Sulfasalazine vs. steroids in Crohn's disease: David vs. Goliath?
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Crohn Disease↗
Biomedical subjects
S B Hanauer
Publications and source records attributed to S B Hanauer.
Testing nicotine gum for ulcerative colitis patients. Experience with single-patient trials.
Epidemiologic studies have documented an association between nonsmoking and ulcerative colitis and case reports have demonstrated that symptoms improve with smoking and worsen with removal of a nicotine source. A double-blind randomized crossover trial for individual ulcerative colitis patients (single-patient trial, or N of 1 clinical trial) was designed to study the safety, patient acceptance, and the effectiveness of nicotine gum in improving patient symptoms and proctoscopic appearance of involved colon. Seven nonsmoking patients chewed up to 10 squares/day (20 mg) of nicotine gum or placebo gum for two weeks. Therapy was crossed-over every two weeks over the eight-week trial. Effectiveness was judged from comparisons between nicotine-gum and placebo-gum periods of patient self-reported symptoms at the conclusion of each two-week period using visual analog scales and proctoscopic appearance using ordered categorical scales. Three of seven patients, all three of whom were former smokers, demonstrated sufficient improvement without adverse effects to warrant institution of nicotine gum into their drug treatment regimens. Three patients demonstrated an uncertain response, despite tolerating the drug, and have not had nicotine gum added to their regimens. One patient could not tolerate the medication and was withdrawn from the study. No serious side effects were noted. We conclude that a randomized trial for an individual patient is a useful method for evaluating treatment regimens for ulcerative colitis and that nicotine gum may be effective therapy for individual patients with ulcerative colitis who demonstrate an objective response with few adverse effects.
Adult↗
Dysplasia and cancer complicating strictures in ulcerative colitis.
Previous studies have found a widely variable prevalence of dysplasia and cancer in colonic strictures in patients with ulcerative colitis. Consequently, therapeutic recommendations are conflicting. To better assess the prevalence, we reviewed the clinical and pathological findings in all 27 patients with ulcerative colitis complicated by stricture who were entered into our Inflammatory Bowel Disease Registry. A true stricture was defined as a persistent localized narrowing of the colon found on air-contrast barium enema or on colonoscopy. Upon careful review, 12 of 27 patients were found to have transient colonic spasm, not a stricture, and were excluded. The remaining 15 patients with true strictures represented 3.2% of all ulcerative colitis patients in the registry. Strictures were identified at 13.3 +/- 9.9 years following the diagnosis of ulcerative colitis. Eleven patients had multiple strictures that were principally located in the left colon. Of the 15 patients, 11 had dysplasia and two had cancer found on colonoscopic biopsy. Ultimately, six patients had carcinoma found at colonoscopy or colectomy (three modified Dukes' stage A, one stage B, and two stage D). All cancers were at the site of a stricture. These findings indicate that a true colonic stricture in ulcerative colitis is frequently associated with dysplasia and cancer, which can be diagnosed with colonoscopic biopsy. A stricture should be considered a strong risk factor for cancer, requiring intensive colonoscopic surveillance. If dysplasia is discovered, or if the stricture cannot be adequately biopsied, consideration should be given to total colectomy.
Adult↗
Lack of association between oral contraceptive use and ulcerative colitis.
Previous epidemiological studies suggesting an association between oral contraceptive use and ulcerative colitis incidence have been weak and conflicting. To measure a possible association, 46 incident cases of ulcerative colitis patients, women aged 18-50 years, were compared with peer-nominated age-matched and sex-matched controls. There were no differences between case and control patients in demographic characteristics. There was no association between oral contraceptive use and ulcerative colitis (current use: odds ratio 0.70, 95% confidence interval 0.27-1.83; former use: odds ratio 1.14, confidence interval 0.41-3.15; current or former use: odds ratio 0.86, confidence interval 0.40-1.85). Stratifying by disease location (pancolitis or left-sided disease) also failed to identify an association. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and ulcerative colitis. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a "dose-response" effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of 2.8 and higher. In this matched case-control study of incident cases and community controls, there was no association between oral contraceptive use and ulcerative colitis incidence. To date, there is no evidence suggesting that women predisposed to the development of ulcerative colitis should be advised to avoid oral contraceptive use.
