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Tolerance of nonsteroidal antiinflammatory drugs in patients with inflammatory bowel disease
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2000 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 95, No. 8, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)01055-8
Tolerance of Nonsteroidal Antiinflammatory Drugs in Patients With Inflammatory Bowel Disease Gregory F. Bonner, M.D., Michelle Walczak, P.A., Laurel Kitchen, P.A., and Manuel Bayona, M.D., Ph.D. Department of Gastroenterology, Cleveland Clinic Florida and the School of Public Health, Nova-Southeastern University, Fort Lauderdale, Florida
OBJECTIVE: We sought to examine whether use of nonsteroidal antiinflammatory drugs (NSAIDs) in an outpatient inflammatory bowel disease (IBD) population is associated with an increased likelihood of active disease. METHODS: We reviewed records of initial outpatient visits of IBD patients to the principal author from June 1995 to December 1997, with regard to use of aspirin and other NSAIDs and disease activity. RESULTS: Of 40 Crohn’s patients seen with active disease, three (7.5%) were using NSAIDs; 14 of 72 (19.4%) Crohn’s patients seen with inactive disease were using NSAIDs. Fifty-eight ulcerative colitis patients were seen with active disease, with eight (13.7%) using NSAIDs. Among 21 UC patients initially seen while in remission, five (23.8%) were using NSAIDs. CONCLUSIONS: Among this group of outpatients, NSAID use was not associated with a higher likelihood of active IBD. NSAID use in IBD deserves further study before recommending that patients refrain from their use under all circumstances. (Am J Gastroenterol 2000;95:1946 –1948. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to cause initial onset of inflammatory bowel disease (IBD) and to be associated with reactivation of quiescent disease. This conclusion has been based largely on case reports and small series of patients (1–9). More recently, authors have noted a higher than expected use of NSAIDs among patients admitted to the hospital for flares of IBD (10, 11). Subsequently, some physicians recommend that IBD patients strictly avoid use of NSAIDs. Our local patient population contains a substantial retirement community, including elderly IBD patients. Our general clinical impression was that NSAID use was relatively common and generally well tolerated. It is not clear how NSAIDs would exacerbate IBD or under what circumstances patients might be susceptible to these adverse events. Prior reports, which focused on patients hospitalized for flares of IBD, might be prejudiced by patients with more severe IBD. It may be that patients with
less severe disease, as is encountered in the outpatient setting, may better tolerate NSAIDs. We examined the relationship of NSAID use with disease activity among our outpatients with inflammatory bowel disease.
MATERIALS AND METHODS Records of initial outpatient office visits of IBD patients to a single gastroenterologist, the principal author, from June 1995 to December 1997 were retrospectively reviewed. General information obtained from the chart on each patient included age, gender, years since disease diagnosis, smoking and alcohol use, hormone replacement therapy for females, and NSAID usage for all patients. Because of the retrospective nature of the study, a numerical disease activity index had not been maintained. Disease activity was therefore categorized only as active or inactive. A decision to categorize disease activity as active was made by the same gastroenterologist retrospectively reviewing the chart, with respect to the clinical impression recorded in the record, symptoms of diarrhea and abdominal pain, and endoscopic and radiographic studies, when available. Active disease included mild, moderate, or severe disease, as well as chronically active disease. Because it was not clear whether NSAID use carried the same risk for different types of IBD, Crohn’s disease patients and ulcerative colitis patients were analyzed separately. Statistical Analysis Epi Info and SPSS statistical packages were used for data analysis (12, 13). Cases of active disease were compared to controls or inactive disease by using a case-control design. The odds ratio and the mean difference were used as measures of association (14). The cornfield or the exact 95% confidence interval was calculated for the odds ratio, and the 2 or Fisher’s exact test was used to assess the statistical significance of the odds ratio. The t test or Wilcoxon test was used to assess the significance of the mean difference (15).
RESULTS There were 112 initial visits for patients with Crohn’s disease and 80 initial visits for patients with ulcerative colitis.
