Crohn Disease: Rogler G

Hoffmann JC, Preiss JC, Autschbach F, Buhr HJ, Häuser W, Herrlinger K, Höhne W, Koletzko S, Krieglstein CF, Kruis W, Matthes H, Moser G, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Sido B, Siegmund B, Stallmach A, Bokemeyer B, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus, Ludwigshafen. · Z Gastroenterol. · Pubmed #18810679 No free full text.

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Vavricka SR, Rogler G. · Klinik für Gastroenterologie und Hepatologie, Department für Innere Medizin, Universitätsspital Zürich. · Praxis (Bern 1994). · Pubmed #19153955 No free full text.

Abstract: The therapy of Crohn's disease depends on its disease activity. For those different disease activities (such as flare, chronic active disease, remission) varying treatment concepts are followed. This overview presents important concepts in the treatment of Crohn's disease.

Nielsen OH, Rogler G, Hahnloser D, Thomsen OØ, Anonymous00022. · Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen,75 Herlev Ringvej, Herlev, Denmark. · Nat Clin Pract Gastroenterol Hepatol. · Pubmed #19153563 No free full text.

Abstract: The transmural inflammation characteristic of Crohn's disease predisposes patients to the formation of fistulas. Up to 50% of patients with Crohn's disease are affected by fistulas, which is a major problem given the considerable morbidity associated with this complication. Appropriate treatment of fistulas requires knowledge of specific pharmacological and surgical therapies. Treatment options depend on the severity of symptoms, fistula location, the number and complexity of fistula tracts, and the presence of rectal complications. Internal fistulas, such as ileoileal or ileocecal fistulas, are mostly asymptomatic and do not require intervention. By contrast, perianal fistulas can be painful and abscesses may develop that require surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. This Review describes the epidemiology and pathology of fistulizing Crohn's disease. Particular focus is given to external and perianal fistulas, for which treatment options are well established. Available therapeutic options, including novel therapies, are discussed. Wherever possible, practical and evidence-based treatment regimens for Crohn's disease-associated fistulas are provided.

Hoffmann JC, Autschbach F, Bokemeyer B, Buhr HJ, Herrlinger K, Höhne W, Krieglstein C, Kruis W, Moser G, Preiss JC, Reinshagen M, Rogler G, Schreiber S, Schreyer AG, Siegmund B, Stallmach A, Stange EF, Zeitz M. · Medizinische Klinik I, St. Marienkrankenhaus Ludwigshafen. · Dtsch Med Wochenschr. · Pubmed #18788069 No free full text.

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Herfarth H, Rogler G. · Dept. of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Endoscopy. · Pubmed #15657857 No free full text.

Abstract: This review summarizes important publications that have appeared during the last year dealing with imaging techniques and endoscopy, as well as the management of low-grade dysplasia and stenosis in inflammatory bowel disease. Magnetic resonance enteroclysis and capsule endoscopy are currently emerging as new imaging techniques for the small bowel in Crohn's disease. While magnetic resonance enteroclysis is, at least in Europe, increasingly being used as a reference method, the value of capsule endoscopy for the management of inflammatory bowel disease is still being evaluated. Chromoendoscopy is being studied in patients with long-lasting ulcerative colitis and may be a promising and sensitive technique for the diagnosis of dysplasia. However, there are conflicting data regarding the appropriate management when low-grade dysplasia is diagnosed in patients with ulcerative colitis. Endoscopic dilation can often be successfully carried out in cases of intestinal stenosis. The results of long-term follow-up studies indicate that several dilation procedures are often necessary and that a relatively high percentage of patients still have to undergo surgery.

Rogler G, Schölmerich J. · Klinik und Poliklinik für Innere Medizin I, Universität Regensburg, Regensburg. · Med Klin (Munich). · Pubmed #15024484 No free full text.

