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01-06-2010 | Review

New pathophysiological insights and modern treatment of IBD

Authors: Matthias A. Engel, Markus F. Neurath

Published in: Journal of Gastroenterology | Issue 6/2010

Abstract

Inflammatory bowel disease (IBD), which comprises two main types, namely, Crohn’s disease and ulcerative colitis, affects approximately 3.6 million people in the USA and Europe, and an alarming rise in low-incidence areas, such as Asia, is currently being observed. In the last decade, spontaneous mutations in a diversity of genes have been identified, and these have helped to elucidate pathways that can lead to IBD. Animal studies have also increased our knowledge of the pathological dialogue between the intestinal microbiota and components of the innate and adaptive immune systems misdirecting the immune system to attack the colon. Present-day medical therapy of IBD consists of salicylates, corticosteroids, immunosuppressants and immunomodulators. However, their use may result in severe side effects and complications, such as an increased rate of malignancies or infectious diseases. In clinical practice, there is still a high frequency of incomplete or absent response to medical therapy, indicating a compelling need for new therapeutic strategies. This review summarizes current epidemiology, pathogenesis and diagnostic strategies in IBD. It also provides insight in today’s differentiated clinical therapy and describes mechanisms of promising future medicinal approaches.

Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.PubMedCrossRef

Morita N, Toki S, Hirohashi T, Minoda T, Ogawa K, Kono S, et al. Incidence and prevalence of inflammatory bowel disease in Japan: nationwide epidemiological survey during the year 1991. J Gastroenterol. 1995;30:1–4.PubMedCrossRef

Yang SK, Hong WS, Min YI, Kim HY, Yoo JY, Rhee PL, et al. Incidence and prevalence of ulcerative colitis in the Songpa-Kangdong District, Seoul, Korea, 1986–1997. J Gastroenterol Hepatol. 2000;15:1037–42.PubMedCrossRef

Lee YM, Fock K, See SJ, Ng TM, Khor C, Teo EK. Racial differences in the prevalence of ulcerative colitis and Crohn’s disease in Singapore. J Gastroenterol Hepatol. 2000;15:622–5.PubMedCrossRef

Loftus EV Jr, Schoenfeld P, Sandborn WJ. The epidemiology and natural history of Crohn’s disease in population-based patient cohorts from North America: a systematic review. Aliment Pharmacol Ther. 2002;16:51–60.PubMedCrossRef

Björnsson S, Jóhannsson JH. Inflammatory bowel disease in Iceland, 1990–1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol. 2000;12:31–8.PubMedCrossRef

Loftus EV Jr, Silverstein MD, Sandborn WJ, Tremaine WJ, Harmsen WS, Zinsmeister AR. Ulcerative colitis in Olmsted County, Minnesota, 1940–1993: incidence, prevalence, and survival. Gut. 2000;46:336–43.PubMedCrossRef

Cho JH, Weaver CT. The genetics of inflammatory bowel disease. Gastroenterology. 2007;133:1327–39.PubMedCrossRef

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cézard JP, Belaiche J, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.PubMedCrossRef

10.

Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–6.PubMedCrossRef

11.

Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–72.PubMedCrossRef

12.

Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem. 2003;278:5509–12.PubMedCrossRef

13.

Bonen DK, Ogura Y, Nicolae DL, Inohara N, Saab L, Tanabe T, et al. Crohn’s disease-associated NOD2 variants share a signaling defect in response to lipopolysaccharide and peptidoglycan. Gastroenterology. 2003;124:140–6.PubMedCrossRef

14.

Lesage S, Zouali H, Cézard JP, Colombel JF, Belaiche J, Almer S, et al. CARD15/NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet. 2002;70:845–57.PubMedCrossRef

15.

Croucher PJ, Mascheretti S, Hampe J, Huse K, Frenzel H, Stoll M, et al. Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations. Eur J Hum Genet. 2003;11:6–16.PubMedCrossRef

16.

Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y. Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet. 2002;47:469–72.PubMedCrossRef

17.

