Crohn Disease: Hommes DW

Hommes DW, Oldenburg B, van Bodegraven AA, van Hogezand RA, de Jong DJ, Romberg-Camps MJ, van der Woude J, Dijkstra G, Anonymous00077. · Academic Medical Centre, Amsterdam, the Netherlands. · Neth J Med. · Pubmed #16929083 links to  free full text

Abstract: Infliximab is an accepted induction and maintenance treatment for patients with Crohn's disease. The effectiveness of infliximab has been demonstrated for both active luminal disease and for enterocutaneous fistulisation. In addition, infliximab can be administered for extraintestinal symptoms of Crohn's disease, such as pyoderma gangrenosum, uveitis and arthropathy. Maintenance treatment with infliximab is effective and is regarded as safe as long as the necessary safety measures are heeded. Infusion reactions occur in 3 to 17% of the patients and are associated with the formation of antibodies to infliximab. A reduction in infusion reactions is possible by the concurrent administration of steroids and the use of immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate). Furthermore, immunosuppressants increase the duration of the response to infliximab. For these reasons, the concomitant use of immunosuppressants with infliximab is recommended. Infections and most specifically tuberculosis need to be ruled out before infliximab is administered. Up to now, there are no indications for a connection between an increased risk for malignancies and treatment with infliximab.

Zelinkova Z, Stokkers P, Hommes DW. · No affiliation provided · Neth J Med. · Pubmed #16186636 links to  free full text

This publication has no abstract.

Noomen CG, Hommes DW, Fidder HH. · Department of Gastroenterology and Hepatology, Leiden University Medical Center, C4-12 Leiden, the Netherlands. · Best Pract Res Clin Gastroenterol. · Pubmed #19414149 No free full text.

Abstract: Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.

van der Woude CJ, Hommes DW. · Erasmus MC, Department of Gastroenterology and Hepatology, Rotterdam, The Netherlands. · Expert Opin Biol Ther. · Pubmed #17696821 No free full text.

Abstract: New insights into the underlying mechanism of Crohn's disease is enabling the development of new therapies. Even though the mechanisms of these drugs have been studied extensively, reliable indicators for implementation of new biologic drugs are still needed. This review presents biologics in Crohn's disease focusing on efficacy, steroid sparing, mucosal healing and safety, including immunogenicity.

de Ridder L, Benninga MA, Taminiau JA, Hommes DW, van Deventer SJ. · Department of Pediatric Gastroenterology, VU University Medical Centre, The Netherlands. · J Pediatr Gastroenterol Nutr. · Pubmed #17592358 No free full text.

Abstract: Infliximab is a chimeric monoclonal antibody (75% human, 25% murine) against tumor necrosis factor-alpha, a cytokine with a central role in the pathogenesis of inflammatory bowel disease. Large randomized controlled trials have shown the efficacy and safety of infliximab for the induction and maintenance of remission in adult patients with active Crohn disease (CD). In children and adolescents, mostly small, nonrandomized, non-placebo-controlled studies have supported the notion that infliximab is a potent drug in a population that does not respond to standard therapies. The safety of infliximab is of major concern, and the most frequent severe adverse events are related to severe infections and reactivation of tuberculosis. Non-life-threatening infusion reactions occur rather frequently and seem to be related to the formation of antibodies. The indications for infliximab treatment are therapy-resistant luminal CD (no efficacy or insufficient efficacy of conventional treatment) and therapy-resistant fistulas. An efficient remission induction strategy consists of 3 initial infliximab infusions at 0, 2, and 6 weeks in a dosage of 5 mg/kg to sustain remission. Patients needing maintenance therapy are subsequently treated with an infliximab infusion every 8 weeks. There are indications that the early stages of CD may be more susceptible to immunomodulation, and the natural history of CD may be altered by the introduction of infliximab early in the disease process instead of waiting until conventional therapy has failed. Major points of discussion are whether infliximab maintenance treatment should be episodic (on demand) or scheduled and when infliximab therapy can be discontinued.