Abstract: Extraintestinal manifestations of Crohn's disease and ulcerative colitis are found in > 50% of all patients. These extraintestinal manifestations sometimes impair the overall life quality much more than the bowel-related symptoms. Extraintestinal manifestations need to be distinguished from secondary diseases or complications of inflammatory bowel diseases, as they require a different and specific therapy. Complications of the intestinal disease, such as vitamin deficiency or osteoporosis, can be treated specifically by substitution of vitamin D, calcium, or other vitamins. However, extraintestinal manifestations of Crohn's disease and ulcerative colitis, such as primary sclerosing cholangitis, arthritis or granulomatous inflammation of the skin, lung, or liver, are much more difficult to treat sufficiently. Almost every organ can be a localization of extraintestinal symptoms of inflammatory bowel diseases. It is important to acquire knowledge on these extraintestinal manifestations of Crohn's disease and ulcerative colitis to start the respective treatment early. Perhaps even more important, these extraintestinal symptoms can be the primary manifestation of Crohn's disease and ulcerative colitis. Therefore, they have to be recognized as extraintestinal manifestations to adequately treat the intestinal disease.

Bogenrieder T, Rogler G, Vogt T, Landthaler M, Stolz W. · Department of Dermatology, University of Regensburg Medical Center, Regensburg, Germany. · Dermatology. · Pubmed #12673090 No free full text.

Abstract: Orofacial granulomatosis (OFG) is a rare and heterogeneous clinical condition that presents with chronic swelling of the oral or facial tissues due to granulomatous inflammation. It is histologically characterized by noncaseating giant cell granulomata and epithelioid histiocytes. OFG includes the previously recognized clinical entities of Melkersson-Rosenthal syndrome and cheilitis granulomatosa (Miescher's cheilitis). A consistently effective medical treatment is not currently available. We describe an adolescent patient with a history of recurrent orofacial swelling preceding gastrointestinal symptoms by several years. He exhibited clinical and histological changes consistent with the diagnosis of OFG. It was resistant to standard therapies such as topical corticosteroids. Thorough history taking and clinical examination suggested Crohn's disease (CD), and further tests confirmed the diagnosis. The patient improved promptly after initiating oral treatment for CD with mesalazine and prednisolone. We conclude that OFG may be under- or misdiagnosed since the clinical manifestation may be misleading and its course is independent of or even preceding CD. Thus, patients with OFG should be asked about gastrointestinal symptoms consistent with CD. Those with suspicious symptoms should undergo a careful gastrointestinal evaluation, possibly including enteroclysis and complete gastrointestinal endoscopic examination, especially when the patient's history is conspicuous.

Fölsch UR, Hoffmann J, Höhne W, Janke KH, Klump B, Rogler G, Schreiber S. · Klinik für Allgemeine Innere Medizin, I. Medizinische Klinik, Universitätsklinikum Kiel, Schittenhelmstrasse 12, 24105 Kiel. · Internist (Berl). · Pubmed #12524923 No free full text.

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Schreyer AG, Gölder S, Scheibl K, Völk M, Lenhart M, Timmer A, Schölmerich J, Feuerbach S, Rogler G, Herfarth H, Seitz J. · Department of Radiology, University Hospital Regensburg, Regensburg, Germany. · Inflamm Bowel Dis. · Pubmed #15803030 No free full text.

Abstract: BACKGROUND: Magnetic resonance enteroclysis (MRE) is a recently introduced imaging technique that assesses the small bowel with similar sensitivity and specificity as the fluoroscopically performed conventional enteroclysis. Magnetic resonance imaging colonography (MRC) seems to be a promising technique for polyp assessment in the colon. In this feasibility study, we evaluated the combination of small bowel MRI with unprepared MRC as an integrative diagnostic approach of the whole bowel in patients with Crohn's disease. METHODS: Thirty patients with known Crohn's disease were prospectively examined. No particular colonic preparation was applied. Applying the dark lumen technique in all patients, MRE and MRC were performed within 1 session using an integrative examination protocol. T2-weighted and contrast-enhanced T1-weighted sequences were acquired. Inflammation assessment (grades 0 to 2) of the colon was compared with conventional colonoscopy in 29 patient and with surgery in 1 patient. The entire colon was graded fair to good distended in all patients. In 11 of 210 evaluated colonic segments, feces hindered an adequate intraluminal bowel assessment. Twenty-three of 30 patients had complete colonoscopy as the gold standard. In 7 patients, complete colonoscopy could not be performed because of an inflamed stenosis. RESULTS: Correct grading of colonic inflammation was performed with 55.1% sensitivity and 98.2% specificity in all segments. Considering only more extensive inflammation (grade 2), the sensitivity of MRC increased to 70.2% with a specificity of 99.2%. CONCLUSIONS: The combination of MRE and MRC could improve the diagnostic value of abdominal MRI evaluation in patients with Crohn's disease. However, MRC can not replace conventional colonoscopy in subtle inflammation assessment.

