Correspondence

Methotrexate for Crohn's Disease

N Engl J Med 1995; 333:600-601August 31, 1995

Article

To the Editor:

Feagan et al. (Feb. 2 issue)1 found that in a group of patients with chronically active Crohn's disease, methotrexate was more effective than placebo in improving symptoms and reducing requirements for prednisone. Further discussion is needed of the role of early treatment with mercaptopurine, rather than methotrexate, for sick patients with Crohn's disease.

Clinical remission after 16 weeks in 39.4 percent of the patients in the methotrexate group, as compared with 19.1 percent of patients in the placebo group, is less impressive than our 67 percent success rate with mercaptopurine (as compared with 8 percent with placebo, P<0.001).2 Feagan et al. state, “Either mercaptopurine or azathioprine is sometimes prescribed to reduce the requirements for corticosteroids.” Mercaptopurine has consistently eliminated, not merely reduced, the requirement for corticosteroids in two thirds of patients.2,3

Feagan et al. refer to our study of the toxic effects of mercaptopurine4 and express “concern” about the toxicity of either mercaptopurine or azathioprine. Our findings and the subsequent long-term observations of others have reduced, not raised, concern. Furthermore, in the study reported by Feagan et al., 17 percent of the patients receiving methotrexate withdrew from treatment because of adverse reactions, as compared with 6 percent of patients receiving mercaptopurine in our study.2

Severe hepatic toxicity occurs rarely in patients treated with mercaptopurine, as compared with those treated with methotrexate; liver biopsies are not required. Because of the risk of teratogenicity, the use of methotrexate is contraindicated in women of childbearing age with Crohn's disease. Teratogenicity has not been observed with mercaptopurine or azathioprine.4

The relatively “rapid response” to methotrexate (improvement at 6 weeks) noted by Feagan et al. is not much different from the response to mercaptopurine (improvement at a mean of 3.1 to 3.4 months), particularly since the methotrexate protocol allowed for continuation of prednisone for 12 weeks and even an increase in the prednisone dose if the condition worsened. In the mercaptopurine study,2 there was no restriction on the rate of reduction of corticosteroids, which were often discontinued within two months.

Feagan et al. also state, “Effective drug therapy to maintain clinical remission in patients with Crohn's disease is currently unavailable.” This is not so. O'Donoghue et al.5 showed that azathioprine prevented relapses among patients who had entered remission. Data from other studies support the observation that treatment with mercaptopurine or azathioprine results in a prolonged remission.3,6

In our experience with patients with inflammatory bowel disease in whom corticosteroids cannot be discontinued and aminosalicylate products have failed, mercaptopurine remains the initial drug of choice. We suggest that methotrexate will have its main role in the treatment of patients who do not have a response to mercaptopurine, cannot tolerate it, or have allergic reactions to it.

Burton I. Korelitz, M.D.
Lenox Hill Hospital, New York, NY 10021

Daniel H. Present, M.D.
Mount Sinai Medical Center, New York, NY 10029

6 References

1. 1

   Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. N Engl J Med 1995;332:292-297
   Full Text | Web of Science | Medline

2. 2

   Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med 1980;302:981-987
   Full Text | Web of Science | Medline

3. 3

   Korelitz BI, Adler DJ, Mendelsohn RA, Sacknoff AL. Long-term experience with 6-mercaptopurine in the treatment of Crohn's disease. Am J Gastroenterol 1993;88:1199-1205
   

4. 4

   Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111:641-649
   Web of Science | Medline

5. 5

   O'Donoghue DO, Dawson AM, Powell-Tuck J, Bown RL, Lennard-Jones JE. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 1978;2:955-957
   CrossRef | Web of Science | Medline

6. 6

   Bouhnik Y, Scemama G, Lemann M, et al. Effect of immunosuppressive therapy withdrawal on the course of Crohn's disease in patients successfully maintained in prolonged remission using azathioprine or 6-mercaptopurine. Gastroenterology 1994;106:Suppl:A655-A655 abstract.
   Web of Science

Author/Editor Response

The authors reply:

To the Editor: The conclusion that mercaptopurine is superior to and safer than methotrexate is not supported by good data. Although the trial of mercaptopurine by Present et al.1 showed an apparently larger treatment effect, the outcomes in their study and ours were different. Our definition of success — complete withdrawal of prednisone and maintenance of remission — results in a conservative estimate of the efficacy of methotrexate. In contrast, Present et al. defined success as “slight symptomatic improvement” and a partial (unquantified) reduction in the use of corticosteroids. All our analyses used the intention-to-treat principle, whereas Present et al. excluded patients who were prematurely withdrawn from treatment with mercaptopurine.

