Correspondence
Immunogenicity of Infliximab in Crohn's Disease
N Engl J Med 2003; 348:2155-2156May 22, 2003
- Article
To the Editor:
Baert et al. (Feb. 13 issue)1 report the formation of antibodies to infliximab in 61 percent of patients with Crohn's disease treated episodically (“on demand”) with infliximab. This rate is higher than the 10 to 15 percent incidence observed in previous trials in patients with Crohn's disease.2-4 In the A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-Term Treatment Regimen (ACCENT) I study,5 the incidence of the formation of antibodies to infliximab was greatly reduced with the administration of an induction regimen at zero, two, and six weeks, followed by maintenance therapy every eight weeks (incidence, <10 percent, as compared with 30 percent among patients treated episodically). Furthermore, the proportions of patients receiving maintenance infusions in whom a clinical response and remission were achieved at one year were the same, regardless of the presence or absence of antibodies to infliximab.5
Baert et al. recommend that treatment with immunomodulators be concomitant with episodic infliximab treatment, but concomitant treatment with immunomodulators in ACCENT I did not result in a substantially increased benefit from the three-dose induction regimen and eight-week maintenance therapy. Thus, the benefit–risk ratio for immunomodulators given concurrently with induction and maintenance therapy is not clear.
Finally, antibody formation is not unique to infliximab. The administration of humanized and fully human monoclonal antibodies may be associated with the development of antibodies to any parenteral protein.
5 ReferencesStephen B. Hanauer, M.D.
University of Chicago, Chicago, IL 60637
shanauer@medicine.bsd. uchicago. edu 1
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
Full Text | Web of Science | Medline2
Targan SR ,Hanauer SB ,van Deventer SJH , et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn's disease. N Engl J Med 1997;337:1029-1035
Full Text | Web of Science | Medline3
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
Full Text | Web of Science | Medline4
Hanauer SB ,Feagan BG ,Lichtenstein GR , et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549
CrossRef | Web of Science | Medline5
Wagner C ,Olson A ,Ford J ,Bao W ,Patel K ,Hanauer S . Effects of antibodies to infliximab on safety and efficacy of infliximab treatment in patients with Crohn's disease. Gastroenterology 2002;122:Suppl:A-613 abstract.
CrossRef | Web of Science
Author/Editor Response
Our findings apply only to episodic (“on flare”) treatment with infliximab. With induction therapy followed by infusions every eight weeks, the effect of antibodies against infliximab is suppressed. However, when therapy is interrupted, immunogenicity becomes important. Hanauer et al. have reported1 that delayed hypersensitivity due to antibodies developed in 25 percent of patients who were re-treated after a long period without drugs. Furthermore, concomitant immunosuppression is beneficial. Vermeire et al.2 showed that immunosuppression was associated with an odds ratio for a response to infliximab of 2.7 (95 percent confidence interval, 1.4 to 5.0). Parsi et al.3 reported that 74 percent of patients receiving immunosuppressive drugs and 39 percent of patients who were not receiving such drugs had a response to infliximab (P=0.007). In the first study of infliximab maintenance therapy,4 75 percent of patients (12 of 16) receiving 10 mg of intravenous infliximab per kilogram of body weight along with immunosuppressive drugs had a sustained response at 44 weeks, as compared with 50 percent (9 of 18) who were not receiving immunosuppressive drugs (P=0.17). Hanauer et al. reported that in ACCENT I,5 50 percent of patients receiving immunosuppressive drugs had a sustained response at week 54, as compared with 41 percent of those not receiving such drugs. There were fewer infusion reactions with immunosuppressive drugs (20 percent) or with immunosuppressive drugs plus cortisone (8 percent) than without (32 percent).
We agree that other antibodies to tumor necrosis factor may also be immunogenic. Hence, it is important to study the influence of these antibodies on efficacy and safety.
5 ReferencesPaul Rutgeerts, M.D., Ph.D.
Filip Baert, M.D.
Maja Noman, M.D.
University Hospital Gasthuisberg, B-3000 Leuven, Belgium
paul.rutgeerts@uz. kuleuven. ac. be 1
Hanauer SB ,Rutgeerts PJ ,D'Haens G , et al. Delayed hypersensitivity to infliximab (Remicaide) re-infusion after a 2-4 year interval without treatment. Gastroenterology 1999;116:A731-A731 abstract.
Web of Science2
Vermeire S ,Louis E ,Carbonez A , et al. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn's disease. Am J Gastroenterol 2002;97:2357-2363
CrossRef | Web of Science | Medline3
Parsi MA ,Achkar JP ,Richardson S , et al. Predictors of response to infliximab in patients with Crohn's disease. Gastroenterology 2002;123:707-713
CrossRef | Web of Science | Medline4
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
CrossRef | Web of Science | Medline5
Hanauer SB ,Feagan BG ,Lichtenstein GR , et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549
CrossRef | Web of Science | Medline
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J. SEIDERER, S. BRAND, J. DAMBACHER, S. PFENNIG, M. JÜRGENS, B. GÖKE, T. OCHSENKÜHN. (2007) Adalimumab in patients with Crohn’s disease - safety and efficacy in an open-label single centre study. Alimentary Pharmacology & Therapeutics 25:7, 787-796
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Pedram J Enayati, Konstantinos A Papadakis. (2005) Association of Anti-tumor Necrosis Factor Therapy With the Development of Multiple Sclerosis. Journal of Clinical Gastroenterology 39:4, 303-306
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Julia Seiderer, Burkhard Göke, Thomas Ochsenkühn. (2004) Safety Aspects of Infliximab in Inflammatory Bowel Disease Patients. Digestion 70:1, 3-9
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