AJG – August, 2000
Tolerance of NSAIDs in IBD Patients
1947
Table 1. NSAID Use Among Patients With Active and Quiescent Crohn’s Disease
Table 2. NSAID Use Among Patients With Active and Quiescent Ulcerative Colitis
NSAID Use
NSAID Use
Yes No
Active Cases
Inactive Cases
Odds Ratio
95% C.I.
p Value
3 (7.5%) 37 (92.5%)
14 (19.4%) 58 (80.6%)
0.34
0.07–1.39
0.157
NSAID ⫽ nonsteroidal antiinflammatory drugs; C.I. ⫽ confidence interval.
Yes No
Active Cases
Inactive Cases
Odds Ratio
95% C.I.
p Value
9 (14.8%) 52 (85.2%)
4 (21.1%) 15 (78.9%)
0.65
0.15–3.31
0.50
Abbreviations as in Table 1.
Reflective of our elderly South Florida retirement community, the average age was 52.9 yr for Crohn’s patients and 61 yr for ulcerative colitis patients. Among Crohn’s disease patients, 40 were seen with active disease and 72 with inactive disease. Sixty-one ulcerative colitis patients were seen with active disease and 19 with inactive disease. Seventy-three Crohn’s disease and 36 ulcerative colitis patients were women. Use of NSAIDs among patients with active and inactive Crohn’s disease is shown in Table 1. Table 2 provides the corresponding data for patients with ulcerative colitis. Contrary to what might have been expected, NSAID use was actually more common among patients with inactive disease for both categories of IBD. For ulcerative colitis, NSAID use was only slightly more common among patients with inactive disease (21.1%), compared to active disease (14.8%). For Crohn’s disease patients, NSAID use was more than twice as common among patients with inactive disease (19.4%), compared to those with active disease (7.5%). This suggestion of a protective effect for NSAID use was not statistically significant. Several other factors were examined for possible correlation with disease activity. Gender, smoking, and alcohol use were not found to correlate (data not shown). As shown in Tables 3 and 4, visits for active disease were associated with a younger patient age for both Crohn’s disease and ulcerative colitis, although this difference reached statistical significance only for Crohn’s disease. For both categories of IBD, active disease visits were statistically associated with fewer years of disease duration. It has previously been suggested that use of birth control pills is associated with an increase in flares of IBD. Use of birth control pills was uncommon because of the age of our patient population. However, hormone replacement therapy was examined. As shown in Tables 3 and 4, use of hormone replacement therapy was not associated with an increased
likelihood of active disease. The incidence of hormone replacement therapy was actually slightly less common among active Crohn’s disease patients, but was not statistically significant. For ulcerative colitis, the use of hormone replacement therapy was equivalent among patients with active or inactive disease.
DISCUSSION Contrary to prior studies, we did not find use of NSAIDs to be associated with an increased risk of active inflammatory bowel disease. One possible explanation is that the association of NSAIDs leading to flares of IBD is simply overstated. Case reports or series of just a few patients suggest but do not prove association. However, the report of Evans et al. (10) was a case-control study of an entire geographic area of more than 300,000 patients and also indicated that use of NSAIDs was associated with an increased likelihood of hospitalization for IBD. Another possible explanation is that not all patients with IBD are equally susceptible to NSAIDs. Some patients may use NSAIDs for IBD-associated arthralgias when their underlying bowel disease may already have begun to flare. If NSAIDs do exert an adverse influence on IBD, it is not clear how this would occur. NSAIDs suppress prostaglandin synthesis as well as exacerbate some experimental models of colitis (16). Most currently available NSAIDs are known to inhibit prostaglandin synthesis through both the COX-1 and COX-2 isoforms of cyclooxygenase. COX-2 is generally expressed in low levels, except in sites of inflammation. COX-2 is expressed at increased levels in colonic mucosa both in experimental colitis (16) and in colitis of IBD (17), and appears to have a beneficial effect in healing experimental colitis (16). Perhaps patients with active IBD and elevated COX-2 levels are susceptible to deterioration from
Table 3. Relationship of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease Activity Among Crohn’s Disease Patients
Factor Age, yr Hormone replacement Yes No Years of disease C.I. ⫽ confidence interval.
Active Cases
Inactive Cases
45.8
56.9
2 (8.7%) 21 (91.3%) 11.3
14 (19.4%) 58 (80.6%) 18.2
Odds Ratio or Mean Difference
95% C.I.
