Drugs

, Volume 64, Issue 10, pp 1069–1089 | Cite as

Maintenance of Remission in Crohn’s Disease

Current and Emerging Therapeutic Options
Review Article

Abstract

Crohn’s disease is a chronic inflammatory bowel disorder with a relapsing and remitting course. Once remission is achieved, the main aim of the management of Crohn’s disease is maintenance of that remission. Significant advances have been made into understanding the aetiology and pathogenesis of inflammatory bowel disease. With these advances in understanding come increasing numbers of new agents and therapies, aimed both at active disease and the subsequent maintenance of remission in Crohn’s disease.

Current therapeutic strategies in maintaining remission in Crohn’s disease include 5-aminosalicylates (e.g. sulfasalazine, mesalazine), thiopurines (e.g. azathioprine, 6-mercaptopurine [mercaptopurine]), methotrexate and infliximab. The 5-aminosalicylates appear to have efficacy limited to either surgically induced remission and/or limited small bowel Crohn’s disease. The immunomodulators now have an established role in Crohn’s maintenance. Azathioprine and 6-mercaptopurine are effective in chronic active disease and corticosteroid-dependant Crohn’s disease. Methotrexate has similar indications, although it appears to be an alternative in patients who are intolerant of, or resistant to, the thiopurines.

The most recent breakthrough has been in the field of biological therapy for maintenance of remission in Crohn’s disease. Treatment of patients with the anti-tumour necrosis factor (TNF)-α antibody infliximab has been shown already to be effective in inducing remission. Recent studies have now confirmed a role for infliximab in delaying relapse and maintaining remission in patients responsive to infliximab induction therapy. However, results with soluble TNFα receptors have been disappointing.

A number of other biological and nonbiological agents have shown potential, though trials of the ‘newer’ biological agents have thus far been disappointing, in the maintenance of remission in Crohn’s disease. The evidence for theses agents is currently limited, in many cases to treating active disease; however, these data are discussed in this article in order to provide an overview of future potential therapies.

The aim of this review is to provide clinicians with an insight into current and emerging therapeutic agents for the maintenance of remission of Crohn’s disease.

