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Maintenance of remission in Crohn's disease: Is 5′-aminosalicylic acid the answer?
GASTROENTEROLOGY 1992;103:694-704
EDITORIALS
Maintenance of Remission in Crohn’s Disease: Is 5’0Aminosalicylic Acid the Answer? Mesalamine is the generic name for 5-aminosalicylic acid (5-ASA); in Europe, it is called mesalazine. The Food and Drug Administration has approved one of the oral forms of mesalamine, Asacol (Procter and Gamble Pharmaceuticals, Inc., Norwich, NY), for prescription use for the treatment of ulcerative colitis. This preparation is a sustained release tablet containing 400 mg of 5-ASA coated with an acrylicbased resin, Eudragit-S, which dissolves to release the 5-ASA when the intraluminal pH increases to >7.0. In this issue of Gastroenterology, Prantera et al.’ report the successful use of this same oral mesalamine preparation for maintenance of remission in patients with Crohn’s disease. These findings support an additional indication for oral mesalamine. It is worthwhile to put this present study into perspective with the previous investigations of medications tested for maintenance of remission in Crohn’s disease. It has been 27 years since Lennard-Jones et al.’ reported the efficacy of another 5-ASA drug, sulfasalazine, for maintenance of remission in ulcerative colitis. Given the many similarities of Crohn’s disease and ulcerative colitis, why has it taken so long to find a treatment for this particular indication in Crohn’s disease? It is certainly not for lack of effort. In addition to several trials of sulfasalazine, both corticosteroids and 6-mercaptopurine have been tested,3 without success. One reason for these failures may have been the higher relapse rate in ulcerative colitis than in Crohn’s disease. For patients with distal ulcerative colitis in remission, Miner and Biddle4 noted a mean of only 35% of patients in remission after 12 months among patients in the placebo arms of multiple trials of sulfasalazine. In contrast, for patients with Crohn’s disease in remission, after 12 months, the remission rates are still about 50%-75%.~3~Because of this lower rate of relapse, more patients are required in a placebo-controlled trial to show efficacy of treatment in Crohn’s disease than are needed in a study of ulcerative colitis. Indeed, this increased chance for a type II statistical error has plagued several studies using sulfasalazine for maintenance of remission in Crohn’s. In the first such trial,6 only 43 patients could be recruited in nine hospitals in the United Kingdom over a 5-year period; the small number of patients was the likely cause of failure of the
drug to show a benefit as compared with placebo. Similar problems arose in the Inter-Nordic Cooperative Study7 in which 66 patients who had undergone resection of Crohn’s disease were randomized to sulfasalazine vs. placebo; the failure of sulfasalazine was again attributed to the relatively small number of patients. In another postoperative study,’ 97 patients received either sulfasalazine plus prednisone or placebo for 33 weeks. No benefit was observed after 1, 2, and 3 years, although technically this was not a maintenance study, because the medication was given for <8 months. Unfortunately, increasing the size of the studypopulation a moderate amount was not the secret to demonstrating efficacy of sulfasalazine for maintenance of remission. In the l¢er American National Crohn’s Disease Cooperative Study (NCCDS),3 159 patients in the phase II portion were randomized to receive placebo or sulfasalazine, without demonstrable benefit of the drug. In the European Cooperative Crohn’s Study,’ a total of 115 patients in remission were in the placebo and sulfasalazine arms, with no demonstrable benefit after 2 years of observation. Sulfasalazine, 1.5 g/day, was used in the NCCDS; the dose was 3.0 g/day in the European Study. The bigger dose did not prove to be any better. However, there were encouraging results reported from a German postoperative study9 in which 232 patients were randomized to sulfasalazine or placebo. The recurrence of disease was significantly less in patients who received sulfasalazine, 3 g/day, after 1 and 2 years. By the third year, there were only 44 patients in the two groups; perhaps a type II statistical error accounted for the apparent failure of sulfasalazine. Nevertheless, it must be concluded that sulfasalazine was unlikely to have a major effect. The development of oral 5-ASA preparations has given new hope to finding an effective therapy for maintenance of remission in Crohn’s disease. The International Mesalazine Study GrouplO had good results with Mesasal-Claversal (Smith Kline & French Laboratories, Philadelphia, PA), a 5-ASA tablet coated with Eudragit-L, which releases the drug when the pH rises above 5.6, in the jejunum and distally. Two hundred and forty-eight patients from eight countries were treated with 1.5 g/day of 5-ASA for up to 12 months. Of note, 16% of the patients had been taking sulfasalazine and an unspecified num-
August
1992
