritable bowel syndrome (IBS) needs to be assessed in large-scale genetic studies. Two independent IBS cohorts were genotyped to assess whether genetic variability in immune, neuronal and barrier integrity genes is associated with IBS. 384 single nucleotide polymorphisms (SNPs) covering 270 genes were genotyped in an exploratory cohort (935 IBS patients, 639 controls). 33 SNPs with Puncorrected<0.05 were validated in an independent set of 497 patients and 887 controls. Genotype distributions of single SNPs were assessed using an additive genetic model in IBS and clinical subtypes, IBS-C and IBS-D, both in individual and combined cohorts. Trait anxiety (N=614 patients, 533 controls), lifetime depression (N=654 patients, 533 controls) and mRNA expression in rectal biopsies (N=22 patients, 29 controls) were correlated with SNP genotypes. Two SNPs associated independently in the exploratory and validation cohort: rs17837965-CDC42 with IBS-C (ORexploratory=1.59 (1.05 to 1.76); ORvalidation=1.76 (1.03 to 3.01)) and rs2349775-NXPH1 with IBS-D (ORexploratory=1.28 (1.06 to 1.56); ORvalidation=1.42 (1.08 to 1.88)). When combining both cohorts, the association of rs2349775 withstood post hoc correction for multiple testing in the IBS-D subgroup. Additionally, three SNPs in immune-related genes (rs1464510-LPP, rs1881457-IL13, rs2104286-IL2RA), one SNP in a neuronal gene (rs2349775-NXPH1) and two SNPs in epithelial genes (rs245051-SLC26A2, rs17837965-CDC42) were weakly associated with total-IBS (Puncorrected<0.05). At the functional level, rs1881457 increased IL13 mRNA levels, whereas anxiety and depression scores did not correlate with rs2349775-NXPH1. Rs2349775 (NXPH1) and rs17837965 (CDC42) were associated with IBS-D and IBS-C, respectively, in two independent cohorts. Further studies are warranted to validate our findings and to determine the mechanisms underlying IBS pathophysiology.
    Gut 09/2013; · 10.73 Impact Factor
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    ABSTRACT: Bacteria play an important role in the onset and perpetuation of intestinal inflammation in inflammatory bowel disease (IBD). Unlike in Crohn's disease (CD), in which dysbiosis has been better characterised, in ulcerative colitis (UC), only small cohorts have been studied and showed conflicting data. Therefore, we evaluated in a large cohort if the microbial signature described in CD is also present in UC, and if we could characterise predominant dysbiosis in UC. To assess the functional impact of dysbiosis, we quantified the bacterial metabolites. The predominant microbiota from 127 UC patients and 87 age and sex-matched controls was analysed using denaturing gradient gel electrophoresis (DGGE) analysis. Differences were quantitatively validated using real-time PCR. Metabolites were quantified using gas chromatography-mass spectrometry. Based on DGGE analysis, the microbial signature previously described in CD was not present in UC. Real-time PCR analysis revealed a lower abundance of Roseburia hominis (p<0.0001) and Faecalibacterium prausnitzii (p<0.0001) in UC patients compared to controls. Both species showed an inverse correlation with disease activity. Short-chain fatty acids (SCFA) were reduced in UC patients (p=0.014), but no direct correlation between SCFA and the identified bacteria was found. The composition of the fecal microbiota of UC patients differs from that of healthy individuals: we found a reduction in R hominis and F prausnitzii, both well-known butyrate-producing bacteria of the Firmicutes phylum. These results underscore the importance of dysbiosis in IBD but suggest that different bacterial species contribute to the pathogenesis of UC and CD.
    Gut 09/2013; · 10.73 Impact Factor

Publication Stats

14k Citations
3,158.67 Total Impact Points


  • 2013
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdam, North Holland, Netherlands
    • Montreal Heart Institute
      • Research Centre
      Montréal, Quebec, Canada
  • 2003–2013
    • McGill University Health Centre
      Montréal, Quebec, Canada
    • University of Alberta
      • Department of Medicine
      Edmonton, Alberta, Canada
  • 2000–2013
    • Universitair Ziekenhuis Leuven
      • Department of Gastroenterology
      Leuven, VLG, Belgium
  • 1998–2013
    • University of Leuven
      • • Department of Clinical and Experimental Medicine
      • • Department of Human Genetics
      Louvain, Flanders, Belgium
  • 2012
    • The University of Western Ontario
      • Robarts Research Institute
      London, Ontario, Canada
    • University of Nice-Sophia Antipolis
      Nice, Provence-Alpes-Côte d'Azur, France
    • Centro Medico Teknon
      Barcino, Catalonia, Spain
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
    • University of Toronto
      Toronto, Ontario, Canada
  • 2009–2012
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
    • Oslo University Hospital
      • Department of Transplantation Medicine
      Oslo, Oslo, Norway
    • Université du Droit et de la Santé Lille 2
      • Faculty of Medicine
      Lille, Nord-Pas-de-Calais, France
    • University of Groningen
      • Department of Gastroenterology and Hepatology
      Groningen, Province of Groningen, Netherlands
  • 2008–2012
    • Christian-Albrechts-Universität zu Kiel
      • Institute of Clinical Molecular Biology
      Kiel, Schleswig-Holstein, Germany
  • 2011
    • Wellcome Trust Sanger Institute
      Cambridge, England, United Kingdom
  • 2010
    • Mayo Clinic - Rochester
      • Department of Gastroenterology and Hepatology
      Rochester, Minnesota, United States
    • University College Cork
      Corcaigh, Munster, Ireland
    • University Medical Center Schleswig-Holstein
      Kiel, Schleswig-Holstein, Germany
  • 2002–2009
    • McGill University
      • Division of Gastroenterology
      Montréal, Quebec, Canada
  • 2007
    • Ben-Gurion University of the Negev
      • Department of Epidemiology and Health Services Evaluation
      Be'er Sheva`, Southern District, Israel
    • University of Cambridge
      • Department of Pathology
      Cambridge, ENG, United Kingdom
  • 2005
    • The Catholic University of America
      Washington, Washington, D.C., United States