Crohn Disease: Stange EF

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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Buhr HJ, Kroesen AJ, Stange EF, Anonymous00109. · Chirurgische Klinik I, Universitätsklinikum Benjamin Franklin, Berlin. · Z Gastroenterol. · Pubmed #12541173 No free full text.

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Stange EF. · Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany. · Inflamm Bowel Dis. · Pubmed #15905711 No free full text.

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Stange EF. · No affiliation provided · Z Gastroenterol. · Pubmed #15095119 No free full text.

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Gersemann M, Wehkamp J, Fellermann K, Stange EF. · Internal Medicine I, Robert Bosch Hospital, Auerbachstrasse 110, Stuttgart, Germany. · World J Gastroenterol. · Pubmed #18810765 links to  free full text

Abstract: Crohn's disease may principally involve the whole gastrointestinal tract. Most commonly, the inflammation occurs in the small intestine and/or in the colon with stable disease location over the years. The pathogenesis of both disease phenotypes is complex, the likely primary defect lies in the innate rather than adaptive immunity, particularly in the chemical antimicrobial barrier of the mucosa. Crohn's ileitis is associated with a reduced expression of the Wnt signalling pathway transcription factor T-cell factor 4 (TCF4), which is regulating Paneth cell differentiation. As a result, the alpha-defensins and principal Paneth cell products HD5 and HD6 are deficiently expressed in ileal disease, independent of current inflammation. In contrast, Crohn's colitis is typically associated with an impaired induction of the beta-defensins HBD2 and HBD3 caused by fewer gene copy numbers in the gene locus of the beta-defensins on chromosome 8. This ileal and colonic defect in innate defence mediated by a deficiency of the protective alpha- and beta-defensins may enable the luminal microbes to invade the mucosa and trigger the inflammation. A better understanding of the exact molecular mechanisms behind ileal and colonic Crohn's disease may give rise to new therapeutic strategies based on a stimulation of the protective innate immune system.

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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Wang G, Stange EF, Wehkamp J. · Institute of Clinical Pharmacology, Dr Margarete Fischer-Bosch Institute and University of Tübingen, Auerbachstr. 112, 70376 Stuttgart, Germany. · Expert Rev Anti Infect Ther. · Pubmed #18039087 No free full text.

Abstract: Defensins are endogenous antibiotics with microbicidal activity against Gram-negative and -positive bacteria, fungi, enveloped viruses and protozoa. A disturbed antimicrobial defense, as provided by Paneth and other epithelial cell defensins, seems to be a critical factor in the pathogenesis of Crohn's disease, an inflammatory disease of the intestinal tract. Different direct and indirect mechanisms leading to a breakdown of antimicrobial barrier function include direct changes in defensin gene numbers (e.g., copy number polymorphism), genetic mutations in pattern-recognition receptors (e.g., nucleotide-binding oligomerization domain 2) and, as described recently, a differentiation problem of epithelial stem cells mediated by the wingless type (Wnt) pathway. Knowledge regarding the regulation and biology of defensins provides an attractive target to open up new therapeutic avenues.

Wehkamp J, Stange EF. · Robert Bosch Hospital, Internal Medicine I, and Dr. Margarete Fischer Bosch Institute for Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. · Ann N Y Acad Sci. · Pubmed #17057212 No free full text.

Abstract: Crohn's disease (CD), a chronic inflammatory disease of the intestinal mucosa is usually located in the small intestine (ileum) and or in the colon. Ileal CD has been linked to a mutation in the NOD2 gene, a bacterial recognition protein. A disturbed antimicrobial defense as provided by an arsenal of different epithelial defensins seems to be a critical factor in disease pathogenesis. Defensins are antimicrobial peptides and in the ileum are mainly expressed in Paneth cells (PCs), epithelial cells that also express NOD2. In the colon, defensins are expressed by enterocytes or metaplastic PCs. Ileal CD patients are characterized by a reduced antibacterial activity and a specific reduction of ileal PC defensins. In ileal Crohn's patients displaying a NOD2 mutation, this decrease is even more pronounced. In contrast, CD of the colon is characterized by an impaired induction of beta defensins in enterocytes. In conclusion, the regional localizations of CD, either ileal or colonic disease, can be linked to different defects in defensin expression. In line with these new findings, we predict that future therapeutic strategies aimed at restoring the host-microbe balance at the intestinal mucosa may prove superior to those that broadly suppress inflammation and adaptive immunity.