Notes

Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Kirsner JB. Non-specific inflammatory bowel disease (ulcerative colitis and Crohn’s disease) after 100 years: what next? Ital J Gastroenterol Hepatol 1999; 31: 651–8PubMedGoogle Scholar
  2. 2.
    Best WR, Becktel LM, Singleton JW, et al. Development of a Crohn’s disease activity index. Gastroenterology 1976; 70: 439–44PubMedGoogle Scholar
  3. 3.
    Boirivant M, Leoni M, Tariciotti D, et al. The clinical significance of serum C reactive protein levels in Crohn’s disease: results of a prospective longitudinal study. J Clin Gastroenterol 1998; 1084: 401–5Google Scholar
  4. 4.
    Wyatt J, Vogelsang H, Hubl W, et al. Intestinal permeability and the prediction of relapse in Crohn’s disease. Lancet 1993; 34: 1437–9CrossRefGoogle Scholar
  5. 5.
    Biancone L, Fantini M, Tosti C, et al. Fecal alpha-1-antitrypsin as a marker of clinical relapse in patients with Crohn’s disease of the distal ileum. Eur J Gastroenterol Hepatol 2003; 15: 261–6PubMedCrossRefGoogle Scholar
  6. 6.
    Tibbie JA, Sightorsson G, Bridger S, et al. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 2000; 119: 15–22CrossRefGoogle Scholar
  7. 7.
    Ogura Y, Bonen DK, Inohara N, et al. A frame shift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411: 603–6PubMedCrossRefGoogle Scholar
  8. 8.
    Hampe J, Cuthbert A, Croucher PJP, et al. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 2001; 357: 1925–8PubMedCrossRefGoogle Scholar
  9. 9.
    Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411: 599–603PubMedCrossRefGoogle Scholar
  10. 10.
    Chamaillard M, Philpott D, Giradin SE. Gene-environment interaction modulated by allelic heterogeneity in inflammatory diseases. Proc Natl Acad Sci U S A 2003; 100(6): 3455–60PubMedCrossRefGoogle Scholar
  11. 11.
    Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor κB in inflammatory bowel disease. Gut 1998; 42: 477–84PubMedCrossRefGoogle Scholar
  12. 12.
    Singh B, Read S, Asseman C, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001; 182: 190–200PubMedCrossRefGoogle Scholar
  13. 13.
    Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J Exp Med 2000; 192: 295–302PubMedCrossRefGoogle Scholar
  14. 14.
    Ina K, Itoh J, Fukushima K, et al. Resistance of Crohn’s disease T cells to multiple apoptotic signals is associated with a Bcl-2/ Bax mucosal imbalance. J Immunol 1999; 163: 1081–90PubMedGoogle Scholar
  15. 15.
    Boirivant M, Marini M, Di Felice G, et al. Lamina propria T cells in Crohn’s disease and other gastrointestinal inflammation show defective CD2 pathway-induced apoptosis. Gastroenterology 1999; 116: 557–65PubMedCrossRefGoogle Scholar
  16. 16.
    Reimund LM, Wittersheim C, Dumont S, et al. Increased production of tumour necrosis factor-α, interleukin-1β, and interleukin-6 by morphologically normal intestinal biopsies from patients with Crohn’s disease. Gut 1996; 39: 684–9PubMedCrossRefGoogle Scholar
  17. 17.
    Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocots from patients with chronic active Crohn’s disease by using a capase-dependant pathway. Gastroenterology 2001; 121: 1145–57PubMedCrossRefGoogle Scholar
  18. 18.
    Van Deventer SJH. Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn’s disease. Gastroenterology 2001; 121: 1242–6PubMedCrossRefGoogle Scholar
  19. 19.
    Papadakis KA, Targan SR. Tumour necrosis factor: biology and therapeutic inhibitors. Gastroenterology 2000; 119: 1148–57PubMedCrossRefGoogle Scholar
  20. 20.
    Burns RC, Rivera-Nieves J, Moskaluk CA, et al. Antibody blockade if ICAM-1 and VCAM-1 ameliorates inflammation in the SAMP-1/Yit adoptive transfer model of Crohn’s disease in mice. Gastroenterology 2001; 121: 1428–36PubMedCrossRefGoogle Scholar
  21. 21.
    Schuppan D, Hahn EG. MMPs in the gut: inflammation hits the matrix. Gut 2000; 47: 12–4PubMedCrossRefGoogle Scholar
  22. 22.
    Pender SL, Tickle SP, Docherty AJ, et al. A major role of matrix metalloproteinases in T cell injury in the gut. J Immunol 1997; 158: 1582–90PubMedGoogle Scholar
  23. 23.
    Rutgeerts P, Lofberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994; 331: 842–5PubMedCrossRefGoogle Scholar
  24. 24.
