Ulcerative Colitis: Kuipers EJ

van der Linde K, Boor PP, Houwing-Duistermaat JJ, Crusius BJ, Wilson PJ, Kuipers EJ, de Rooij FW. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. · Eur J Gastroenterol Hepatol. · Pubmed #17489054 No free full text.

Abstract: OBJECTIVES: The single nucleotide variations R702W, G908R and L1007fs in the CARD15 gene have been found to be independently associated with Crohn's disease. The aim of this study was to evaluate the prevalence of these gene variations in Dutch multiple inflammatory bowel disease-affected families, in sporadic inflammatory bowel disease patients and in healthy controls. METHODS: Dutch Caucasians from multiple inflammatory bowel disease-affected families were recruited, including 78 probands with Crohn's disease, 34 probands with ulcerative colitis and 71 inflammatory bowel disease-affected and 100 non-affected family members. In addition, 45 sporadic inflammatory bowel disease patients (36 Crohn's disease and nine ulcerative colitis), and 77 unrelated healthy controls were included. Genomic DNA was isolated to determine CARD15 R702W, G908R and L1007fs. For these mutations, we evaluated disease susceptibility and correlation with inflammatory bowel disease phenotypes. RESULTS: In all included unrelated inflammatory bowel disease-affected probands, the R702W, G908R and L1007fs allele frequencies were 8.8, 6.1 and 11.0%, respectively, for Crohn's disease, and 4.7, 0 and 2.3% for ulcerative colitis. In controls, the allele frequencies were 5.9, 0.7 and 1.9%, respectively. G908R and L1007fs were associated with Crohn's disease (P=0.006 and 0.001, respectively). Compound heterozygotes for any of the three mutations were 11 (9.2%) in Crohn's disease patients, but none in ulcerative colitis patients nor controls. Carriage of CARD15 mutations was not associated with familial disease (P>or=0.38). Inflammatory bowel disease-affected family members of Crohn's disease probands carrying L1007fs, however, were carriers significantly more often than expected (P<0.001). In Crohn's disease patients, a significant trend was found between carriage of at least one CARD15 mutation and between carriage of L1007fs and behaviour of disease, including more carriers with stricturing and even more with penetrating disease (P=0.006 and 0.017, respectively). CONCLUSION: In the Dutch population, CARD15 G908R and L1007fs are associated with Crohn's disease. Although no difference was found between sporadic and familial cases, in L1007fs-positive multiple affected families the inflammatory bowel disease-affected relatives are more likely than expected to carry this mutation. In Crohn's disease, carriage of at least one CARD15 mutation is associated with a more complicated disease behaviour.

van Dieren JM, van der Woude CJ, Kuipers EJ, Escher JC, Samsom JN, Blumberg RS, Nieuwenhuis EE. · Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, and Department of Pediatric Gastroenterology, Sophia Children's Hospital, Rotterdam, the Netherlands. · Inflamm Bowel Dis. · Pubmed #17476670 links to  free full text

Abstract: Natural killer T (NKT) cells are a subset of lymphocytes that express cell surface molecules of both conventional T cells and natural killer cells and share the features of both innate and adaptive immune cells. NKT cells have been proposed to make both protective and pathogenic contributions to inflammatory bowel diseases (IBD). On the one hand, recent studies have shown that these cells are involved in the maintenance of mucosal homeostasis. On the other, NKT cells were shown to play a pathogenic role in human ulcerative colitis. Similar contrasting data have been generated in murine models of IBD. Whether the apparent differences in NKT response patterns depend on variations in NKT antigens and/or on the presence of specific subsets of mucosal NKT cells remains to be elucidated. In this article we review the current literature on intestinal NKT cells and their roles in IBD pathogenesis. Specifically, the nomenclature, NKT antigens, and immune mechanisms of NKT cells within the intestinal mucosa are discussed.

van Dieren JM, van Bodegraven AA, Kuipers EJ, Bakker EN, Poen AC, van Dekken H, Nieuwenhuis EE, van der Woude CJ. · Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. · Inflamm Bowel Dis. · Pubmed #18825773 No free full text.

