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Drug Insight: antagonists of tumor-necrosis factor-α in the treatment of inflammatory bowel disease

Nature Clinical Practice Gastroenterology & Hepatology volume 3, pages 220–228 (2006)Cite this article

Abstract

In the past decade, advances in the understanding of the pathogenesis of inflammatory bowel disease have permitted the development of agents directed against rational therapeutic targets. In particular, various antagonists of tumor-necrosis factor-α have been developed. These include infliximab, adalimumab, certolizumab (CDP870), CDP571, etanercept, and onercept. Clinical trials of these agents have demonstrated varying degrees of clinical efficacy. The use of these agents can be limited by infection, immunogenicity, acute infusion reactions, delayed hypersensitivity reactions, and autoimmune phenomena. This review provides insights into the use of antagonists of tumor-necrosis factor-α for the treatment of inflammatory bowel disease.

Key Points

  • Infliximab is effective in the induction and maintenance of clinical remission in luminal and fistulizing Crohn's disease, as well as in ulcerative colitis

  • Adalimumab and certolizumab are effective in the induction and maintenance of clinical remission in Crohn's disease

  • Potential limitations of the TNF-α antagonists include infection, infusion reactions, autoimmune phenomena, and immunogenicity

  • The capacity to induce apoptosis of TNF-α-expressing cells and neutralization of TNF-α alone are insufficient for clinical efficacy in Crohn's disease

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Figure 1: Components of the TNF-α antagonists.

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References

  1. Bamias G et al. (2005) New concepts in the pathophysiology of inflammatory bowel disease. Ann Intern Med 143: 895–904

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Eckmann L and Karin M (2005) NOD2 and Crohn's disease: loss or gain of function? Immunity 22: 661–667

    Article  CAS  Google Scholar 

  4. Papadakis KA and Targan SR (2000) Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 119: 1148–1157

    Article  CAS  Google Scholar 

  5. Papadakis KA and Targan SR (2000) Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51: 289–298

    Article  CAS  Google Scholar 

  6. Braegger CP et al. (1992) Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339: 89–91

    Article  CAS  Google Scholar 

  7. Murch SH et al. (1993) Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut 34: 1705–1709

    Article  CAS  Google Scholar 

  8. Heller F et al. (2005) Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129: 550–564

    Article  CAS  Google Scholar 

  9. Heller F et al. (2002) Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17: 629–638

    Article  CAS  Google Scholar 

  10. Fossati G and Nesbitt AM (2005) Effect of the anti-TNF agents, adalimumab, etanercept, infliximab, and certolizumab PEGOL (CDP870) on the induction of apoptosis in activated peripheral blood lymphocytes and monocytes [abstract]. Am J Gastroenterol 100: S298

    Google Scholar 

  11. Lugering A et al. (2001) Infliximab induces apoptosis in monocytes from patients with chronic active Crohn's disease by using a caspase-dependent pathway. Gastroenterology 121: 1145–1157

    Article  CAS  Google Scholar 

  12. Shen C et al. (2005) Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 21: 251–258

    Article  CAS  Google Scholar 

  13. Van den Brande JM et al. (2003) Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 124: 1774–1785

    Article  CAS  Google Scholar 

  14. Waetzig GH et al. (2005) Soluble tumor necrosis factor (TNF) receptor-1 induces apoptosis via reverse TNF signaling and autocrine transforming growth factor-beta1. FASEB J 19: 91–93

    Article  CAS  Google Scholar 

  15. Hanauer SB et al. (2002) Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 359: 1541–1549

    Article  CAS  Google Scholar 

  16. Present DH et al. (1999) Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 340: 1398–1405

    Article  CAS  Google Scholar 

  17. Sands BE et al. (2004) Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 350: 876–885

    Article  CAS  Google Scholar 

  18. Targan SR et al. (1997) 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 337: 1029–1035

    Article  CAS  Google Scholar 

  19. Hanauer SB et al. (2004) A randomized, double-blind, placebo-controlled trial of the human anti-monoclonal antibody adalimumab for the induction of remission in patients with moderate to severely active crohn's disease [abstract]. Gastroenterology 127: a331

    Google Scholar 

  20. Sandborn WJ et al. (2005) Maintenance of remission over 1 year in patients with active Crohn's disease treated with adalimumab: results of a blinded, placebo-controlled study [abstract]. Am J Gastroenterol 100: S311

    Article  Google Scholar 

  21. Sandborn WJ et al. (2005) Remission and clinical response induced and maintained in patients with active Crohn's disease treated for 1-year open-label with adalimumab [abstract]. Am J Gastroenterol 100: S316

    Article  Google Scholar 

  22. Schreiber S et al. (2005) Certolizumab Pegol, a humanised anti-TNF PEGylated Fab' fragment, is safe and effective in the maintenance of response and remission following induction in active Crohn's disease: a Phase III study (PRECiSE). Presented at the 13th United European Gastroenterology Week: 2005 October 15–19; Copenhagen, OP-G-355

  23. Rutgeerts P et al. The Onercept Study Group. (2004) Onercept (recombinant human soluble p55 tumour necrosis factor receptor) treatment in patients with active Crohn's disease: randomized, placebo-controlled, dose-finding phase II study [abstract]. Gut 53: a47