    Gross V, Andus T, Caesar I, et al. Oral pH-dependant budesonide versus 6-methylprednisilone in active Crohn’s disease: German/Austrian Budesonide Study Group. Eur J Gastroenterol Hepatol 1996; 8: 905–9PubMedGoogle Scholar
  25. 25.
    Kane SV, Schoenfeld P, Sandborn WJ, et al. Systematic review: the effectiveness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther 2002; 16(8): 1509–17PubMedCrossRefGoogle Scholar
  26. 26.
    Makins RJ, Cowen RE. 5-Amino-salicylate in the management of inflammatory bowel disease. Colorectal Dis 2001; 3(4): 218–22PubMedCrossRefGoogle Scholar
  27. 27.
    Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Aliment Pharmacol Ther 2001; 15: 1699–708PubMedCrossRefGoogle Scholar
  28. 28.
    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn’s disease. N Engl J Med 1995; 332: 292–7PubMedCrossRefGoogle Scholar
  29. 29.
    Vandell AG, DiPiro JT. Low dosage methotrexate for the treatment and maintenance of remission in patients with inflammatory bowel disease. Pharmacotherapy 2002; 22(5): 613–20CrossRefGoogle Scholar
  30. 30.
    Targan SR, Hanauer SB, Van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumour necrosis factor-α for Crohn’s disease. N Engl J Med 1997; 337: 1029–35PubMedCrossRefGoogle Scholar
  31. 31.
    Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405PubMedCrossRefGoogle Scholar
  32. 32.
    Ricart E, Pannacione R, Leftus EV, et al. Infliximab for Crohn’s disease in clinical practice at the Mayo Clinic: the first 100 patients. Am J Gastroenterol 2001; 96: 722–9PubMedCrossRefGoogle Scholar
  33. 33.
    Farrell RJ, Shah SA, Lodhavia PJ, et al. Clinical experience with infliximab therapy in 100 patients with Crohn’s disease. Am J Gastroenterol 2000; 95: 3490–7PubMedCrossRefGoogle Scholar
  34. 34.
    Camma C, Giunta M, Rosselli M, et al. 5-Aminosalicyclic acid in the maintenance treatment of Crohn’s disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997; 113: 1465–73PubMedCrossRefGoogle Scholar
  35. 35.
    Lochs H, Mayer M, Fleig WE, et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalamine: European Cooperative Crohn’s Disease Study VI. Gastroenterology 2000; 118: 264–73PubMedCrossRefGoogle Scholar
  36. 36.
    Clemett D, Markham A. Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000; 59(4): 929–56PubMedCrossRefGoogle Scholar
  37. 37.
    Pearson DC, May GA, Fick G, et al. Azathioprine for maintaining remission of Crohn’s disease. Cochrane Database Syst Rev 2000; 2: CD2000067Google Scholar
  38. 38.
    Cuillerier E, Lemann M, Bouhnik Y, et al. Azathioprine for prevention of post-operative recurrence in Crohn’s disease: a retrospective study. Eur J Gastroenterol Hepatol 2001; 13(11): 1291–6PubMedCrossRefGoogle Scholar
  39. 39.
    Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine: a long-term randomised double-blind study. N Engl J Med 1980; 302: 981–7PubMedCrossRefGoogle Scholar
  40. 40.
    Bowen DG, Selby WS. Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine. Dig Dis Sci 2000; 45(9): 1810–3PubMedCrossRefGoogle Scholar
  41. 41.
    Boulton-Jones JR, Pritchard K, Mahmoud AA. The use of 6-mercaptopurine in patients with inflammatory bowel disease after failure of azathioprine therapy. Aliment Pharmacol Ther 2000; 14: 1561–5PubMedCrossRefGoogle Scholar
  42. 42.
    Feagan BG, Fedorak RN, Irving EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. Gastroenterology 1999; 28: 297–321Google Scholar
  43. 43.
    Oren R, Moshkowitz M, Odes S, et al. Methotrexate in chronic active Crohn’s disease: a double-blind, randomised, Israeli multicenter trial. Am J Gastroenterol 1997; 92: 2203–9PubMedGoogle Scholar
  44. 44.
    Arora S, Katkov W, Cooley J, et al. Methotrexate in Crohn’s disease: results of a randomised, double-blind, placebo-controlled trial. Hepatogastroenterology 1999; 46: 1724–9PubMedGoogle Scholar
  45. 45.
    Lemann M, Zenjari T, Bouhnik Y, et al. Methotrexate in Crohn’s disease: long-term safety and toxicity. Am J Gastroenterol 2000; 95: 1730–4PubMedGoogle Scholar
  46. 46.
    Baron TH, Truss CD, Elson CO. Low dose methotrexate in refractory inflammatory bowel disease. Dig Dis Sci 1993; 38: 1851–6PubMedCrossRefGoogle Scholar
  47. 47.
    Vandeputte L, D’Haens G, Baert F, et al. Methotrexate in refractory Crohn’s disease. Inflamm Bowel Dis 1999; 5: 11–5CrossRefGoogle Scholar
  48. 48.