Wehkamp J, Stange EF. · Robert Bosch Hospital and Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. · Curr Opin Gastroenterol. · Pubmed #17053443 No free full text.

Abstract: PURPOSE OF REVIEW: To review recently published studies presenting novel and relevant information on Paneth cells and their function. RECENT FINDINGS: Paneth cells are secretory epithelial cells which are predominantly found in the small-intestinal crypts of Lieberkühn. Their most abundant products are alpha-defensins, which are endogenous antibiotics with activity against gram-negative and gram-positive bacteria, fungi, viruses and protozoa. The differentiation from stem-cell progenitors to Paneth cells is regulated by Wnt signalling via a complex gene programme, terminally including defensins. A disturbance of Paneth-cell differentiation and function may predispose to intestinal infections and appears to be a critical factor in the pathogenesis of ileal Crohn's disease, an inflammatory disease of the intestinal tract. SUMMARY: It is conceivable that these recent findings together with a better understanding of underlying mechanisms involved in the regulation and biology of Paneth cells will open up new therapeutic avenues for preventing infection as well as for causally treating inflammatory bowel diseases.

Kübler I, Stange EF, Fellermann K, Wehkamp J. · Dr. Margarete Fischer Bosch Institut für Klinische Pharmakologie (IKP), Stuttgart. · Dtsch Med Wochenschr. · Pubmed #16967396 No free full text.

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Stange EF. · Abteilung für Innere Medizin 1 Schwerpunkte Gastroenterologie, Hepatologie und Endokrinologie, Robert Bosch Krankenhaus, Stuttgart, Germany. · Aliment Pharmacol Ther. · Pubmed #16961748 No free full text.

Abstract: Ulcerative colitis and, maybe to a similar extent, Crohn's disease are associated with an increased risk of colorectal carcinoma. As a consequence of this increased risk, surveillance strategies have been proposed to prevent colorectal carcinoma through early detection of dysplasia, which may herald malignant disease. These surveillance strategies are controversial for several reasons discussed in this review. It may be concluded from the relevant studies that regular use of at least 1.2 g of mesalazine per day may effectively prevent about two out of three colon cancers in ulcerative colitis. In contrast, there seems to be no role for either mercaptopurine or folic acid in protection from colon cancer.

Wehkamp J, Fellermann K, Stange EF. · Department of Microbiology and Immunology, University of California, Davis, Calif., USA. · Chem Immunol Allergy. · Pubmed #15976487 No free full text.

Abstract: Crohn's disease, a transmural inflammation of the gut, has been linked to good childhood hygiene, frequent use of antibiotics before diagnosis, adherent or invasive mucosal bacteria and a break in the tolerance of luminal bacteria. A decrease or lack of mucosal peptide antibiotics may play a central role in the etiopathogenesis of Crohn's disease. The dysregulated adaptive immune system may reflect only the primary break of the mucosal defence since the immune response is mostly directed against luminal bacteria. Crohn's disease patients with ileal involvement, as compared to controls and Crohn's disease patients without ileal disease, are characterized by a diminished expression of the ileal Paneth cell defensins. This decrease is even more pronounced in Crohn's disease patients with a mutation in the NOD2 gene, which is associated with Crohn's disease and ileal involvement. NOD2 is an intracellular peptidoglycan receptor and is expressed in Paneth cells. In contrast to ulcerative colitis, Crohn's disease of the colon is characterized by an impaired induction of human beta defensins 2 and 3. The hypothesis of an impaired mucosal antibacterial activity is also consistent with the benefit from antibiotic or probiotic treatment in certain disease states.

Wehkamp J, Stange EF. · University of California-Davis School of Medicine, Department of Microbiology and Immunology, 1 Shield Avenue, Tupper Hall 3146, Davis, CA 95616, USA. · Trends Mol Med. · Pubmed #15955743 No free full text.