ber of patients had been taking prednisone in a dose of 2.5 mg/day, and the medications were stopped during the month preceding entry into the trial. One could question if these patients who were on medication just before study entry were actually in remission or had active disease controlled by the oral 5ASA. Using a life table estimate of the cumulative rate of relapse, there were significantly fewer relapses in the patients who received 5-ASA than in patients receiving placebo. Although patients were not stratified according to the location of involvement of bowel disease, the terminal ileum was the only area for which the relapse rate was significantly lower among patients on 5-ASA than placebo (8.3% vs. 31%). Also, patients who had previously had a bowel resection benefited more from 5-ASA maintenance treatment. The Mesasal-Claversal preparation is stable at a pH < 6.0 and releases the drug in the terminal ileum and proximal colon. It is noteworthy that a study cohort of more than 2~10patients was required to demonstrate efficacy. However, a subsequent study using another preparation that releases 5-ASA in the ileum failed to show a benefit. Brignola et al.‘l randomized a smaller cohort of 44 patients with Crohn’s disease in remission to either Pentasa (Marion Merrell Dow, Inc., Kansas City, MO), 2 g/day, or placebo for 4 months. Pentasa contains microgranules of 5-ASA coated with ethyl cellulose, which is slowly dissolved, releasing 5-ASA in the proximal jejunum and throughout the small bowel and colon. There was no significant difference in the relapse rate of the placebo-treated and drug-treated patients. Of the 19 patients who had ileal disease alone, 30% of those who received Pentasa had a relapse compared with 68% in the placebo group. Although the difference was not statistically significant, there was a trend to improvement in this subgroup of ileal disease. In another placebo-controlled study of Pentasa,12 there were fewer recurrences in patients who received treatment within 3 months of the last relapse but not in patients who had been in remission for 3-24 months at the onset of treatment. Only about 12% of the patients in the study had ileitis alone, and patients were not stratified for disease location. Thus, no particular insight can be drawn about the effect on the patients with ileitis. In the current study by Prantera,’ all of the 125 patients were in remission and had required no medication for at least 3 months but no more than 24 months. This design eliminated patients who would likely flare as a result of the recent withdrawal from medication and also patients with disease that had been dormant for many years. There was a slightly higher than usual relapse rate in the placebo group at
EDITORIALS
695
1 year (55%), perhaps due to the exclusion of those patients with remote, inactive disease. Moreover, 56% of the patients had disease limited to the ileum, compared with the usual 30%‘~ in most series. As in two previous 5-ASA trials,‘o*11patients were not stratified as to disease location, but there appeared to be a benefit primarily for those with ileal disease. The relapse rate was also less in the placebo group for patients with a previous bowel resection and in patients with remissions >9 months. In this study, the 5-ASA drug was Asacol, which releases 5-ASA in the terminal ileum and proximal co10n.14 As noted, there are now three placebo-controlled studies that suggest that oral 5-ASA in the form of mesalamine prevents relapses of Crohn’s ileitis.**“~‘2 In contrast, no controlled trials have shown benefit of sulfasalazine in ileal Crohn’s disease. Although falling short of showing statistical significant in a controlled design, several studies support a beneficial effect of sulfasalazine for treatment of Crohn’s ileitis. Goldstein et a1.16 reported 28 patients with ileitis who went into clinical remission with sulfasalazine treatment and observed that 11 of the patients with ileitis in remission relapsed when maintenance sulfasalazine was discontinued or the dose was reduced. In a placebo-controlled trial of sulfasalazine, in 5 of the 7 van Hees et a1.17 noted improvement patients with Crohn’s ileitis who were treated. The favorable effects with sulfasalazine in these small studies supports the conclusions of investigators who have attempted placebo-controlled studies with sulfasalazine that the drug has failed because of type II errors, and not because of a lack of efficacy. Because sulfasalazine also contains 5-ASA, what is the explanation for these apparently conflicting findings in the sulfasalazine trials compared with the mesalamine trials in Crohn’s disease? Clearly, the difference is not the site of action; bacterial action releases 5-ASA from sulfasalazine in the terminal ileum and co10n,15 the same location where several of the oral 5-ASA drugs are released. Most likely, the difference is dose related, with a higher dose of 5ASA delivered in the mesalamine studies than when sulfasalazine has been used. In the study by Prantera et al.,’ 2.4 g/day of oral 5-ASA was given, comparable with the amount of 5-ASA in 6.0 g/day of sulfasalazine, which is more than has been used in any of the maintenance trials of sulfasalazine. Because of the adverse effects that would be expected if sulfasalazine were used in doses of 6.0 g/day,” it is unlikely that the medication will ever be shown in a controlled study to be effective in Crohn’s ileitis. There are still unanswered questions regarding the role of 5-ASA in the maintenance of remission in Crohn’s disease. What is the optimal dose? Will doses of 5-ASA > 2.4 g/day be even better in Crohn’s dis-
696
EDITORIALS
ease? Is 5-ASA effective for ileitis, ileocolitis, and for colitis? Are there side effects with long-term treatment above and beyond those noted in patients with ulcerative colitis who are treated with 5-ASA? In any case, patients with Crohn’s disease will be glad to learn that some further progress has been made in the management of the disorder.