    Chong RY, Hanauer SG, Cohen RD. Efficacy of parenteral methotrexate in refractory Crohn’s disease. Aliment Pharmacol Ther 2001; 15: 35–44PubMedCrossRefGoogle Scholar
  49. 49.
    Rutgeerts P, D’Haens ER, Targan SR, et al. Efficacy and safety of retreatment with anti-tumour necrosis factor antibody to maintain remission in Crohn’s disease. Gastroenterology 1999; 117: 761–9PubMedCrossRefGoogle Scholar
  50. 50.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT 1 randomised trial. Lancet 2002; 359: 1541–9PubMedCrossRefGoogle Scholar
  51. 51.
    Summers RW, Switz DM, Sesssions Jr JT, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology 1979; 77: 847–69PubMedGoogle Scholar
  52. 52.
    Hanauer SB, Meyers S. Management of Crohn’s disease in adults. Am J Gastroenterol 1997; 92: 559–66PubMedGoogle Scholar
  53. 53.
    Steinhart AH, Ewe K, Griffiths AM, et al. Corticosteroids for maintenance of remission in Crohn’s disease (Cochrane Review). Cochrane Database Syst Rev 2001; 1: CD000301Google Scholar
  54. 54.
    Greenberg GR, Feagan BG, Martin F, et al. Oral budesonide as maintenance treatment for Crohn’s disease: a placebo-controlled, dose ranging study. Canadian Inflammatory Bowel Disease Study Group. Gastroenterology 1996; 110(1): 45–51Google Scholar
  55. 55.
    Papi C, Luchetti R, Gili L, et al. Budesonide in the treatment of Crohn’s disease: a meta-analysis. Aliment Pharmacol Ther 2000; 14(11): 1419–28PubMedCrossRefGoogle Scholar
  56. 56.
    Stuck AE, Minder CE, Frey EJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 1989; 11: 954–63PubMedCrossRefGoogle Scholar
  57. 57.
    Gurwitz JH, Bohn RL, Glynn RJ, et al. Glucocorticoids and the risk for initiation of hypoglycaemic therapy. Arch Intern Med 1994; 154: 97–101PubMedCrossRefGoogle Scholar
  58. 58.
    Valentine JF, Sninsky CA. Prevention and treatment of osteoporosis in patients with inflammatory bowel disease. Am J Gastroenterol 1999; 94: 878–83PubMedCrossRefGoogle Scholar
  59. 59.
    Malchow H, Ewe K, Brandes JW, et al. European Cooperative Crohn’s Disease Study (ECCDS): results of drug treatment. Gastroenterology 1984; 86(2): 249–66PubMedGoogle Scholar
  60. 60.
    Lennard-Jones JE. Sulphasalazine in asymptomatic Crohn’s disease: a multicentre trial. Gut 1977; 18: 69–72PubMedCrossRefGoogle Scholar
  61. 61.
    Wenckert A, Kristensen M, Eklund AE, et al. The long-term prophylactic effect of salazosulphapyridine (Salazopyrin) in primary resected patients with Crohn’s disease: a controlled double-blind trial. Scand J Gastroenterol 1978; 13: 161–7PubMedCrossRefGoogle Scholar
  62. 62.
    Bergman L, Krause U. Postoperative treatment with corticosteroid and salazosulphapyridine (Salazopyrin) after radical resection for Crohn’s disease. Scand J Gastroenterol 1976; 11: 651–6PubMedGoogle Scholar
  63. 63.
    Modigliani R, Colombel JF, Dupas JL, et al. Mesalamine in Crohn’s disease with steroid-induced remission: effect on steroid withdrawal and remission maintenance. Gastroenterology 1996; 110: 688–93PubMedCrossRefGoogle Scholar
  64. 64.
    Sutherland LR. Prevention of relapse of Crohn’s disease. Inflamm Bowel Dis 2000; 6: 321–8PubMedGoogle Scholar
  65. 65.
    Chan GL, Erdmann GR, Gruber SA, et al. Azathioprine metabolism: pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in transplant patients. J Clin Pharmacol 1990; 30: 358–63PubMedGoogle Scholar
  66. 66.
    Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992; 43: 329–39PubMedCrossRefGoogle Scholar
  67. 67.
    Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(10): 1743–50PubMedCrossRefGoogle Scholar
  68. 68.
    Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyl-transferase activity. Am J Hum Genet 1980; 32: 651–62PubMedGoogle Scholar
  69. 69.
    Bach JF. The mode of action of immunosuppressive agents. Front Biol 1975; 41: 1–374PubMedGoogle Scholar
  70. 70.
    Campbell AC, Skinner JM, Maclennan IF, et al. Immunosuppression in the treatment of inflammatory bowel disease. II: the effect of azathioprine on lymphoid cell populations in a double blind trial in ulcerative colitis. Clin Exp Immunol 1976; 24: 249–58Google Scholar
  71. 71.
    Szawlowski PW, Al Safi SA, Dooley T, et al. Azathioprine suppresses the mixed lymphocyte reaction of patients with Lesch-Nyhan syndrome. Br J Clin Pharmacol 1985; 20: 489–91PubMedCrossRefGoogle Scholar
  72. 72.