Abstract: Many patients with ileal Crohn's disease, a chronic intestinal inflammation, carry mutations in the gene encoding NOD2 (CARD15), but the mechanistic details of how this mutation leads to disease are not fully understood. NOD2 is expressed in antigen-presenting cells and Paneth cells, which are secretory epithelial cells of the small intestine. Two complementary studies using genetically engineered murine models help to explain the association of NOD2 malfunction and mucosal disease. One study observes a dysregulation of proinflammatory responses, suggesting that the most common NOD2 mutation in humans results in a gain of function. The other study determined that NOD2-null mutations impair the Paneth-cell antimicrobial response, which is consistent with recent findings in humans. Together, these studies fuel optimism that new therapeutic directions might emerge to better treat this severe mucosal disease.

McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. · Medicine, LHSC - UC, A-LL132, 339 Windermere Road, London, Ontario, Canada, N6A 5A5. · Cochrane Database Syst Rev. · Pubmed #15846602 No free full text.

Abstract: BACKGROUND: Cyclosporine was first found to be an effective and well-tolerated immunosuppressive agent in organ transplant recipients, and subsequently in several autoimmune diseases. It was reported in open studies that cyclosporine is effective for induction of remission in Crohn's disease. Four randomized controlled trials have been performed to determine whether the results observed in these open studies were valid. This systematic review summarizes the evidence on the use of oral cyclosporine for the induction of remission in Crohn's disease. OBJECTIVES: To evaluate the effectiveness of oral cyclosporine for induction of remission in patients with active Crohn's disease in the presence and absence of concomitant steroid therapy. Secondary objectives were to evaluate clinical response rates and adverse events associated with cyclosporine. SEARCH STRATEGY: Computer-assisted searches of the on-line bibliographic databases MEDLINE and EMBASE were performed to identify potentially relevant publications between 1980 and July 2004. The MeSH terms "Crohn Disease" or "Inflammatory Bowel disease" and "Cyclosporin" (exploded) were used to perform key word searches of the databases. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed. Abstracts from major gastroenterological meetings, The Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease Group Specialized Trials Register were also searched for relevant studies. Appropriate officials at Sandoz Corporation were contacted to seek information on any unpublished trials. SELECTION CRITERIA: Prospective, randomized, double-blinded, placebo-controlled trials of parallel design with treatment duration of a minimum 12 weeks comparing oral cyclosporine therapy with placebo for treatment of patients with active Crohn's disease were eligible for inclusion. DATA COLLECTION AND ANALYSIS: All data were analyzed on an intention-to-treat basis. Data were extracted from the original research articles and converted into 2x2 tables (cyclosporine vs. placebo). Where available, individual 2x2 tables for strata within studies were also used. Heterogeneity was assessed using the chi-square test (p < 0.10 was regarded as statistically significant). For non-pooled data, p-values were derived using the chi-square test. For pooled data, summary test statistics were derived using the Peto odds ratio and 95% confidence intervals. A fixed effects model was used for pooling of data. For continuous data, summary test statistics were derived using the weighted mean difference and 95% confidence intervals. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. MAIN RESULTS: Brynskov 1989a found that patients receiving high dose cyclosporine (median 7.6 mg/kg/day) had statistically significant clinical improvement at 12 weeks compared to placebo patients. None of the other studies found any statistically significant benefit for clinical improvement or induction of remission for low dose cyclosporine treatment (5 mg/kg/day) used by itself or in combination with corticosteroids compared to placebo. Cyclosporine was associated with a significantly higher proportion of adverse events and withdrawals due to adverse events relative to placebo. AUTHORS' CONCLUSIONS: Brynskov 1989a enrolled a small number of patients and the modified clinical grading scale used in the study has not been validated in other studies. Furthermore, statistically significant clinical improvement does not imply induction of clinical remission. Indeed, Brynskov 1989a found no statistically significant differences in the mean Crohn's Disease Activity Index score at 12 weeks indicating that cyclosporine was no more effective than placebo for induction of remission in Crohn's disease. The results of this review demonstrate that low dose (5 mg/kg/day) oral cyclosporine is not effective for the induction of remission in Crohn's disease. Patients treated with low dose oral cyclosporine are more likely than placebo treated patients to experience adverse events including renal dysfunction. The use of low dose oral cyclosporine for the treatment of chronic active Crohn's disease does not appear to be justified. Oral dosing at higher levels or parenteral administration of cyclosporine have not been adequately evaluated in controlled clinical trials. Higher doses of cyclosporine are not likely to be useful for the long-term management of Crohn's disease because of the risk of nephrotoxicity and the availability of other proven interventions.