Quaglietta L, te Velde A, Staiano A, Troncone R, Hommes DW. · Department of Pediatrics, University Federico II, Naples, Italy. · J Pediatr Gastroenterol Nutr. · Pubmed #17460484 No free full text.

Abstract: Crohn disease (CD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract. Its etiology remained obscure until recently, when, through an overwhelming body of research, the main theme of its origin became clear. CD develops in individuals who carry risk alleles for the disease that can cause a loss of physiological tolerance to commensal bacteria. As a consequence, immune responses develop that activate a whole range of immunocompetent cells, resulting in the secretion of proinflammatory mediators that ultimately cause mucosal breaks and the formation of ulceration, edema, and loss of proper function.

Polle SW, Wind J, Ubbink DT, Hommes DW, Gouma DJ, Bemelman WA. · Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. · Dig Surg. · Pubmed #17164582 No free full text.

Abstract: BACKGROUND: No consensus exists whether ileocolic resection for Crohn's disease (CD) should be carried out by a laparoscopic or open approach. A systematic review was conducted to assess the evidence for short-term advantages of laparoscopic compared to open resection for ileocolic CD. METHODS: The literature search was conducted over the period 01/1991 to 02/2006. Only randomized controlled trials (RCTs), clinical controlled trials and comparative studies comparing laparoscopic with open resection for ileocolic CD were included. A quality assessment was performed for all retrieved articles. The main outcome parameters were operating times, conversion rates, major and minor morbidity and hospital stays. RESULTS: 14 publications encompassing 729 patients were included - 2 were RCTs, 12 were non-RCTs of which 2 were case-matched studies. Although pooling data of operating times was statistically not possible, they were longer for the laparoscopic procedure in the individual studies ranging from 75 to 185 min. Conversions varied between 0 and 16.7%. Postoperative complications requiring reoperation or reported overall morbidity were not different (risk difference -0.01 and -0.05, respectively). Hospital stay after the laparoscopic procedure was 1.90 days shorter (95% CI: 0.83-2.97). CONCLUSION: There is evidence that laparoscopic ileocolic resection for CD is associated with shorter hospital stay compared to open ileocolic resection, while morbidity rates are equal and conversion rates are acceptable.

Braat H, Peppelenbosch MP, Hommes DW. · Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, NL-1105 AZ Amsterdam, The Netherlands. · Ann N Y Acad Sci. · Pubmed #17057196 No free full text.

Abstract: The immense microbiological load of the gastrointestinal tract poses a daunting challenge for the mucosal immune system: whereas it should tolerate the vast number of commensal bacteria, it should adequately attack pathogenic organisms. Millions of years of co-evolution have produced an intricate system in which interactions between the endogenous flora and mucosal immune system manage to perform this difficult balancing act. When components of this interaction are defective, for instance by mutation, inflammatory bowel disease may result. In the present review, we comprehensively discuss the mucosal immune system in the context of Crohn's disease (CD) and its genetic risk factors, describe the clinical management of the disease, and discuss how knowledge of the mucosal immune system may yield novel therapeutical avenues for dealing with this debilitating disease.

Derijks LJ, Gilissen LP, Hooymans PM, Hommes DW. · Department of Clinical Pharmacy, Máxima Medical Center, Veldhoven, The Netherlands. · Aliment Pharmacol Ther. · Pubmed #16918876 No free full text.

