Paul Rutgeerts

Publications of Paul Rutgeerts

• Impaired expression of genes involved in the butyrate oxidation pathway in Crohn's disease patients.

  Authors: Vicky De Preter, Paul Rutgeerts, Frans Schuit, Kristin Verbeke, Ingrid Arijs

  Inflammatory bowel diseases. 04/2012;

• Abatacept for Crohn's Disease and Ulcerative Colitis.

  Authors: William J Sandborn, Jean-Frederic Colombel, Bruce E Sands, Paul Rutgeerts, Stephan R Targan, Remo Panaccione, Brian Bressler, Karl Geboes, Stefan Schreiber, Richard Aranda, Sheila Gujrathi, Allison Luo, Yun Peng, Luisa Salter-Cid, Stephen B Hanauer

  Gastroenterology. 04/2012;

  BACKGROUND: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Four placebo-controlled trials evaluated theBACKGROUND: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo and dosed at Weeks 0, 2, 4 and 8. In MP, 90 patients with CD and 131 with UC who responded to abatacept at Week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through Week 52. RESULTS: In CD-IP, 17.2, 10.2 and 15.5% of patients receiving abatacept 30, 10 and 3 mg/kg achieved a clinical response at Weeks 8 and 12, versus 14.4% receiving placebo (P=0.611, P=0.311 and P=0.812, respectively). In UC-IP1, 21.4, 19.0 and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at Week 12, versus 29.5% receiving placebo (P=0.124, P=0.043 and P=0.158, respectively). In CD-MP, 23.8 versus 11.1% of abatacept versus placebo patients were in remission at Week 52. In UC-MP, 12.5 versus 14.1% of patients receiving abatacept versus placebo were in remission at Week 52. Safety was generally comparable between groups. CONCLUSIONS: The studies demonstrated that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.

• Decreased mucosal sulfide detoxification is related to an impaired butyrate oxidation in ulcerative colitis.

  Authors: Vicky De Preter, Ingrid Arijs, Karen Windey, Wiebe Vanhove, Severine Vermeire, Frans Schuit, Paul Rutgeerts, Kristin Verbeke

  Inflammatory bowel diseases. 03/2012;

  BACKGROUND: Defective detoxification of sulfides leads to damage to the mucosa and may play a role in the etiology of ulcerative colitis (UC). The colonic mucosal thiosulfate sulfurtransferase (TST)BACKGROUND: Defective detoxification of sulfides leads to damage to the mucosa and may play a role in the etiology of ulcerative colitis (UC). The colonic mucosal thiosulfate sulfurtransferase (TST) enzyme removes H(2) S by conversion to the less toxic thiocyanate. In this study we measured colonic mucosal TST enzyme activity and gene expression in UC and controls. In addition, the influence of sulfides on butyrate oxidation was evaluated. METHODS: Colonic mucosal biopsies were collected from 92 UC patients and 24 controls. TST activity was measured spectrophotometrically. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (RT-PCR). In 20 UC patients, gene expression was reassessed after their first treatment with infliximab. To evaluate the effect of sulfides on butyrate oxidation, biopsies were incubated with 1.5 mM NaHS. RESULTS: TST enzyme activity and gene expression were significantly decreased in UC patients vs. controls (P < 0.001). UC patients, classified into disease activity subgroups, showed a significantly decreased TST activity and gene expression in the subgroups as compared to healthy subjects (P < 0.05 for all). In 20 patients, gene expression was reassessed after their first infliximab therapy. In responders to infliximab, a significant increase in TST gene expression was observed. However, TST mRNA levels did not return to control values after therapy in the responders. In controls, but not in UC, sulfide significantly decreased butyrate oxidation. CONCLUSIONS: We found an impaired detoxification mechanism of sulfide at TST protein and RNA level in UC. Inflammation was clearly associated with the observed TST deficiency. (Inflamm Bowel Dis 2012;).

• Fecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel disease.