    Campbell AC, Skinner JM, Hersey P, et al. Immunosuppression in the treatment of inflammatory bowel disease. I: changes in lymphoid sub-populations in the blood and rectal mucosa following cessation of treatment with azathioprine. Clin Exp Immunol 1974; 16: 521–33Google Scholar
  73. 73.
    Kinlen LJ, Sheil AG, Peto J, et al. Collaborative United Kingdom-Australasian study of cancer in patients treated with immunosuppressive drugs. BMJ 1979; 2: 1461–6PubMedCrossRefGoogle Scholar
  74. 74.
    Connell WR, Kamm MA, Dickson M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994; 343: 1249–52PubMedCrossRefGoogle Scholar
  75. 75.
    Fraser AF, Orchard TR, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine: a 30-year study. Gut 2002; 50(4): 485–9PubMedCrossRefGoogle Scholar
  76. 76.
    Candy S, Wright J, Gerber M, et al. A controlled double-blind study of azathioprine in the management of Crohn’s disease. Gut 1995; 37: 674–8PubMedCrossRefGoogle Scholar
  77. 77.
    Bouhnik Y, Lemann M, Mary JY, et al. Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet 1996; 347: 215–9PubMedCrossRefGoogle Scholar
  78. 78.
    Snow JL, Gibson LE. The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatological patients. Arch Dermatol 1995; 131: 193–7PubMedCrossRefGoogle Scholar
  79. 79.
    Snow JL, Gibson LE. A pharmacogenetic basis for the safe use of azathioprine and other thiopurine drugs in dermatologie patients. J Am Acad Dermatol 1995; 32: 114–6PubMedCrossRefGoogle Scholar
  80. 80.
    Cuffouri C, Hunt S, Bayless T. Utilisation of erythroctye 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001; 48: 642–6CrossRefGoogle Scholar
  81. 81.
    Lowry PW, Franklin CL, Weaver AL, et al. Measurement of thiopurine methyl transferase activity with azathioprine metabolites in patients with inflammatory bowel disease. Gut 2001; 49: 665–70PubMedCrossRefGoogle Scholar
  82. 82.
    Modigliani R. Immunosuppressors for inflammatory bowel disease: how long is long enough? Inflamm Bowel Dis 2000; 6: 251–7PubMedCrossRefGoogle Scholar
  83. 83.
    Fraser AG, Morton D, McGovern D, et al. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002; 16(4): 693–7PubMedCrossRefGoogle Scholar
  84. 84.
    Moshkowitz M, Oren R, Tishler M, et al. The absorption of low-dose methotrexate in patients with inflammatory bowel disease. Aliment Pharmacol Ther 1997; 11: 569–73PubMedCrossRefGoogle Scholar
  85. 85.
    Rampton DS. Methotrexate in Crohn’s disease. Gut 2001; 48: 790–1PubMedCrossRefGoogle Scholar
  86. 86.
    Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000; 95: 3150–6PubMedCrossRefGoogle Scholar
  87. 87.
    Connell WR. Safety of drug therapy in pregnant and nursing women. Inflamm Bowel Dis 1996; 2: 33–47Google Scholar
  88. 88.
    Siegal SA, Shealy DJ, Nakada MT, et al. The mouse/human chimeric monoclonal antibody cA2 neutralizes TNF in vivo and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 1995; 7: 251–9CrossRefGoogle Scholar
  89. 89.
    Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Cytokine 1995; 7: 15–25CrossRefGoogle Scholar
  90. 90.
    Parsi MA, Achkar JP, Richardson S, et al. Predictors of response to infliximab in patients with Crohn’s disease. Gastroen-terology 2002; 123(3): 707–13CrossRefGoogle Scholar
  91. 91.
    Vermeire S, Louis E, Carbonez A, et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumour necrosis factor (Infliximab) treatment in Crohn’s disease. Am J Gastroenterol 2002; 97(9): 2357–63PubMedCrossRefGoogle Scholar
  92. 92.
    Martinez-Borra J, Lopez-Larrea C, Gonzalez S, et al. High serum tumour necrosis factor alpha levels are associated with lack of response to infliximab in fistulizing Crohn’s disease. Am J Gastroenterol 2002; 97(9): 2350–6PubMedGoogle Scholar
  93. 93.
    Rutgeerts P. A critical assessment of new therapies in inflammatory bowel disease. J Gastronterol Hepatol 2002; 17: 5176–85Google Scholar
  94. 94.
    Keane J, Gershan S, Wise RP. Tuberculosis associated with infliximab, a tumour necrosis factor-α neutralizing agent. N Engl J Med 2001; 345: 1098–104PubMedCrossRefGoogle Scholar
  95. 95.
    Bebb JR, Logan RP. Review article: does the use of immunosuppressive therapy in inflammatory bowel disease increase the risk of developing lymphoma? Aliment Pharmacol Ther 2001; 15(12): 1843–9PubMedCrossRefGoogle Scholar