Leong RW, Armuzzi A, Ahmad T, Wong ML, Tse P, Jewell DP, et al. NOD2/CARD15 gene polymorphisms and Crohn’s disease in the Chinese population. Aliment Pharmacol Ther. 2003;17:1465–70.PubMedCrossRef

18.

Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J Hum Genet. 2007;52:575–83.PubMedCrossRef

19.

Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, Weaver CT. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206:260–76.PubMedCrossRef

20.

Beckwith J, Cong Y, Sundberg JP, Elson CO, Leiter EH. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology. 2005;129:1473–84.PubMedCrossRef

21.

Farmer MA, Sundberg JP, Bristol IJ, Churchill GA, Li R, Elson CO, et al. A major quantitative trait locus on chromosome 3 controls colitis severity in IL-10-deficient mice. Proc Natl Acad Sci USA. 2001;98:13820–5.PubMedCrossRef

22.

Kozaiwa K, Sugawara K, Smith MF Jr, Carl V, Yamschikov V, Belyea B, et al. Identification of a quantitative trait locus for ileitis in a spontaneous mouse model of Crohn’s disease: SAMP1/YitFc. Gastroenterology. 2003;125:477–90.PubMedCrossRef

23.

Sugawara K, Olson TS, Moskaluk CA, Stevens BK, Hoang S, Kozaiwa K, et al. Linkage to peroxisome proliferator-activated receptor-gamma in SAMP1/YitFc mice and in human Crohn’s disease. Gastroenterology. 2005;128:351–60.PubMedCrossRef

24.

Eckburg PB, Relman DA. The role of microbes in Crohn’s disease. Clin Infect Dis. 2007;44:256–62.PubMedCrossRef

25.

Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514–21.PubMedCrossRef

26.

Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407.PubMedCrossRef

27.

Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.PubMedCrossRef

28.

Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–94.PubMedCrossRef

29.

Swidsinski A, Ladhoff A, Pernthaler A, Swidsinski S, Loening-Baucke V, Ortner M, et al. Mucosal flora in inflammatory bowel disease. Gastroenterology. 2002;122:44–54.PubMedCrossRef

30.

Pierik M, Joossens S, Van Steen K, Van Schuerbeek N, Vlietinck R, Rutgeerts P, et al. Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis. 2006;12:1–8.PubMedCrossRef

31.

Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–11.PubMedCrossRef

32.

Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39:596–604.PubMedCrossRef

33.

Hansen J, Sartor RB. Insights from animal models. In: Bernstein CN, editor. IBD yearbook. London: Remedica; 2007. p. 19–55.

34.

Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007;133:1670–89.PubMedCrossRef

35.

Mintz R, Feller ER, Bahr RL, Shah SA. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:135–9.PubMedCrossRef

36.

Ghosh S, Cowen S, Hannan WJ, Ferguson A. Low bone mineral density in Crohn’s disease, but not in ulcerative colitis, at diagnosis. Gastroenterology. 1994;107:1031–9.PubMed

37.

Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. Br Med J. 1989;298:82–6.CrossRef

38.

Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology. 1976;70:439–44.PubMed

39.

Wolfson DM, Sachar DB, Cohen A, Goldberg J, Styczynski R, Greenstein AJ, et al. Granulomas do not affect postoperative recurrence rates in Crohn’s disease. Gastroenterology. 1982;83:405–9.PubMed

40.

Keller KM, Bender SW, Kirchmann H, Ball F, Schmitz-Moormann P, Wirth S, et al. Diagnostic significance of epithelioid granulomas in Crohn’s disease in children. Multicenter Paediatric Crohn’s Disease Study Group. J Pediatr Gastroenterol Nutr. 1990;10:27–32.PubMedCrossRef

41.

Bernstein CN, Greenberg H, Boult I, Chubey S, Leblanc C, Ryner L. A prospective comparison study of MRI versus small bowel follow-through in recurrent Crohn’s disease. Am J Gastroenterol. 2005;100:2493–502.PubMedCrossRef

42.

Masselli G, Brizi GM, Parrella A, Minordi LM, Vecchioli A, Marano P. Crohn disease: magnetic resonance enteroclysis. Abdom Imaging. 2004;29:326–34.PubMedCrossRef

43.