Adult↗
The role of mesalazine in Crohn's disease.
Sulfasalazine continues to be a common treatment for active Crohn's disease. It has been shown to be more effective than placebo in patients with colonic disease and in patients without prior surgical resection. There is no clear clinical evidence for its use as maintenance therapy in quiescent Crohn's disease; nevertheless, it is widely used to prevent symptom recurrence in patients whose active disease responded to sulfasalazine. In a few preliminary controlled studies, mesalazine has been shown to be superior to placebo in the treatment of active Crohn's disease. Until recently, the results of trials of mesalazine as maintenance therapy in quiescent Crohn's disease were equivocal but promising.
Aminosalicylic Acids↗
Inflammatory bowel disease revisited: newer drugs.
The development of new drug therapy is an evolutionary process progressing from clinical success with current treatments through an understanding of interactions in the immune and inflammatory events that culminate in the tissue injury of IBD. The basic immunoinflammatory response is reviewed, with identification of the recognized and potential sites of activity of current therapies. Potential sites and implications for future interventions by newer therapies are discussed as we anticipate the discovery of the etiology and eventual cure for ulcerative colitis and Crohn's disease.
Adrenal Cortex Hormones↗
Aminosalicylates: old and new.
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Administration, Oral↗
Colon cancer surveillance in chronic ulcerative colitis: historical cohort study.
Screening for dysplasia in ulcerative colitis is expected to improve cancer-related survival by advancing the diagnosis of cancer to a more favorable pathologic stage or by identifying patients for prophylactic colectomy who are at at high risk of developing cancer. To evaluate the effectiveness of a surveillance program of annual colonoscopy and mucosal sampling, 91 screened and 95 control ulcerative colitis patients with extensive disease for at least 8 yr were compared for differences in survival, cancer detection, and colectomy rates. The two groups were of similar age at symptom onset, duration of disease, and sex. In the surveillance group, there were eight fewer deaths (p less than 0.05 by survival-curve analysis), but two more cancer deaths (not significant). Colectomy was less common (p less than 0.05) and was performed 4 yr later in the surveillance group. The effect of surveillance was not confounded by age at symptom onset, sex, or duration of disease. In our program, screening for cancer in ulcerative colitis was associated with improved survival and delayed colectomy. However, improvement was not related to the anticipated benefits of improved cancer-related survival.
Adolescent↗
Hazard rates for dysplasia and cancer in ulcerative colitis. Results from a surveillance program.
The risk of colon cancer in patients with ulcerative colitis is related to the duration and extent of disease. Prior reports have suggested that patients with onset of disease in childhood have a high risk of cancer. These risk factors were analyzed in 99 patients in a surveillance program of annual colonoscopy to detect mucosal dysplasia. All patients had pancolitis for at least eight years. The mean age at symptom onset was 23.2 years and the mean duration of disease at entry was 17 years. An average of 4.2 tests/patient were performed, and 91% were completely followed through 1985. Cancer risk was expressed as the hazard rate or the annual probability that a patient free of cancer would develop cancer after survival to a given time period. The hazard rate for high-grade dysplasia or cancer in patients with pancolitis measured from symptom onset was 2.5% at 20 years, 4% at 25 years, 7% at 30 years, 13% at 35 years, and 20% at 40 years. Sex was not a significant predictor of cancer, but older age at symptom onset was a predictor of dysplasia and cancer. From these data, the annual hazard rate of developing high-grade dysplasia or cancer can be estimated in patients with pancolitis based on an individual's age at symptom onset and duration of disease.
Age Factors↗
Preoperative total parenteral nutrition for bowel resection in Crohn's disease.