Schreyer AG, Geissler A, Albrich H, Schölmerich J, Feuerbach S, Rogler G, Völk M, Herfarth H. · Department of Radiology, University of Regensburg, Germany. · Clin Gastroenterol Hepatol. · Pubmed #15181618 No free full text.

Abstract: BACKGROUND & AIMS: Diagnostic results of magnetic resonance (MR) enteroclysis correlate highly with those from conventional enteroclysis; nevertheless, intubation of the patient and positioning of an intestinal tube is still necessary for the examination, which is often remembered as the most embarrassing part of the examination by the patient. A more comfortable and highly sensitive examination of the small bowel therefore would increase patient acceptance for recurring examinations, which are often necessary, for example, in patients with Crohn's disease. This study evaluates the diagnostic efficacy of abdominal MR imaging (MRI) of the small bowel after drinking contrast agent only compared with conventional enteroclysis and abdominal MRI performed after enteroclysis in patients with suspected or proven Crohn's disease. METHODS: Twenty-one patients with Crohn's disease referred for conventional enteroclysis underwent abdominal MRI after enteroclysis. Additionally, 1 to 3 days before or after these examinations, abdominal MRI was performed using only orally administered contrast. All MRI examinations were performed using a 1.5T scanner. RESULTS: All pathological findings on conventional enteroclysis were shown correctly with MRI after enteroclysis and MRI after oral contrast only. Additional information by MRI was obtained in 6 of 21 patients. No statistically significant differences were found in assessing the diagnostic efficacy of the 3 examinations. CONCLUSIONS: Abdominal MRI with oral contrast only can be used as a diagnostic tool for evaluation of the small bowel in patients with Crohn's disease and has the potential to replace conventional enteroclysis as follow-up.

Andus T, Klebl F, Rogler G, Bregenzer N, Schölmerich J, Straub RH. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Aliment Pharmacol Ther. · Pubmed #12562454 links to  free full text

Abstract: BACKGROUND: Dehydroepiandrosterone is a steroid hormone used as an 'over-the-counter' drug in the USA. Treatment with dehydroepiandrosterone was effective in randomized controlled trials in patients with systemic lupus erythematosus. Dehydroepiandrosterone sulphate concentrations are decreased in patients with inflammatory bowel disease. Dehydroepiandrosterone inhibits nuclear factor-kappaB and the secretion of interleukin-6 and interleukin-12 via the peroxisome proliferator-activated receptor alpha. AIM: A phase II pilot trial was started to evaluate the effect of dehydroepiandrosterone in active inflammatory bowel disease. METHODS: Twenty patients with chronic active inflammatory bowel disease [seven Crohn's disease (Crohn's disease activity index, 242 +/- 51; mean +/- s.d.); 13 ulcerative colitis (clinical activity index, 7.8 +/- 2.1)] took 200 mg dehydroepiandrosterone per day orally for 56 days. RESULTS: Six of the seven patients with Crohn's disease and eight of the 13 patients with ulcerative colitis responded to treatment, with a decrease in the Crohn's disease activity index of > 70 points and a decrease in the clinical activity index of > 4 points, respectively. Six Crohn's disease patients and six ulcerative colitis patients went into remission (Crohn's disease activity index < 150; clinical activity index <or= 4). No patient withdrew from the study because of side-effects. CONCLUSIONS: In a pilot study, dehydroepiandrosterone was effective and safe in patients with refractory Crohn's disease or ulcerative colitis. Adjustment of the dehydroepiandrosterone dosage may further improve the treatment success.

Herfarth H, Obermeier F, Andus T, Rogler G, Nikolaus S, Kuehbacher T, Schreiber S. · No affiliation provided · Am J Gastroenterol. · Pubmed #12385472 No free full text.

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Gelbmann CM, Rogler G, Gross V, Gierend M, Bregenzer N, Andus T, Schölmerich J. · Department of Internal Medicine I, University of Regensburg, Germany. · Am J Gastroenterol. · Pubmed #12094862 No free full text.

