Journal of Gastroenterology

, Volume 45, Issue 6, pp 571–583 | Cite as

New pathophysiological insights and modern treatment of IBD

  • Matthias A. Engel
  • Markus F. NeurathEmail author


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.


Crohn’s disease IBD diagnostics Inflammatory bowel diseases Pathogenesis Therapeutic strategies and options Ulcerative colitis 


  1. 1.
    Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–17.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    Björnsson S, Jóhannsson JH. Inflammatory bowel disease in Iceland, 1990–1994: a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol. 2000;12:31–8.PubMedCrossRefGoogle Scholar
  7. 7.
    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.PubMedCrossRefGoogle Scholar
  8. 8.
    Cho JH, Weaver CT. The genetics of inflammatory bowel disease. Gastroenterology. 2007;133:1327–39.PubMedCrossRefGoogle Scholar
  9. 9.
    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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 24.
    Eckburg PB, Relman DA. The role of microbes in Crohn’s disease. Clin Infect Dis. 2007;44:256–62.PubMedCrossRefGoogle Scholar
  25. 25.
    Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514–21.PubMedCrossRefGoogle Scholar
  26. 26.
    Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006;3:390–407.PubMedCrossRefGoogle Scholar
  27. 27.
    Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008;134:577–94.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 33.
    Hansen J, Sartor RB. Insights from animal models. In: Bernstein CN, editor. IBD yearbook. London: Remedica; 2007. p. 19–55.Google Scholar
  34. 34.
    Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007;133:1670–89.PubMedCrossRefGoogle Scholar
  35. 35.
    Mintz R, Feller ER, Bahr RL, Shah SA. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:135–9.PubMedCrossRefGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 42.
    Masselli G, Brizi GM, Parrella A, Minordi LM, Vecchioli A, Marano P. Crohn disease: magnetic resonance enteroclysis. Abdom Imaging. 2004;29:326–34.PubMedCrossRefGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 52.
    Farrell RJ, LaMont JT. Pathogenesis and clinical manifestations of Clostridium difficile diarrhea and colitis. Curr Top Microbiol Immunol. 2000;250:109–25.PubMedGoogle Scholar
  53. 53.
    Trnka YM, LaMont JT. Association of Clostridium difficile toxin with symptomatic relapse of chronic inflammatory bowel disease. Gastroenterology. 1981;80:693–6.PubMedGoogle Scholar
  54. 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.PubMedCrossRefGoogle Scholar
  55. 55.
    Bolton RP, Sherriff RJ, Read AE. Clostridium difficile associated diarrhea: a role in inflammatory bowel disease? Lancet. 1980;1:383–4.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 57.
    Cleary RK. Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment. Dis Colon Rectum. 1998;41:1435–49.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 66.
    Vernier G, Sendid B, Poulain D, Colombel JF. Relevance of serologic studies in inflammatory bowel disease. Curr Gastroenterol Rep. 2004;6:482–7.PubMedCrossRefGoogle Scholar
  67. 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.PubMedCrossRefGoogle Scholar
  68. 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.PubMedCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedCrossRefGoogle Scholar
  75. 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.PubMedGoogle Scholar
  76. 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.PubMedGoogle Scholar
  77. 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.PubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 80.
    Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative treatments in ulcerative colitis: a meta-analysis. Gut. 1997;40:775–81.PubMedCrossRefGoogle Scholar
  81. 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.PubMedCrossRefGoogle Scholar
  82. 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.PubMedCrossRefGoogle Scholar
  83. 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.CrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedCrossRefGoogle Scholar
  86. 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.CrossRefGoogle Scholar
  87. 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.PubMedCrossRefGoogle Scholar
  88. 88.
    Truelove SC, Watkinson G, Draper G. Comparison of corticosteroid and sulphasalazine therapy in ulcerative colitis. Br Med J. 1962;5321:1708–11.CrossRefGoogle Scholar
  89. 89.
    Reissmann A, Bischoff SC, Fleig W. Ulcerative colitis. Acute episode. Z Gastroenterol. 2004;42:994–8.PubMedCrossRefGoogle Scholar
  90. 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.PubMedCrossRefGoogle Scholar
  91. 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.PubMedCrossRefGoogle Scholar
  92. 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.PubMedCrossRefGoogle Scholar
  93. 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.PubMedGoogle Scholar
  94. 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.PubMedCrossRefGoogle Scholar
  95. 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.PubMedCrossRefGoogle Scholar
  96. 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.PubMedCrossRefGoogle Scholar
  97. 97.
    Truelove SC, Witts LJ. Cortisone and corticotrophin in ulcerative colitis. Br Med J. 1959;34:387–94.CrossRefGoogle Scholar
  98. 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.CrossRefGoogle Scholar
  99. 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.PubMedCrossRefGoogle Scholar