  Authors: Geert D'Haens, Marc Ferrante, Severine Vermeire, Filip Baert, Maja Noman, Liesbeth Moortgat, Patricia Geens, Doreen Iwens, Isolde Aerden, Gert Van Assche, Gust Van Olmen, Paul Rutgeerts

  Inflammatory bowel diseases. 02/2012;

  BACKGROUND: Fecal calprotectin is a marker of inflammation in inflammatory bowel disease (IBD). Since mucosal healing has become a goal of treatment in IBD we examined how reliably calprotectinBACKGROUND: Fecal calprotectin is a marker of inflammation in inflammatory bowel disease (IBD). Since mucosal healing has become a goal of treatment in IBD we examined how reliably calprotectin levels reflect mucosal disease activity. METHODS: In all, 126 IBD patients and 32 irritable bowel syndrome (IBS) patients needing colonoscopy delivered a sample of feces prior to the start of bowel cleansing. Besides collection of symptom scores and blood tests, experienced endoscopists recorded the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients and the Mayo endoscopic score in ulcerative colitis (UC) patients. Stool samples were shipped for central calprotectin PhiCal Assay (enzyme-linked immunosorbent assay [ELISA]). Correlation analysis was done with Pearson statistics. RESULTS: The median (interquartile range [IQR]) fecal calprotectin levels were 175 (44-938) μg/g in CD, 465 (61-1128) μg/g in UC, and 54 (16-139) μg/g in IBS. Correlations were significant with endoscopic disease scores in both CD and in UC. Using ROC statistics, a cutoff value of 250 μg/g indicated the presence of large ulcers with a sensitivity of 60.4% and a specificity of 79.5% (positive predictive value [PPV] 78.4%, negative predictive value [NPV] 62.0%) in CD. Levels ≤250 μg/g predicted endoscopic remission (CDEIS ≤3) with 94.1% sensitivity and 62.2% specificity (PPV 48.5%, NPV 96.6%). In UC, a fecal calprotectin >250 μg/g gave a sensitivity of 71.0% and a specificity of 100.0% (PPV 100.0%, NPV 47.1%) for active mucosal disease activity (Mayo >0). Calprotectin levels significantly correlated with symptom scores in UC (r = 0.561, P < 0.001), but not in CD. CONCLUSIONS: Fecal calprotectin levels correlate significantly with endoscopic disease activity in IBD. The test appears useful in clinical practice for assessment of endoscopic activity and remission. (Inflamm Bowel Dis 2012;).

• Adalimumab Induces and Maintains Mucosal Healing in Patients With Crohn's Disease: Data From the EXTEND Trial.

  Authors: Paul Rutgeerts, Gert Van Assche, William J Sandborn, Douglas C Wolf, Karel Geboes, Jean-Frédéric Colombel, Walter Reinisch, Ashish Kumar, Andreas Lazar, Anne Camez, Kathleen G Lomax, Paul F Pollack, Geert D'haens

  Gastroenterology. 02/2012;

  BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind,BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of adalimumab through endoscopic healing [EXTEND]) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg adalimumab or placebo every other week through week 52. Open-label adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. RESULTS: Twenty-seven percent of patients receiving adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo (P = .056). At week 52, rates of mucosal healing were 24% and 0, respectively (P < .001). Remission rates, based on the Crohn's Disease Endoscopic Index of Severity, were 52% for adalimumab and 28% for placebo at week 12 (P = .006) and 28% and 3%, respectively, at week 52 (P < .001). Rates of clinical remission based on the Crohn's Disease Activity Index were greater among patients given continuous adalimumab therapy versus placebo at weeks 12 (47% vs 28%; P = .021) and 52 (33% vs 9%; P = .001). Five serious (1 during induction and 4 during open-label therapy) and 3 opportunistic infections (1 in each group during double-blind therapy and 1 during open-label therapy) were reported (n = 135). CONCLUSIONS: Following induction therapy with adalimumab, patients with moderately to severely active CD who continue to receive adalimumab are more likely to achieve mucosal healing than those given placebo.

• Genetic variants in autophagy-related genes and granuloma formation in a cohort of surgically treated Crohn's disease patients.

  Authors: Marko Brinar, Séverine Vermeire, Isabelle Cleynen, Bart Lemmens, Xavier Sagaert, Liesbet Henckaerts, Gert Van Assche, Karel Geboes, Paul Rutgeerts, Gert De Hertogh

  Journal of Crohn's & colitis. 02/2012; 6(1):43-50.

  Granulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial componentsGranulomas are a characteristic microscopic finding in Crohn's disease. Their clinical significance is controversial and their pathogenesis is unknown, but impaired processing of bacterial components has been suggested. Autophagy is a fundamental process involved in the elimination of intracellular bacteria. Genetic variants in autophagy genes IRGM and ATG16L1 have been associated with susceptibility to Crohn's disease. We therefore investigated whether variants in autophagy genes contribute to granuloma formation. Surgical specimens from 464 clinically well-documented Crohn's patients were reviewed and scored for the presence and distribution of granulomas. All patients were genotyped for the CD-associated SNPs in ATG16L1 and IRGM as well as for 77 haplotype tagging SNPs in 13 additional autophagy genes. Granulomas were found in 75% of the patients. Their frequency increased with more distal involvement of the GI tract. Granuloma positive patients were significantly younger at the time of diagnosis and surgery, and were more likely to smoke. We identified associations between granulomas and autophagy gene variants ATG4A (rs5973822), FNBP1L (rs17109951) and ATG4D (rs7248026; rs2304165; rs10439163). These findings suggest that granuloma formation is a marker of a more aggressive disease course, and that variants in autophagy genes ATG4A, ATG2A, FNBP1L and ATG4D, may contribute to granuloma formation.

• Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease.

  Authors: Maureen J Koslowski, Zora Teltschik, Julia Beisner, Elke Schaeffeler, Guoxing Wang, Irmgard Kübler, Michael Gersemann, Rachel Cooney, Derek Jewell, Walter Reinisch, Séverine Vermeire, Paul Rutgeerts, Matthias Schwab, Eduard F Stange, Jan Wehkamp

  PLoS genetics. 02/2012; 8(2):e1002523.

  Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensinsIleal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD-associated genes including NOD2, ATG16L1, and recently the β-catenin-dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.

• The future of inflammatory bowel disease management: Combining progress in trial design with advances in targeted therapy.

  Authors: Simon Travis, Brian G Feagan, Paul Rutgeerts, Sander van Deventer

  Journal of Crohn's & colitis. 02/2012; 6 Suppl 2:S250-9.

  Anti-tumour necrosis factor antagonists have appreciably improved patient outcomes in Crohn's disease, shifting the goals of treatment from control of symptoms to clinical remission (Crohn's diseaseAnti-tumour necrosis factor antagonists have appreciably improved patient outcomes in Crohn's disease, shifting the goals of treatment from control of symptoms to clinical remission (Crohn's disease activity index <150) combined with mucosal healing - the new concept of 'deep remission'. Achieving deep remission brings clinically meaningful benefits, including reduced hospitalization and reduced need for surgery. Aspects such as the dose, timing and intensification of anti-tumour necrosis factor therapy affect the likelihood of achieving deep remission, but definitive evidence on long-term benefits and the risk/benefit profile of treatment intensification is needed. A consequence of the success of anti-tumour necrosis factor therapies has been a change in the disease characteristics of the patient population entering clinical trials. Therefore, new clinical study paradigms, such as cluster randomization and therapeutic strategy trials, are needed. High placebo response rates and the ethics of testing emerging agents against placebo in an era of effective therapies are challenges to traditional randomized controlled trials. Overcoming these challenges will not only help to optimize anti-tumour necrosis factor therapy, but also advance development of emerging treatments for Crohn's disease.

• Genes associated with intestinal permeability in ulcerative colitis: Changes in expression following infliximab therapy.

  Authors: Gary Toedter, Katherine Li, Sarah Sague, Keying Ma, Colleen Marano, Michael Macoritto, Jennifer Park, Renée Deehan, Andrea Matthews, Gary D Wu, James D Lewis, Ingrid Arijs, Paul Rutgeerts, Frédéric Baribaud

  Inflammatory bowel diseases. 01/2012;

  BACKGROUND: Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, can induce clinicalBACKGROUND: Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, can induce clinical response in UC. Gene expression in colonic biopsies taken from responders and nonresponders to infliximab can provide insight into the mechanisms of the altered intestinal permeability at a molecular level. METHODS: Colonic biopsies (n = 18 anti-TNFα naïve UC patients; n = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) were analyzed for mRNA expression using gene expression microarrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment. Quantitative reverse-transcription polymerase chain reaction (qPCR) was used to confirm differentially expressed genes. RESULTS: Reverse causal reasoning on mRNA expression data from anti-TNFα-naïve UC and normal samples provided a mechanistic disease model of the biology of gene expression observed in UC. mRNA expression data from the ACT 1 study enabled construction of a mechanistic model describing the biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples. Gene expression changes identified as central to intestinal permeability dysregulation were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. Gene expression returned toward normal levels in infliximab responders, but not in nonresponders. CONCLUSION: Gene expression analysis and causal network modeling in combination showed that aberrant mRNA expression of genes involved in intestinal epithelial permeability for infliximab responders was restored toward levels observed in normal samples. Infliximab nonresponders showed no equivalent restoration in the expression of these genes. (Inflamm Bowel Dis 2012;).

