Current Gastroenterology Reports

, Volume 4, Issue 6, pp 506–512 | Cite as

Advances in medical therapy for Crohn’s disease

  • Geert D’Haens
  • Marco Daperno
Article

Abstract

Management of Crohn’s disease has changed considerably in recent years. The discovery of tumor necrosis factor (TNF) as a pivotal cytokine in the inflammatory cascade has led to the development of several neutralizing antibodies, soluble receptors, and small molecules, interfering with TNF gene transcription and expression. Infliximab is the only monoclonal antibody that is commercially available. This potent molecule is effective for both active and fistulizing disease in the acute and maintenance phases of treatment. In addition to anti-TNF agents, weekly methotrexate injection and the classic "antimetabolites" azathioprine and 6-mercaptopurine remain highly valuable as maintenance drugs. "Tailored" antimetabolite therapy has now become possible with metabolite measurements and determination of the TPMT gene. The active metabolite thioguanine itself could be a promising alternative in patients who are intolerant of 6-mercaptopurine. In fistulizing disease, infliximab is becoming the treatment of choice, although fistula tracks do not disappear permanently and many patients still need surgical intervention.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance

  1. 1.
    Munkholm P, Langholz E, Davidsen M, Binder V: Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 1994, 35:360–362.PubMedGoogle Scholar
  2. 2.
    Rutgeerts P, Lofberg R, Malchow H, et al.: A comparison of budesonide with prednisolone for active Crohn’s disease. N Engl J Med 1994, 331:842–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Bar-Meir S, Chowers Y, Lavy A, et al.: Budesonide versus prednisone in the treatment of active Crohn’s disease. Gastroenterology 1998, 115:835–840.PubMedCrossRefGoogle Scholar
  4. 4.
    Thomsen OO, Cortot A, Jewell D, et al.: A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide-Mesalamine Study Group. N Engl J Med 1998, 339:370–374.PubMedCrossRefGoogle Scholar
  5. 5.
    Papi C, Luchetti R, Gili L, et al.: Budesonide in the treatment of Crohn’s disease: a meta-analysis. Aliment Pharmacol Ther 2000, 14:1419–1428.PubMedCrossRefGoogle Scholar
  6. 6.
    Targan SR, Hanauer SB, van Deventer SJ, et al.: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997, 337:1029–1035.PubMedCrossRefGoogle Scholar
  7. 7.
    D’Haens G, van Deventer S, Van Hogezand R, et al.: Endoscopic and histological healing with infliximab antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999, 116:1029–1034.PubMedCrossRefGoogle Scholar
  8. 8.
    Ten Hove T, van Montfrans C, Peppelenbosch MP, van Deventer SJH: Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002, 50:206–211.PubMedCrossRefGoogle Scholar
  9. 9.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al.: Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002, 359:1541–1549. The largest controlled trial in Crohn’s disease to date. Because of its meticulous but complex design, many questions were addressed at the same time. Results show that both systematic and "on demand" retreatment with infliximab are effective.PubMedCrossRefGoogle Scholar
  10. 10.
    Kugathasan S, Werlin SL, Martinez A, et al.: Prolonged duration of response to infliximab in early but not late pediatric Crohn’s disease. Am J Gastroenterol 2000, 95:3089–3194.CrossRefGoogle Scholar
  11. 11.
    Keane J, Gershon S, Wise RP, Mirabile-Levens E: Tuberculosis associated with infliximab, a tumor necrosis factor alphaneutralizing agent. N Engl J Med 2001, 345:1098–1104.PubMedCrossRefGoogle Scholar
  12. 12.
    Mow WS, Abreu MT, Papadakis KA, et al.: High incidence of anergy limits the usefulness of PPD screening for tuberculosis prior to Remicade in inflammatory bowel disease [abstract]. Gastroenterology 2002, 122:A100.Google Scholar
  13. 13.
    Noman M, Baert F, Vermeire S, et al.: Post infusion infliximab levels determine duration of response in Crohn’s disease and are directly related to infusion reactions [abstract]. Gastroenterology 2002, 122:A100.Google Scholar
  14. 14.
    Alsahli M, Jeen YT, Peppercorn M, et al.: A randomized, double-blind, placebo-controlled trial of intravenous hydrocortisone in reducing human anti-chimeric antibody following infliximab therapy [abstract]. Gastroenterology 2002, 122:A100.Google Scholar
  15. 15.
    Sandborn WJ, Feagan BG, Hanauer SB, et al.: An engineered human antibody to TNF (CDP571) for active Crohn’s disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001, 120:1330–1338. This study confirmed the earlier British CDP-571 trial showing efficacy in inducing remission in active Crohn’s disease. Although this antibody was considered less immunogenic, antibodies to CDP-571 were nonetheless detected in up to 5% of the patients. The retreament phase for maintenance of remission was, somewhat surprisingly, negative.PubMedCrossRefGoogle Scholar