To examine the effect of preoperative total parenteral nutrition (TPN) on patients with Crohn's disease undergoing bowel resection, an historical cohort was assembled of 103 patients resected between 1982 and 1984 by a single surgical team. Preoperative, perioperative, and postoperative variables were compared between patients receiving TPN and patients not receiving TPN. Analysis was stratified for three surgical procedures: segmental small bowel resection, ileocectomy, and segmental or total colectomy The effect of TPN was most pronounced in patients having small bowel surgery. For segmental small bowel resection, 12 of 17 patients had TPN, and these patients had 20.4 +/- 14.3 cm less bowel resected than did those in the non-TPN group, an effect not dependent on duration of TPN. For ileocectomy patients, 31 of 62 patients received TPN, and these patients had 11.2 +/- 4.2 cm less small bowel resected than the non-TPN group, an effect not dependent on the duration of TPN. For large bowel resection patients, 6 of 24 patients had TPN, and there was no difference in length of bowel resection, preoperative and perioperative variables, or recurrence. The total hospital stay was 13.5 +/- 2.6 days longer for those having TPN; 3.5 +/- 1.9 days of the longer stay was postoperative. In conclusion, TPN was associated with reduced length of small bowel resection at the expense of longer hospital stay.
Cecum↗
Effect of folate supplementation on the incidence of dysplasia and cancer in chronic ulcerative colitis. A case-control study.
Folate deficiency has been associated with dysplasia in human cancer models. Patients with ulcerative colitis commonly have decreased folate levels, which are partially due to sulfasalazine, a competitive inhibitor of folate absorption. To study the effect of folate supplementation on the risk of dysplasia or cancer (neoplasia) in ulcerative colitis, records from 99 patients with pancolitis for greater than 7 yr and enrolled in a surveillance program were reviewed. Thirty-five patients with neoplasia were compared with 64 patients in whom dysplasia was never found to determine the effect of folate supplementation on the rate of development of neoplasia using case-control methodology. At the time of the index colonoscopy, patients with neoplasia were older (43 +/- 11 vs. 39 +/- 12 yr) and had disease of longer duration (20 +/- 8 vs. 15 +/- 7 yr, p less than 0.05). Folate supplementation was associated with a 62% lower incidence of neoplasia compared with individuals not receiving supplementation (odds ratio, 0.38; 95% confidence interval, 0.12-1.20). There was no appreciable change in this effect when models were fit to adjust for sulfasalazine dose, duration of disease, age at symptom onset, prednisone dose, sulfa allergy, sex, race, or family history of colon cancer. The statistical power of the association between folate supplementation and neoplasia was 72%. Correction of risk factors before the development of neoplasia may prevent this serious complication. Pending a larger case-control study, folate supplementation during sulfasalazine administration is recommended to possibly prevent the complication of dysplasia or cancer in ulcerative colitis.
Adult↗
Lack of association between oral contraceptive use and Crohn's disease: a community-based matched case-control study.
Previous epidemiologic studies have suggested a weak association between oral contraceptive use and Crohn's disease, specifically Crohn's colitis. To measure a possible etiologic association, 51 women with Crohn's disease who were 18-50 yr old were studied and compared with peer-nominated age- and sex-matched controls. There were no differences between cases and controls with respect to race, religion, marital status, and number of pregnancies. There was no association between oral contraceptive use and Crohn's disease incidence [current use: odds ratio (OR) 0.73, 95% confidence interval (CI) 0.34-1.59; former use: OR 1.80, CI 0.61-5.29; current or former use: OR 1.00, CI 0.46-2.16]. Stratifying by disease location also failed to identify an association. Cigarette smoking was significantly associated with Crohn's disease incidence. Controlling for possible confounding effects of cigarette smoking did not alter the lack of association between oral contraceptive use and Crohn's disease. Similarly, testing for interaction failed to demonstrate any effect modification. Analyzing for duration of current oral contraceptive use or time interval since last use failed to demonstrate a "dose-response" effect. The study was of sufficient size to detect statistical significance for oral contraceptive use for odds ratios of greater than or equal to 2.76. From this community-based matched case-control study, there was no association between oral contraceptive use and Crohn's disease, and women need not be advised to discontinue oral contraceptive use when a diagnosis of Crohn's disease is made.