  100. 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.PubMedCrossRefGoogle Scholar
  101. 101.
    Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet. 1974;1:1067–70.PubMedCrossRefGoogle Scholar
  102. 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.PubMedGoogle Scholar
  103. 103.
    Jarnerot G, Rolny P, Sandberg-Gertzen H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology. 1985;89:1005–13.PubMedGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedGoogle Scholar
  106. 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.PubMedGoogle Scholar
  107. 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.PubMedGoogle Scholar
  108. 108.
    Peppercorn MA. 6-mercaptopurine for the management of ulcerative colitis: a concept whose time has come. Am J Gastroenterol. 1996;91:1689–90.Google Scholar
  109. 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.PubMedCrossRefGoogle Scholar
  110. 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.PubMedCrossRefGoogle Scholar
  111. 111.
    Van Deventer SJ. Tumour necrosis factor and Crohn’s disease. Gut. 1997;40:443–8.PubMedGoogle Scholar
  112. 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.PubMedCrossRefGoogle Scholar
  113. 113.
    Rutgeerts P, Vermeire S, Van Assche G. Biological therapies for inflammatory bowel diseases. Gastroenterology. 2009;136:1182–97.PubMedCrossRefGoogle Scholar
  114. 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.PubMedCrossRefGoogle Scholar
  115. 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.PubMedCrossRefGoogle Scholar
  116. 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.PubMedCrossRefGoogle Scholar
  117. 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.PubMedCrossRefGoogle Scholar
  118. 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.PubMedCrossRefGoogle Scholar
  119. 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.PubMedCrossRefGoogle Scholar
  120. 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.PubMedCrossRefGoogle Scholar
  121. 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.PubMedCrossRefGoogle Scholar
  122. 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.PubMedCrossRefGoogle Scholar
  123. 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.PubMedCrossRefGoogle Scholar
  124. 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.PubMedCrossRefGoogle Scholar
  125. 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.PubMedCrossRefGoogle Scholar
  126. 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.PubMedCrossRefGoogle Scholar
  127. 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.PubMedCrossRefGoogle Scholar
  128. 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.PubMedCrossRefGoogle Scholar
  129. 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.PubMedCrossRefGoogle Scholar
  130. 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.CrossRefGoogle Scholar
  131. 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.PubMedCrossRefGoogle Scholar
  132. 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.PubMedGoogle Scholar
  133. 133.
    Ito H. Treatment of Crohn’s disease with anti-IL-6 receptor antibody. J Gastroenterol Suppl. 2005;16:32–4.CrossRefGoogle Scholar
  134. 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.PubMedGoogle Scholar
  135. 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.PubMedCrossRefGoogle Scholar
  136. 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.PubMedGoogle Scholar
  137. 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.PubMedGoogle Scholar
  138. 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.PubMedCrossRefGoogle Scholar
  139. 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.PubMedGoogle Scholar
  140. 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.PubMedCrossRefGoogle Scholar
  141. 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.PubMedCrossRefGoogle Scholar
  142. 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.PubMedCrossRefGoogle Scholar
  143. 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.PubMedCrossRefGoogle Scholar
  144. 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.PubMedCrossRefGoogle Scholar
  145. 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.PubMedGoogle Scholar
  146. 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.PubMedCrossRefGoogle Scholar
  147. 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.PubMedCrossRefGoogle Scholar
  148. 148.
    Brittan M, Wright NA. Gastrointestinal stem cells. J Pathol. 2002;197:492–509.PubMedCrossRefGoogle Scholar
  149. 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.PubMedCrossRefGoogle Scholar
  150. 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.PubMedCrossRefGoogle Scholar
  151. 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.PubMedCrossRefGoogle Scholar
  152. 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.PubMedCrossRefGoogle Scholar
  153. 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.PubMedCrossRefGoogle Scholar
  154. 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.PubMedGoogle Scholar
  155. 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.PubMedCrossRefGoogle Scholar
  156. 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.PubMedCrossRefGoogle Scholar
  157. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  1. 1.First Department of MedicineUniversity of Erlangen-NurembergErlangenGermany
  2. 2.Institute of Physiology and PathophysiologyUniversity of Erlangen-NurembergErlangenGermany

Personalised recommendations