Abstract: BACKGROUND: Tacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and safety of tacrolimus for distal colitis. METHODS: Patients with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2-4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment. RESULTS: Nineteen patients with left-sided colitis (n = 7) or proctitis (n = 12) were treated. Two patients with left-sided colitis had Crohn's disease (CD), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group. CONCLUSIONS: This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

Baars JE, Siegel CA, Kuipers EJ, van der Woude CJ. · Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands. · Digestion. · Pubmed #19246918 No free full text.

Abstract: BACKGROUND/AIM: We hypothesized that limited information is given to patients on the risks and benefits of individual therapy, and feedback is lacking to verify if patients correctly interpreted the given information. We assessed the perspectives of patients with inflammatory bowel disease (IBD) concerning the treatment-associated risks/benefits of infliximab. METHODS: Patients were asked to complete a survey regarding the benefits and risks of infliximab. Results are reported as descriptive statistics. Comparisons between groups were analyzed using independent t tests and the Kruskal-Wallis test. RESULTS: In total, 152 IBD patients completed the questionnaire. Fifty-seven percent (78/138) estimated the 1-year remission rate from infliximab to be >50%. Seventy-one percent (104/146) indicated they would not take a drug with risks reflecting those estimated for infliximab if the 1-year remission rate was <75%. Crohn's disease patients and those recalling a discussion regarding the risks/benefits of infliximab treatment had higher estimates of the 1-year remission rate with infliximab than ulcerative colitis patients (p = 0.03) and patients who did not recall previous information (p = 0.03). Perceptions were independent of age and disease duration. CONCLUSION: IBD patients misperceive the risks and benefits of infliximab. The majority of patients would not accept treatment-related risks if the 1-year remission rate was <75%. Counseling on treatment-associated risks and benefits should be ameliorated.

de Lau LM, de Vries JM, van der Woude CJ, Kuipers EJ, Siepman DA, Sillevis Smitt PA, Hintzen RQ. · Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands. · Inflamm Bowel Dis. · Pubmed #19023898 No free full text.

Abstract: BACKGROUND: Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation. METHODS: Two cases of patients diagnosed with inflammatory bowel disease developing neurological symptoms with corresponding lesions in the white matter of the central nervous system led us to search a neurological database with clinical and radiological data for similar cases. RESULTS: We identified five patients who presented with acute neurological deficits preceding or following a diagnosis of inflammatory bowel disease with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infetcion, coagulation disorders, or vasculitis. CONCLUSIONS: These cases, together with previous reports, suggest that white matter lesions may be another extraintestinal manifestation of inflammatory bowel disease.

van der Linde K, Boor PP, Mejissen MA, Sandkuijl LA, Houwing-Duistermaat JJ, Kuipers EJ, Wilson JH, de Rooij FW. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. · Hepatogastroenterology. · Pubmed #17708278 No free full text.

Abstract: BACKGROUND/AIMS: The pathogenesis of inflammatory bowel disease is complex, multifactorial, and involves genetic predisposition. This predisposition is likely to include various chromosomal loci, but simple Mendelian inheritance cannot be excluded in a subset of families with inflammatory bowel disease. METHODOLOGY: We evaluated allele-sharing in 17 sib-pairs with inflammatory bowel disease as an approach to select candidate genes for further studies in individual families. It was determined whether each sib-pair had inherited the same alleles for interleukin-2, interleukin-2 receptor beta, interleukin-4, interleukin-4 receptor, interleukin-10, interleukin-10 receptor, tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 and 2. RESULTS: The results were very different per individual family. The estimated probability of sharing both alleles identical-by-descent at interleukin-4 receptor, interleukin-10, interleukin-10 receptor, and tumor necrosis factor alpha were 50%, 39%, 40%, and 33% respectively. The LOD score was significant for interleukin-4 receptor (p = 0.04). CONCLUSIONS: In this small group of sib-pairs with inflammatory bowel disease a modestly increased allele-sharing was found for some inflammatory related genes. Different results per family may suggest genetic heterogeneity. This method can be useful as a first step to further evaluation of specific candidate genes which may play a pathogenetic role in individual families.

van Dekken H, Wink JC, Vissers KJ, Franken PF, Ruud Schouten W, J Hop WC, Kuipers EJ, Fodde R, Janneke van der Woude C. · Department of Pathology, Erasmus Medical Center, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands. · Acta Histochem. · Pubmed #17445872 No free full text.