GASTROENTEROLOGY
section
References
9.
10.
11.
12.
1. Prantera
2.
3.
4.
5.
6. 7.
a.
C, Pallone F, Brunetti G, Cottone M, Miglioli M. Oral 5-ASA in the maintenance treatment of Crohn’s disease. Results of a randomized placebo controlled trial with Asacol. Gastroenterology 1992. Misiewicz JJ, Lennard-Jones JE, Connell AM, Baron JH, Jones FA. Controlled trial of sulfasalazine in maintenance therapy for ulcerative colitis. Lancet i965;ii:ia5-188. Summers RW, Sitz DM, Sessions JT, Becktel JM, Best WR, Kern F, Singleton JW. National cooperative Crohn’s disease study: results of drug treatment. Gastroenterology 1979; 77:847-869. Miner PB, Biddle WL. Maintaining remission in distal ulcerative colitis and ulcerative proctitis. Can J Gastroenterol 1990;4:476-480. Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European cooperative Crohn’s disease study [ECCDS]: results of drug treatment. Gastroenterology 1984;86:249-266. Baron JH, Bennett PN, Lennard-Jones JE, Swarbrick ET. Sulfasalazine in asymptomatic Crohn’s disease. Gut 1977;16:69-72. Wenckert A, Kristensen M, Eklund AE, Barany F, Jarnum S, Worning H, Folkenborg 0, Holtz A, Bonnevie 0, Riis P. The long-term prophylactic effect of salazosulphapyridine (salazopyrin) in primarily resected patients with Crohn’s disease. A controlled double blind trial. Stand J Gastroenterol 1978;13:161-167. Bergman L, Krause U. Postoperative treatment with corticosteroids and salazosulphapyridine (salazopyrin) after radical re-
disease.
Stand
J Gastroenterol
1976;
11:651-656.
WILLIAM J. TREMAINE, M.D.
Mayo Clinic Rochester, Minnesota
for Crohn’s
Vol. 103, No. 2
13.
14.
15. 16.
17.
ia.
Ewe K, Herfarth C, Malchow H, Jesdinsky HJ. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: a multicenter trial. Digestion i989;42:224-232. Thomson ABR, International Mesalazine Study Group. Coated oral 5-aminosalicylic acid vs placebo in maintaining remission of inactive Crohn’s disease. Aliment Pharmacol Therap 1990;4:55-64. Brignola C, Iannone P, Pasquali S, Campieri M, Giouchetti P, Belluzzi A, Basso 0, Miglioli M, Barbar L. Placebo-controlled trial of oral 5-ASA and relapse prevention of Crohn’s disease. Dig Dis Sci 1992;37:29-32. Gendre JP, Mary JY, Florent C, Modigliani R, Colombel JF, Soule JC, Aillet L. Does pentasa prevent relapse in quiescent Crohn’s disease (QCD)? A multicenter placebo controlled trial (161 patients) (abstr). Gastroenterology 1990;96:A171. Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s disease. Gastroenterology 1985;88:18181825. Martin F. Oral 5-ASA preparations. In: Bayless TM. Current management of inflammatory bowel disease. Philadelphia: BC Decker, 1969;72-77. Peppercorn MA. Advances in the drug therapy for inflammatory bowel disease. Ann Intern Med 1990;112:50-60. Goldstein F, Farquhar S, Thornton JJ, Abramson J. Favorable effects of sulfasalazine on small bowel Crohn’s disease: alongterm study. Am J Gastroenterol 1987;82:84a-853. van Hees PAM, van Lier HJJ, van Elteren PH, van Driessen WMM, Hogesand RA, van Velde GPM, ten Bakker JH, Tongeren JHM. Effect of sulfasalazine in patients with active Crohn’s disease: a controlled double blind study. Gut i9ai;22:404-409. Das KM, Eastwood MA, McManus JPA, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and relation with drug metabolism and acetylatorphenotype. N Engl J Med i973;289:49i-495.