Maconi G, Parente F, Bollani S, Cesana B, Bianchi Porro G. Abdominal ultrasound in the assessment of extent and activity of Crohn’s disease: clinical significance and implication of bowel wall thickening. Am J Gastroenterol. 1996;91:1604–9.PubMed

44.

Bremner AR, Griffiths M, Argent JD, Fairhurst JJ, Beattie RM. Sonographic evaluation of inflammatory bowel disease: a prospective, blinded, comparative study. Pediatr Radiol. 2006;36:947–53.PubMedCrossRef

45.

Heyne R, Rickes S, Bock P, Schreiber S, Wermke W, Lochs H. Non-invasive evaluation of activity in inflammatory bowel disease by power Doppler sonography. Z Gastroenterol. 2002;40:171–5.PubMedCrossRef

46.

Fraquelli M, Colli A, Casazza G, Paggi S, Colucci A, Massironi S, et al. Role of US in detection of Crohn disease: meta-analysis. Radiology. 2005;236:95–101.PubMedCrossRef

47.

Parente F, Greco S, Molteni M, Anderloni A, Sampietro GM, Danelli PG, et al. Oral contrast enhanced bowel ultrasonography in the assessment of small intestine Crohn’s disease. A prospective comparison with conventional ultrasound, X-ray studies, and ileocolonoscopy. Gut. 2004;53:1652–7.PubMedCrossRef

48.

Papadakis KA, Tung JK, Binder SW, Kam LY, Abreu MT, Targan SR, et al. Outcome of cytomegalovirus infections in patients with inflammatory bowel disease. Am J Gastroenterol. 2001;96:2137–42.PubMedCrossRef

49.

Vega R, Bertran X, Menacho M, Domenech E, Moreno de Vega V, Hombrados M, et al. Cytomegalovirus in patients with inflammatory bowel disease. Am J Gastroenterol. 1999;94:1053–6.PubMedCrossRef

50.

Pfau P, Kochman ML, Furth EE, Lichtenstein GR. Cytomegalovirus colitis complicating ulcerative colitis in the steroid-naive patient. Am J Gastroenterol. 2001;96:895–9.PubMedCrossRef

51.

Cottone M, Pietrosi G, Martorana G, Casa A, Pecoraro G, Oliva L, et al. Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn’s colitis. Am J Gastroenterol. 2001;96:773–5.PubMedCrossRef

52.

Farrell RJ, LaMont JT. Pathogenesis and clinical manifestations of Clostridium difficile diarrhea and colitis. Curr Top Microbiol Immunol. 2000;250:109–25.PubMed

53.

Trnka YM, LaMont JT. Association of Clostridium difficile toxin with symptomatic relapse of chronic inflammatory bowel disease. Gastroenterology. 1981;80:693–6.PubMed

54.

Greenfield C, Aguilar Ramirez JR, Pounder RE, Williams T, Danvers M, et al. Clostridium difficile and inflammatory bowel disease. Gut. 1983;24:713–7.PubMedCrossRef

55.

Bolton RP, Sherriff RJ, Read AE. Clostridium difficile associated diarrhea: a role in inflammatory bowel disease? Lancet. 1980;1:383–4.PubMedCrossRef

56.

Markowitz JE, Brown KA, Mamula P, Drott HR, Piccoli DA, Baldassano RN. Failure of single-toxin assays to detect Clostridium difficile infection in pediatric inflammatory bowel disease. Am J Gastroenterol. 2001;96:2688–90.PubMedCrossRef

57.

Cleary RK. Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment. Dis Colon Rectum. 1998;41:1435–49.PubMedCrossRef

58.

Standaert-Vitse A, Jouault T, Vandewalle P, Mille C, Seddik M, Sendid B, et al. Candida albicans is an immunogen for anti-Saccharomyces cerevisiae antibody markers of Crohn’s disease. Gastroenterology. 2006;130:1764–75.PubMedCrossRef

59.

Peeters M, Joossens S, Vermeire S, Vlietinck R, Bossuyt X, Rutgeerts P. Diagnostic value of anti-Saccharomyces cerevisiae and antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease. Am J Gastroenterol. 2001;96:730–4.PubMedCrossRef

60.