Present et al. used a crossover design, which was only partially followed, making data analysis difficult. They did, however, provide the outcomes for a subgroup of patients who did not cross over to the second group assignment, and these data approximate those in a conventional parallel-group design. In this subgroup of patients, only those who had “excellent improvement” might have approached the degree of symptomatic improvement or withdrawal from steroids observed in our study. Table 1Table 1Successful Treatment with Mercaptopurine, as Compared with Methotrexate, in Patients with Crohn's Disease. compares these results with those in our high-prednisone stratum, which was similar to the group treated by Present et al. There were no substantial differences in the responses.

There is a more rapid therapeutic response to methotrexate than to azathioprine. All our patients who had responses did so by 12 weeks, as compared with 50 percent of the patients treated with purine antimetabolites.1,2

In support of their contention that long-term antimetabolite therapy is effective, Korelitz and Present cite a study of 51 patients3 in which those who had responses to azathioprine were assigned to continued treatment with that drug or to a placebo, but they do not cite the larger National Cooperative Crohn's Disease Study, which had negative results.4 In our view, purine antimetabolites for maintenance therapy are not widely accepted; in a recent study, only 10 of 305 patients (3 percent) who had had Crohn's disease for a mean period of eight years had ever received these drugs.5

Antimetabolites are associated with serious toxic effects, including fatal sepsis and lymphoma.6 Although Korelitz and Present suggest that the use of methotrexate is contraindicated in women because of the risk of teratogenicity, appropriate means of birth control obviate this risk. Conversely, we do not accept the view that purine antimetabolites are safe during pregnancy. Given the large risk of a type II error associated with the existing data, we do not believe it is justified to suggest that the use of azathioprine and mercaptopurine is “safe,” whereas methotrexate is contraindicated. Present et al. advised three patients who became pregnant while receiving mercaptopurine to undergo therapeutic abortion.1 Either drug should be used in women with childbearing potential only after a careful discussion of the benefits of treatment and the risk of teratogenicity.

Brian G. Feagan, M.D.
John W.D. McDonald, M.D.
University of Western Ontario, London, ON N6A 5A5, Canada

for the North American Crohn's Study Group investigators

6 References

1. 1

   Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine: a long-term, randomized, double-blind study. N Engl J Med 1980;302:981-987
   Full Text | Web of Science | Medline

2. 2

   O'Brien JJ, Bayless TM, Bayless JA. Use of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease. Gastroenterology 1991;101:39-46
   Web of Science | Medline

3. 3

   O'Donoghue DP, Dawson AM, Powell-Tuck J, Bown RL, Lennard-Jones JE. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn's disease. Lancet 1978;2:955-957
   CrossRef | Web of Science | Medline

4. 4

   Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979;77:847-869
   Web of Science | Medline

5. 5

   Feagan BG, McDonald JWD, Rochon J, et al. Low-dose cyclosporine for the treatment of Crohn's disease. N Engl J Med 1994;330:1846-1851
   Full Text | Web of Science | Medline

6. 6

   Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111:641-649
   Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Geert D'Haens, Filip Baert, Gert van Assche, Philip Caenepeel, Philippe Vergauwe, Hans Tuynman, Martine De Vos, Sander van Deventer, Larry Stitt, Allan Donner, Severine Vermeire, Frank J Van De Mierop, Jean-Charles R Coche, Janneke van der Woude, Thomas Ochsenkühn, Ad A van Bodegraven, Philippe P Van Hootegem, Guy L Lambrecht, Fazia Mana, Paul Rutgeerts, Brian G Feagan, Daniel Hommes. (2008) Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. The Lancet 371:9613, 660-667
   CrossRef

2. 2

   Brian G Feagan, Ahmad Alfadhli. (2004) Methotrexate in inflammatory bowel disease. Gastroenterology Clinics of North America 33:2, 407-420
   CrossRef

3. 3

   Burton I. Korelitz. (2002) Steroids for Crohn's Disease???An Appreciation and a Vote of Confidence. Inflammatory Bowel Diseases 8:3, 219-222
   CrossRef

4. 4

   Feagan, Brian G., Fedorak, Richard N., Irvine, E. Jan, Wild, Gary, Sutherland, Lloyd, Steinhart, A. Hillary, Greenberg, Gordon R., Koval, John, Wong, Cindy J., Hopkins, Marybeth, Hanauer, Stephen B., McDonald, John W.D., . (2000) A Comparison of Methotrexate with Placebo for the Maintenance of Remission in Crohn's Disease. New England Journal of Medicine 342:22, 1627-1632
   Full Text