11.1 0.34 6.9
p Value 0.001
0.07–1.39
0.157 0.004
1948
Bonner et al.
AJG – Vol. 95, No. 8, 2000
Table 4. Relationships of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease Activity Among Ulcerative Colitis Patients
Factor Age Hormone replacement Yes No Years of disease
Active Cases
Inactive Cases
Odds Ratio or Mean Difference
95% C.I.
p Value
60.1
64
3.92
0.15–3.31
0.474
9 (33.3%) 18 (66.6%) 9.93
3 (33.3%) 6 (66.7%) 13.47
1.0
0.16–7.63
0.999
3.54
0.036
C.I. ⫽ confidence interval.
use of NSAIDs, whereas those with quiescent disease or only mildly active disease are not. There are significant limitations that should be placed on interpretation of the available data because of the retrospective nature of this study. As no quantitative disease activity index was kept, there is no way to exclude the possibility of flares associated with NSAID use being more serious than flares among patients not using NSAIDs. Though the principle author would generally enquire regarding NSAID use, it is certainly possible with the retrospective nature of this study that use of over-the-counter NSAIDs by some patients may not have been captured. It is also possible that some of our patients with active IBD were selecting against the use of NSAIDs, having previously been informed of potential adverse effects or having previously experienced problems with use of NSAIDs. Nonetheless, the data indicate that—at least for many patients— use of NSAIDs is not associated with activation of their IBD. NSAID use in IBD deserves further study before recommending that patients refrain from their use under all circumstances. Reprint requests and correspondence: Gregory F. Bonner, M.D., Department of Gastroenterology, Cleveland Clinic Florida, 3000 W. Cypress Creek Road, Ft. Lauderdale, FL 33309. Received Dec. 10, 1998; accepted Mar. 3, 2000.
REFERENCES 1. Kaufmann HJ, Taubin, HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987;107:513– 6. 2. Rampton DS, Sladen GE. Relapse of ulcerative proctocolitis during treatment with non-steroidal anti-inflammatory drugs. Postgrad Med J 1981;57:297–9. 3. Walt RP, Hawkey CJ, Langman MJS. Colitis associated with
4.
5.
6. 7. 8. 9.
10.
11.
12.
13. 14. 15. 16.
17.
non-steroidal anti- inflammatory drugs. Br Med J 1984;288: 238. Rampton DS, McNeil NI, Sarner M. Analgesic ingestion and other factors preceding relapse in ulcerative colitis. Gut 1983; 24:187–9. Pearson DJ, Stones NH, Bentley SJ. Proctocolitis induced by salicylates and associated with asthma and recurrent nasal polyps. Br Med J 1983;287:1675. Rutherford D, Stockdill G, Hamer-Hodges DW, et al. Proctocolitis induced by salicylate. Br Med J 1984;288:794. Chakraborty TK, Bhatia D, Heading RC, et al. Salicylate induced exacerbation of ulcerative colitis. Gut 1987;28:613–5. Shanahan F, Targan S. Sulfasalazine and salicylate-induced exacerbation of ulcerative colitis. N Engl J Med 1987;317:455. Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti- inflammatory drugs. Arch Intern Med 1992; 152:625–32. Evans JMM, McMahon AD, Murray FE, et al. Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut 1997;40:619 –22. Felder JB, Korelitz BI. The influence of non-steroidal antiinflammatory drugs on inflammatory bowel disease. Am J Gastroenterol 1992;87:316. Dean AG, Dean JA, Coulombier D, et al. Epi Info, Version 6. A word-processing, database, and statistics program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention, 1995. SPSS, Inc. SPSS Statistics 8.0 Update. Chicago: SPSS, 1997. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown and Company, 1987. Rosner B. Fundamentals of biostatistics. Belmont: Duxbury Press, 1995. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997;112:1000 –16. Singer II, Kawka DW, Schloemann S, et al. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 1998;115:297–306.