Riis L, Vind I, Vermeire S, Wolters F, Katsanos K, Politi P, et al. The prevalence of genetic and serologic markers in an unselected European population-based cohort of IBD patients. Inflamm Bowel Dis. 2007;13:24–32.PubMedCrossRef

61.

Mow WS, Vasiliauskas EA, Lin YC, Fleshner PR, Papadakis KA, Taylor KD, et al. Association of antibody responses to microbial antigens and complications of small bowel Crohn’s disease. Gastroenterology. 2004;126:414–24.PubMedCrossRef

62.

Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, et al. Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest. 2004;113:1296–306.PubMed

63.

Targan SR, Landers CJ, Yang H, Lodes MJ, Cong Y, Papadakis KA, et al. Antibodies to CBir1 flagellin define a unique response that is associated independently with complicated Crohn’s disease. Gastroenterology. 2005;128:2020–8.PubMedCrossRef

64.

Sutton CL, Kim J, Yamane A, Dalwadi H, Wei B, Landers C, et al. Identification of a novel bacterial sequence associated with Crohn’s disease. Gastroenterology. 2000;119:23–31.PubMedCrossRef

65.

Landers CJ, Cohavy O, Misra R, Yang H, Lin YC, Braun J, et al. Selected loss of tolerance evidenced by Crohn’s disease-associated immune responses to auto- and microbial antigens. Gastroenterology. 2002;123:689–99.PubMedCrossRef

66.

Vernier G, Sendid B, Poulain D, Colombel JF. Relevance of serologic studies in inflammatory bowel disease. Curr Gastroenterol Rep. 2004;6:482–7.PubMedCrossRef

67.

Ruemmele FM, Targan SR, Levy G, Dubinsky M, Braun J, Seidman EG. Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease. Gastroenterology. 1998;115:822–9.PubMedCrossRef

68.

Papp M, Altorjay I, Norman GL, Shums Z, Palatka K, Vitalis Z, et al. Seroreactivity to microbial components in Crohn’s disease is associated with ileal involvement, noninflammatory disease behavior and NOD2/CARD15 genotype, but not with risk for surgery in a Hungarian cohort of IBD patients. Inflamm Bowel Dis. 2007;13:984–92.PubMedCrossRef

69.

Zholudev A, Zurakowski D, Young W, Leichtner A, Bousvaros A. Serologic testing with ANCA, ASCA, and anti-OmpC in children and young adults with Crohn’s disease and ulcerative colitis: diagnostic value and correlation with disease phenotype. Am J Gastroenterol. 2004;99:2235–41.PubMedCrossRef

70.

Joossens S, Colombel JF, Landers C, Poulain D, Geboes K, Bossuyt X, et al. Anti-outer membrane of porin C and anti-I2 antibodies in indeterminate colitis. Gut. 2006;55:1667–9.PubMedCrossRef

71.

Schreiber S, Nikolaus S, Hampe J, Hämling J, Koop I, Groessner B, et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn’s disease. Lancet. 1999;353:459–61.PubMedCrossRef

72.

Tibble J, Teahon K, Thjodleifsson B, Roseth A, Sigthorsson G, Bridger S, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut. 2000;47:506–13.PubMedCrossRef

73.

Costa F, Mumolo MG, Ceccarelli L, Bellini M, Romano MR, Sterpi C, et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn’s disease. Gut. 2005;54:364–8.PubMedCrossRef

74.

Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology. 2000;119:15–22.PubMedCrossRef

75.

Wyatt J, Oberhuber G, Pongratz S, Püspök A, Moser G, Novacek G, et al. Increased gastric and intestinal permeability in patients with Crohn’s disease. Am J Gastroenterol. 1997;92:1891–6.PubMed

76.

Teahon K, Smethurst P, Pearson M, Levi AJ, Bjarnason I. The effect of elemental diet on intestinal permeability and inflammation in Crohn’s disease. Gastroenterology. 1991;101:84–9.PubMed

77.

Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986;105:883–5.PubMed

78.

Olaison G, Sjodahl R, Tagesson C. Decreased gastrointestinal absorption of peroral polyethyleneglycols (PEG 1000) in Crohn’s disease. A sign of jejunal abnormality. Acta Chir Scand. 1987;153:373–7.PubMed

79.

Heuman R, Sjodahl R, Tagesson C. Passage of molecules through the wall of the gastrointestinal tract. Intestinal permeability to polyethyleneglycol 1000 in patients with Crohn’s disease. Acta Chir Scand. 1982;148:281–4.PubMed

80.

Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut. 1997;40:775–81.PubMedCrossRef

81.

Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol. 2000;95:1263–76.PubMedCrossRef

82.

Mulder CJ, Fockens P, Meijer JW, van der Heide H, Wiltink EH, Tytgat GN. Beclomethasone dipropionate (3 mg) versus 5-aminosalicylic acid (2 g) versus the combination of both (3 mg/2 g) as retention enemas in active ulcerative proctitis. Eur J Gastroenterol Hepatol. 1996;8:549–53.PubMedCrossRef

83.

Somerville KW, Langman MJ, Kane SP, MacGilchrist AJ, Watkinson G, Salmon P. Effect of treatment on symptoms and quality of life in patients with ulcerative colitis: comparative trial of hydrocortisone acetate foam and prednisolone 21-phosphate enemas. Br Med J (Clin Res Ed). 1985;291:866.CrossRef

84.

Lofberg R, Ostergaard Thomsen O, Langholz E, Langholz E, Schioler R, et al. Budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Aliment Pharmacol Ther. 1994;8:623–9.PubMedCrossRef

85.

Lemann M, Galian A, Rutgeerts P, Van Heuverzwijn R, Cortot A, Viteau JM, et al. Comparison of budesonide and 5-aminosalicylic acid enemas in active distal ulcerative colitis. Aliment Pharmacol Ther. 1995;9:557–62.PubMedCrossRef

86.

Bianchi Porro G, Prantera C, Campieri M. Comparative trial of methylprednisolone and budesonide enemas in inactive distal ulcerative colitis. Eur J Gastroenterol Hepatol. 1994;6:125–30.CrossRef

87.

Lofberg R, Danielsson A, Suhr O, Suhr O, Nilsson A, Schioler R, et al. Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis. Gastroenterology. 1996;110:1713–8.PubMedCrossRef

88.

Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. Br Med J. 1962;5321:1708–11.CrossRef

89.

Reissmann A, Bischoff SC, Fleig W. Ulcerative colitis. Acute episode. Z Gastroenterol. 2004;42:994–8.PubMedCrossRef

90.

Thomsen OO, Cortot A, Jewel D, Wright JP, Winter T, Veloso FT, et al. A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide-Mesalamine Study Group. N Engl J Med. 1998;339:370–4.PubMedCrossRef

91.

Bar-Meir S, Chowers Y, Lavy A, Lavy A, Abramovitch D, Sternberg A, et al. Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli Budesonide Study Group. Gastroenterology. 1998;115:835–40.PubMedCrossRef

92.

Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell D, et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med. 1994;331:842–5.PubMedCrossRef

93.

Gross V, Andus T, Caesar I, Bischoff SC, Lochs H, Tromm A, et al. Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn’s disease. German/Austrian Budesonide Study Group. Eur J Gastroenterol Hepatol. 1996;8:905–9.PubMed

94.

Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral budesonide is as effective as oral prednisolone in active Crohn’s disease. The Global Budesonide Study Group. Gut. 1997;41:209–14.PubMedCrossRef

95.

Kane SV, Schoenfeld P, Sandborn WJ, Tremaine W, Hofer T, Feagan BG. The effectiveness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther. 2002;16:1509–17.PubMedCrossRef

96.

Van Hees PA, Van Lier HJ, Van Elteren PH, Driessen M, Van Hogezand RA, Ten Velde GP, et al. Effect of sulphasalazine in patients with active Crohn’s disease: a controlled double-blind study. Gut. 1981;22:404–9.PubMedCrossRef

97.