• Recommendations for the treatment of Crohn's disease with tumor necrosis factor antagonists: an expert consensus report.

  Authors: Brian G Feagan, Marc Lémann, Ragnar Befrits, William Connell, Geert D'Haens, Subrata Ghosh, Pierre Michetti, Thomas Ochsenkühn, Remo Panaccione, Stefan Schreiber, Mark Silverberg, Dario Sorrentino, C Janneke van der Woude, Severine Vermeire, Paul Rutgeerts

  Inflammatory bowel diseases. 01/2012; 18(1):152-60.

  Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists.Symptom relief is the traditional treatment goal in Crohn's disease (CD). New goals including mucosal healing and bowel preservation are now achievable with tumor necrosis factor (TNF) antagonists. Infliximab and adalimumab are approved as second-line treatments for severe, active CD. Certolizumab pegol is approved only in the U.S. and Switzerland as second-line treatment for moderate-to-severe, active CD. Data from trials of infliximab suggest that high-risk patients and patients with active inflammation (CRP elevation and/or ileocolonic ulcers) may benefit from earlier use of this drug. A Delphi survey was used to obtain consensus on issues surrounding bowel preservation and use of TNF antagonists. At the time of this survey, infliximab was the only TNF antagonist approved for the treatment of CD in Europe, Canada, and Australia. An expert panel of 12 gastroenterologists with substantial clinical experience using infliximab in clinical practice and trials in these areas participated. The experts agreed that bowel preservation and mucosal healing are relevant and achievable goals, and form a rationale for using TNF antagonists in CD patients. Control of inflammation and induction of mucosal healing were considered essential for bowel preservation. Consensus areas: 1) mucosal healing is predictive of improved long-term disease course and increases the likelihood of steroid-free remission; 2) infliximab induces sustained mucosal healing, promotes bowel preservation, and reduces hospitalizations and surgeries; 3) benefits of infliximab in relation to mucosal healing, bowel preservation, and clinical remission increase when therapy is initiated earlier. Treatment with TNF antagonists helps preserve the bowel in CD patients.

• Assessment of the microbiota in microdissected tissues of Crohn's disease patients.

  Authors: Gert De Hertogh, Bart Lemmens, Peter Verhasselt, Ronald de Hoogt, Xavier Sagaert, Marie Joossens, Gert Van Assche, Paul Rutgeerts, Severine Vermeire, Jeroen Aerssens

  International journal of inflammation. 01/2012; 2012:505674.

  The microbiota of the gastrointestinal tract is frequently mentioned as one of the key players in the etiopathogenesis of Crohn's disease (CD). Four hypotheses have been suggested: the single, stillThe microbiota of the gastrointestinal tract is frequently mentioned as one of the key players in the etiopathogenesis of Crohn's disease (CD). Four hypotheses have been suggested: the single, still unknown bacterial pathogen, an abnormal overall composition of the bowel microbiota ("dysbiosis"), an abnormal immunological reaction to an essentially normally composed microbiota, and increased bacterial translocation. We propose that laser capture microdissection of selected microscopic structures, followed by broad-range 16S rRNA gene sequencing, is an excellent method to assess spatiotemporal alterations in the composition of the bowel microbiota in CD. Using this approach, we demonstrated significant changes of the composition, abundance, and location of the gut microbiome in this disease. Some of these abnormal findings persisted even after macroscopic mucosal healing. Further investigations along these lines may lead to a better understanding of the possible involvement of the bowel bacteria in the development of clinical Crohn's disease.

• Intestinal expression of SHIP in inflammatory bowel diseases.

  Authors: Ingrid Arijs, Gert De Hertogh, Bart Lemmens, Jan Van der Goten, Séverine Vermeire, Frans Schuit, Paul Rutgeerts

  Gut. 11/2011;

• Immune reactivity to β-tubulin isotype 5 and vesicular integral-membrane protein 36 in patients with autoimmune gastrointestinal disorders.

  Authors: Katrijn Op De Beéck, Karolien Van den Bergh, Séverine Vermeire, Sofie Decock, Rita Derua, Etienne Waelkens, Paul Rutgeerts, Frederik Nevens, Xavier Bossuyt

  Gut. 11/2011; 60(11):1601-2.

• Cytokine blockade in inflammatory bowel diseases.

  Authors: Clémentine Perrier, Paul Rutgeerts

  Immunotherapy. 11/2011; 3(11):1341-52.

  Inflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role inInflammatory bowel diseases (IBDs) are chronic disabling diseases with significant morbidity. A deregulated immune response towards the intestinal microbiota is thought to play an important role in the pathogenesis of IBD, and thus biological therapies targeting key molecules such as cytokines have been designed. Several anti-TNF-α agents are currently being used to treat Crohn's disease and ulcerative colitis. Although these molecules dramatically improved the treatment of patients, side effects and the development of antidrug antibodies limits their application. There is thus an urgent need for alternative approaches to decrease inflammation and limit immunogenicity. Small neutralizing molecules, active immunization, gene silencing, selective transcription inhibitors and delivery of agents through the oral route are some of the currently developed strategies to meet these needs. In parallel, neutralizing antibodies targeting other pathways of the immune system have been developed and tested. Antibodies targeting IL-12/IL-23 pathways, and proinflammatory cytokines such as IFN-γ, IL-17A, IL-2 and IL-6 often showed an initial promising result, but for none of these agents efficacy has unequivocally been established. Administration of the regulatory cytokines IL-10 and IL-11 also failed to induce reproducible clinical effects. This article focuses on the anti-TNF therapies and the current challenges with monoclonal antibody therapies, discusses the innovative strategies targeting cytokine pathways to decrease inflammation in the bowel, and summarizes the recently developed agents neutralizing proinflammatory cytokines.

• Impaired butyrate oxidation in ulcerative colitis is due to decreased butyrate uptake and a defect in the oxidation pathway.

  Authors: Vicky De Preter, Ingrid Arijs, Karen Windey, Wiebe Vanhove, Severine Vermeire, Frans Schuit, Paul Rutgeerts, Kristin Verbeke

  Inflammatory bowel diseases. 10/2011;

  BACKGROUND: In ulcerative colitis (UC) butyrate metabolism is impaired due to a defect in the butyrate oxidation pathway and/or transport. In the present study we correlated butyrate uptake andBACKGROUND: In ulcerative colitis (UC) butyrate metabolism is impaired due to a defect in the butyrate oxidation pathway and/or transport. In the present study we correlated butyrate uptake and oxidation to the gene expression of the butyrate transporter SLC16A1 and the enzymes involved in butyrate oxidation (ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2) in UC and controls. METHODS: Colonic mucosal biopsies were collected during endoscopy of 88 UC patients and 20 controls with normal colonoscopy. Butyrate uptake and oxidation was measured by incubating biopsies with (14) C-labeled Na-butyrate. To assess gene expression, total RNA from biopsies was used for quantitative reverse-transcription polymerase chain reaction (qRT-PCR). In 20 UC patients, gene expression was reassessed after treatment with infliximab. RESULTS: Butyrate uptake and oxidation were significantly decreased in UC versus controls (P < 0.001 for both). Butyrate oxidation remained significantly reduced in UC after correction for butyrate uptake (P < 0.001), suggesting that the butyrate oxidation pathway itself is also affected. Also, the mucosal gene expression of SLC16A1, ACSM3, ACADS, ECHS1, HSD17B10, and ACAT2 was significantly decreased in UC as compared with controls (P < 0.001 for all). In a subgroup of patients (n = 20), the gene expression was reassessed after infliximab therapy. In responders to therapy, a significant increase in gene expression was observed. Nevertheless, only ACSM3 mRNA levels returned to control values after therapy in the responders groups. CONCLUSIONS: The deficiency in the colonic butyrate metabolism in UC is initiated at the gene expression level and is the result of a decreased expression of SLC16A1 and enzymes in the β-oxidation pathway of butyrate. (Inflamm Bowel Dis 2011;).

• Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab: prospective randomised SWITCH trial.

  Authors: Gert Van Assche, Séverine Vermeire, Vera Ballet, Frederik Gabriels, Maja Noman, Geert D'Haens, Christophe Claessens, Evelien Humblet, Niels Vande Casteele, Ann Gils, Paul Rutgeerts

  Gut. 09/2011; 61(2):229-34.