Abstract: BACKGROUND: In the past 10-20 years, knowledge of both thiopurine pharmacology and -pharmacogenetics has been extended dramatically and used to develop new strategies to improve efficacy and reduce toxicity. AIM: To review thiopurine efficacy, toxicity, pharmacology, pharmacogenetics, interactions in patients with inflammatory bowel disease. Special attention was paid to new strategies for optimization of pharmacotherapy. METHODS: To collect relevant scientific articles, a Pubmed search was performed from 1966 through January 2006 with the following key words (MeSH terms preferentially) in multiple combinations: 'azathioprine', '6-mercaptopurine', '6-MP', '6-thioguanine', '6-TG', 'thiopurine(s)', 'metabolites', 'level(s)', 'TDM', 'TMPT', 'ITPA', 'genotype(s)', 'phenotype(s)', 'inflammatory bowel disease', 'Crohn('s) disease', 'ulcerative colitis'. RESULTS: Strategies for optimization of pharmacotherapy include therapeutic drug monitoring of thiopurine metabolites, geno- or phenotyping crucial enzymes in thiopurine metabolism like thiopurine S-methyltransferase and inosine triphosphate pyrophosphatase, and the use of thioguanine as such. CONCLUSIONS: Thiopurine S-methyltransferase genotyping and therapeutic drug monitoring are useful instruments for individualizing thiopurine pharmacotherapy of inflammatory bowel disease. Inosine triphosphate pyrophosphatase genotyping may be helpful in case of unexplainable myelotoxicity. In case of azathioprine- or mercaptopurine-intolerance, thioguanine seems a promising alternative. However, more knowledge needs to be gathered about its potential hepatotoxicity.

van den Brande J, Hommes DW, Peppelenbosch MP. · Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. · J Rheumatol Suppl. · Pubmed #15742461 No free full text.

Abstract: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract of unknown origin. Therapies include immune modulating agents, biological therapies, and surgery. The activity and efficacy of the anti-tumor necrosis factor (TNF) therapies infliximab and etanercept have proved to be different: infliximab is effective to induce and maintain remission in refractory CD, while etanercept is not. This brief review considers the question of whether this disparity can be explained by the different structure of the proteins, their different binding affinities, or the subsequent effects on T lymphocytes.

Hommes DW, Sterringa G, van Deventer SJ, Tytgat GN, Weel J. · Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands. · Inflamm Bowel Dis. · Pubmed #15290919 No free full text.

Abstract: During recent years, a clear association between complicated courses of ulcerative colitis and the presence of cytomegalovirus (CMV) has been established. The exact pathogenic role of CMV in these patients remains unclear despite a great number of published reports. Therefore, we undertook a systematic review to appraise critically all available evidence in the literature on the role of CMV during inflammatory bowel disease. We identified and analyzed more than 30 case reports and 9 case series. Based on these results, we propose a model for viral replication during inflammation and provide recommendations for future research.

Hommes DW, van Deventer SJ. · Department of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. · Neth J Med. · Pubmed #12852717 links to  free full text

Abstract: Infliximab has become a valuable addition to the therapeutic arsenal for Crohn's disease. Although the rate of adverse events was relatively low in the premarketing trials, several investigators have recently reported experience in large groups of patients. This has shed more light on safety aspects of infliximab therapy, which should change the approach towards patients prior to infliximab infusion. This review discusses some immunological aspects that are relevant for infliximab therapy and provides guidelines for daily practice.

Hommes DW, van Deventer SJ. · Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands. · Curr Opin Clin Nutr Metab Care. · Pubmed #10871234 No free full text.

Abstract: Crohn's disease is a chronic inflammatory bowel disease of unknown origin. The understanding of the pathogenesis of inflammatory bowel diseases has been greatly advanced by manipulations of the immune system in mice using targeted disruptions of genes that encode specific anti- and proinflammatory cytokines, as well as T-cell subsets. The outcome of these experiments has implicated CD4+ lymphocytes and certain proinflammatory cytokines (tumour necrosis factor-alpha, interleukin-12) as playing a central role in the pathogenesis of mucosal inflammation in Crohn's disease. The present review focuses on these recent important immunological observations, and discusses several newly developed therapeutic strategies that are based either on blocking proinflammatory cytokines or on the administration of anti-inflammatory cytokines.