Vol. 95, No. 8, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)01055-8
Tolerance of Nonsteroidal Antiinflammatory Drugs in Patients With Inflammatory Bowel Disease Gregory F. Bonner, M.D., Michelle Walczak, P.A., Laurel Kitchen, P.A., and Manuel Bayona, M.D., Ph.D. Department of Gastroenterology, Cleveland Clinic Florida and the School of Public Health, Nova-Southeastern University, Fort Lauderdale, Florida
OBJECTIVE: We sought to examine whether use of nonsteroidal antiinflammatory drugs (NSAIDs) in an outpatient inflammatory bowel disease (IBD) population is associated with an increased likelihood of active disease. METHODS: We reviewed records of initial outpatient visits of IBD patients to the principal author from June 1995 to December 1997, with regard to use of aspirin and other NSAIDs and disease activity. RESULTS: Of 40 Crohn’s patients seen with active disease, three (7.5%) were using NSAIDs; 14 of 72 (19.4%) Crohn’s patients seen with inactive disease were using NSAIDs. Fifty-eight ulcerative colitis patients were seen with active disease, with eight (13.7%) using NSAIDs. Among 21 UC patients initially seen while in remission, five (23.8%) were using NSAIDs. CONCLUSIONS: Among this group of outpatients, NSAID use was not associated with a higher likelihood of active IBD. NSAID use in IBD deserves further study before recommending that patients refrain from their use under all circumstances. (Am J Gastroenterol 2000;95:1946 –1948. © 2000 by Am. Coll. of Gastroenterology)
INTRODUCTION Nonsteroidal antiinflammatory drugs (NSAIDs) have been reported to cause initial onset of inflammatory bowel disease (IBD) and to be associated with reactivation of quiescent disease. This conclusion has been based largely on case reports and small series of patients (1–9). More recently, authors have noted a higher than expected use of NSAIDs among patients admitted to the hospital for flares of IBD (10, 11). Subsequently, some physicians recommend that IBD patients strictly avoid use of NSAIDs. Our local patient population contains a substantial retirement community, including elderly IBD patients. Our general clinical impression was that NSAID use was relatively common and generally well tolerated. It is not clear how NSAIDs would exacerbate IBD or under what circumstances patients might be susceptible to these adverse events. Prior reports, which focused on patients hospitalized for flares of IBD, might be prejudiced by patients with more severe IBD. It may be that patients with
less severe disease, as is encountered in the outpatient setting, may better tolerate NSAIDs. We examined the relationship of NSAID use with disease activity among our outpatients with inflammatory bowel disease.
MATERIALS AND METHODS Records of initial outpatient office visits of IBD patients to a single gastroenterologist, the principal author, from June 1995 to December 1997 were retrospectively reviewed. General information obtained from the chart on each patient included age, gender, years since disease diagnosis, smoking and alcohol use, hormone replacement therapy for females, and NSAID usage for all patients. Because of the retrospective nature of the study, a numerical disease activity index had not been maintained. Disease activity was therefore categorized only as active or inactive. A decision to categorize disease activity as active was made by the same gastroenterologist retrospectively reviewing the chart, with respect to the clinical impression recorded in the record, symptoms of diarrhea and abdominal pain, and endoscopic and radiographic studies, when available. Active disease included mild, moderate, or severe disease, as well as chronically active disease. Because it was not clear whether NSAID use carried the same risk for different types of IBD, Crohn’s disease patients and ulcerative colitis patients were analyzed separately. Statistical Analysis Epi Info and SPSS statistical packages were used for data analysis (12, 13). Cases of active disease were compared to controls or inactive disease by using a case-control design. The odds ratio and the mean difference were used as measures of association (14). The cornfield or the exact 95% confidence interval was calculated for the odds ratio, and the 2 or Fisher’s exact test was used to assess the statistical significance of the odds ratio. The t test or Wilcoxon test was used to assess the significance of the mean difference (15).
RESULTS There were 112 initial visits for patients with Crohn’s disease and 80 initial visits for patients with ulcerative colitis.
AJG – August, 2000
Tolerance of NSAIDs in IBD Patients
1947
Table 1. NSAID Use Among Patients With Active and Quiescent Crohn’s Disease
Table 2. NSAID Use Among Patients With Active and Quiescent Ulcerative Colitis
NSAID Use
NSAID Use
Yes No
Active Cases
Inactive Cases
Odds Ratio
95% C.I.
p Value
3 (7.5%) 37 (92.5%)
14 (19.4%) 58 (80.6%)
0.34
0.07–1.39
0.157
NSAID ⫽ nonsteroidal antiinflammatory drugs; C.I. ⫽ confidence interval.