  96. 96.
    Hanauer SB. Review article: safety of infliximab in clinical trial. Aliment Pharmacol Ther 1999; 13 Suppl. 4: 16–22PubMedCrossRefGoogle Scholar
  97. 97.
    Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol 2002; 97(12): 2962–72PubMedCrossRefGoogle Scholar
  98. 98.
    MacPherson A, Khoo UY, Forgacs I, et al. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 1996; 38: 365–75PubMedCrossRefGoogle Scholar
  99. 99.
    Shanahan F. Inflammatory bowel disease: immunodiagnostics, immunotherapeutics and ecotherapeutics. Gastroenterology 2001; 120: 622–35PubMedCrossRefGoogle Scholar
  100. 100.
    Sutherland L, Singleton J, Sessions J, et al. Double blind, placebo controlled trial of metronidazole in Crohn’s disease. Gut 1991; 32(9): 1071–5PubMedCrossRefGoogle Scholar
  101. 101.
    Greenbloom SL, Steinhart AH, Greenberg GR. Combination ciprofloxacin and metronidazole for active Crohn’s disease. Can J Gastroenterol 1998; 12: 53–6PubMedGoogle Scholar
  102. 102.
    Prantera C, Zannoni F, Scribano ML, et al. An antibiotic regimen for the treatment of active Crohn’ s disease: a randomized controlled clinical trial of metronidazole plus ciprofloxacin. Am J Gastroenterol 1996; 91: 328–32PubMedGoogle Scholar
  103. 103.
    Rutgeerts P, Hiele M, Geboes K, et al. Controlled trial of metronidazole for prevention of Crohn’s recurrence after ileal resection. Gastroenterology 1995; 108: 1617–21PubMedCrossRefGoogle Scholar
  104. 104.
    Rutgeerts P, Van Assche G, D’Haens G, et al. Ornidazole for prophylaxis of post operative Crohn’s disease: final results of a double blind placebo-controlled trial [abstract]. Gastroenterology 2002; 122: A60CrossRefGoogle Scholar
  105. 105.
    Cosnes J, Carbonnel F, Carrat F, et al. Respective effects of current and former cigarette smoking on the clinical course of Crohn’s disease. Aliment Pharmacol Ther 1999; 13: 1403–11PubMedCrossRefGoogle Scholar
  106. 106.
    Lindberg E, Jarnerot G, Huitfeldt B. Smoking in Crohn’s disease: effect on localisation and clinical course. Gut 1992; 33: 779–82PubMedCrossRefGoogle Scholar
  107. 107.
    Russel MG, Nieman FH, Bergers JM, et al. Cigarette smoking and quality of life in patients with inflammatory bowel disease. Eur J Gastroenterol 1996; 8: 1075–81CrossRefGoogle Scholar
  108. 108.
    Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of smoking on long-term course of Crohn’s disease. Gastroenterology 1996; 110: 424–31PubMedCrossRefGoogle Scholar
  109. 109.
    Cottone M, Rosselli M, Orlando A, et al. Smoking habits and recurrence in Crohn’s disease. Gastrenterology 1994; 106: 643–8Google Scholar
  110. 110.
    Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn’s disease: an intervention study. Gastroenterology 2001; 120: 1093–9PubMedCrossRefGoogle Scholar
  111. 111.
    Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989; 34: 1841–54PubMedCrossRefGoogle Scholar
  112. 112.
    Heuschkel RB, Menache CC, Megerian JT, et al. Enterai nutrition and corticosteroids in the treatment of acute Crohn’s disease in children. J Pediatr Gastroenterol Nutr 2000; 31: 8–15PubMedCrossRefGoogle Scholar
  113. 113.
    Pearson M, Teahon K, Levi AJ, et al. Food intolerance and Crohn’s disease. Gut 1993; 34: 783–7PubMedCrossRefGoogle Scholar
  114. 114.
    Riordan AM, Hunter JO, Cowan RE, et al. Treatment of active Crohn’s disease by exclusion diet: East Anglian multicentre controlled trial. Lancet 1993; 342: 1131–4PubMedCrossRefGoogle Scholar
  115. 115.
    Verma S, Kirkwood B, Brown S, et al. Oral nutrition supplementation is effective in the maintenance of remission in Crohn’s disease. Dig Liver Dis 2000; 32: 769–74PubMedCrossRefGoogle Scholar
  116. 116.
    Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med 1996; 334: 1557–60PubMedCrossRefGoogle Scholar
  117. 117.
    Lamah M, Scott HJ. Inflammatory bowel disease during pregnancy. Int J Colorectal Dis 2002; 17: 216–22PubMedCrossRefGoogle Scholar
  118. 118.
    Norgard B, Fonager K, Pederson L, et al. Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study. Gut 2003; 52(2): 243–7PubMedCrossRefGoogle Scholar
  119. 119.
    Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynaecol 1993; 82: 348–52Google Scholar
  120. 120.