  Elective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectivelyElective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectively the impact of elective switching of patients with Crohn's disease well controlled with intravenous infliximab to subcutaneous adalimumab in a controlled trial. An open-label randomised single-centre trial recruited 73 patients with ongoing response to at least 6 months of scheduled maintenance infliximab. Patients were randomised to continue intravenous 5 mg/kg infliximab or to switch to subcutaneous adalimumab 80 mg at baseline followed by 40 mg every other week for 1 year. Dose optimisation was allowed for intermittent flares, and patients with loss of response or intolerance could cross over to the alternative treatment group. Tolerability, patient preference and efficacy of both treatment options were the primary outcomes. Dose optimisation or interruption of treatment occurred in 17/36 patients (47%) in the adalimumab group and in 6/37 patients (16%) in the infliximab group (p=0.006). One patient interrupted infliximab treatment and 10 patients interrupted adalimumab treatment (p=0.003), mostly for loss of tolerance. Overall, patients preferred adalimumab treatment. All five serious adverse events were related to complicated Crohn's disease and occurred in patients randomised to adalimumab. Injection site reactions were more frequent than infusion reactions (8 vs 1, p=0.01), but only the latter caused cessation of further dosing. Anti-TNF serum levels were stable throughout the 1-year period in both groups. Elective switching from infliximab to adalimumab is associated with loss of tolerance and loss of efficacy within 1 year. Adherence to the first anti-TNF agent is recommended.

• Octreotide for the treatment of diarrhoea in patients with ileal pouch anal anastomosis: a placebo-controlled crossover study.

  Authors: G Van Assche, M Ferrante, S Vermeire, M Noman, K Rans, L Van der Biest, F Penninckx, A Wolthuis, P Rutgeerts, A D'Hoore

  Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 09/2011; 14(4):e181-6.

  Aim  Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea andAim  Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. Method  Patients were randomized to octreotide subcutaneously (SC), 500 μg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. Results  Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, -4 to 0), Δplacebo: -1 (IQR, -1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. Conclusion  Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA.

• Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro.

  Authors: Anne Christine W Vos, Manon E Wildenberg, Ingrid Arijs, Marjolijn Duijvestein, Auke P Verhaar, Gert de Hertogh, Séverine Vermeire, Paul Rutgeerts, Gijs R van den Brink, Daniel W Hommes

  Inflammatory bowel diseases. 09/2011; 18(3):401-8.

  Regulatory macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψ(ind) ) by the anti-tumor necrosis factor (TNF)Regulatory macrophages play an important role in wound healing and gut homeostasis and have antiinflammatory properties. Induction of this cell type (Mψ(ind) ) by the anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab, has recently been shown in vitro. Also, the superiority of infliximab/azathioprine combination therapy over infliximab or azathioprine monotherapy has recently been established, but the mechanism behind this remains unclear. The aim of this study was to examine the induction of regulatory macrophages in patients with and without mucosal healing in response to infliximab. In addition, we studied the effect of infliximab/azathioprine combination treatment on the differentiation and function of regulatory macrophages. Inflammatory bowel disease (IBD) patients (n = 10) underwent endoscopy before and after first infliximab treatment. Immunohistochemical staining of CD68 and CD206 was performed in all patients. Mixed lymphocyte reactions (MLRs) were treated with infliximab, azathioprine, or both. Macrophage phenotype was evaluated by flow cytometry and inhibition of T-cell proliferation was measured in a secondary MLR containing macrophages and third-party lymphocytes. A significant induction of regulatory macrophages was observed in patients with mucosal healing after treatment with infliximab; this induction was absent in patients without mucosal healing. In addition, Mψ(ind) have the ability to induce wound healing in an in vitro model, further suggesting a key role for infliximab-induced macrophages in mucosal healing. Upon infliximab/azathioprine combination treatment, an increased number of regulatory macrophages was observed. These macrophages also displayed stronger immunosuppressive properties than macrophages induced by infliximab monotherapy. These data show that regulatory macrophages may be involved in mucosal healing and provide a rationale for the superiority of infliximab/azathioprine combination treatment observed in the clinic. (Inflamm Bowel Dis 2012;).

• Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy.

  Authors: Fabian Schnitzler, Herma Fidder, Marc Ferrante, Vera Ballet, Maja Noman, Gert Van Assche, Bernard Spitz, Ilse Hoffman, Kristel Van Steen, Séverine Vermeire, Paul Rutgeerts

  Inflammatory bowel diseases. 09/2011; 17(9):1846-54.

  Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/riskInfliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy. This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women. Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis. Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.

• Effect of oligofructose-enriched inulin (OF-IN) on bacterial composition and disease activity of patients with Crohn's disease: results from a double-blinded randomised controlled trial.

  Authors: Marie Joossens, Vicky De Preter, Vera Ballet, Kristin Verbeke, Paul Rutgeerts, Severine Vermeire

  Gut. 07/2011;