Abstract: OBJECTIVES: Some patients with Crohn's disease (CD) do not respond to corticosteroid therapy. Furthermore, corticosteroids frequently cause side effects. Thus, predictive parameters for treatment refractoriness would be helpful for treatment decisions. METHODS: A total of 300 patients with active CD (i.e., with a Crohn's Disease Activity Index [CDAI] >200) entered the study. Treatment started with 60-100 mg/day prednisolone equivalent, which was then tapered to 10-15 mg/day within 6 wk and maintained at that dose for another 4 wk. After 10 wk of treatment, response to steroids was defined by a CDAI <150, steroid resistance by a CDAI always > or =150 and steroid dependency by a relapse after dose reduction. Of 239 eligible patients, 196 were responders, 26 were steroid resistant, and 17 were steroid dependent. RESULTS: Prior bowel resections, a high initial CDAI, and perianal disease were associated with steroid resistance. Of the steroid resistant patients 53.9% were bowel-resected compared to 20.4% of the responders (relative risk = 3.63; 95% CI = 1.79-7.36). Perianal disease was observed in 42.3% of steroid resistant patients versus 21.9% of responders (relative risk = 2.28; 95% CI = 1.12-4.66) and initial CDAI was 347+/-91 in resistant patients versus 301+/-81 in responders (p < 0.05). Parameters for steroid dependent patients were not significantly different from those of responders. CONCLUSIONS: In this study (thus far the largest study for the evaluation of predictive factors for treatment refractoriness to corticosteroids in CD), only prior bowel resection, perianal disease, and a high initial CDAI were found to be predictive of resistance to steroid treatment.

Gelbmann CM, Rogler G, Gierend M, Gross V, Schölmerich J, Andus T. · Department of Internal Medicine I, University of Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #11742191 No free full text.

Abstract: OBJECTIVE: Associations between HLA-DR genotypes and susceptibility to Crohn's disease (CD) have been reported. However, it is not known whether certain HLA-DR genotypes or IL-1ra gene polymorphism are associated with responsiveness to treatment or different clinical patterns of disease. DESIGN/SETTING: In a large, randomized, controlled multicentre trial, 318 patients with CD were treated with daily doses of 6, 9 or 18 mg budesonide. Patients were stratified into two groups: patients without steroid pretreatment and with active CD (CDAI > 150) and patients with conventional steroid pretreatment of < or= 30 mg prednisolone per day, which was replaced by oral budesonide within 3 weeks. MAIN OUTCOME MEASURES: The HLA-DRB1 genotypes 1-16 and the IL-1ra gene polymorphism were examined for an association with budesonide treatment failure. RESULTS: Only HLA-DR 8 was associated with treatment failure of budesonide. HLA-DR 8 is not very common. Only 17/243 patients who could be evaluated expressed this genotype, and 13 of these 17 patients did not respond to budesonide (P < 0.00067). Neither the other HLA-DR genotypes nor the IL-1ra gene polymorphism had an influence on treatment outcome of budesonide therapy. No significant association of fistulas, perianal disease, need for bowel resections, and disease localization with certain HLA-DRB1 genotypes or the IL-1ra gene polymorphism were found. CONCLUSIONS: This is the first description of an association of a certain HLA-DR genotype (HLA-DR 8) with treatment failure in inflammatory bowel disease (IBD).

Rogler G, Gelbmann CM, Vogl D, Brunner M, Schölmerich J, Falk W, Andus T, Brand K. · Dept. of Internal Medicine I, University of Regensburg, Germany. · Scand J Gastroenterol. · Pubmed #11336164 No free full text.