  16. 16.
    Feagan BG, Sandborn WJ, Baker J, et al.: A randomized, double-blind, placebo-controlled, multi-center trial of the engineered human antibody to TNF (CDP 571) for steroidsparing and maintenance of remission in patients with steroid-dependent Crohn’s disease [abstract]. Gastroenterology 2000, 118:A655.CrossRefGoogle Scholar
  17. 17.
    D’Haens G, Swijsen C, Noman M, et al.: Etanercept in the treatment of active refractory Crohn’s disease: a single-center pilot trial. Am J Gastroenterol, 2001, 256:4–8.Google Scholar
  18. 18.
    Sandborn WJ, Hanauer SB, Katz S, et al.: Etanercept for active Crohn’s disease: a randomized, double-blind, placebocontrolled trial. Gastroenterology 2001, 121:1088–1094. After initial enthusiasm based on a Belgian pilot trial, this study failed to demonstrate the efficacy of etanercept in active Crohn’s disease. A potential explanation may be that etanercept, unlike infliximab, does not induce apoptosis of the inflammatory cells.PubMedCrossRefGoogle Scholar
  19. 19.
    Rutgeerts P, Lemmens L, Van Assche G, et al.: Recombinant soluble p55 receptor induces remission, is non-immunogenic and well tolerated in active Crohn’s disease: results of a randomized pilot trial [abstract]. Gastroenterology 2001, 120:A452.CrossRefGoogle Scholar
  20. 20.
    Hommes D, van den Blink B, Plasse T, et al.: Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease. Gastroenterology 2002, 122:7–14. This rigorous pilot trial with endoscopic documentation demonstrates that the inflammatory cascade leading to enhanced production of TNF can be altered with small molecules and that this type of intervention may effectively reduce mucosal inflammation. Further trials and safety analyses, particularly with regard to hepatic toxicity, are warranted.PubMedCrossRefGoogle Scholar
  21. 21.
    Ehrenpreis ED, Kane SV, Cohen LB, et al.: Thalidomide therapy for patients with refractory Crohn’s disease: an open-label trial. Gastroenterology 1999, 117:1271–1277.PubMedCrossRefGoogle Scholar
  22. 22.
    Vasiliauskas EA, Kam LY, Abreu-Martin MT, et al.: An openlabel pilot study of low-dose thalidomide in chronically active, steroid-dependent Crohn’s disease. Gastroenterology 1999, 177:1278–1287.CrossRefGoogle Scholar
  23. 23.
    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, 16:399–406.PubMedCrossRefGoogle Scholar
  24. 24.
    Fedorak RN, Gangl A, Elson CO, 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, 119:1473–1482.PubMedCrossRefGoogle Scholar
  25. 25.
    Schreiber S, Fedorak RN, Nielsen OH, et al.: Safety and efficacy of recombinant interleukin 10 in chronic active Crohn’s disease. Gastroenterology 2000, 119:1461–1472.PubMedCrossRefGoogle Scholar
  26. 26.
    Colombel JF, Rutgeerts P, Malchow H, et al.: Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn’s disease. Gut 2001, 49:42–46.PubMedCrossRefGoogle Scholar
  27. 27.
    Gordon FH, Lai CW, Hamilton MI, et al.: A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease. Gastroenterology 2001, 121:268–274. In this controlled trial, a promising mechanism in inflammatory diseases has been targeted. Early experience is encouraging, not only in Crohn’s disease but also in multiple sclerosis. The pharmacokinetics of this treatment make frequent reinfusions necessary, most likely at least every month.PubMedCrossRefGoogle Scholar
  28. 28.
    Ghosh S, Goldin E, Malchow H, et al.: A randomized, doubleblind, placebo-controlled, pan-European study of a recombinant humanized antibody to alpha4 integrin (Antegren) [abstract]. Gastroenterology 2001, 120:A127.Google Scholar
  29. 29.
    Schreiber S, Nikolaus S, Malchow H, et al.: Absence of efficacy of subcutaneous antisense ICAM-1 treatment of chronic active Crohn’s disease. Gastroenterology 2001, 120:1339–1346.PubMedCrossRefGoogle Scholar
  30. 30.
    Rutgeerts P, Reinisch W, Colombel JF, et al.: Preliminary results of a phase I/II study of Huzaf, an anti-IFN-alpha monoclonal antibody, in patients with moderate to severe active Crohn’s disease [abstract]. Gastroenterology 2002, 122:A61.Google Scholar
  31. 31.
    Slonim AE, Bulone L, Damore MB, et al.: A preliminary study of growth hormone therapy for Crohn’s disease. N Engl J Med 2000, 342:1633–1637.PubMedCrossRefGoogle Scholar
  32. 32.
    Korzenik J, Dieckgraefe B: Immunostimulation in Crohn’s disease: results of a pilot study of G-CSF in mucosal and fistulizing Crohn’s disease [abstract]. Gastroenterology 2000, 118:A874.CrossRefGoogle Scholar
  33. 33.
    Korzenik J, Pittler A, Dieckgraefe B: Immunostimulation in Crohn’s disease: retreatment and maintenance therapy with GM-CSF [abstract]. Gastroenterology 2002, 122:A432 (abstract).Google Scholar
  34. 34.
    Stallmach A, Wittig BM, Moser C, et al.: Safety and efficacy of intravenous pulse cyclophosphamide in severe, steroidrefractory inflammatory bowel disease (IBD) [abstract]. Gastroenterology 2002, 122:A61.Google Scholar
  35. 35.