Truelove SC, Witts LJ. Cortisone and corticotrophin in ulcerative colitis. Br Med J. 1959;34:387–94.CrossRef

98.

Lennard-Jones JE, Mickiewicz JJ, Connell AM, Baron JH, Jones FA. Prednisone as maintenance treatment for ulcerative colitis in remission. Lancet. 1965;191:188–9.CrossRef

99.

Powell-Tuck J, Bown RL, Chambers TJ, Lennard-Jones JE. A controlled trial of alternate day prednisolone as a maintenance treatment for ulcerative colitis in remission. Digestion. 1981;22:263–70.PubMedCrossRef

100.

Truelove SC, Willoughby CP, Lee EG, Kettlewell MG. Further experience in the treatment of severe attacks of ulcerative colitis. Lancet. 1978;2:1086–8.PubMedCrossRef

101.

Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet. 1974;1:1067–70.PubMedCrossRef

102.

Meyers S, Sachar DB, Goldberg JD, Janowitz HD. Corticotropin versus hydrocortisone in the intravenous treatment of ulcerative colitis. A prospective, randomized, double-blind clinical trial. Gastroenterology. 1983;85:351–7.PubMed

103.

Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology. 1985;89:1005–13.PubMed

104.

Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet. 1994;343:1249–52.PubMedCrossRef

105.

Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641–9.PubMed

106.

Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol. 1996;91:423–33.PubMed

107.

Haber CJ, Meltzer SJ, Present DH, Korelitz BI. Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease. Gastroenterology. 1986;91:982–6.PubMed

108.

Peppercorn MA. 6-mercaptopurine for the management of ulcerative colitis: a concept whose time has come. Am J Gastroenterol. 1996;91:1689–90.

109.

Kandiel A, Fraser AG, Korelitz BI, Brensinger C, Lewis JD. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut. 2005;54:1121–5.PubMedCrossRef

110.

Lichtenstein GR, Abreu MT, Cohen R, Tremaine W, American Gastroenterological Association. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:940–87.PubMedCrossRef

111.

Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40:443–8.PubMed

112.

Schwartz DA, Wiersema MJ, Dudiak KM, Fletcher JG, Clain JE, Tremaine WJ, et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology. 2001;121:1064–72.PubMedCrossRef

113.

Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–97.PubMedCrossRef

114.

Kitchin JE, Pomeranz MK, Pak G, Washenik K, Shupack JL. Rediscovering mycophenolic acid: a review of its mechanism, side effects, and potential uses. J Am Acad Dermatol. 1997;37:445–9.PubMedCrossRef

115.

Orth T, Peters M, Schlaak JF, Krummenauer F, Wanitschke R, Mayet WJ, et al. Mycophenolate mofetil versus azathioprine in patients with chronic active ulcerative colitis: a 12-month pilot study. Am J Gastroenterol. 2000;95:1201–7.PubMedCrossRef

116.

Papadimitriou JC, Cangro CB, Lustberg A, Khaled A, Nogueira J, Wiland A, et al. Histologic features of mycophenolate mofetil-related colitis: a graft-versus host disease-like pattern. Int J Surg Pathol. 2003;11:295–302.PubMedCrossRef

117.

Dalle IJ, Maes BD, Geboes KP, Lemahieu W, Geboes K. Crohn’s-like changes in the colon due to mycophenolate? Colorectal Dis. 2005;7:27–34.PubMedCrossRef

118.

Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–6.PubMedCrossRef

119.

Zhang Z, Zheng M, Bindas J, Schwarzenberger P, Kolls JK. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis. 2006;12:382–8.PubMedCrossRef

120.

Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn’s disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody. Inflamm Bowel Dis. 2006;12:9–15.PubMedCrossRef

121.

Schmidt C, Giese T, Ludwig B, Mueller-Molaian I, Marth T, Zeuzem S, et al. Expression of interleukin-12-related cytokine transcripts in inflammatory bowel disease: elevated interleukin-23p19 and interleukin-27p28 in Crohn’s disease but not in ulcerative colitis. Inflamm Bowel Dis. 2005;11:16–23.PubMedCrossRef

122.

