Correspondence

Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn's Disease

N Engl J Med 1998; 338:333-334January 29, 1998

Article

To the Editor:

We question whether the study of monoclonal antibody cA2 to tumor necrosis factor α, reported by Targan and colleagues (Oct. 9 issue),1 specifically establishes the efficacy of the strategy of using antibody to tumor necrosis factor α. The cA2 binds complement and has been reported to cause a profound monocytopenia in patients with rheumatoid arthritis,2 an action that could itself be therapeutic in patients with Crohn's disease (though potentially hazardous) and that might explain why the results reported by Targan et al. were not dose-dependent. Did monocytopenia occur in the present study? If so, was there any relation between therapeutic efficacy and the monocyte count? Have any patients had adverse consequences of immunosuppression or monocytopenia with prolonged use of cA2? The data we reported, to which Targan et al. referred,3 were obtained with a monoclonal antibody that has been humanized to reduce immunogenicity and that does not bind complement or suppress the monocyte count.

Christopher J. Hawkey, D.M.
William A. Stack, M.D.
University Hospital, Nottingham NG7 2UH, United Kingdom

3 References

1. 1

   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 | Medline

2. 2

   Lorenz HM, Antoni C, Valerius T, et al. In vivo blockade of TNF-alpha by intravenous infusion of a chimeric monoclonal TNF-alpha antibody in patients with rheumatoid arthritis: short term cellular and molecular effects. J Immunol 1996;156:1646-1653
   Web of Science | Medline

3. 3

   Stack, WA, Mann SD, Roy AJ, et al. Randomised controlled trial of CDP571 antibody to tumor necrosis factor-alpha in Crohn's disease. Lancet 1997;349:521-524
   CrossRef | Web of Science | Medline

To the Editor:

Targan et al. defined refractory Crohn's disease as unsuccessful treatment with one of the following: mesalamine for eight or more weeks, corticosteroids (up to 40 mg per day) for at least eight weeks, or mercaptopurine or azathioprine for six or more months. Our main concern is the potential heterogeneity of these patients; aminosalicylates appear to be much less potent than corticosteroids in the treatment of Crohn's disease.1,2 Moreover, the full effects of aminosalicylate treatment may be achieved no earlier than 8 to 12 weeks after the treatment has been initiated.3 Unsuccessful therapy with aminosalicylates is not quite comparable to a failure of corticosteroid therapy, immunosuppressive therapy, or both. Detailed information (i.e., the number of patients who did not have responses to aminosalicylate therapy and whether this subgroup had a different response to cA2 treatment) would be helpful.

Jürgen Bauditz, M.D.
Herbert Lochs, M.D.
Stefan Schreiber, M.D.
Charité University Hospital, 10117 Berlin, Germany

3 References

1. 1

   Singleton JW, Hanauer SB, Gitnick GL, et al. Mesalamine capsules for the treatment of active Crohn's disease: results of a 16-week trial. Gastroenterology 1993;104:1293-1301
   Web of Science | Medline

2. 2

   Thomsen OO, Cortot A, Jewell D, et al. Budesonide CIR is more effective than mesalazine in active Crohn's disease: a 16 week, international, randomized, double-blind multicentre trial. Gut 1997;41:Suppl 3:A70-A70 abstract.
   CrossRef | Web of Science

3. 3

   Tremaine WJ, Schroeder KW, Harrison JM, Zinsmeister AR. A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn's colitis and ileocolitis. J Clin Gastroenterol 1994;19:278-282
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Bauditz et al. ask whether a substantial number of patients enrolled in our study were receiving aminosalicylates as their only therapy and whether, as a result, they may have had less treatment-refractory disease than those receiving other therapies. Only 13.9 percent of the patients were receiving aminosalicylate therapy alone, 9.3 percent were not receiving any concurrent therapy, and 76.8 percent were receiving corticosteroids or immunosuppressive therapy (mercaptopurine or azathioprine) or both. Thus, three fourths of the patients were receiving intensive or second-line therapies for Crohn's disease yet still had moderate-to-severe disease activity. Furthermore, as we reported, the treatment benefit of cA2 was consistent when the analysis was stratified according to concurrent therapy.

Hawkey and Stack suggest monocytopenia as a potential mechanism by which cA2 induced a treatment response. There was a slight increase in the monocyte count after treatment. More important, at four weeks, there was no significant difference in the change from the base-line monocyte count between the 54 patients who had responses to cA2 (+1.1±2.5 percent) and the 29 who did not (+1.5±3.1 percent, P = 0.79). Therefore, decreases in peripheral monocyte counts did not contribute to the treatment benefit of cA2.

A recent study demonstrated the down-regulation of T helper 1 cytokine–producing cells within the lamina propria after successful treatment with cA2.1 This investigation also included an evaluation of peripheral blood and showed an increase in T helper 1 cells. Further investigations of the mucosal effects of cA2 in the treatment of Crohn's disease must be performed with an ongoing comparison with associated changes in the circulation.

Investigations comparing cA2 with CDP571 (the monoclonal antibody referred to by Hawkey and Stack) and other monoclonal antibodies to tumor necrosis factor α are required to determine whether the treatment effect may be dependent on binding to complement. However, the complement-binding properties of cA2 may represent an intriguing explanation for the lasting benefit of cA2 treatment in reducing mucosal inflammation.

Stephan R. Targan, M.D.
Cedars–Sinai Medical Center, Los Angeles, CA 90048

Thomas F. Schaible, Ph.D.
Centocor, Malvern, PA 19355

1 References

1. 1

   Plevy SE, Landers CJ, Prehn J, et al. A role for TNF-α and mucosal T helper-1 cytokines in the pathogenesis of Crohn's disease. J Immunol 1997;159:6276-6282
   Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Anthony Markham, Harriet M. Lamb. (2000) Infliximab. Drugs 59:6, 1341-1359
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2. 2

   Geoffrey C. Wall, Catherine Heyneman, Timothy P. Pfanner. (1999) Medical Options for Treating Crohn’s Disease in Adults: Focus on Antitumor Necrosis Factor-α Chimeric Monoclonal Antibody. Pharmacotherapy 19:10, 1138-1152
   CrossRef