Address requests for reprints to: William J. Tremaine, M.D., Division of Gastroenterology, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. 0 1992 by the American Gastroenterological Association
The Epidemiology of Inflammatory Bowel Disease: Are We Learning Anything New? Epidemiologic studies provide important clues as to the nature of disease and the identity of preventable risk factors. In a classical sense, the epidemiologist characterizes disease with regard to person, place, and time and assesses correlations between changes in disease incidence and changes in environmental determinants. Migrant studies showing a correlation between corresponding changes in geographical location and incidence of disease provide powerful evidence for an environmental etiology. The techniques of classical epidemiology were first developed in the early part of this century to determine the occur-
rence, spread, and prevention of many infectious diseases. These classic methods subsequently have been applied to chronic illnesses, including ulcerative colitis (UC) and Crohn’s disease (CD),’ and have provided important information, such as the predominance of Jewish patients in some countries (United States, England, Sweden), the association with genetic diseases (UC with ankylosing spondylitis and CD with psoriasis), the increased frequency of colorectal cancer in patients with UC and CD, the familial occurrences of UC and especially CD, the higher incidence of inflammatory bowel disease (IBD)
EDITORIALS
Maintenance of Remission in Crohn’s Disease: Is 5’0Aminosalicylic Acid the Answer? Mesalamine is the generic name for 5-aminosalicylic acid (5-ASA); in Europe, it is called mesalazine. The Food and Drug Administration has approved one of the oral forms of mesalamine, Asacol (Procter and Gamble Pharmaceuticals, Inc., Norwich, NY), for prescription use for the treatment of ulcerative colitis. This preparation is a sustained release tablet containing 400 mg of 5-ASA coated with an acrylicbased resin, Eudragit-S, which dissolves to release the 5-ASA when the intraluminal pH increases to >7.0. In this issue of Gastroenterology, Prantera et al.’ report the successful use of this same oral mesalamine preparation for maintenance of remission in patients with Crohn’s disease. These findings support an additional indication for oral mesalamine. It is worthwhile to put this present study into perspective with the previous investigations of medications tested for maintenance of remission in Crohn’s disease. It has been 27 years since Lennard-Jones et al.’ reported the efficacy of another 5-ASA drug, sulfasalazine, for maintenance of remission in ulcerative colitis. Given the many similarities of Crohn’s disease and ulcerative colitis, why has it taken so long to find a treatment for this particular indication in Crohn’s disease? It is certainly not for lack of effort. In addition to several trials of sulfasalazine, both corticosteroids and 6-mercaptopurine have been tested,3 without success. One reason for these failures may have been the higher relapse rate in ulcerative colitis than in Crohn’s disease. For patients with distal ulcerative colitis in remission, Miner and Biddle4 noted a mean of only 35% of patients in remission after 12 months among patients in the placebo arms of multiple trials of sulfasalazine. In contrast, for patients with Crohn’s disease in remission, after 12 months, the remission rates are still about 50%-75%.~3~Because of this lower rate of relapse, more patients are required in a placebo-controlled trial to show efficacy of treatment in Crohn’s disease than are needed in a study of ulcerative colitis. Indeed, this increased chance for a type II statistical error has plagued several studies using sulfasalazine for maintenance of remission in Crohn’s. In the first such trial,6 only 43 patients could be recruited in nine hospitals in the United Kingdom over a 5-year period; the small number of patients was the likely cause of failure of the