Fujino S, Andoh A, Bamba S, Ogawa A, Hata K, Araki Y, et al. Increased expression of interleukin 17 in inflammatory bowel disease. Gut. 2003;52:65–70.PubMedCrossRef

123.

Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med. 2000;6:583–8.PubMedCrossRef

124.

Kusugami K, Fukatsu A, Tanimoto M, Shinoda M, Haruta J, Kuroiwa A, et al. Elevation of interleukin-6 in inflammatory bowel disease is macrophage- and epithelial cell-dependent. Dig Dis Sci. 1995;40:949–59.PubMedCrossRef

125.

Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, et al. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989;58:573–81.PubMedCrossRef

126.

Reinisch W, Gasché C, Tillinger W, Wyatt J, Lichtenberger C, Willheim M, et al. Clinical relevance of serum interleukin-6 in Crohn’s disease: single point measurements, therapy monitoring, and prediction of clinical relapse. Am J Gastroenterol. 1999;94:2156–64.PubMedCrossRef

127.

Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, et al. Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol. 1993;94:174–81.PubMedCrossRef

128.

Van Kemseke C, Belaiche J, Louis E. Frequently relapsing Crohn’s disease is characterized by persistent elevation in interleukin-6 and soluble interleukin-2 receptor serum levels during remission. Int J Colorectal Dis. 2000;15:206–10.PubMedCrossRef

129.

Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V, et al. A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol. 1997;9:939–44.PubMedCrossRef

130.

Mülberg J, Schooltink H, Stoyan T, Günther M, Graeve L, Buse G, et al. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol. 1993;23:473–80.CrossRef

131.

Mitsuyama K, Toyonaga A, Sasaki E, Ishida O, Ikeda H, Tsuruta O, et al. Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut. 1995;36:45–9.PubMedCrossRef

132.

Yamamoto M, Yoshizaki K, Kishimoto T, Ito H. IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol. 2000;164:4878–82.PubMed

133.

Ito H. Treatment of Crohn’s disease with anti-IL-6 receptor antibody. J Gastroenterol Suppl. 2005;16:32–4.CrossRef

134.

Stronkhorst A, Radema S, Yong SL, Bijl H, ten Berge IJ, Tytgat GN, et al. CD4 antibody treatment in patients with active Crohn’s disease: a phase 1 dose finding study. Gut. 1997;40:320–7.PubMed

135.

Westbrook CA, Chmura SJ, Arenas RB, Kim SY, Otto G. Human APC gene expression in rodent colonic epithelium in vivo using liposomal gene delivery. Hum Mol Genet. 1994;3:2005–10.PubMedCrossRef

136.

Schmid RM, Weidenbach H, Draenert GF, Lerch MM, Liptay S, Schorr J, et al. Liposome mediated in vivo gene transfer into different tissues of the gastrointestinal tract. Z Gastroenterol. 1994;32:665–70.PubMed

137.

Katsel PL, O’Connell B, Mizuno TM, Mobbs CV, Greenstein RJ. Liposome mediated gene transfer into GH3 cells, and rat brain, liver and gut: comparison of different polar or aliphatic domains. Int J Surg Investig. 2000;1:415–29.PubMed

138.

Lozier JN, Yankaskas JR, Ramsey WJ, Chen L, Berschneider H, Morgan RA. Gut epithelial cells as targets for gene therapy of hemophilia. Hum Gene Ther. 1997;8:1481–90.PubMedCrossRef

139.

Li M, Lonial H, Citarella R, Lindh D, Colina L, Kramer R. Tumor inhibitory activity of anti-ras ribozymes delivered by retroviral gene transfer. Cancer Gene Ther. 1996;3:221–9.PubMed

140.

Seppen J, Barry SC, Klinkspoor JH, Katen LJ, Lee SP, Garcia JV, et al. Apical gene transfer into quiescent human and canine polarized intestinal epithelial cells by lentivirus vectors. J Virol. 2000;74:7642–5.PubMedCrossRef

141.