Abstract: Long-standing ulcerative colitis (UC) has been associated with a high risk of developing colonic adenocarcinoma. Importantly, both low- and high-grade dysplasia are strongly related to the presence or development of malignancy. The canonical Wnt/beta-catenin signaling pathway is of crucial importance in cancer development and progression, but its role in UC-related carcinogenesis remains to be determined. We evaluated the immunolabeling patterns of beta-catenin, as well as the products of Wnt-associated cancer genes E-cadherin, cyclin D1 and c-myc, along the dysplasia-carcinoma pathway in UC. For this purpose, immunohistochemistry (IHC) was performed on 18 adenocarcinomas and 17 dysplasias, derived from 21 patients. We found that intracellular beta-catenin accumulation, the hallmark of Wnt signaling activation, is observed in dysplasia, together with enhanced labeling of nuclear protein cyclin D1 and reduction of membranous labeling of E-cadherin. c-myc displayed moderate immunolabeling in the (pre)malignant lesions. Thus, the Wnt pathway is activated in early stages of malignant progression in UC. Furthermore, upregulation of the oncogene cyclin D1 and downregulation of tumor suppressor E-cadherin also occurs in the (pre)neoplastic state. This may contribute to the high potential for malignant degeneration of dysplasia in UC-related colitis.

van der Woude CJ, van Dekken H, Kuipers EJ. · Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands. · Endoscopy. · Pubmed #17440848 No free full text.

This publication has no abstract.

van Dieren JM, Wink JC, Vissers KJ, van Marion R, Hoogmans MM, Dinjens WN, Schouten WR, Tanke HJ, Szuhai K, Kuipers EJ, van der Woude CJ, van Dekken H. · Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands. · Diagn Mol Pathol. · Pubmed #17122649 No free full text.

Abstract: Longstanding ulcerative colitis (UC) is associated with a high risk of developing UC-related colonic adenocarcinoma (UCC). These carcinomas originate from nonadenomatous dysplastic regions referred to as dysplasia associated lesion or mass (DALM). We evaluated chromosomal and microsatellite instability (MSI) in 21 DALM/UCCs. Chromosomal instability was determined by high-resolution array comparative genomic hybridization with a 3500-element BAC-PAC array. MSI was assessed with markers BAT25 and BAT26 and by immunohistochemical analysis of mismatch repair genes. Comparative genomic hybridization revealed frequent losses of array clones (>20% of tumors) at chromosome arms 4p, 5q, and 18q, frequent gains of array clones (>20% of tumors) were found at 1q, 5p, 6p, 7p, 7q, 8p, 8q, 11p, 11q, 12q, 14q, 17q, 19q, 20p, and 20q. The pattern of alterations is dominated by gains on 5p and 20q with loss of 4p, all of which were already present in a patient with carcinoma in situ. Immunohistochemical analysis of mismatch repair genes MLH1, PMS2, MSH2, and MSH6 showed negative immunostaining in 1 neoplasm (5%). MSI of BAT25 and BAT26 was seen in 3 tumors (14%) including the neoplasm with aberrant immunostaining. In conclusion, we constructed a genomic profile of DALM/UCC including several novel genetic alterations. Further, we found a low percentage of MSI. Thus, DALM/UCCs display profound chromosomal instability, but this is not associated with concurrent MSI.

van Dekken H, Wink JC, Vissers KJ, van Marion R, Franken PF, Hoogmans MM, Dinjens WN, Schouten WR, Kuipers EJ, van der Woude CJ. · Department of Pathology, Erasmus Medical Center, Josephine Nefkens Institute, Dr. Molewaterplein 50, 3015GE Rotterdam, The Netherlands. · Virchows Arch. · Pubmed #17091253 No free full text.

