Current Gastroenterology Reports

, Volume 5, Issue 6, pp 501–505 | Cite as

Optimizing anti-tumor necrosis factor strategies in inflammatory bowel disease

  • William J. Sandborn


The introduction of infliximab, a mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is an important advance in the treatment of Crohn’s disease. Infliximab is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease. The development of human antichimeric antibodies (HACAs) has led to infusion reactions and loss of efficacy in patients treated with infliximab. Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0, 2, and 6 weeks followed by systematic maintenance dosing every 8 weeks; concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and premedication with intravenous corticosteroids. Humanized or fully human anti-TNF biotechnologic agents, including CDP571, CDP870, etanercept, adalimumab, and onercept, are theoretically less immunogenic than the chimeric antibody infliximab. Etanercept is not effective for Crohn’s disease. CDP571 is not effective in unselected patients with active Crohn’s disease, but it may be effective in patients with elevated C-reactive protein. The efficacy of CDP870, adalimumab, and onercept is under investigation. The different mechanisms of action of these anti-TNF agents may account for their variable efficacy. Their benefits, however, must be considered in the context of their risks, including infusion reaction; delayed hypersensitivitylike reaction; new onset of autoimmunity, with rare cases of drug-induced lupus and new-onset demyelination; and the potential for rare but serious infections.