Yes No
Active Cases
Inactive Cases
Odds Ratio
95% C.I.
p Value
9 (14.8%) 52 (85.2%)
4 (21.1%) 15 (78.9%)
0.65
0.15–3.31
0.50
Abbreviations as in Table 1.
Reflective of our elderly South Florida retirement community, the average age was 52.9 yr for Crohn’s patients and 61 yr for ulcerative colitis patients. Among Crohn’s disease patients, 40 were seen with active disease and 72 with inactive disease. Sixty-one ulcerative colitis patients were seen with active disease and 19 with inactive disease. Seventy-three Crohn’s disease and 36 ulcerative colitis patients were women. Use of NSAIDs among patients with active and inactive Crohn’s disease is shown in Table 1. Table 2 provides the corresponding data for patients with ulcerative colitis. Contrary to what might have been expected, NSAID use was actually more common among patients with inactive disease for both categories of IBD. For ulcerative colitis, NSAID use was only slightly more common among patients with inactive disease (21.1%), compared to active disease (14.8%). For Crohn’s disease patients, NSAID use was more than twice as common among patients with inactive disease (19.4%), compared to those with active disease (7.5%). This suggestion of a protective effect for NSAID use was not statistically significant. Several other factors were examined for possible correlation with disease activity. Gender, smoking, and alcohol use were not found to correlate (data not shown). As shown in Tables 3 and 4, visits for active disease were associated with a younger patient age for both Crohn’s disease and ulcerative colitis, although this difference reached statistical significance only for Crohn’s disease. For both categories of IBD, active disease visits were statistically associated with fewer years of disease duration. It has previously been suggested that use of birth control pills is associated with an increase in flares of IBD. Use of birth control pills was uncommon because of the age of our patient population. However, hormone replacement therapy was examined. As shown in Tables 3 and 4, use of hormone replacement therapy was not associated with an increased
likelihood of active disease. The incidence of hormone replacement therapy was actually slightly less common among active Crohn’s disease patients, but was not statistically significant. For ulcerative colitis, the use of hormone replacement therapy was equivalent among patients with active or inactive disease.
DISCUSSION Contrary to prior studies, we did not find use of NSAIDs to be associated with an increased risk of active inflammatory bowel disease. One possible explanation is that the association of NSAIDs leading to flares of IBD is simply overstated. Case reports or series of just a few patients suggest but do not prove association. However, the report of Evans et al. (10) was a case-control study of an entire geographic area of more than 300,000 patients and also indicated that use of NSAIDs was associated with an increased likelihood of hospitalization for IBD. Another possible explanation is that not all patients with IBD are equally susceptible to NSAIDs. Some patients may use NSAIDs for IBD-associated arthralgias when their underlying bowel disease may already have begun to flare. If NSAIDs do exert an adverse influence on IBD, it is not clear how this would occur. NSAIDs suppress prostaglandin synthesis as well as exacerbate some experimental models of colitis (16). Most currently available NSAIDs are known to inhibit prostaglandin synthesis through both the COX-1 and COX-2 isoforms of cyclooxygenase. COX-2 is generally expressed in low levels, except in sites of inflammation. COX-2 is expressed at increased levels in colonic mucosa both in experimental colitis (16) and in colitis of IBD (17), and appears to have a beneficial effect in healing experimental colitis (16). Perhaps patients with active IBD and elevated COX-2 levels are susceptible to deterioration from
Table 3. Relationship of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease Activity Among Crohn’s Disease Patients
Factor Age, yr Hormone replacement Yes No Years of disease C.I. ⫽ confidence interval.
Active Cases
Inactive Cases
45.8
56.9
2 (8.7%) 21 (91.3%) 11.3
14 (19.4%) 58 (80.6%) 18.2
Odds Ratio or Mean Difference
95% C.I.
11.1 0.34 6.9
p Value 0.001
0.07–1.39
0.157 0.004
1948
Bonner et al.