Wehkamp J, Schmid M, Fellermann K, Stange EF. · Department of Microbiology and Immunology, University of California, Davis, CA 95616, USA. · J Leukoc Biol. · Pubmed #15618294 links to  free full text

Abstract: Crohn's disease is a chronic, inflammatory disease of the intestinal mucosa. Although intestinal bacteria are implicated in disease pathogenesis, the etiology is still unclear. The main location of disease is the small intestine (ileum) and the colon. Ileal disease has been linked to a mutation in the NOD2 gene. Defensins are antimicrobial peptides and in the ileum, are mainly expressed in Paneth cells, epithelial cells that also express NOD2. In the colon, defensins are expressed by enterocytes or metaplastic Paneth cells. Crohn's disease patients with ileal involvement, compared with controls or Crohn's patients without ileal involvement, have diminished expression of ileal Paneth cell defensins. This decrease is even more pronounced in Crohn's patients displaying a NOD2 mutation. In contrast, Crohn's disease of the colon is characterized by an impaired induction of beta-defensins in enterocytes. The colonic expression of the constitutive beta-defensin 1 is also decreased in the inflamed colonic mucosa, but this decrease is less specific to Crohn's disease, as it can also be found in ulcerative colitis patients. In conclusion, the regional localizations of Crohn's disease, ileal or colonic disease, can be linked to different defensin profiles. Crohn's disease of the ileum is associated with diminished defensin expression in Paneth cells. Crohn's disease of the colon is associated with diminished beta-defensin expression in enterocytes. Thus, it can be speculated that decreased defensin levels lead to a weakened intestinal barrier function to intestinal microbes and might be crucial in the pathophysiology of Crohn's disease.

Herrlinger K, Stange EF. · Abteilung Innere Medizin 1, Zentrum für Innere Medizin, Robert-Bosch-Krankenhaus, Stuttgart. · Dtsch Med Wochenschr. · Pubmed #15529447 No free full text.

This publication has no abstract.

Fellermann K, Wehkamp J, Herrlinger KR, Stange EF. · Department of Internal Medicine I, Robert Bosch Krankenhaus, Stuttgart, Germany. · Eur J Gastroenterol Hepatol. · Pubmed #12840673 No free full text.

Abstract: This comprehensive review promotes the novel concept that a defensin deficiency, i.e. lack of mucosal peptide antibiotics, may play a pivotal role in the aetiopathogenesis of Crohn's disease. Such an impaired function of this chemical barrier is consistent with the epidemiological relationship of good domestic hygiene with the incidence of inflammatory bowel diseases. The disregulated adaptive immune system, formerly believed to be the major cause in the development of Crohn's disease, may reflect only the primary break of the mucosal defence since the immune response is mostly directed against lumenal bacteria. Recent work has identified five different defensins expressed in colonic mucosa. In contrast to ulcerative colitis, Crohn's disease is characterised by an impaired induction of human beta defensins 2 and 3. This deficient induction may be due to changes in the intracellular transcription by NFkappaB and the intracellular peptidoglycan receptor NOD2, mutated in Crohn's disease. These findings are consistent with the mucosal attachment of lumenal bacteria in inflammatory bowel diseases and the frequent occurrence of other infectious agents. The hypothesis of an impaired mucosal antibacterial activity is also consistent with the benefit from antibiotic or probiotic treatment in certain inflammatory bowel disease states.