    Subhani JM, Hamiliton MI. Review article: the management of inflammatory bowel disease during pregnancy. Aliment Pharmacol Ther 1998; 12: 1039–52PubMedCrossRefGoogle Scholar
  121. 121.
    Antoni CE, Furst DE, Manger B, et al. Outcome of pregnancy in women receiving Remicade® (infliximab) for the treatment of Crohn’s disease or rheumatoid arthritis [abstract]. Arthritis Rheum 2001; 44 Suppl. 9: S152Google Scholar
  122. 122.
    Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomised, double-blind, placebo-controlled trial. Gastroenterology 2001; 121(5): 1242–6CrossRefGoogle Scholar
  123. 123.
    Rutgeerts P, Lemmens L, Van Assche G, et al. Treatment of Crohn’s disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomised, open-label, pilot study. Aliment Pharmacol Ther 2003; 17(2): 185–92PubMedCrossRefGoogle Scholar
  124. 124.
    Stack WA, Mann SD, Roy AJ, et al. Randomised controlled trial of CDP-571 antibody to tumour necrosis factor-α in Crohn’s disease. Lancet 1997; 349: 521–4PubMedCrossRefGoogle Scholar
  125. 125.
    Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF (CDP-571) for active Crohn’s disease: a randomized double-blind placebo-controlled. Gastroenterology 2001; 120: 1130–8CrossRefGoogle Scholar
  126. 126.
    Kuhn R, Lohler J, Rennick DM, et al. Interleukin-10-deficient mice develop chronic enterolcolitis. Cell 1993; 75(2): 263–74PubMedCrossRefGoogle Scholar
  127. 127.
    Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest 1996; 98(4): 1010–20PubMedCrossRefGoogle Scholar
  128. 128.
    Davidson NJ, Hudak SA, Lesley RE, et al. IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol 1998; 161(6): 3143–9PubMedGoogle Scholar
  129. 129.
    Asseman C, Mauze S, Leach MW, et al. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 1999; 190(7): 995–1005PubMedCrossRefGoogle Scholar
  130. 130.
    Van-Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in a steroid-refractory Crohn’s disease. Gastroenterology 1997; 113(2): 383–9PubMedCrossRefGoogle Scholar
  131. 131.
    Schreiber S, Fedorak RN, Nielson OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Gastroenterology 2000; 119: 1461–72PubMedCrossRefGoogle Scholar
  132. 132.
    Colombel JF, Rutgeerts P, Malchow HA, et al. Interleukin 10 in the prevention of postoperative recurrence of Crohn’s disease. Gut 2001; 49: 42–6PubMedCrossRefGoogle Scholar
  133. 133.
    Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N Engl J Med 2002; 348(1): 24–32CrossRefGoogle Scholar
  134. 134.
    Gordon FH, Lai CWY, Hamilton MI, et al. A randomized placebo-controlled trial of humanized monoclonal antibody to α4 integrin in active Crohn’s disease. Gastroenterology 2001; 121: 268–74PubMedCrossRefGoogle Scholar
  135. 135.
    Jones SC, Banks RE, Haidar A, et al. Adhesion molecules in inflammatory bowel disease. Gut 1995; 36: 724–30PubMedCrossRefGoogle Scholar
  136. 136.
    Yacyshyn BR, Bowen Yacyshyn MB, Jewells L, et al. A placebo-controlled trial of ICAM-1 antisense oligonucleotide in the treatment of Crohn’s disease. Gastroenterology 1998; 114: 1133–42PubMedCrossRefGoogle Scholar
  137. 137.
    Yacyshyn BR, Chey WY, Goff J, et al. Double-blind, placebo-controlled trial of the remission inducing and steroid sparing properties of an ICAM-1 antisense oligodeoxynucleotide, alicaforsen (ISIS-2302) in active steroid-dependant Crohn’s disease. Gut 2002; 51(1): 30–6PubMedCrossRefGoogle Scholar
  138. 138.
    Yacyshyn BR, Barish C, Goff J, et al. Dose ranging pharmacokinetics trial of high-dose alicaforsen (intercellular adhesion molecule-1 antisense oligodeoxynucleotide) (ISIS 2302) in active Crohn’s disease. Aliment Pharmacol Ther 2002; 16(10): 1761–70PubMedCrossRefGoogle Scholar
  139. 139.
    Dieckgraefe BK, Korzenik JR. Treatment of active Crohn’s disease with recombinant human granulocyte-macrophage colony-stimulating factor. Lancet 2002; 360: 1478–80PubMedCrossRefGoogle Scholar
  140. 140.
    Sands BE, Winston BD, Salzberg B, et al. Randomized, controlled trial of recombinant human interleukin 11 in patients with active Crohn’s disease. Aliment Pharmacol Ther 2002; 16(3): 399–406PubMedCrossRefGoogle Scholar
  141. 141.
    Slonim AE, Bulone L, Damore MB, et al. A preliminary study of growth hormone therapy for Crohn’s disease. N Engl J Med 2000; 342(22): 1633–7PubMedCrossRefGoogle Scholar
  142. 142.