Abstract: BACKGROUND: Fibroblasts and myofibroblasts are known to secrete a wide spectrum of cytokines, but the individual spectrum is tissue-specific. We investigated the effect of cell activation on cytokine secretion of isolated human colonic fibroblasts/myofibroblasts from control patients and patients with mucosal inflammation. METHODS: Primary cultures of human colonic submucosal fibroblasts/myofibroblasts were incubated with IL-1alpha (100 U/ml), IL-Ibeta (10 ng/ml), IL-10 (10 ng/ml), TNF (10 ng/ml), PMA (10 ng/ml), LPS (50 ng/ml), IL-4 (10 ng/ml), or a combination of IL-1 and TNF. Secreted cytokines were determined by ELISA. NF-kappaB activation was demonstrated by electrophoretic mobility-shift assays (EMSA). RESULTS: Incubation of colonic fibroblasts/myofibroblasts with IL-1, LPS, TNF and PMA induced secretion of IL-6, IL-8, M-CSF and GM-CSF. IL-8 and IL-6 secretion could be stimulated by IL-1alpha, IL-1beta, TNF, PMA and LPS within 6 h of incubation. IL-6 secretion was stimulated from 0.5 +/- 0.01 pg/h x microg fibroblast protein to 18.5 +/- 2.6 pg/h x microg fibroblast protein with IL-1beta (P < 0.01). IL-8 secretion was stimulated from 1.0 +/- 0.1 pg/h x microg fibroblast protein to 41.1 +/- 3.6 pg/h x microg (P < 0.005). IL-4 and IL-10 did not change cytokine secretion significantly. No significant differences between cultures from normal and inflamed mucosa were observed. TNF and IL-1 induced NF-kappaB activation. ALLN, a proteasome and NF-kappaB activation inhibitor, reduced TNF-mediated IL-8, GM-CSF and M-CSF induction significantly, whereas induction of IL-6 secretion remained unchanged. CONCLUSION: Human colonic myofibroblasts can secrete large amounts of IL-6, IL-8, M-CSF and GM-CSF upon stimulation. The induction of IL-8, M-CSF and GM-CSF, but not of IL-6 secretion, is mediated mainly by NF-kappaB activation. The cytokine profile and the total amounts of cytokines released suggest that colonic myofibroblasts can play a role in leukocyte recruitment and during mucosal inflammation. They therefore have to be regarded as an important part of the mucosal immune system.

Funke B, Autschbach F, Kim S, Lasitschka F, Strauch U, Rogler G, Gdynia G, Li L, Gretz N, Macher-Goeppinger S, Sido B, Schirmacher P, Meuer SC, Roth W. · Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany. · Gut. · Pubmed #19039087 No free full text.

Abstract: AIMS: Both epithelial barrier dysfunction and apoptosis resistance of immune cells contribute to the pathogenesis of Crohn's disease. The soluble decoy receptor 3 (DcR3) acts in an anti-apoptotic manner by neutralising the death ligand CD95L. Here, we investigated the possible involvement of DcR3 in Crohn's disease. METHODS: The epithelial fraction of human small intestinal mucosa samples was obtained by laser microdissection. Expression of DcR3 was examined by global gene expression profiling, quantitative reverse transcription polymerase chain reaction, immunoblot analysis, and immunohistochemistry. DcR3 concentrations in the serum of patients with Crohn's disease were measured by enzyme-linked immunosorbent assay. Apoptosis assays were performed to study the effects of DcR3 in intestinal epithelial cells and lamina propria T cells. RESULTS: DcR3 is over-expressed in the epithelial layer of ileum specimens in patients with Crohn's disease, both at actively inflamed and non-active sites. DcR3 serum levels are significantly elevated in patients with active and non-active Crohn's disease as compared to healthy controls. The expression of DcR3 in intestinal epithelial cells is induced by tumour necrosis factor alpha. Increased DcR3 expression is associated with activation of nuclear factor kappa B (NF-kappaB) and results in protection of intestinal epithelial cells and lamina propria T cells from CD95L-induced apoptosis. CONCLUSIONS: DcR3 may promote inflammation in Crohn's disease by inhibiting CD95L-induced apoptosis of epithelial and immune cells as well as by inducing NF-kappaB activation.

Lang M, Schlechtweg M, Kellermeier S, Brenmoehl J, Falk W, Schölmerich J, Herfarth H, Rogler G, Hausmann M. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Inflamm Bowel Dis. · Pubmed #18839425 No free full text.

Abstract: BACKGROUND: A frequent complication of Crohn's disease (CD) is the formation of strictures and stenoses. Strictures are characterized by a fibrosis of the bowel wall, induced by abnormal wound healing. Functional changes of colonic lamina propria fibroblasts (CLPF) reflected by increased proliferation and collagen synthesis, increased contractility or reduced migratory potential, indicate a change of the phenotype. We aimed to investigate differences in gene expression profiles between CLPF isolated from normal, inflamed and strictured areas of CD patients. METHODS: We applied two methods of gene expression analysis, subtractive hybridisation and Affimetrix microarrays to find differences in mRNA expression patterns. Findings were verified by dot blot analysis. RESULTS: Using subtractive screening and dot blot analysis 74 clones could be confirmed to be differentially expressed in CD CLPF from nonstrictured areas compared to control CLPF. Fibronectin (transcript variant 1, NM_002026) could be confirmed as being upregulated in CD with a ratio of 143. Collagen (type I, NM_000089) was upregulated in CD with a ratio of 17.41 clones could be confirmed as differentially expressed in CD CLPF derived from strictures compared to control CLPF. Five clones were identified as chitinase 3-like 1 (cartilage glycoprotein-39) and confirmed with dot blot with a ratio of 2.1.In an independent approach, microarray analysis showed upregulation of chitinase 3-like 1 (signal log ratio 1.9) in CD CLPF from strictures compared to control CLPF thus confirming subtractive hybridization. CONCLUSIONS: In the light of the current literature a number of interesting candidates resulted from the multiplicity of identified genes. In regard to the functional changes of CLPF during stenosis and other dysfunctions some proteins might represent a therapeutic target.