Stange EF, Schreiber S, Fölsch UR, von Herbay A, Schölmerich J, Hoffmann J, Zeitz M, Fleig WE, Buhr HJ, Kroesen AJ, Moser G, Matthes H, Adler G, Reinshagen M, Stein J, Anonymous00103. · Abteilung Innere Medizin 1, Robert-Bosch-Krankenhaus, Stuttgart. · Z Gastroenterol. · Pubmed #12541167 No free full text.

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Herrlinger K, Fellermann K, Stange EF. · Abteilung Innere Medizin 1, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart. · Internist (Berl). · Pubmed #12524917 No free full text.

This publication has no abstract.

Stange EF. · Abteilung für Innere Medizin 1, Robert-Bosch-Krankenhaus Stuttgart. · Praxis (Bern 1994). · Pubmed #12501498 No free full text.

Abstract: The standard therapy in Crohn's disease and ulcerative colitis is based on corticosteroids and aminosalicylates. Chronic active as well as fulminant disease usually require immunosuppressive therapy. The new biological have mostly disappointed because of lacking efficacy (Il-10, IL-11 or others) or serious adverse events (infliximab).

Metzler J, Stange EF. · Zentrum für Innere Medizin 1, Robert-Bosch-Krankenhaus, Stuttgart. · Med Klin (Munich). · Pubmed #12078390 No free full text.

Abstract: BACKGROUND: For the treatment of inflammatory bowel diseases in recent years several antibodies, cytokines and antisense oligonucleotides have been developed using recombinant technology and were tested as so-called "biological therapeutics". EFFECTIVENESS OF BIOLOGICAL THERAPEUTICS: Infliximab, a chimeric TNF-alpha antibody, is the only biological remedy approved for the treatment of refractory and fistulizing Crohn's disease. Because of inherent risks for severe side effects, such as sepsis, the indication should be restricted to truly refractory patients and treated patients must be followed very carefully. In clinical trials other anti-TNF-alpha-effective substances (CDP 571, etanercept, thalidomide), interleukin-10, interleukin-11, ICAM-1-antisense-oligonucleotides and antibodies against alpha 4-integrin were evaluated for the treatment of Crohn's disease. In summary, for all a slight effect was noted but their place in the therapeutical repertoire is not yet defined. None of these substances is approved for patients with inflammatory bowel disease. Future developments are eagerly awaited.

Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, Modigliani R, Present DH, Rutgeerts P, Schölmerich J, Stange EF, Sutherland LR. · The Clinical Trials Task Force of the International Organization of Inflammatory Bowel Disease. · Gastroenterology. · Pubmed #11832465 No free full text.

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Schölmerich J, Stange EF. · Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, 93042 Regensburg. · Internist (Berl). · Pubmed #11326736 No free full text.

This publication has no abstract.

Herrlinger K, Stange EF. · Medizinische Klinik I, Bereich Gastroenterologie, Universität Lübeck. · Med Klin (Munich). · Pubmed #10808301 No free full text.

Abstract: AIM: An overview on the evidence-based indications for an immunosuppressive treatment with azathioprine in chronic inflammatory bowel diseases is given. CROHN'S DISEASE: In Crohn's disease, these are the induction of remission in chronic active Crohn's disease, steroid-dependent Crohn's disease, fistulizing Crohn's disease and the maintenance of remission in Crohn's disease. The optimal dose is 2.5 mg/kg body weight, treatment should be maintained for at least 4 years. ULCERATIVE COLITIS: In ulcerative colitis, these are steroid dependency, the maintenance of remission in chronic active ulcerative colitis and the maintenance of remission after induction of remission with cyclosporin or tacrolimus in acute attacks of disease.

Stange EF. · Bereich Gastroenterologie, Medizinische Klinik, Universität Lübeck. · Med Klin (Munich). · Pubmed #10194947 No free full text.

Abstract: Budesonide in both galenic forms is suitable for the treatment of a flare of Crohn's disease of up to moderate activity. The same holds true for 5-amino-salicylates, although they are less effective. Topical steroids delay but do not prevent relapses. Aminosalicylates may be used in the postoperative situation for prevention of relapse but are not significantly effective after drug-induced remission.