Van den Brande JM, Koehler TC, Zelinkova Z, Bennink RJ, te Velde AA, ten Cate FJ, van Deventer SJ, Peppelenbosch MP, Hommes DW. · Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Gut. · Pubmed #17082252 No free full text.

Abstract: BACKGROUND: The human anti-tumour necrosis factor (TNF) antibody infliximab binds to the membrane TNF and subsequently induces apoptosis of activated lamina propria T lymphocytes in patients with Crohn's disease in vitro. AIM: To test whether the ability of rapid anti-TNF-induced apoptosis in the gut predicts the efficacy of anti-TNF treatment in inflammatory bowel disease. METHODS: (99m)Technetium-annexin V single-photon emission computer tomography (SPECT) was performed in 2 models of murine experimental colitis and in 14 patients with active Crohn's disease as assessed by the Crohńs Disease Activity Index (CDAI) to study the effect of anti-TNF treatment on apoptosis in the intestine during active colitis. Disease activity was evaluated 2 weeks after infliximab infusion using the CDAI (definition response: drop of >100 points). RESULTS: Colonic uptake of (99m)Tc-annexin V significantly increased in 2,4,6-trinitrobenzene sulphonate-induced colitis as well as in transfer colitis on administration of anti-TNF antibodies compared with a control antibody as determined with dedicated animal pinhole SPECT. In addition, uptake of (99m)Tc-annexin V significantly increased in patients with active Crohn's disease responding to infliximab treatment. Colonic (99m)Tc-annexin V uptake ratio (mean (SEM)) increased from 0.24 (0.03) to 0.41(0.07) (p<0.01), 24 h after infliximab infusion (5 mg/kg). A mean increase of 98.7% in colonic uptake of (99m)Tc-annexin V could be detected in 10 of the 14 responding patients (CDAI >100 points at week 2) compared with 15.2% in non-responding patients (p = 0.03). Analysis of the mucosal biopsy specimens identified lamina propria T cells as target cells undergoing apoptosis. CONCLUSIONS: These in vivo observations support the notion that colonic uptake of (99m)Tc-annexin V correlates with clinical benefit of anti-TNF treatment and might be predictive of therapeutic success.

Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L. · Department of Experimental Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands. · Clin Gastroenterol Hepatol. · Pubmed #16716759 No free full text.

Abstract: BACKGROUND & AIMS: The use of living, genetically modified bacteria is an effective approach for topical delivery of immunomodulatory proteins. This strategy circumvents systemic side effects and allows long-term treatment of chronic diseases. However, treatment of patients with a living, genetically modified bacterium raises questions about the safety for human subjects per se and the biologic containment of the transgene. METHODS: We treated Crohn's disease patients with genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human interleukin-10. Ten patients were included in a placebo-uncontrolled trial. Patients were assessed daily for the presence of potential adverse effects by direct questioning and assessment of disease activity. We evaluated the presence and kinetics of LL-Thy12 release in the stool of patients by conventional culturing and quantitative polymerase chain reaction of LL-Thy12 gene sequences. RESULTS: Treatment with LL-Thy12 was safe because only minor adverse events were present, and a decrease in disease activity was observed. Moreover, fecally recovered LL-Thy12 bacteria were dependent on thymidine for growth and interleukin-10 production, indicating that the containment strategy was effective. CONCLUSIONS: Here we show that the use of genetically modified bacteria for mucosal delivery of proteins is a feasible strategy in human beings. This novel strategy avoids systemic side effects and is biologically contained; therefore it is suitable as maintenance treatment for chronic intestinal disease.

Hommes DW, Mikhajlova TL, Stoinov S, Stimac D, Vucelic B, Lonovics J, Zákuciová M, D'Haens G, Van Assche G, Ba S, Lee S, Pearce T. · Department Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, the Netherlands. · Gut. · Pubmed #16507585 No free full text.