During MJ, Xu R, Young D, Kaplitt MG, Sherwin RS, Leone P. Peroral gene therapy of lactose intolerance using an adeno-associated virus vector. Nat Med. 1998;4:1131–5.PubMedCrossRef

142.

During MJ, Symes CW, Lawlor PA, Lin J, Dunning J, Fitzsimons HL, et al. An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science. 2000;287:1453–60.PubMedCrossRef

143.

Wirtz S, Galle PR, Neurath MF. Efficient gene delivery to the inflamed colon by local administration of recombinant adenoviruses with normal or modified fibre structure. Gut. 1999;44:800–7.PubMedCrossRef

144.

Cheng DY, Kolls JK, Lei D, Noel RA. In vivo and in vitro gene transfer and expression in rat intestinal epithelial cells by E1-deleted adenoviral vector. Hum Gene Ther. 1997;8:755–64.PubMedCrossRef

145.

Huard J, Lochmüller H, Acsadi G, Jani A, Massie B, Karpati G. The route of administration is a major determinant of the transduction efficiency of rat tissues by adenoviral recombinants. Gene Ther. 1995;2:107–15.PubMed

146.

Croyle MA, Walter E, Janich S, Roessler BJ, Amidon GL. Role of integrin expression in adenovirus-mediated gene delivery to the intestinal epithelium. Hum Gene Ther. 1998;9:561–73.PubMedCrossRef

147.

Foreman PK, Wainwright MJ, Alicke B, Kovesdi I, Wickham TJ, Smith JG, et al. Adenovirus-mediated transduction of intestinal cells in vivo. Hum Gene Ther. 1998;9:1313–21.PubMedCrossRef

148.

Brittan M, Wright NA. Gastrointestinal stem cells. J Pathol. 2002;197:492–509.PubMedCrossRef

149.

Booth C, O’Shea JA, Potten CS. Maintenance of functional stem cells in isolated and cultured adult intestinal epithelium. Exp Cell Res. 1999;249:359–66.PubMedCrossRef

150.

Ishikawa T, Iwanami K, Okuda T, Zhu Y, Fukuda A, Zhang S, et al. Intestinal function and morphology after ex vivo irradiated small bowel transplantation. Transplant Proc. 2002;34:988–9.PubMedCrossRef

151.

Kitani A, Fuss IJ, Nakamura K, Schwartz OM, Usui T, Strober W. Treatment of experimental (trinitrobenzene sulfonic acid) colitis by intranasal administration of transforming growth factor (TGF)-beta1 plasmid: TGF-beta1-mediated suppression of T helper cell type 1 response occurs by interleukin (IL)-10 induction and IL-12 receptor beta2 chain downregulation. J Exp Med. 2000;192:41–52.PubMedCrossRef

152.

Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM. Interleukin 10 gene transfer prevents experimental colitis in rats. Gut. 2000;46:344–9.PubMedCrossRef

153.

Lindsay J, Van Montfrans C, Brennan F, Van Deventer S, Drillenburg P, Hodgson H, et al. IL-10 gene therapy prevents TNBS-induced colitis. Gene Ther. 2002;9:1715–21.PubMedCrossRef

154.

Lindsay JO, Ciesielski CJ, Scheinin T, Hodgson HJ, Brennan FM. The prevention and treatment of murine colitis using gene therapy with adenoviral vectors encoding IL-10. J Immunol. 2001;166:7625–33.PubMed

155.

Van Montfrans C, Rodriguez Pena MS, Pronk I, Ten Kate FJ, Te Velde AA, Van Deventer SJ. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology. 2002;123:1865–76.PubMedCrossRef

156.

Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, et al. Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn’s disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group. Gastroenterology. 2000;119:1473–82.PubMedCrossRef

157.

Tilg H, van Montfrans C, van den Ende A, Kaser A, van Deventer SJ, Schreiber S, et al. Treatment of Crohn’s disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma. Gut. 2002;50:191–5.PubMedCrossRef

Title: New pathophysiological insights and modern treatment of IBD
Authors: Matthias A. Engel
Markus F. Neurath
Publication date: 01-06-2010
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 6/2010
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-010-0219-3

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