, Volume 64, Issue 16, pp 1767–1777 | Cite as

Managing Immunogenic Responses to Infliximab

Treatment Implications for Patients with Crohn’s Disease
  • Peter D. Han
  • Russell D. Cohen
Therapy In Practice


Infliximab is a tumour necrosis factor (TNF)-α antagonist that has revolutionised the treatment of Crohn’s disease and rheumatoid arthritis. However, infliximab therapy can be complicated by a variety of adverse reactions. Acute infusion reactions occur during or shortly after infusion and typically consist of fever, chills, nausea, dyspnoea and headaches. Delayed reactions, characterised by myalgias, arthralgias, fever, rash, pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache may occur 3–12 days after infusion. Although the mechanisms of these reactions are not yet clearly defined, emerging evidence indicates that these reactions may be associated with the immune response against infliximab and the development of antibodies to infliximab.

A number of studies have identified protective factors that may minimise adverse reactions, presumably related to the immune response against infliximab. Factors that may be protective by helping to establish immune tolerance for the foreign infliximab protein include concomitant administration of immunomodulators or corticosteroids, starting infliximab therapy with a 0, 2, 6-week induction regimen, maintenance dose administration with infusions every 8 weeks or less, and avoiding long periods between infusions.

Infliximab therapy also may have other immunological consequences. There is evidence that infliximab may impede the appropriate immune response to a number of pathogens, prohibiting its use in patients with active infections. In addition, patients should be screened and appropriately treated for tuberculosis before initiating infliximab therapy. The development of autoantibodies, such as antinuclear antibody or anti-ds-DNA, has also been described with infliximab therapy, although the development of clinical lupus-like syndrome is rare. While there is a theoretical risk of increased rate of malignancies due to antagonism of TNFα, to date there is no clear evidence of such an effect. In addition, cardiac and neurological adverse events associated with infliximab therapy have been described. The mechanism for these adverse events is unclear.

In summary, infliximab therapy can be an effective treatment for Crohn’s disease; however, a number of immunological consequences and adverse events may complicate the infusion of this agent. Appropriate prophylaxis and therapy of these adverse reactions will allow infliximab to be used safely in the vast majority of patients.


Infliximab Infusion Reaction Infliximab Therapy Infliximab Infusion Delayed Reaction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Russell Cohen would like to declare the following: Speakers’ Bureau — Proctor and Gamble, Salix Pharmaceuticals, Shire Pharmaceuticals, Axcan-Scandipharm, Solvay Pharmaceuticals, Centocor, Astra-Zeneca; Research Grants — Centocor, Salix Pharmaceuticals; Consultant Celltech, Centocor, Isis Pharmaceuticals, Elan; Spouse — employee of Centocor, shareholder in Johnson & Johnson.

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.