Abstract: INTRODUCTION: Interferon gamma is a potent proinflammatory cytokine implicated in the inflammation of Crohn's disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe CD. METHODS: A total of 133 patients with Crohn's disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI < or =150). RESULTS: There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups after a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p = 0.02) and 67% (21/31, p = 0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated. CONCLUSION: Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo.

Hommes DW, van de Heisteeg BH, van der Spek M, Bartelsman JF, van Deventer SJ. · Department of Gastroenterology and Hepatology, Academic Medical Center, C2-116, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Inflamm Bowel Dis. · Pubmed #11854604 No free full text.

Abstract: The aim of this study was to report the 1-year clinical experience with infliximab treatment for Crohn's disease (CD) in the Netherlands. All 73 CD patients receiving infliximab infusions were prospectively followed during 1 year after the drugs' registration in the Netherlands. Clinical response and adverse events were assessed for both active luminal disease as well as fistulous disease. A total of 212 infusions were administered to 57 patients with active luminal CD and 16 patients with fistulous CD. The mean duration between infusions was 60 days. In 17% of patients, adverse events were recorded, of which one was serious. The response rate was 81% in active luminal CD and 87% in fistulous disease. Response rates were highest in patients receiving concomitant methotrexate as maintenance therapy. Steroids could successfully be tapered off in 73% of responding luminal CD patients and 100% of responding CD patients with fistulae. Eleven patients showed a loss of response to continuous infliximab readministration. Our clinical experience with infliximab for active luminal and fistulous CD showed that the administration is safe, effective, and has high steroid-sparing efficacy. Higher response rates were seen with methotrexate as concomitant medication.

Weersma RK, Stokkers PC, van Bodegraven AA, van Hogezand RA, Verspaget HW, de Jong DJ, van der Woude CJ, Oldenburg B, Linskens RK, Festen EA, van der Steege G, Hommes DW, Crusius JB, Wijmenga C, Nolte IM, Dijkstra G, Anonymous00042. · Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands. · Gut. · Pubmed #18824555 No free full text.

Abstract: BACKGROUND: Crohn's disease and ulcerative colitis have a complex genetic background. We assessed the risk for both the development and severity of the disease by combining information from genetic variants associated with inflammatory bowel disease (IBD). METHODS: We studied 2804 patients (1684 with Crohn's disease and 1120 with ulcerative colitis) and 1350 controls from seven university hospitals. Details of the phenotype were available for 1600 patients with Crohn's disease and for 800 with ulcerative colitis. Genetic association for disease susceptibility was tested for the nucleotide-binding and oligomerisation domain 2 gene (NOD2), the IBD5 locus, the Drosophila discs large homologue 5 and autophagy-related 16-like 1 genes (DLG5 and ATG16L1) and the interleukin 23 receptor gene (IL23R). Interaction analysis was performed for Crohn's disease using the most associated single nucleotide polymorphism (SNP) for each locus. Odds ratios were calculated in an ordinal regression analysis with the number of risk alleles as an independent variable to analyse disease development and severity. RESULTS: Association with Crohn's disease was confirmed for NOD2, IBD5, DLG5, ATG16L1 and IL23R. Patients with Crohn's disease carry more risk alleles than controls (p = 3.85 x 10(-22)). Individuals carrying an increasing number of risk alleles have an increasing risk for Crohn's disease, consistent with an independent effects multiplicative model (trend analysis p = 4.25 x 10(-23)). Patients with Crohn's disease with a more severe disease course, operations or an age of onset below 40 years have more risk alleles compared to non-stricturing, non-penetrating behaviour (p = 0.0008), no operations (p = 0.02) or age of onset above 40 years (p = 0.028). CONCLUSION: Crohn's disease is a multigenic disorder. An increase in the number of risk alleles is associated with an increased risk for the development of Crohn's disease and with a more severe disease course. Combining information from the known common risk polymorphisms may enable clinicians to predict the course of Crohn's disease.