    Markowitz J, Grancher K, Kohn N, et al.: A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000, 119:895–902.PubMedCrossRefGoogle Scholar
  36. 36.
    Lemann M, Bouhnik Y, Colombel JF, et al.: Randomized, double-blind, placebo-controlled, multi-center, azathioprine withdrawal trial in Crohn’s disease [abstract]. Gastroenterology 2002, 122:A23. This interesting study tackles the question of how long azathioprine therapy needs to be continued in patients in remission. Although prolongation of antimetabolite therapy was superior to discontinuation, the relapse rate in the placebo group was surprisingly low. In addition, this study showed that absence of endoscopic healing was not predictive of earlier relapse.Google Scholar
  37. 37.
    Dubinsky MC, Lamothe S, Yang HY, et al.: Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000, 118:705–713.PubMedCrossRefGoogle Scholar
  38. 38.
    Yates CR, Krynetski EY, Loennechen T, et al.: Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997, 126:608–614.PubMedGoogle Scholar
  39. 39.
    Colombel J-F, Ferrari N, Debuysere H, et al., for Groupe d’etudes therapeutique des affections inflammatoires digestive (GETAID): Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn’s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000, 118:1025–1030.PubMedCrossRefGoogle Scholar
  40. 40.
    Cuffari C, Hunt S, Bayless T: Utilization of erythrocyte 6-thioguanine metabolite levels to optimize azathioprine therapy in patients with inflammatory bowel disease. Gut 2001, 48:642–646.PubMedCrossRefGoogle Scholar
  41. 41.
    Dubinsky MC, Yang H, Hassard PV, et al.: 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology 2002, 12:904–915. This elegant study reveals a lot of new information with practical implications for daily azathioprine and 6-MP use. It also emphasizes the fact that dose increase will only be effective in a subgroup of patients who can probably be identified genetically.CrossRefGoogle Scholar
  42. 42.
    Dubinsky MC, Hassard PV, Seidman EG, et al.: An open-label pilot study using thioguanine as a therapeutic alternative in Crohn’s disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 2001, 7:181–189. 6-TG is a promising alternative to 6-MP or azathioprine, particularly in patients who are intolerant of these drugs. Because intracellular 6-TGN levels become extremely high during this treatment, however, much more information with regard to safety (carcinogenicity) needs to be collected before general use can be advocated.PubMedCrossRefGoogle Scholar
  43. 43.
    Feagan B, Fedorak RN, Irvine EJ, et al.: A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med 2000, 342:1664–1666.CrossRefGoogle Scholar
  44. 44.
    Rutgeerts P, D’Haens G, Targan S, et al.: Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999, 117:761–169.PubMedCrossRefGoogle Scholar
  45. 45.
    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, 340:1398–1405.PubMedCrossRefGoogle Scholar
  46. 46.
    Sands B, Van Deventer S, Bernstein C, et al.: Long-term treatment of fistulizing Crohn’s disease: response to infliximab in the Accent II trial through 54 weeks [abstract]. Gastroenterology 2002, 122:A81. Largest trial ever for fistulizing Crohn’s disease. The proportion of patients in "fistula remission" at the end of 1 year with systemic infliximab infusions every 8 weeks is lower than the rate of remission in active Crohn’s disease. In addition, abscess formation is a commonly observed adverse event, and many fistulas do not seem to have healed based on sonographic evidence.Google Scholar
  47. 47.
    van Bodegraven AA, Sloots CE, Felt-Bersma RJ, Meuwissen SG: Endosonographic evidence of persistence of Crohn’s diseaseassociated fistulas after infliximab treatment, irrespective of clinical response. Dis Colon Rectum 2002, 45:39–45.PubMedCrossRefGoogle Scholar
  48. 48.
    Schwartz DA, Wiersema MJ, Dudiak KM, et al.: A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001, 121:1064–1072.PubMedCrossRefGoogle Scholar
  49. 49.
    Lowry PW, Weaver AL, Tremaine WJ, Sandborn WJ: Combination therapy with oral tacrolimus (FK506) and azathioprine or 6-mercaptopurine for treatment-refractory Crohn’s disease perianal fistulas. Inflamm Bowel Dis 1999, 5:239–245.PubMedCrossRefGoogle Scholar
  50. 50.
    Sandborn WJ, Present DH, Isaacs KL, et al.: Tacrolimus (FK506) for the treatment of perianal and enterocutaneous fistulas in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled trial [abstract]. Gastroenterology 2002, 122:A81. Well-controlled fistula trial with similar endpoints to those used in the trials with infliximab. The most striking finding is the high rate of adverse events with tacrolimus and an unacceptably high nephrotoxicity.Google Scholar

Copyright information

© Current Science Inc. 2002

Authors and Affiliations

  • Geert D’Haens
    • 1
  • Marco Daperno
    • 1
  1. 1.Department of GastroenterologyUniversity of LeuvenLeuvenBelgium

Personalised recommendations