AJG – Vol. 95, No. 8, 2000
Table 4. Relationships of Age, Hormone Replacement Therapy, and Years of Disease Duration With Regard to Disease Activity Among Ulcerative Colitis Patients
Factor Age Hormone replacement Yes No Years of disease
Active Cases
Inactive Cases
Odds Ratio or Mean Difference
95% C.I.
p Value
60.1
64
3.92
0.15–3.31
0.474
9 (33.3%) 18 (66.6%) 9.93
3 (33.3%) 6 (66.7%) 13.47
1.0
0.16–7.63
0.999
3.54
0.036
C.I. ⫽ confidence interval.
use of NSAIDs, whereas those with quiescent disease or only mildly active disease are not. There are significant limitations that should be placed on interpretation of the available data because of the retrospective nature of this study. As no quantitative disease activity index was kept, there is no way to exclude the possibility of flares associated with NSAID use being more serious than flares among patients not using NSAIDs. Though the principle author would generally enquire regarding NSAID use, it is certainly possible with the retrospective nature of this study that use of over-the-counter NSAIDs by some patients may not have been captured. It is also possible that some of our patients with active IBD were selecting against the use of NSAIDs, having previously been informed of potential adverse effects or having previously experienced problems with use of NSAIDs. Nonetheless, the data indicate that—at least for many patients— use of NSAIDs is not associated with activation of their IBD. NSAID use in IBD deserves further study before recommending that patients refrain from their use under all circumstances. Reprint requests and correspondence: Gregory F. Bonner, M.D., Department of Gastroenterology, Cleveland Clinic Florida, 3000 W. Cypress Creek Road, Ft. Lauderdale, FL 33309. Received Dec. 10, 1998; accepted Mar. 3, 2000.
REFERENCES 1. Kaufmann HJ, Taubin, HL. Nonsteroidal anti-inflammatory drugs activate quiescent inflammatory bowel disease. Ann Intern Med 1987;107:513– 6. 2. Rampton DS, Sladen GE. Relapse of ulcerative proctocolitis during treatment with non-steroidal anti-inflammatory drugs. Postgrad Med J 1981;57:297–9. 3. Walt RP, Hawkey CJ, Langman MJS. Colitis associated with
4.
5.
6. 7. 8. 9.
10.
11.
12.
13. 14. 15. 16.
17.
non-steroidal anti- inflammatory drugs. Br Med J 1984;288: 238. Rampton DS, McNeil NI, Sarner M. Analgesic ingestion and other factors preceding relapse in ulcerative colitis. Gut 1983; 24:187–9. Pearson DJ, Stones NH, Bentley SJ. Proctocolitis induced by salicylates and associated with asthma and recurrent nasal polyps. Br Med J 1983;287:1675. Rutherford D, Stockdill G, Hamer-Hodges DW, et al. Proctocolitis induced by salicylate. Br Med J 1984;288:794. Chakraborty TK, Bhatia D, Heading RC, et al. Salicylate induced exacerbation of ulcerative colitis. Gut 1987;28:613–5. Shanahan F, Targan S. Sulfasalazine and salicylate-induced exacerbation of ulcerative colitis. N Engl J Med 1987;317:455. Gibson GR, Whitacre EB, Ricotti CA. Colitis induced by nonsteroidal anti- inflammatory drugs. Arch Intern Med 1992; 152:625–32. Evans JMM, McMahon AD, Murray FE, et al. Non-steroidal anti-inflammatory drugs are associated with emergency admission to hospital for colitis due to inflammatory bowel disease. Gut 1997;40:619 –22. Felder JB, Korelitz BI. The influence of non-steroidal antiinflammatory drugs on inflammatory bowel disease. Am J Gastroenterol 1992;87:316. Dean AG, Dean JA, Coulombier D, et al. Epi Info, Version 6. A word-processing, database, and statistics program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention, 1995. SPSS, Inc. SPSS Statistics 8.0 Update. Chicago: SPSS, 1997. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little, Brown and Company, 1987. Rosner B. Fundamentals of biostatistics. Belmont: Duxbury Press, 1995. Wallace JL. Nonsteroidal anti-inflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997;112:1000 –16. Singer II, Kawka DW, Schloemann S, et al. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 1998;115:297–306.