Meijer MJ, Mieremet-Ooms MA, Sier CF, van Hogezand RA, Lamers CB, Hommes DW, Verspaget HW. · LUMC, Department of Gastroenterology-Hepatology, Leiden, The Netherlands. · Inflamm Bowel Dis. · Pubmed #18634035 No free full text.

Abstract: BACKGROUND: Recurrence of disease after surgically induced remission constitutes a major and largely unpredictable problem in Crohn's disease (CD). Matrix metalloproteinases (MMP) and the tissue inhibitors of metalloproteinases (TIMP) are involved in the (etio)pathogenesis of CD and may thereby also affect postsurgical outcome. We studied the predictive value of 1) allelic composition at MMP, TIMP, and TNF-alpha single nucleotide polymorphism loci, and 2) MMP and TIMP intestinal protein levels relative to important clinical variables for recurrence of CD after resection of diseased bowel. METHODS: From 87 CD patients with a full medical record, surgically resected tissue was homogenized and analyzed for single nucleotide polymorphism (SNP) genotype and MMP-TIMP protein levels. The prognostic value of these parameters was determined using the uni- and multivariate Cox proportional hazards analyses. RESULTS: The T allele at TIMP-1 SNP +372 T/C was found to be associated with an increased risk for surgical recurrence. Higher levels of TIMP-1, TIMP-2, and MMP-9 in noninflamed CD tissue, but not in inflamed tissue, and negative smoking status independently protected against diagnostic and/or surgical recurrence. CONCLUSIONS: The TIMP-1 SNP +372 T allele with an increased risk of recurrence is in line with our previous results demonstrating increased CD susceptibility and low TIMP-1 protein expression associated with this allele. High TIMP and MMP-9 levels in noninflamed tissue are predictive of a favorable disease recurrence in CD. The contribution of MMP-9 and TIMPs to disease recurrence appears not to be mediated by smoking status, since no correlation with this parameter could be demonstrated.

Eshuis EJ, Polle SW, Slors JF, Hommes DW, Sprangers MA, Gouma DJ, Bemelman WA. · Department of Surgery, Academic Medical Centre, G4-146.1, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands. · Dis Colon Rectum. · Pubmed #18266036 links to  free full text

Abstract: PURPOSE: Several studies have compared conventional open ileocolic resection with a laparoscopic-assisted approach. However, long-term outcome after laparoscopic-assisted ileocolic resection remains to be determined. This study was designed to compare long-term results of surgical recurrence, quality of life, body image, and cosmesis in patients who underwent laparoscopic-assisted or open ileocolic resection for Crohn's disease. METHODS: Seventy-eight consecutive patients who underwent ileocolic resection during the period 1995 to 1998 were analyzed; 48 underwent a conventional open approach in the Academic Medical Centre (Amsterdam, The Netherlands) and 30 underwent a laparoscopic-assisted approach in the Leiden University Medical Centre (Leiden, The Netherlands). Primary outcome parameters were reoperation and readmission rate. Secondary outcome parameters were quality of life, body image, and cosmesis. RESULTS: The two groups were comparable for characteristics of sex, age, and immunosuppressive therapy. Seventy-one patients had a complete follow-up of median 8.5 years. Resection for recurrent Crohn's disease was performed in 6 of 27 (22 percent) and 10 of 44 (23 percent) patients in the laparoscopic and open groups, respectively. Reoperations for incisional hernia were only performed after conventional open ileocolic resection (3/44 = 6.8 percent). Quality of life and body image were comparable, but cosmesis scores were significantly higher in the laparoscopic group. CONCLUSIONS: Despite small numbers, we found that surgical recurrence and quality of life after laparoscopic-assisted and open ileocolic resection were comparable. Incisional hernias occurred only after open ileocolic resection, and laparoscopic-assisted ileocolic resection resulted in a significantly better cosmesis.