drug to show a benefit as compared with placebo. Similar problems arose in the Inter-Nordic Cooperative Study7 in which 66 patients who had undergone resection of Crohn’s disease were randomized to sulfasalazine vs. placebo; the failure of sulfasalazine was again attributed to the relatively small number of patients. In another postoperative study,’ 97 patients received either sulfasalazine plus prednisone or placebo for 33 weeks. No benefit was observed after 1, 2, and 3 years, although technically this was not a maintenance study, because the medication was given for <8 months. Unfortunately, increasing the size of the studypopulation a moderate amount was not the secret to demonstrating efficacy of sulfasalazine for maintenance of remission. In the l¢er American National Crohn’s Disease Cooperative Study (NCCDS),3 159 patients in the phase II portion were randomized to receive placebo or sulfasalazine, without demonstrable benefit of the drug. In the European Cooperative Crohn’s Study,’ a total of 115 patients in remission were in the placebo and sulfasalazine arms, with no demonstrable benefit after 2 years of observation. Sulfasalazine, 1.5 g/day, was used in the NCCDS; the dose was 3.0 g/day in the European Study. The bigger dose did not prove to be any better. However, there were encouraging results reported from a German postoperative study9 in which 232 patients were randomized to sulfasalazine or placebo. The recurrence of disease was significantly less in patients who received sulfasalazine, 3 g/day, after 1 and 2 years. By the third year, there were only 44 patients in the two groups; perhaps a type II statistical error accounted for the apparent failure of sulfasalazine. Nevertheless, it must be concluded that sulfasalazine was unlikely to have a major effect. The development of oral 5-ASA preparations has given new hope to finding an effective therapy for maintenance of remission in Crohn’s disease. The International Mesalazine Study GrouplO had good results with Mesasal-Claversal (Smith Kline & French Laboratories, Philadelphia, PA), a 5-ASA tablet coated with Eudragit-L, which releases the drug when the pH rises above 5.6, in the jejunum and distally. Two hundred and forty-eight patients from eight countries were treated with 1.5 g/day of 5-ASA for up to 12 months. Of note, 16% of the patients had been taking sulfasalazine and an unspecified num-
August
1992
ber of patients had been taking prednisone in a dose of 2.5 mg/day, and the medications were stopped during the month preceding entry into the trial. One could question if these patients who were on medication just before study entry were actually in remission or had active disease controlled by the oral 5ASA. Using a life table estimate of the cumulative rate of relapse, there were significantly fewer relapses in the patients who received 5-ASA than in patients receiving placebo. Although patients were not stratified according to the location of involvement of bowel disease, the terminal ileum was the only area for which the relapse rate was significantly lower among patients on 5-ASA than placebo (8.3% vs. 31%). Also, patients who had previously had a bowel resection benefited more from 5-ASA maintenance treatment. The Mesasal-Claversal preparation is stable at a pH < 6.0 and releases the drug in the terminal ileum and proximal colon. It is noteworthy that a study cohort of more than 2~10patients was required to demonstrate efficacy. However, a subsequent study using another preparation that releases 5-ASA in the ileum failed to show a benefit. Brignola et al.‘l randomized a smaller cohort of 44 patients with Crohn’s disease in remission to either Pentasa (Marion Merrell Dow, Inc., Kansas City, MO), 2 g/day, or placebo for 4 months. Pentasa contains microgranules of 5-ASA coated with ethyl cellulose, which is slowly dissolved, releasing 5-ASA in the proximal jejunum and throughout the small bowel and colon. There was no significant difference in the relapse rate of the placebo-treated and drug-treated patients. Of the 19 patients who had ileal disease alone, 30% of those who received Pentasa had a relapse compared with 68% in the placebo group. Although the difference was not statistically significant, there was a trend to improvement in this subgroup of ileal disease. In another placebo-controlled study of Pentasa,12 there were fewer recurrences in patients who received treatment within 3 months of the last relapse but not in patients who had been in remission for 3-24 months at the onset of treatment. Only about 12% of the patients in the study had ileitis alone, and patients were not stratified for disease location. Thus, no particular insight can be drawn about the effect on the patients with ileitis. In the current study by Prantera,’ all of the 125 patients were in remission and had required no medication for at least 3 months but no more than 24 months. This design eliminated patients who would likely flare as a result of the recent withdrawal from medication and also patients with disease that had been dormant for many years. There was a slightly higher than usual relapse rate in the placebo group at
EDITORIALS
695