  1. 1.
    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(15): 1029–35PubMedCrossRefGoogle Scholar
  2. 2.
    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(18): 1398–405PubMedCrossRefGoogle Scholar
  3. 3.
    van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995; 109(1): 129–35PubMedCrossRefGoogle Scholar
  4. 4.
    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(4): 761–9PubMedCrossRefGoogle Scholar
  5. 5.
    D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endos 1999; 50(5): 667–71CrossRefGoogle Scholar
  6. 6.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359(9317): 1541–9PubMedCrossRefGoogle Scholar
  7. 7.
    Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344(8930): 1105–10PubMedCrossRefGoogle Scholar
  8. 8.
    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(9): 1552–63PubMedCrossRefGoogle Scholar
  9. 9.
    Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354(9194): 1932–9PubMedCrossRefGoogle Scholar
  10. 10.
    Cohen RD, Tsang JF, Hanauer SB. Infliximab in Crohn’s disease: first anniversary clinical experience. Am J Gastroenterol 2000; 95(12): 3469–77PubMedCrossRefGoogle Scholar
  11. 11.
    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(12): 3490–7PubMedCrossRefGoogle Scholar
  12. 12.
    Colombel J, 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(1): 19–31PubMedCrossRefGoogle Scholar
  13. 13.
    Stephens MC, Shepanski MA, Mamula P, et al. Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol 2003; 98(1): 104–11PubMedCrossRefGoogle Scholar
  14. 14.
    Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98(6): 1315–24PubMedCrossRefGoogle Scholar
  15. 15.
    Duhem C, Dicato MA, Ries F. Side-effects of intravenous immune globulins. Clin Exp Immunol 1994; 97 Suppl. 1: 79–83PubMedGoogle Scholar
  16. 16.
    Bagdasarian A, Tonetta S, Harel W, et al. IVIG adverse reactions: potential role of cytokines and vasoactive substances. Vox Sang 1998; 74(2): 74–82PubMedCrossRefGoogle Scholar
  17. 17.
    Schiavotto C, Ruggeri M, Rodeghiero F. Adverse reactions after high-dose intravenous immunoglobulin: incidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature. Haematologica 1993; 78 (6 Suppl. 2): 35–40PubMedGoogle Scholar
  18. 18.
    Misbah SA, Chapel HM. Adverse effects of intravenous immu-noglobulin. Drug Saf 1993; 9(4): 254–62PubMedCrossRefGoogle Scholar
  19. 19.
    McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16(8): 2825–33PubMedGoogle Scholar
  20. 20.
    Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD 20. Blood 1994; 83(2): 435–45PubMedGoogle Scholar
  21. 21.
    Dillman RO. Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. Cancer Metastasis Rev 1999; 18(4): 465–71PubMedCrossRefGoogle Scholar
  22. 22.
    Osterborg A, Dyer MJ, Bunjes D, et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia: European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 1997; 15(4): 1567–74PubMedGoogle Scholar
  23. 23.
    Osterborg A, Fassas AS, Anagnostopoulos A, et al. Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukaemia. Br J Haematol 1996; 93(1): 151–3PubMedCrossRefGoogle Scholar
  24. 24.
    Baert F, Noman M, Vermeire S, et al. Influence of immuno-genicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003; 348(7): 601–8PubMedCrossRefGoogle Scholar
  25. 25.
    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(4): 917–24PubMedCrossRefGoogle Scholar
  26. 26.
    Weiss ME. Drug allergy. Med Clin North Am 1992; 76(4): 857–82PubMedGoogle Scholar
  27. 27.
    O’Connor M, Buchman A, Marshall G. Anaphylaxis-like reaction to infliximab in a patient with Crohn’s disease. Dig Dis sci 2002; 47(6): 1323–5PubMedCrossRefGoogle Scholar
  28. 28.
    Hanauer SB, Rutgeerts PJ, D’Haens G, et al. Delayed hypersensitivity to infliximab (Remicade) re-infusion after 2–4 year interval without treatment [abstract]. Gastroenterology 1999; 116: A731Google Scholar
  29. 29.
    Kam LY, Vasiliauskas EA, Abreu MT. Attenuation of response to multiple retreatment infliximab infusions for active Crohn’s disease: potential factors that minimize decreased response [abstract]. Gastroenterology 2000; 118: A65Google Scholar
  30. 30.
    Panccione R. Overcoming ‘delayed-type hypersensitivity reactions’ in patients receiving repeated doses of infliximab: a report of 5 cases [abstract]. Gastroenterology 2002; 122 (4 Suppl. 1): A613Google Scholar
  31. 31.
    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
  32. 32.
    Remicade (infliximab) for IV injection [package insert]. Malvern (PA): Centocor Inc., 2003Google Scholar
  33. 33.
    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(15): 1098–104PubMedCrossRefGoogle Scholar
  34. 34.
    Hanauer SB. Review article: safety of infliximab in clinical trials. Aliment Pharmacol Ther 1999; 13 Suppl. 4: 16–22PubMedCrossRefGoogle Scholar
  35. 35.
    Klapman JB, Ene-Stroescu D, Becker MA, et al. A lupus-like syndrome associated with infliximab therapy. Inflamm Bowel Dis 2003; 9(3): 176–8PubMedCrossRefGoogle Scholar
  36. 36.
    Schaible TF. Long term safety of infliximab. Can J Gastroenterol 2000; 14 Suppl. C: 29C–32CPubMedGoogle Scholar
  37. 37.
    Charles PJ, Smeenk RJ, De Jong J, et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000; 43(11): 2383–90PubMedCrossRefGoogle Scholar
  38. 38.
    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(1): 32–9PubMedCrossRefGoogle Scholar
  39. 39.
    Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease: a population-based study. Cancer 2001; 91(4): 854–62PubMedCrossRefGoogle Scholar
  40. 40.
    Jones M, Symmons D, Finn J, et al. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risks in rheumatoid arthritis? A matched cohort study. Br J Rheumatol 1996; 35(8): 738–45PubMedCrossRefGoogle Scholar
  41. 41.
    Levine B, Kaiman J, Mayer L, et al. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323(4): 236–41PubMedCrossRefGoogle Scholar
  42. 42.
    Louis A, Cleland JG, Crabbe S, et al. Clinical trials update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 2001; 3(3): 381–7PubMedCrossRefGoogle Scholar
  43. 43.
    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(10): 807–11PubMedGoogle Scholar
  44. 44.
    Chung ES, Packer M, Lo KH, et al. 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 2003; 107(25): 3133–40PubMedCrossRefGoogle Scholar
  45. 45.
    Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol Suppl 2002; 65: 33–8PubMedGoogle Scholar
  46. 46.
    Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001; 44(12): 2862–9PubMedCrossRefGoogle Scholar
  47. 47.
    Wagner C, Olson A, Ford J, et al. Effects of antibodies to infliximab on safety and efficacy of infliximab treatment in patients with Crohn’s disease [abstract]. Gastroenterology 2002; 122 (4 Suppl. 1): A613Google Scholar
  48. 48.
    Kugathasan S, Levy MB, Saeian K, et al. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002; 97(6): 1408–14PubMedCrossRefGoogle Scholar
  49. 49.
    Tuvlin JA, Schaefer KG, Sane NP, et al. Infliximab is not a bridge to immunomodulators in Crohn’s disease [abstract]. Gastroenterology 2003; 124 (4 Suppl. 1): A518CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  1. 1.Section of GastroenterologyUniversity of Chicago HospitalsChicagoUSA

Personalised recommendations