Ott C, Obermeier F, Thieler S, Kemptner D, Bauer A, Schölmerich J, Rogler G, Timmer A. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #18794607 No free full text.

Abstract: OBJECTIVE: Although important advances in understanding the aetiology and pathogenesis of inflammatory bowel disease (IBD) have been made, many questions remain unanswered. As the most recent data available on the incidence of IBD in Germany were collected about 15 years ago, we set up a new population-based cohort to determine current incidence data for a defined region in Germany and to establish a basic cohort for prospective follow-up. METHODS: All patients living in the region of Oberpfalz newly diagnosed with IBD between 1 January 2004 and 31 December 2006 were included in this study by setting up a network of reporting clinicians and general practitioners in hospitals as well as in private practices. Demographic and clinical characteristics such as age at first diagnosis, localization of the disease, extraintestinal manifestations or family history on IBD were documented. Age-adjusted incidence rates are presented with 95% Poisson confidence intervals (CIs), based on the European standard population. RESULTS: In total, 286 newly diagnosed patients with IBD were reported in this region, 168 patients suffering from Crohn's disease (CD), 105 patients with ulcerative colitis. Age-standardized incidence rates were 11.0/10(5) (95% CI: 9.1-11.6) for IBD, 6.6/10(5) (95% CI: 5.6-7.7) for CD and 3.9/10(5) (95% CI: 3.2-4.7) for ulcerative colitis. Peak incidences were found in the age interval of 16-24 years for both diseases, predominantly for CD. Age at first diagnosis was lower, extraintestinal manifestations and a positive family history on IBD were more common in patients with CD. CONCLUSION: The incidence rate in IBD seems to be stable in Germany as compared with previously reported data, as is the remarkable predominance of CD. Prospective follow-up studies will be based on this incidence cohort.

Brenmoehl J, Falk W, Göke M, Schölmerich J, Rogler G. · Department of Internal Medicine II, University of Jena, 07747 Jena, Germany. · Int J Colorectal Dis. · Pubmed #18633626 No free full text.

Abstract: BACKGROUND: Migration of colonic lamina propria fibroblasts (CLPF) plays an important role during mucosal wound healing as well as fibrosis and fistula formation in Crohn's disease (CD). Recently, we showed that the migratory potential of CD-CLPF was significantly reduced compared to control CLPF. Fistula-derived CD-CLPF migrated less and fibrosis-CLPF more than CLPF from inflamed CD mucosa. These changes in migratory behavior were associated with changes in production of the migration-inducing fibronectin (FN) isoforms ED-A and ED-B. A permanent reduction of the migratory potential of CLPF was mediated by IFN-gamma and tumor necrosis factor (TNF) modulate FN isofom expression in CLPF and thereby might regulate CLPF migration. MATERIALS AND METHODS: Control CLPF were incubated for 72 h with IFN-gamma, TNF, IFN-gamma plus TNF, or TGF-beta1. Messenger RNA (mRNA) was isolated and expression of FN and isoforms ED-A and ED-B was quantified by real-time polymerase chain reaction. FN, ED-A, and ED-B were investigated by Western blotting. FN receptor integrin alpha5beta1 was analyzed by FACS. RESULTS: No difference was found for the surface display of integrin alpha5beta1 between stimulated and non-stimulated cells. In TGF-beta1 incubated CLPF mRNA amount of FN and isoforms ED-A and ED-B was slightly increased. IFN-gamma only decreased FN in CLPF, TNF significantly reduced FN-mRNA by 40%, FN ED-A mRNA by 25%, and ED-B mRNA by 50%. The TNF-mediated mRNA downregulation resulted in a decreased protein amount as revealed by Western blotting. CONCLUSION: Cytokines such as IFN-gamma, TNF, and TGF-beta1 modulate the production of fibronectin isoforms. Our data indicate that inflammation-induced modulation of FN-isoform production is involved in the alterations of migratory potential of CLPF isolated from CD mucosa.

Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, Strauch U, Farkas S, Fürst A, Hofstädter F, Schölmerich J, Herfarth H, Rogler G. · Institute of Pathology, University of Regensburg, Regensburg, Germany. · Inflamm Bowel Dis. · Pubmed #18626977 No free full text.

Abstract: BACKGROUND: The pathogenesis of fistulae in Crohn's disease (CD) patients is barely understood. We recently showed that more than two-thirds of CD fistulae are covered with flat, mesenchymal-like cells (transitional cells [TC]) forming a patchy basement membrane. Epithelial-to-mesenchymal transition (EMT) is a process of reprogramming epithelial cells, allowing them to migrate more effectively and giving epithelial cells an "invasive" potential. EMT has been suggested to be crucial in fibrosis found in different tissues and diseases. We therefore investigated whether EMT could be involved in the pathogenesis of fistulae formation in CD. METHODS: In all, 18 perianal fistulae, 2 enteroenteric, and 1 enterovesical fistulae from 17 CD patients were analyzed. In addition 2 perianal fistulae of non-CD patients were studied. Hematoxylin and eosin staining, immunohistochemistry for the expression of cytokeratins 8 and 20, beta6-integrin, E-cadherin, beta-catenin, vimentin, and TGF-beta1 and 2 were performed according to standard techniques. RESULTS: The TC covering perianal or enteroenteric fistulae were strongly positive for cytokeratins 8 and 20 but negative for vimentin, indicating their epithelial origin. beta6-Integrin and TGF-beta had the highest staining intensities in the transitional zone between the epithelium and the TC. Expression of junctional proteins such as E-cadherin was reduced in TC as compared to regular fistulae epithelium. In addition, a translocation of beta-catenin from the membrane to the cytoplasm was observed. CONCLUSIONS: Our data for the first time indicate an expression pattern of epithelial and mesenchymal markers in TC associated with fistulae formation that is characteristic for EMT. Studying the pathways of EMT during intestinal fistulae formation may help to develop new therapeutic strategies.

Hafner S, Timmer A, Herfarth H, Rogler G, Schölmerich J, Schäffler A, Ehrenstein B, Jilg W, Ott C, Strauch UG, Obermeier F. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #18467916 No free full text.

Abstract: BACKGROUND: Environmental factors are likely to be involved in the pathogenesis of inflammatory bowel disease (IBD), as the incidence of both Crohn's disease (CD) and ulcerative colitis (UC) increased with improved living standards in Europe after World War II. On the basis of earlier reports suggesting that hygienic standards may also play a role in the pathogenesis of IBD, we investigated the influence of hepatitis A seroprevalence as an indicator for poorer hygienic conditions and worm infestations in IBD. METHODS: Hepatitis A seroprevalence was examined in patients with UC and CD. Patients with minor endocrinological disorders served as controls. All patients were questioned about immunizations, parasitic infections (worms), contact with animals, living on a farm, and ever traveling abroad. Patients were excluded for active hepatitis A immunization or recent passive immunization. Results are presented as Mantel-Haenszel odds ratios with 95% confidence interval, adjusted for age group. RESULTS: The sample included 307 patients (73 CD, 48 UC, and 186 controls). Hepatitis A seroprevalence was strongly associated with age older than 50 years. Age adjusted Mantel-Haenszel odds ratios were 0.25 (0.09-0.71) for UC and 0.75 (0.38-1.46) for CD versus controls. For parasitic infections, the odds ratios were 1.15 (0.52-2.53) for UC and 0.34 (0.13-0.89) for CD. CONCLUSION: We were able to demonstrate a negative association of hepatitis A infection with UC only. In contrast, a novel finding was a strong protective effect of worm infestations for the occurrence of CD, but not UC.