Zelinkova Z, van Beelen AJ, de Kort F, Moerland PD, Ver Loren van Themaat E, te Velde AA, van Deventer SJ, de Jong EC, Hommes DW. · Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands. · Inflamm Bowel Dis. · Pubmed #17941075 links to  free full text

Abstract: BACKGROUND: Mutations in the gene encoding the nucleotide-binding oligomerization domain 2 (NOD2) protein are associated with Crohn's disease (CD), but the mechanism underlying this is not completely understood. To study the mechanism of CD resulting from NOD2 mutations, we analyzed NOD2-dependent whole-genome expression profiles of patient-derived antigen-presenting cells. PATIENTS AND METHODS: Monocyte-derived dendritic cells (DCs) from CD carriers of double-dose NOD2 mutations, wild-type CD patients, and wild-type healthy volunteers were stimulated with the NOD2 ligand muramyl dipeptide. Whole-genome microarrays were used to assess the differential gene expression. The clustering of significantly changed genes was analyzed by online gene ontology mapping software. RESULTS: In the DCs from the wild-type CD patient group, 683 genes were significantly changed, with most of the genes clustering in the pathways of inflammatory response. In addition, a significant number of genes clustered in the apoptosis regulation-related pathway. In the DCs from the healthy volunteer group, only 50 genes were significantly changed, predominantly those belonging to the response to pathogen pathway. Analysis of differentially expressed gene ontology pathways in the DCs from the NOD2 mutant CD patient group showed that the transcription of pathogen response genes was absent. In this group, 298 genes were significantly changed, predominantly clustering in the negative apoptosis regulation and cell organization and biogenesis pathways. CONCLUSIONS: Our results suggest that NOD2 mutations may result in perpetuation of mucosal inflammation through insufficient pathogen elimination. Further, these observations implicate a possible role of defective regulation of dendritic cell apoptosis in CD pathogenesis.

van Beelen AJ, Zelinkova Z, Taanman-Kueter EW, Muller FJ, Hommes DW, Zaat SA, Kapsenberg ML, de Jong EC. · Department of Cell Biology and Histology, Academic Medical Centre of the University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. · Immunity. · Pubmed #17919942 No free full text.

Abstract: How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells. The role of NOD2 in this IL-23-IL-1-IL-17 axis could be confirmed in NOD2-deficient DCs, such as DCs from selected Crohn's disease patients. Thus, antibacterial Th17-mediated immunity in humans is orchestrated by DCs upon sensing bacterial NOD2-ligand MDP.

van Leuven SI, Hezemans R, Levels JH, Snoek S, Stokkers PC, Hovingh GK, Kastelein JJ, Stroes ES, de Groot E, Hommes DW. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · J Lipid Res. · Pubmed #17890779 links to  free full text

Abstract: A chronic inflammatory state is a risk factor for accelerated atherogenesis. The aim of our study was to explore whether Crohn's disease (CD), characterized by recurrent inflammatory episodes, is also associated with accelerated atherogenesis. In 60 CD patients and 122 matched controls, carotid intima media thickness (IMT), a validated marker for the burden and progression of atherosclerosis, was assessed ultrasonographically. Additional subgroup analyses, including plasma levels of acute phase reactants and HDL protein profiling, were performed in 11 consecutive patients with CD in remission, 10 patients with active CD, and 15 healthy controls. Carotid IMT in patients with CD was increased compared with healthy volunteers: 0.71 (0.17) versus 0.59 (0.14) mm (P < 0.0001), respectively. In the subgroup analysis, HDL levels in controls and patients in remission were identical [(1.45 (0.48) and 1.40 (0.46) mmol/l; P = 0.797], whereas HDL during exacerbation was profoundly reduced: 1.02 (0.33) (P = 0.022). HDL from patients with active CD and CD patients in remission was characterized by a reduced ability to attenuate oxidation compared with controls (P = 0.008 and P = 0.024 respectively). Patients with CD have increased IMT compared with matched controls, indicative of accelerated atherogenesis. The changes during CD exacerbation in terms of HDL concentration and composition imply a role for impaired HDL protection in these patients.