1 year (55%), perhaps due to the exclusion of those patients with remote, inactive disease. Moreover, 56% of the patients had disease limited to the ileum, compared with the usual 30%‘~ in most series. As in two previous 5-ASA trials,‘o*11patients were not stratified as to disease location, but there appeared to be a benefit primarily for those with ileal disease. The relapse rate was also less in the placebo group for patients with a previous bowel resection and in patients with remissions >9 months. In this study, the 5-ASA drug was Asacol, which releases 5-ASA in the terminal ileum and proximal co10n.14 As noted, there are now three placebo-controlled studies that suggest that oral 5-ASA in the form of mesalamine prevents relapses of Crohn’s ileitis.**“~‘2 In contrast, no controlled trials have shown benefit of sulfasalazine in ileal Crohn’s disease. Although falling short of showing statistical significant in a controlled design, several studies support a beneficial effect of sulfasalazine for treatment of Crohn’s ileitis. Goldstein et a1.16 reported 28 patients with ileitis who went into clinical remission with sulfasalazine treatment and observed that 11 of the patients with ileitis in remission relapsed when maintenance sulfasalazine was discontinued or the dose was reduced. In a placebo-controlled trial of sulfasalazine, in 5 of the 7 van Hees et a1.17 noted improvement patients with Crohn’s ileitis who were treated. The favorable effects with sulfasalazine in these small studies supports the conclusions of investigators who have attempted placebo-controlled studies with sulfasalazine that the drug has failed because of type II errors, and not because of a lack of efficacy. Because sulfasalazine also contains 5-ASA, what is the explanation for these apparently conflicting findings in the sulfasalazine trials compared with the mesalamine trials in Crohn’s disease? Clearly, the difference is not the site of action; bacterial action releases 5-ASA from sulfasalazine in the terminal ileum and co10n,15 the same location where several of the oral 5-ASA drugs are released. Most likely, the difference is dose related, with a higher dose of 5ASA delivered in the mesalamine studies than when sulfasalazine has been used. In the study by Prantera et al.,’ 2.4 g/day of oral 5-ASA was given, comparable with the amount of 5-ASA in 6.0 g/day of sulfasalazine, which is more than has been used in any of the maintenance trials of sulfasalazine. Because of the adverse effects that would be expected if sulfasalazine were used in doses of 6.0 g/day,” it is unlikely that the medication will ever be shown in a controlled study to be effective in Crohn’s ileitis. There are still unanswered questions regarding the role of 5-ASA in the maintenance of remission in Crohn’s disease. What is the optimal dose? Will doses of 5-ASA > 2.4 g/day be even better in Crohn’s dis-
696
EDITORIALS
ease? Is 5-ASA effective for ileitis, ileocolitis, and for colitis? Are there side effects with long-term treatment above and beyond those noted in patients with ulcerative colitis who are treated with 5-ASA? In any case, patients with Crohn’s disease will be glad to learn that some further progress has been made in the management of the disorder.
GASTROENTEROLOGY
section
References
9.
10.
11.
12.
1. Prantera
2.
3.
4.
5.
6. 7.
a.
C, Pallone F, Brunetti G, Cottone M, Miglioli M. Oral 5-ASA in the maintenance treatment of Crohn’s disease. Results of a randomized placebo controlled trial with Asacol. Gastroenterology 1992. Misiewicz JJ, Lennard-Jones JE, Connell AM, Baron JH, Jones FA. Controlled trial of sulfasalazine in maintenance therapy for ulcerative colitis. Lancet i965;ii:ia5-188. Summers RW, Sitz DM, Sessions JT, Becktel JM, Best WR, Kern F, Singleton JW. National cooperative Crohn’s disease study: results of drug treatment. Gastroenterology 1979; 77:847-869. Miner PB, Biddle WL. Maintaining remission in distal ulcerative colitis and ulcerative proctitis. Can J Gastroenterol 1990;4:476-480. Malchow H, Ewe K, Brandes JW, Goebell H, Ehms H, Sommer H, Jesdinsky H. European cooperative Crohn’s disease study [ECCDS]: results of drug treatment. Gastroenterology 1984;86:249-266. Baron JH, Bennett PN, Lennard-Jones JE, Swarbrick ET. Sulfasalazine in asymptomatic Crohn’s disease. Gut 1977;16:69-72. Wenckert A, Kristensen M, Eklund AE, Barany F, Jarnum S, Worning H, Folkenborg 0, Holtz A, Bonnevie 0, Riis P. The long-term prophylactic effect of salazosulphapyridine (salazopyrin) in primarily resected patients with Crohn’s disease. A controlled double blind trial. Stand J Gastroenterol 1978;13:161-167. Bergman L, Krause U. Postoperative treatment with corticosteroids and salazosulphapyridine (salazopyrin) after radical re-
disease.
