Etanercept for Crohn's Disease
http://www.100md.com
《新英格兰医药杂志》
To the Editor: I would like to correct an error in the Perspective by Kupper (Nov. 20 issue)1 on immunologic targets in psoriasis. Dr. Kupper indicated that etanercept (Enbrel), a tumor necrosis factor (TNF-)–receptor fusion protein, has demonstrated efficacy in inflammatory bowel disease. In fact, in the most authoritative published experience with etanercept in the treatment of inflammatory bowel disease (a randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Crohn's disease), the drug was shown to be ineffective,2 and it does not have marketing approval for any indication in inflammatory bowel disease.
Suzanne B. Travers, M.D.
Centocor
Malvern, PA 19355
References
Kupper TS. Immunologic targets in psoriasis. N Engl J Med 2003;349:1987-1990.
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.
Dr. Kupper replies: Although TNF- blockade as a therapeutic approach has been effective in inflammatory bowel disease, Dr. Travers is quite correct that etanercept has been strikingly (and surprisingly) less effective in Crohn's disease than infliximab, a humanized monoclonal antibody directed against TNF-,1 and etanercept is neither approved nor marketed for this indication. Some studies suggested that etanercept may have some efficacy in Crohn's disease,2 but in the authoritative randomized, controlled trial cited by Travers, etanercept failed to have efficacy in inflammatory bowel disease.3 The study investigators state, "The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease."
Although it may well be a dosing phenomenon, more recent evidence suggests that not all TNF- blockers act in the same mechanistic fashion. In a very recent in vitro study, examination of T lymphocytes from lamina propria of patients with Crohn's disease showed that, whereas both etanercept and infliximab neutralized TNF-, only infliximab bound to lesional T lymphocytes and induced apoptosis of these cells.4 If one can extrapolate these in vitro results to the disease state in vivo, then infliximab, but not etanercept, might be expected to eliminate (through induction of apoptosis) lesional disease–related T cells, providing a biologic basis for its apparent superiority as a therapeutic agent in this setting. If this were true, then increasing the dose of etanercept alone in Crohn's disease might not be efficacious. Clearly, further studies will be required to sort out these important issues.
Thomas S. Kupper, M.D.
Brigham and Women's Hospital
Boston, MA 02115
References
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549.
D'Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial. Am J Gastroenterol 2001;96:2564-2568.
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.
Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 2003;124:1774-1785.
Suzanne B. Travers, M.D.
Centocor
Malvern, PA 19355
References
Kupper TS. Immunologic targets in psoriasis. N Engl J Med 2003;349:1987-1990.
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.
Dr. Kupper replies: Although TNF- blockade as a therapeutic approach has been effective in inflammatory bowel disease, Dr. Travers is quite correct that etanercept has been strikingly (and surprisingly) less effective in Crohn's disease than infliximab, a humanized monoclonal antibody directed against TNF-,1 and etanercept is neither approved nor marketed for this indication. Some studies suggested that etanercept may have some efficacy in Crohn's disease,2 but in the authoritative randomized, controlled trial cited by Travers, etanercept failed to have efficacy in inflammatory bowel disease.3 The study investigators state, "The dose of etanercept administered in this study is that approved for rheumatoid arthritis. Higher doses or more frequent dosing may be required to attain a response in patients with active Crohn's disease."
Although it may well be a dosing phenomenon, more recent evidence suggests that not all TNF- blockers act in the same mechanistic fashion. In a very recent in vitro study, examination of T lymphocytes from lamina propria of patients with Crohn's disease showed that, whereas both etanercept and infliximab neutralized TNF-, only infliximab bound to lesional T lymphocytes and induced apoptosis of these cells.4 If one can extrapolate these in vitro results to the disease state in vivo, then infliximab, but not etanercept, might be expected to eliminate (through induction of apoptosis) lesional disease–related T cells, providing a biologic basis for its apparent superiority as a therapeutic agent in this setting. If this were true, then increasing the dose of etanercept alone in Crohn's disease might not be efficacious. Clearly, further studies will be required to sort out these important issues.
Thomas S. Kupper, M.D.
Brigham and Women's Hospital
Boston, MA 02115
References
Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549.
D'Haens G, Swijsen C, Noman M, et al. Etanercept in the treatment of active refractory Crohn's disease: a single-center pilot trial. Am J Gastroenterol 2001;96:2564-2568.
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.
Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn's disease. Gastroenterology 2003;124:1774-1785.