    Google Scholar 

  24. Sandborn WJ et al. (2004) 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 53: 1485–1493

    Article  CAS  Google Scholar 

  25. Sandborn WJ et al. (2001) Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121: 1088–1094

    Article  CAS  Google Scholar 

  26. Rutgeerts P et al. (2005) Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 353: 2462–2476

    Article  CAS  Google Scholar 

  27. Baert F et al. (2003) Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 348: 601–608

    Article  CAS  Google Scholar 

  28. Hanauer SB et al. (2004) Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn's disease. Clin Gastroenterol Hepatol 2: 542–553

    Article  CAS  Google Scholar 

  29. Cheifetz A et al. (2003) The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 98: 1315–1324

    Article  CAS  Google Scholar 

  30. Colombel JF et al. (2004) The safety profile of infliximab in patients with Crohn's disease: the Mayo clinic experience in 500 patients. Gastroenterology 126: 19–31

    Article  CAS  Google Scholar 

  31. Lichtenstein GR et al. (2005) Safety of infliximab and other Crohn's disease therapies- updated treat registry data with over 10,000 patient-years of follow-up [abstract]. Gastroenterology 128: a580

    Article  Google Scholar 

  32. Keane J et al. (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345: 1098–1104

    Article  CAS  Google Scholar 

  33. Lee JH et al. (2002) Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 46: 2565–2570

    Article  CAS  Google Scholar 

  34. Singh SM et al. (2004) Cutaneous nocardiosis complicating management of Crohn's disease with infliximab and prednisone. CMAJ 171: 1063–1064

    Article  Google Scholar 

  35. Velayos FS and Sandborn WJ (2004) Pneumocystis carinii pneumonia during maintenance anti-tumor necrosis factor-alpha therapy with infliximab for Crohn's disease. Inflamm Bowel Dis 10: 657–660

    Article  Google Scholar 

  36. Warris A et al. (2001) Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 344: 1099–1100

    Article  CAS  Google Scholar 

  37. Vermeire S et al. (2003) Autoimmunity associated with anti-tumor necrosis factor alpha treatment in Crohn's disease: a prospective cohort study. Gastroenterology 125: 32–39

    Article  CAS  Google Scholar 

  38. Kwon HJ et al. (2003) Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 138: 807–811

    Article  Google Scholar 

  39. Chung ES et al. (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107: 3133–3140

    Article  CAS  Google Scholar 

  40. Remicade [http://www.remicade.com]

  41. Esteve M et al. (2004) Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut 53: 1363–1365

    Article  CAS  Google Scholar 

  42. Germano V et al. (2005) Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis 64: 1519–1520

    Article  CAS  Google Scholar 

  43. Michel M et al. (2003) Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still's disease. J Rheumatol 30: 1624–1625

    PubMed  Google Scholar 

  44. Brown SL et al. (2002) Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46: 3151–3158

    Article  CAS  Google Scholar 

  45. Furst DE et al. (2003) Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 30: 2563–2571

    CAS  PubMed  Google Scholar 

  46. Weinblatt ME et al. (2003) Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 48: 35–45

    Article  CAS  Google Scholar 

  47. van de Putte LB et al. (2004) Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann Rheum Dis 63: 508–516

    Article  CAS  Google Scholar 

  48. Keystone EC et al. (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50: 1400–1411

    Article  CAS  Google Scholar 

  49. Schreiber S et al. (2005) A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease. Gastroenterology 129: 807–818

    Article  CAS  Google Scholar 

  50. Sandborn WJ et al. (2001) An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial. Gastroenterology 120: 1330–1338

    Article  CAS  Google Scholar 

  51. Bathon JM et al. (2000) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343: 1586–1593

    Article  CAS  Google Scholar 

  52. Rutgeerts P et al. (2003) 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 17: 185–192

    Article  CAS  Google Scholar 

  53. Serono [http://www.serono.com/]

  54. Evans RC et al. (1997) Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571. Aliment Pharmacol Ther 11: 1031–1035

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Fellow in Gastroenterology Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    John T Chang

  2. Professor of Medicine and Director of the Division of Gastroenterology, Center for Inflammatory Bowel Diseases, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Gary R Lichtenstein

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  1. John T Chang
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Corresponding author

Correspondence to Gary R Lichtenstein.

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Competing interests

Gary R Lichtenstein has served as a consultant to Abbott Corporation, AstraZeneca Inc., Axcan, Celltech Inc., Centocor Inc., Elan, Faro Pharmaceuticals, Human Genome Sciences, Proctor and Gamble, Prometheus Laboratories Inc., Protein Design Labs, Protomed Scientific, Salix Pharmaceuticals, Schering-Plough Corporation, Serono, Shire Pharmaceuticals, Smith Kline Beecham Corporation, Solvay Pharmaceuticals, Synta Pharmaceuticals, UCB, and Wyeth. He has received research support from Abbott Corporation, Berlex, Celgene Corporation, Celltech Inc., Centocor Inc., Genetics Institute, Human Genome Sciences, Inkine Inc., Intesco Corporation, ISIS Corporation, Millenium Pharmaceuticals, Otsuka Corporation, Protein Design Labs, Protomed Scientific, and Salix Pharmaceuticals. He has served on the Speakers Bureau for AstraZeneca, Axcan, Centocor Inc., Faro Pharmaceuticals, Proctor and Gamble, Salix Pharmaceuticals, Schering-Plough Corporation, Shire Pharmaceuticals, and Solvay Pharmaceuticals. He has received an honorarium from Falk Pharma.

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Chang, J., Lichtenstein, G. Drug Insight: antagonists of tumor-necrosis factor-α in the treatment of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 3, 220–228 (2006). https://doi.org/10.1038/ncpgasthep0447

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  • DOI: https://doi.org/10.1038/ncpgasthep0447

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