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  1. 1.
    Lugering A, Schmidt M, Lugering N, et al.: Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 2001, 121:1145–57.PubMedCrossRefGoogle Scholar
  2. 2.
    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, 50:206–11.PubMedCrossRefGoogle Scholar
  3. 3.
    van den Brande JMH, Braat H, van den Brink GR, et al.: Infliximab but not etanercept induces apopotosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003, 124:1774–1785.PubMedCrossRefGoogle Scholar
  4. 4.
    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. Landmark trial demonstrating the efficacy of infliximab for active Crohn’s disease.PubMedCrossRefGoogle Scholar
  5. 5.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al.: Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002, 359:1541–1549. Landmark trial demonstrating the efficacy of infliximab as maintenance therapy for Crohn’s disease.PubMedCrossRefGoogle Scholar
  6. 6.
    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. Landmark trial demonstrating the efficacy of infliximab for closing actively draining fistulae in patients with Crohn’s disease.PubMedCrossRefGoogle Scholar
  7. 7.
    Sands B, Van Deventer S, Bernstein C, et al.: Long-term treament of fistulizing Crohn’s disease: response to infliximab in the ACCENT II trial through 54 weeks. Gastroenterology 2002, 122:A81.Google Scholar
  8. 8.
    SandbornWJ, Hanauer SB, Katz S, et al.: Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001, 121:1088–1094. Important study demonstrating that etanercept is not effective for the treatment of active Crohn’s disease.PubMedCrossRefGoogle Scholar
  9. 9.
    Stack WA, Mann SD, Roy AJ, et al.: Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn’s disease. Lancet 1997, 349:521–524.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Sandborn W, Feagan B, Radford-Smith G, et al.: Randomized, placebo-controlled trial of CDP571, a humanized monoclonal antibody to TNF-a, in patients with moderate to severe Crohn’s disease [abstract]. Gastroenterology 2003, 124:A-61.Google Scholar
  12. 12.
    Feagan BG, Sandborn WJ, Baker J, et al.: A randomized, double-blind, placebo-controlled, multi-center trial of the engineered human antibody to TNF (CDP571) for steroid sparing and maintenance of remission in patients with steroiddependent Crohn’s disease [abstract]. Gastroenterology 2000, 118:A655.CrossRefGoogle Scholar
  13. 13.
    Celltech announces results from CDP 571 studies in Crohn’s disease. Scholar
  14. 14.
    Schreiber S, Rutgeerts P, Fedorak R, et al., and the CDP870 Crohn’s Disease Study Group: CDP870, a humanized anti-TNF antibody fragment, induces clinical response with remission in patients with active Crohn’s disease (CD) [abstract]. Gastroenterology 2003, 124:A-61.CrossRefGoogle Scholar
  15. 15.
    Rutgeerts P, Lemmens L, Van Assche G, et al.: Treatment of active Crohn’s disease with onercept (recombinant human soluble p55 tumour necrosis factor receptor): results of a randomized, open-label, pilot study. Aliment Pharmacol Ther 2003, 17:185–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Mayer L, Han C, Bala M, et al.: Three dose induction regimen of infliximab (Remicade) is superior to a single dose in patients with Crohn’s disease. Am J Gastroenterol 2001, 96:S303.CrossRefGoogle Scholar
  17. 17.
    Vermeire S, Noman M, Van Assche G, et al.: Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn’s disease: a prospective cohort study. Gastroenterology 2003, 125:32–39.PubMedCrossRefGoogle Scholar
  18. 18.
    Cheifetz A, Smedley M, Martin S, et al.: The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenerol 2003, 98:1315–1324.CrossRefGoogle Scholar
  19. 19.
    Hanauer S, Rutgeerts P, Targan S, et al.: Delayed hypersensitivity to infliximab (Remicade) re-infusion after a 2–4 year interval without treatment [abstract]. Gastroenterology 1999, 116:A731.Google Scholar
  20. 20.
    Mohan N, Edwards ET, Cupps TR, et al.: Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001, 44:2862–2869.PubMedCrossRefGoogle Scholar
  21. 21.
    Brown SL, Greene MH, Gershon SK, et al.: Tumor necrosis factor antagonist therapy and lymphoma development: twentysix cases reported to the Food and Drug Administration. Arthritis Rheum 2002, 46:3151–3158.PubMedCrossRefGoogle Scholar
  22. 22.
    Kwon HJ, Cote TR, Cuffe MS, et al.: Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003, 138:807–811.PubMedGoogle Scholar
  23. 23.
    Remicade (infliximab) for IV injection [package insert]. Malvern, PA: Centocor; 2002.Google Scholar
  24. 24.
    Hanauer SB. Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 1999, 13(Suppl 4):16–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Schaible TF: Long term safety of infliximab. Can J Gastroenterol 2000, 14(Suppl C):29C-32C.PubMedGoogle Scholar
  26. 26.
    Sandborn WJ, Hanauer SB: Infliximab in the treatment of Crohn’s disease: a user’s guide for clinicians. Am J Gastroenterol 2002, 97:2962–2972.PubMedCrossRefGoogle Scholar
  27. 27.
    Keane J, Gershon S, Wise RP, et al.: Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001, 345:1098–1104.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee JH, Slifman NR, Gershon SK, et al.: Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002, 46:2565–2570.PubMedCrossRefGoogle Scholar
  29. 29.
    Maini RN, Breedveld FC, Kalden JR, et al.: Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998, 41:1552–1563.PubMedCrossRefGoogle Scholar
  30. 30.
    LoBuglio AF, Wheeler RH, Trang J, et al.: Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc Natl Acad Sci U S A 1989, 86:4220–4224.PubMedCrossRefGoogle Scholar
  31. 31.
    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, 117:761–769.PubMedCrossRefGoogle Scholar
  32. 32.
    Remicade (infliximab) for IV injection [prescribing information]. Malvern, PA: Centocor; 2002.Google Scholar
  33. 33.
    Sandborn WJ: Preventing antibodies to infliximab in patients with Crohn’s disease: optimize not immunize. Gastroenterology 2003, 124:1140–1145.PubMedGoogle Scholar
  34. 34.
    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. Landmark study demonstrating the immunogenicity of episodically administered infliximab in patients with Crohn’s disease.PubMedCrossRefGoogle Scholar
  35. 35.
    Farrell RJ, Alsahli M, Jeen YT, et al.: Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003, 124:917–924. Important study demonstrating the immunogenicity of infliximab and the protective effect of pretreatment with corticosteroids.PubMedCrossRefGoogle Scholar
  36. 36.
    Hanauer S, Present D, Targan SR, et al.: CDP571, a humanized monoclonal antibody to TNF-a, is well tolerated in Crohn’s disease patients with previous hypersensitivity to infliximab [abstract]. Gastroenterology 2003, 124:A-517.CrossRefGoogle Scholar
  37. 37.
    Winter T, Wright J, Ghosh S, et al.: Intravenous CDP870, a humanized anti-TNF antibody fragment, in patients with active Crohn’s disease: an exploratory study [abstract]. Gastroenterology 2003, 124:A-377.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2003

Authors and Affiliations

  • William J. Sandborn
    • 1
  1. 1.Division of Gastroenterology and HepatologyMayo ClinicRochesterUSA

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