Abstract: Long-standing ulcerative colitis is associated with an elevated risk of developing colonic adenocarcinoma. A very limited group of patients present with multiple synchronous cancers. This could be due to either a multifocal presentation of the same neoplastic clone or different tumors arising in a large area of polyclonal dysplastic colonic mucosa ("field cancerization"). Here, we describe a patient with long-standing colitis and three different tumors in the rectosigmoid part of the large bowel. Clonal evaluation of the lesions was performed by array-based comparative genomic hybridization. These three neoplasms showed a comparable pattern of genomic alterations characterized by gains of chromosomes 12, 13, and 20. Noteworthy, dysplastic mucosa distal to the three cancers displayed a completely different pattern of genomic changes indicating that different cell lineages were present. In addition, all three carcinomas were microsatellite stable and revealed identical immunoprofiles for several cancer-associated genes. We conclude that these three multifocal tumors must have originated from the same preneoplastic lineage.

Gosselink MP, West RL, Kuipers EJ, Hansen BE, Schouten WR. · Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands. · Dis Colon Rectum. · Pubmed #15981069 No free full text.

Abstract: PURPOSE: The aim of the present study was to assess the integrity of the anal sphincters after handsewn pouch-anal anastomosis performed with the help of a Scott retractor. For this purpose the anal sphincters were visualized with three-dimensional endoanal ultrasonography. METHODS: Patients undergoing a colonic pouch-anal anastomosis or an ileal pouch-anal anastomosis were included. Before and six months after the procedure, the length and volume of both sphincters were assessed with three-dimensional endoanal ultrasonography, and anal manometry was performed. Continence scores were determined using the Fecal Incontinence Severity Index (FISI). RESULTS: Fifteen patients with a colonic pouch and 13 patients with an ileal pouch were examined. Six months after the procedure, three-dimensional endoanal ultrasonography showed significant alterations of the internal anal sphincter in eight patients with a colonic pouch-anal anastomosis (53 percent) and in eight patients with an ileal pouch-anal anastomosis (62 percent). These alterations were characterized by asymmetry or thinning. No defects were seen in the colonic pouch group, but, in two patients with an ileal pouch, a small defect in the internal anal sphincter was found. A decrease in internal anal sphincter volume was seen only in patients with a colonic pouch-anal anastomosis (P = 0.009). In both groups the length of the internal anal sphincter and the length, thickness, and volume of the external anal sphincter remained the same. After the procedure a reduction of maximum anal resting pressure was found in both groups (colonic pouch: P < 0.001, ileal pouch: P = 0.001). Maximum anal squeeze pressure was reduced in only patients with an ileal pouch-anal anastomosis (P = 0.006). The observed alterations of the internal anal sphincter and the manometric findings showed no correlation with the postoperative Fecal Incontinence Severity Index scores. CONCLUSION: Handsewn pouch-anal anastomosis, performed with the help of a Scott retractor, only rarely leads to internal anal sphincter defects, but three-dimensional endoanal ultrasonography shows alterations of the internal anal sphincter in 57 percent of the patients. No correlation was observed between these alterations and the functional outcome.

Grool TA, Kuipers EJ. · Erasmus Universitair Medisch Centrum, afd. Maag-, Darm- en Leverziekten, Postbus 2040, 3000 CA Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #15497776 No free full text.

