Skip to main content

Advertisement

SpringerLink
Log in

Novel biological therapies for inflammatory bowel disease

  • Published:
Current Treatment Options in Gastroenterology Aims and scope Submit manuscript

Opinion statement

The success of biological therapy is best advocated by infliximab (IFX), which has dramatically improved medical therapy for Crohn’s disease and now has been shown to be effective in the treatment of ulcerative colitis. Other anti-tumor necrosis factor (TNF) compounds have been tested in the treatment of Crohn’s disease and will soon appear in the therapeutic armament. However, neutralization of TNF does not seem to be the most important mechanism of action of these therapies. Apoptosis of activated T cells was demonstrated after IFX treatment, and this may be the key to its success. Thus, other therapies that induce apoptosis in activated T cells, such as visilizumab, have a great chance to be of benefit. Biological therapies applied in inflammatory bowel disease appear to be safe, although therapy-related adverse events clearly have been recognized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Bouma G, Strober W: The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 2003, 3:521–533.

    Article  PubMed  CAS  Google Scholar 

  2. MacDonald TT, Monteleone G: Immunity, inflammation, and allergy in the gut. Science 2005, 307:1920–1925.

    Article  PubMed  CAS  Google Scholar 

  3. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006, 6:9–20. This review focuses on the role of TLR and NOD proteins in the pathogenesis of disease, discussing the role of the disease-associated mutations in CARD15/NOD2 in a functional context.

    Article  PubMed  CAS  Google Scholar 

  4. Sandborn WJ, Targan SR: Biologic therapy of inflammatory bowel disease. Gastroenterology 2002, 122:1592–1608.

    Article  PubMed  CAS  Google Scholar 

  5. Stokkers PC, Hommes DW: New cytokine therapeutics for inflammatory bowel disease. Cytokine 2004, 28:167–173.

    Article  PubMed  CAS  Google Scholar 

  6. Tilg H, van Montfrans C, van den Ende A, et al.: Treatment of Crohn’s disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma. Gut 2002, 50:191–195.

    Article  PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. Schreiber S, Fedorak RN, Nielsen OH, et al.: Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s Disease IL-10 Cooperative Study Group. Gastroenterology 2000, 119:1461–1472.

    Article  PubMed  CAS  Google Scholar 

  9. Van Deventer SJ, Elson CO, Fedorak RN: Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn’s disease. Crohn’s Disease Study Group. Gastroenterology 1997, 113:383–389.

    Article  PubMed  Google Scholar 

  10. Steidler L, Hans W, Schotte L, et al.: Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000, 289:1352–1355.

    Article  PubMed  CAS  Google Scholar 

  11. Braat H, Steidler L, Neirynck S, et al.: Turbo-Probiotics as a tool for cell based (mucosal) delivery of interleukin-10 [abstract]. Gastroenterology 2005, 128(Suppl 4):A27.

    Google Scholar 

  12. Braat H, Rottiers P, Huyghebaert N, et al.: Interleukin-10 producing Lactococcus lactis for the treatment of Crohn’s disease [abstract]. Gastroenterology 2005, 128(Suppl 4):A685.

    Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Musch E, Andus T, Kruis W, et al.: Interferon-beta-1a for the treatment of steroid-refractory ulcerative colitis: a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2005, 3:581–586.

    Article  PubMed  CAS  Google Scholar 

  15. Nikolaus S, Rutgeerts P, Fedorak R, et al.: Interferon beta-1a in ulcerative colitis: a placebo controlled, randomised, dose escalating study. Gut 2003, 52:1286–1290.

    Article  PubMed  CAS  Google Scholar 

  16. Tilg H, Vogelsang H, Ludwiczek O, et al.: A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis. Gut 2003, 52:1728–1733.

    Article  PubMed  CAS  Google Scholar 

  17. Korzenik JR, Dieckgraefe BK, Valentine JF, et al.: Sargramostim for active Crohn’s disease. N Engl J Med 2005, 352:2193–2201. This trial leaves the immune suppression paradigm for the treatment of Crohn’s disease by boosting innate immunity with GM-CSF.

    Article  PubMed  CAS  Google Scholar 

  18. Sandborn WJ, Hanauer SB, Katz S, et al.: Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001, 121:1088–1094.

    Article  PubMed  CAS  Google Scholar 

  19. Akobeng AK, Zachos M: Tumor necrosis factor-alpha antibody for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2004, 1:CD003574.

    PubMed  Google Scholar 

  20. Rutgeerts P, Van AG, Vermeire S: Optimizing anti-TNF treatment in inflammatory bowel disease. Gastroenterology 2004, 126:1593–1610.

    Article  PubMed  CAS  Google Scholar 

  21. Ten Hove T, van Montfrans C, Peppelenbosch MP, Van Deventer SJ: Infliximab treatment induces apoptosis of lamina propria T lymphocytes in Crohn’s disease. Gut 2002, 50:206–211.

    Article  PubMed  Google Scholar 

  22. Targan SR, Hanauer SB, Van Deventer SJ, et al.: A shortterm 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.

    Article  PubMed  CAS  Google Scholar 

  23. Hanauer SB, Feagan BG, Lichtenstein GR, et al.: Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002, 359:1541–1549.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. Sands BE, Anderson FH, Bernstein CN, et al.: Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004, 350:876–885.

    Article  PubMed  CAS  Google Scholar 

  26. Hommes DW, Baert F, Van Assche G, et al.: Therapy management of recent onset Crohn’s disease: a controlled, randomized trial comparing step-up and topdown therapy [abstract]. Gastroenterology 2005, 129:371.

    Article  Google Scholar 

  27. Baert F, Noman M, Vermeire S, et al.: Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003, 348:601–608.

    Article  PubMed  CAS  Google Scholar 

  28. Travis SP, Stange EF, Lemann M, et al.: European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006, 55(Suppl 1):i16-i35.