Stand
J Gastroenterol
1976;
11:651-656.
WILLIAM J. TREMAINE, M.D.
Mayo Clinic Rochester, Minnesota
for Crohn’s
Vol. 103, No. 2
13.
14.
15. 16.
17.
ia.
Ewe K, Herfarth C, Malchow H, Jesdinsky HJ. Postoperative recurrence of Crohn’s disease in relation to radicality of operation and sulfasalazine prophylaxis: a multicenter trial. Digestion i989;42:224-232. Thomson ABR, International Mesalazine Study Group. Coated oral 5-aminosalicylic acid vs placebo in maintaining remission of inactive Crohn’s disease. Aliment Pharmacol Therap 1990;4:55-64. Brignola C, Iannone P, Pasquali S, Campieri M, Giouchetti P, Belluzzi A, Basso 0, Miglioli M, Barbar L. Placebo-controlled trial of oral 5-ASA and relapse prevention of Crohn’s disease. Dig Dis Sci 1992;37:29-32. Gendre JP, Mary JY, Florent C, Modigliani R, Colombel JF, Soule JC, Aillet L. Does pentasa prevent relapse in quiescent Crohn’s disease (QCD)? A multicenter placebo controlled trial (161 patients) (abstr). Gastroenterology 1990;96:A171. Farmer RG, Whelan G, Fazio VW. Long-term follow-up of patients with Crohn’s disease. Gastroenterology 1985;88:18181825. Martin F. Oral 5-ASA preparations. In: Bayless TM. Current management of inflammatory bowel disease. Philadelphia: BC Decker, 1969;72-77. Peppercorn MA. Advances in the drug therapy for inflammatory bowel disease. Ann Intern Med 1990;112:50-60. Goldstein F, Farquhar S, Thornton JJ, Abramson J. Favorable effects of sulfasalazine on small bowel Crohn’s disease: alongterm study. Am J Gastroenterol 1987;82:84a-853. van Hees PAM, van Lier HJJ, van Elteren PH, van Driessen WMM, Hogesand RA, van Velde GPM, ten Bakker JH, Tongeren JHM. Effect of sulfasalazine in patients with active Crohn’s disease: a controlled double blind study. Gut i9ai;22:404-409. Das KM, Eastwood MA, McManus JPA, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and relation with drug metabolism and acetylatorphenotype. N Engl J Med i973;289:49i-495.
Address requests for reprints to: William J. Tremaine, M.D., Division of Gastroenterology, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. 0 1992 by the American Gastroenterological Association
The Epidemiology of Inflammatory Bowel Disease: Are We Learning Anything New? Epidemiologic studies provide important clues as to the nature of disease and the identity of preventable risk factors. In a classical sense, the epidemiologist characterizes disease with regard to person, place, and time and assesses correlations between changes in disease incidence and changes in environmental determinants. Migrant studies showing a correlation between corresponding changes in geographical location and incidence of disease provide powerful evidence for an environmental etiology. The techniques of classical epidemiology were first developed in the early part of this century to determine the occur-
rence, spread, and prevention of many infectious diseases. These classic methods subsequently have been applied to chronic illnesses, including ulcerative colitis (UC) and Crohn’s disease (CD),’ and have provided important information, such as the predominance of Jewish patients in some countries (United States, England, Sweden), the association with genetic diseases (UC with ankylosing spondylitis and CD with psoriasis), the increased frequency of colorectal cancer in patients with UC and CD, the familial occurrences of UC and especially CD, the higher incidence of inflammatory bowel disease (IBD)