Abstract: Three female patients, 68, 75 and 68 years of age, were treated symptomatically for long-standing abdominal complaints such as gastralgia, diarrhoea and loss of blood or mucus with the stools. In all cases there was no clear diagnosis and treatment did not relieve the complaints, even after surgery. Inflammatory bowel disease was ultimately established on the basis of histological analysis of both resection specimens and biopsies in combination with endoscopy. Clinical improvement was achieved after adequate treatment. Aspecific abdominal complaints in elderly patients have multiple differential diagnoses. The most important of these are diverticulitis, ischaemia and colon carcinoma. In contrast, inflammatory bowel disease (both Crohn's disease and ulcerative colitis) is usually diagnosed at a younger age. Ignoring inflammatory bowel disease as a cause of abdominal complaints in elderly patients could be responsible for inadequate treatment, higher morbidity and an increase of symptoms.

van Nuenen MH, Venema K, van der Woude JC, Kuipers EJ. · TNO Nutrition and Food Research, PO Box 360, 3700 AJ Zeist, The Netherlands. · Dig Dis Sci. · Pubmed #15139503 No free full text.

Abstract: The hypothesis was studied that intestinal microbial metabolites play a role in the pathogenesis of inflammatory bowel disease. For that purpose, an in vitro model of the colon was inoculated with fresh feces of six healthy individuals and eight inflammatory bowel disease patients. Samples were taken from the model over time to analyze metabolites from both saccharolytic and proteolytic fermentation. Microbiotas from inflammatory bowel disease patients produced significantly more short-chain fatty acids and ammonia than microbiotas from healthy individuals. Furthermore, the branched-chain fatty acid production was 25% higher after inoculation with microbiotas from patients than after inoculation with microbiotas from healthy individuals. Phenolic compounds were produced by all microbiotas, with large interindividual variation. The production of (potentially toxic) metabolites may play a role in the onset or chronicity of inflammatory bowel disease, because they were produced in higher amounts by microbiotas from these patients than by microbiotas from healthy individuals.

Linde K, Boor PP, Houwing-Duistermaat JJ, Kuipers EJ, Wilson JH, de Rooij FW. · Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands. · Am J Gastroenterol. · Pubmed #12650796 No free full text.

Abstract: OBJECTIVES: Single nucleotide variations in the CARD15 gene have recently been shown to be associated with Crohn's disease (CD). Of special interest is a cytosine insertion at position 3020 of exon 11 (3020insC), which leads to a stop codon, truncation of the CARD15 protein, and an altered function of CARD15. The aim of the study was to evaluate this frameshift mutation in Dutch, multiple-affected families with inflammatory bowel disease (IBD). METHODS: Ninety-three Caucasian, multiple-affected families with IBD were recruited by interviewing patients attending our department. Sixty-one probands had CD, and 32 probands ulcerative colitis (UC). The diagnosis of probands and affected family members was verified according to standard criteria. In addition, 81 healthy, unrelated controls were included. Genomic DNA was isolated from venous blood of all participants to determine the CARD15 3020insC mutation by using an allele-specific polymerase chain reaction, followed by agarose gel electrophoresis and DNA sequencing. RESULTS: Association with CARD15 3020insC was statistically significant for CD, but not for UC. In one of the multiple-affected families, middle-aged and elderly homozygous carriers were identified without CD. CONCLUSIONS: Although CARD15 3020insC appears to be etiologically important in CD, homozygous carriage does not always lead to IBD.

West RL, van de Vrie W, Schouten WR, van Dekken H, Kuipers EJ. · Afd. Maag-, Darm- en Leverziekten, Erasmus Universitair Medisch Centrum, Postbus 2040, 3000 CA Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #12532661 No free full text.

Abstract: Patients with chronic inflammatory bowel disease (IBD) have a higher risk of colorectal carcinoma, and present with this malignancy at a younger age than non-IBD individuals. In three patients, two men aged 20 and 36 years and one woman aged 34 years, colorectal cancer developed at a young age, following a long history of ulcerative colitis. Surveillance for colorectal cancer in IBD patients needs to be performed by regular colonoscopy with extensive biopsy sampling for the detection of dysplasia, regarded by many as predictive for colon carcinoma. Whenever a dysplasia-associated lesion or mass or a highgrade dysplasia is identified, there is a strong indication for colectomy. When low-grade dysplasia is found, the findings should be discussed with the patient and it should be decided whether the patient should resume surveillance or opt for colectomy.