    Article  PubMed  Google Scholar 

  29. Chey WY, Hussain A, Ryan C, et al.: Infliximab for refractory ulcerative colitis. Am J Gastroenterol 2001, 96:2373–2381.

    Article  PubMed  CAS  Google Scholar 

  30. Sands BE, Tremaine WJ, Sandborn WJ, et al.: Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study. Inflamm Bowel Dis 2001, 7:83–88.

    Article  PubMed  CAS  Google Scholar 

  31. Rutgeerts P, Sandborn WJ, Feagan BG, et al.: Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005, 353:2462–2476. Here, the results of the ACT 1 and 2 trials are described. These trials provide strong arguments for registration of IFX for the treatment of UC.

    Article  PubMed  CAS  Google Scholar 

  32. Jarnerot G, Hertervig E, Friis-Liby I, et al.: Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005, 128:1805–1811.

    Article  PubMed  CAS  Google Scholar 

  33. Arts J, D’Haens G, Zeegers M, et al.: Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis. Inflamm Bowel Dis 2004, 10:73–78.

    Article  PubMed  Google Scholar 

  34. Colombel JF, Loftus EV, Tremaine WJ, et al.: The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004, 126:19–31.

    Article  PubMed  CAS  Google Scholar 

  35. Keane J, Gershon S, Wise RP, et al.: Tuberculosis associated with infliximab, a tumor necrosis factor alphaneutralizing agent. N Engl J Med 2001, 345:1098–1104.

    Article  PubMed  CAS  Google Scholar 

  36. Papadakis KA, Shaye OA, Vasiliauskas EA, et al.: Safety and efficacy of adalimumab (D2E7) in Crohn’s disease patients with an attenuated response to infliximab. Am J Gastroenterol 2005, 100:75–79.

    Article  PubMed  CAS  Google Scholar 

  37. Sandborn WJ, Hanauer S, Loftus EV, et al.: An openlabel study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am J Gastroenterol 2004, 99:1984–1989.

    Article  PubMed  CAS  Google Scholar 

  38. Hanauer SB, Sandborn WJ, Rutgeerts P, et al.: Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006, 130:323–333. The results of the phase III trial that paves the way for the second effective anti-TNF compound that can be used for treatment of Crohn’s disease.

    Article  PubMed  CAS  Google Scholar 

  39. Feagan BG, Sandborn WJ, Lichtenstein G, et al.: CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for steroid-dependent Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Aliment Pharmacol Ther 2006, 23:617–628.

    Article  PubMed  CAS  Google Scholar 

  40. Sandborn WJ, Feagan BG, Radford-Smith G, et al.: CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn’s disease: a randomised, double blind, placebo controlled trial. Gut 2004, 53:1485–1493.

    Article  PubMed  CAS  Google Scholar 

  41. Dinarello CA: Differences between anti-tumor necrosis factor-alpha monoclonal antibodies and soluble TNF receptors in host defense impairment. J Rheumatol Suppl 2005, 74:40–47.

    PubMed  CAS  Google Scholar 

  42. Schreiber S, Rutgeerts P, Fedorak RN, et al.: A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 2005, 129:807–818.

    Article  PubMed  CAS  Google Scholar 

  43. Mannon PJ, Fuss IJ, Mayer L, et al.: Anti-interleukin-12 antibody for active Crohn’s disease. N Engl J Med 2004, 351:2069–2079.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. Ghosh S, Goldin E, Gordon FH, et al.: Natalizumab for active Crohn’s disease. N Engl J Med 2003, 348:24–32.

    Article  PubMed  CAS  Google Scholar 

  46. Gordon FH, Hamilton MI, Donoghue S, et al.: A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther 2002, 16:699–705.

    Article  PubMed  CAS  Google Scholar 

  47. Sandborn WJ, Colombel JF, Enns R, et al.: Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med 2005, 353:1912–1925.

    Article  PubMed  CAS  Google Scholar 

  48. Yousry TA, Major EO, Ryschkewitsch C, et al.: Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006, 354:924–933.

    Article  PubMed  CAS  Google Scholar 

  49. Carpenter PA, Pavlovic S, Tso JY, et al.: Non-Fc receptorbinding humanized anti-CD3 antibodies induce apoptosis of activated human T cells. J Immunol 2000, 165:6205–6213.

    PubMed  CAS  Google Scholar 

  50. Carpenter PA, Appelbaum FR, Corey L, et al.: A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versushost disease. Blood 2002, 99:2712–2719.

    Article  PubMed  CAS  Google Scholar 

  51. Targan S, Salzberg B, Mayer L, et al.: A phase I-II study: Multiple dose levels of visilizumab are well tolerated and produce rapid and sustained improvement in ulcerative colitis patinets refractory to treatment with IV steroids [abstract]. Gastroenterology 2005, 128:A493.

    Article  CAS  Google Scholar 

  52. Hommes DW, Plevy SE, Salzberg B, et al.: Epstein Barr Virus (EBV) replication in severe active, steroid resistant ulcerative colitis (UC) patients treated with visilizumab, an anti-CD3 antibody [abstract]. Gastroenterology 2005, 128:A494.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ, 00-31-566 9111, Amsterdam, The Netherlands

    Pieter C. F. Stokkers MD, PhD

Authors
  1. Pieter C. F. Stokkers MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel W. Hommes MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stokkers, P.C.F., Hommes, D.W. Novel biological therapies for inflammatory bowel disease. Curr Treat Options Gastro 9, 201–210 (2006). https://doi.org/10.1007/s11938-006-0039-y

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11938-006-0039-y

Keywords

Search

Navigation