Hausmann M, Paul G, Kellermeier S, Frey I, Schölmerich J, Falk W, Menzel K, Fried M, Herfarth H, Rogler G. · Department of Internal Medicine I, University of Regensburg, Germany. · Clin Exp Immunol. · Pubmed #18460015 links to  free full text

Abstract: Haem oxygenase-1 (HO-1) up-regulation was suggested to reduce mucosal tissue damage in inflammatory bowel disease (IBD) and an up-regulation of HO-1 expression in patients with Crohn's disease (CD) and ulcerative colitis (UC) was demonstrated. A HO-1 gene promoter microsatellite (GT)(n) dinucleotide repeat polymorphism was associated with regulation of HO-1 in response to inflammatory stimuli. We therefore hypothesized that IBD patients might segregate into phenotypes with high or low HO-1 inducibility. Ethylenediamine tetraacetic acid blood samples were obtained from 179 CD patients, 110 UC patients and 56 control patients without inflammation. Genomic DNA was purified and the 5'-flanking region of the HO-1 gene containing the (GT)(n) dinucleotide repeat was amplified. Polymerase chain reaction (PCR) products were purified and the length of the PCR fragments was analysed. The number of (GT)(n) repeats in the population studied ranged from 13 to 42. The distribution of the allele frequencies was comparable in patients and controls for both the short and the long alleles. The frequencies of short-, middle- and long-sized alleles were not changed among the groups studied. No correlation was found between IBD and microsatellite instability detected in five individals. Our data indicate that (GT)(n) dinucleotide repeats of the HO-1 promotor region have no significance for the pathophysiology and disease course of IBD.

Lippert E, Gunckel M, Brenmoehl J, Bataille F, Falk W, Scholmerich J, Obermeier F, Rogler G. · Department of Internal Medicine I, University of Regensburg, Regensburg, Germany. · Clin Exp Immunol. · Pubmed #18336593 links to  free full text

Abstract: Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.

Kaltz B, Bokemeyer B, Hoffmann J, Porschen R, Rogler G, Schmiegel W. · Die Institutsangaben sind am Ende des Beitrags gelistet. · Z Gastroenterol. · Pubmed #17427117 No free full text.

Abstract: It has been assumed that cancer surveillance colonoscopy in patients with ulcerative colitis is not conducted according to the guidelines in Germany. An inquiry of the self-help organisation German Crohn's Disease/Ulcerative Colitis Association (DCCV) among organisation members belonging to colorectal cancer risk groups confirmed that the number of biopsies taken during colonoscopy is less than that proposed by the guidelines. Only with 9.2 % of the risk group did a guideline-conformal colonoscopy take place. In more than 50 % of the cases less than 10 biopsies were taken.

Shkoda A, Werner T, Daniel H, Gunckel M, Rogler G, Haller D. · Else-Kroener-Fresenius Center for Experimental Nutritional Medicine, Molecular Nutrition, Technical University of Munich, Freising-Weihenstephan, Germany. · J Proteome Res. · Pubmed #17330946 No free full text.

Abstract: The loss of intestinal epithelial cell (IEC) function is a critical component in the initiation and perpetuation of chronic intestinal inflammation in the genetically susceptible host. We applied proteome analysis (PA) to characterize changes in the protein expression profile of primary IEC from patients with Crohn's disease (CD) and ulcerative colitis (UC). Surgical specimens from 18 patients with active CD (N = 6), UC (N = 6), and colonic cancer (N = 6) were used to purify primary IEC from ileal and colonic tissues. Changes in protein expression were identified using 2D-gel electrophoreses (2D SDS-PAGE) and peptide mass fingerprinting via MALDI-TOF mass spectrometry (MS) as well as Western blot analysis. PA of primary IEC from inflamed ileal tissue of CD patients and colonic tissue of UC patients identified 21 protein spots with at least 2-fold changes in steady-state expression levels compared to the noninflamed tissue of control patients. Statistical significance was achieved for 9 proteins including the Rho-GDP dissociation inhibitor alpha that was up-regulated in CD and UC patients. Additionally, 40 proteins with significantly altered expression levels were identified in IEC from inflamed compared to noninflamed tissue regions of single UC (N = 2) patients. The most significant change was detected for programmed cell death protein 8 (7.4-fold increase) and annexin 2A (7.7-fold increase). PA in primary IEC from IBD patients revealed significant expression changes of proteins that are associated with signal transduction, stress response as well as energy metabolism. The induction of Rho GDI alpha expression may be associated with the destruction of IEC homeostasis under condition of chronic intestinal inflammation.