Meijer MJ, Mieremet-Ooms MA, van der Zon AM, van Duijn W, van Hogezand RA, Sier CF, Hommes DW, Lamers CB, Verspaget HW. · Department of Gastroenterology-Hepatology, C4P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. · Dig Liver Dis. · Pubmed #17602907 No free full text.

Abstract: BACKGROUND AND OBJECTIVE: Matrix metalloproteinases are associated with matrix turnover in both physiological and pathological conditions. We postulate an association between aberrant matrix metalloproteinases proteolytic activity and the intestinal tissue destruction, seen in patients with Crohn's disease and/or ulcerative colitis. MATERIALS AND METHODS: Surgically resected inflamed and non-inflamed ileum and colon with/without extensive fibrosis from 122 Crohn's disease, 20 ulcerative colitis and 62 control patients were homogenized. Protein levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured by enzyme-linked immunosorbent assays (ELISA), while matrix metalloproteinases and myeloperoxidase activity were measured by specific activity assays. RESULTS: Expression of total levels of matrix metalloproteinases-1, -2, -3 and -9 relative to tissue inhibitor of metalloproteinases-1 and -2 was increased in inflamed inflammatory bowel disease compared to non-inflamed inflammatory bowel disease and control intestinal mucosa. Also, net matrix metalloproteinases-1, -2, -3 and -9 activity in inflamed inflammatory bowel disease was increased, with similar expression profiles in Crohn's disease and ulcerative colitis. Within inflamed inflammatory bowel disease, a close correlation of matrix metalloproteinases with myeloperoxidase was observed. The expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases was similar in inflamed Crohn's disease tissue with or without extensive fibrosis and not related to fistulizing disease. CONCLUSIONS: We have shown increased net matrix metalloproteinases activity in intestinal inflammatory bowel disease tissue, likely to contribute to the tissue damage and remodelling seen in inflammatory bowel disease.

Meijer MJ, Mieremet-Ooms MA, van Hogezand RA, Lamers CB, Hommes DW, Verspaget HW. · Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. · World J Gastroenterol. · Pubmed #17589947 links to  free full text

Abstract: AIM: To study the (functional) relevance of single nucleotide polymorphisms (SNPs) in genes encoding matrix metalloproteinases (MMP)-1, -2, -3, -9, tissue inhibitors of metalloproteinases (TIMP)-1, -2 and tumor necrosis factor (TNF)-alpha in the etiopathogenesis of inflammatory bowel diseases (IBD), that may enhance susceptibility and/or disease severity. METHODS: Genomic DNA from 134 Crohn' s disease (CD), 111 ulcerative colitis (UC) patients and 248 control subjects was isolated from resected intestinal tissue or blood. Allelic composition at SNP loci was determined by PCR-RFLP or tetra primer ARMS PCR. RESULTS: The TIMP-1 genotype TT in women and T in men at SNP +372 T/C was found to increase CD susceptibility (39% vs 23.8%, P = 0.018 and 67.9% vs 51.6%, P = 0.055, respectively), while women with this genotype were less prone to development of fistulae during follow-up (41.4% vs 68.3%, P = 0.025). Male IBD or CD patients carrying the TIMP-1 +372 T-allele expressed lower levels of TIMP-1 in surgically resected macroscopically inflamed tissue (0.065 < P < 0.01). The 5T5T genotype at MMP-3 SNP -1613 5T/6T increased the chance of stenotic complications in CD during follow-up (91.2% vs 71.8%, P = 0.022) but seemed to protect against colonic involvement of this disease at first endoscopic/radiologic examination (35.3% vs 59.5%, P = 0.017). CONCLUSION: Allelic composition at the examined SNPs in genes coding for TIMP-1 and MMP-3 affect CD susceptibility and/or phenotype, i.e., fistulizing disease, stricture pathogenesis and first disease localisation. These findings reinforce the important role of these proteins in IBD.