    Franklin TJ, Cook JM. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J 1969; 113: 515–24PubMedGoogle Scholar
  143. 143.
    Miehsler W, Reinisch W, Moser G, et al. Is mycophenolate mofetil an effective alternative in azathioprine-intolerant patients with chronic active Crohn’s disease? Am J Gastroenterol 2001; 96(3): 782–7PubMedCrossRefGoogle Scholar
  144. 144.
    Hassard PV, Vasiliauskas EA, Kam LY, et al. Efficacy of mycophenolate mofetil in patients failing 6-mercaptopurine or azathioprine therapy for Crohn’s disease. Inflamm Bowel Dis 2000; 6(1): 16–20PubMedCrossRefGoogle Scholar
  145. 145.
    Strange EF, Modgiliani R, Pena AS, et al. European trial of cyclosporine in chronic active Crohn’s disease: a 12-month study. The European Study Group. Gastroenterology 1995; 109: 774–82CrossRefGoogle Scholar
  146. 146.
    Jewell DP, Lennard-Jones JE, and The Cyclosporin Study Group of Great Britain and Ireland. Oral cyclosporin for chronic active Crohn’s disease: a multi-centre controlled trial. Eur J Gastroenterol Hepatol 1994; 6: 499–505CrossRefGoogle Scholar
  147. 147.
    Feagan BG, McDonald JW, Rochon J, et al. Low dose cyclosporin for the treatment of Crohn’s disease: the Canadian Crohn’s Relapse Prevention Trial Investigators. N Engl J Med 1994; 330: 1846–51PubMedCrossRefGoogle Scholar
  148. 148.
    Ierardi E, Principi M, Pisani RF, et al. Oral tacrolimus long-term therapy in patients with Crohn’s disease and steroid resistance. Aliment Pharmacol Ther 2001; 15(3): 371–7PubMedCrossRefGoogle Scholar
  149. 149.
    Casson DH, Eltumi M, Tomlin S, et al. Topical tacrolimus may be effective in the treatment of oral and perianal Crohn’s disease. Gut 2000; 47: 436–40PubMedCrossRefGoogle Scholar
  150. 150.
    Moreira A, Sampaio E, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumour necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993; 177: 1675–80PubMedCrossRefGoogle Scholar
  151. 151.
    Wettstein A, Meagher A. Thalidomide in Crohn’s disease. Lancet 1997; 350: 1445–6PubMedCrossRefGoogle Scholar
  152. 152.
    Fishman S, Feins N, D’Amato R, et al. Long-term remission of Crohn’s disease treated with thalidomide: a seminal case report. Angiogenesis 2000; 3: 29–36Google Scholar
  153. 153.
    Vasiliauskas EA, Kam L, Abreu-Martin M, et al. An open-label study of low dose thalidomide in chronically active, steroid-dependant Crohn’s disease. Gastroenterology 1999; 117: 1278–87PubMedCrossRefGoogle Scholar
  154. 154.
    Ethrenpreis ED, Kane SV, Cohen LB, et al. Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999; 117: 1271–7CrossRefGoogle Scholar
  155. 155.
    Sabate JM, Villarejo J, Lemann M, et al. An open-label study of thalidomide for maintenance therapy in chronically active and fistulizing refractory Crohn’s disease. Aliment Pharmacol Ther 2002; 16(6): 1117–24PubMedCrossRefGoogle Scholar
  156. 156.
    Lilly DM, Stillwell RH. Probiotics: growth promoting factors produced by microorganisms. Science 1965; 47: 747–8CrossRefGoogle Scholar
  157. 157.
    Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics: approaching a definition. Am J Clin Nutr 2001 Feb; 73 (2 Suppl.): 361S–4SPubMedGoogle Scholar
  158. 158.
    Malchow HA. Crohn’s disease and Escherichia coli: a new approach in therapy to maintain remission of colonic Crohn’ s disease? J Clin Gastroenterol 1997; 25: 653–8PubMedCrossRefGoogle Scholar
  159. 159.
    Guslandi M, Mezzi G, Sorghi M, et al. Saccharomyces boulardii in maintenance treatment of Crohn’s disease. Dig Dis Sci 2000; 45(7): 1462–4PubMedCrossRefGoogle Scholar
  160. 160.
    Prantera C, Scribano ML, Galasco G, et al. Ineffectiveness of probiotics in preventing recurrence after curative resection for Crohn’s disease: a randomized controlled trial with Lactobacillus GG. Gut 2002; 51: 405–9PubMedCrossRefGoogle Scholar
  161. 161.
    Campieri M, Rizzello F, Venturi A, et al. Combination of antibiotic and probiotic treatment is efficacious in prophylaxis of post operative recurrence of Crohn’s disease: a randomized controlled trial vs mesalazine [abstract]. Gastroenterology 2000; 118: A781CrossRefGoogle Scholar

Copyright information

© Adis data information BV 2004

Authors and Affiliations

  1. 1.Department of GastroenterologyCity General HospitalNorth StaffordshireEngland

Personalised recommendations