Adult↗
5-ASA enema therapy.
5-Aminosalicylic acid (5-ASA) enema therapy has been a direct extension of our understanding of the pharmacology and metabolism of sulfasalazine. Clinical studies have documented the efficacy and safety of topical 5-ASA therapy in distal ulcerative colitis. Future clinical experience should clarify the role of topical 5-ASA in a variety of inflammatory bowel disease syndromes.
Aminosalicylic Acids↗
Cigarette smoking in Crohn's disease.
Crohn's disease is a chronic disease of unknown etiology. Previous reports have suggested that cigarette smoking may be associated with the development of Crohn's disease. To examine this association, we conducted a case-control study of patients referred to a single practice over a 7-month period. The cigarette-smoking habits of 115 patients with Crohn's disease were compared with the cigarette-smoking exposure of 109 patients with the irritable bowel syndrome. Patients with Crohn's disease were more likely to smoke at the time of symptom onset than were irritable bowel syndrome controls (age and sex adjusted odds ratio 3.71, 95% confidence interval 1.93-7.13). After the diagnosis of Crohn's disease, patients were less likely to quit smoking (odds ratio 0.35, 95% confidence interval 0.18-0.69) than controls. This study demonstrates an association and a temporal relationship between cigarette smoking and Crohn's disease. For the exposure to be considered an etiologic factor for disease, biologic plausibility and pathophysiologic mechanisms require elucidation.
Adult↗
Fecal incontinence in the elderly.
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Aged↗
Effect of disodium azodisalicylate on electrolyte transport in rabbit ileum and colon in vitro. Comparison with sulfasalazine and 5-aminosalicylic acid.
Azodisalicylate, used to treat ulcerative colitis, causes diarrhea in up to 12.5% of patients. We compared the in vitro effects of azodisalicylate, sulfasalazine, and 5-aminosalicylic acid on rabbit intestinal electrolyte transport. Distal ileal mucosae mounted in Ussing chambers were exposed to varying concentrations of the drugs. Mucosal addition of azodisalicylate (greater than 5 mM) caused the greatest anion-dependent increase in short-circuit current of 83 microA/cm2 (ED50 = 0.3 mM). Isotope flux measurements suggest that azodisalicylate may stimulate predominantly electrogenic HCO3 secretion and induces net NaCl secretion. In contrast, serosal addition of azodisalicylate and sulfasalazine (greater than 5 mM) decreased short-circuit current, and 5-aminosalicylic acid had no effect. Azodisalicylate had no effect on ion transport in distal colon. The effects of azodisalicylate in ileum were not inhibited with piroxicam (an inhibitor of cyclooxygenase). Mucosal cyclic adenosine monophosphate and cyclic guanosine monophosphate levels were unchanged after ileal exposure to azodisalicylate. Azodisalicylate appears to be a mechanistically unusual secretagogue, possibly explaining the increased incidence of diarrhea seen in patients taking the drug.
Aminosalicylic Acids↗
Optimal timing of colonoscopy to screen for cancer in ulcerative colitis.
Patients with ulcerative colitis have a high risk of colon cancer that increases with duration of disease. Annual colonoscopy with biopsies for 99 patients with pancolitis and a mean duration of disease at entry of 17 years was evaluated. The outcomes of mucosal dysplasia or cancer were analyzed to determine the annual risk (hazard rate) of high-grade dysplasia or colon cancer. The hazard rates were used to recommend screening intervals. The delay in the diagnosis of cancer is minimized for any given number of tests when the time between tests is inversely proportional to the square root of the hazard rate. Since the hazard rate for cancer increases with duration of disease, intervals for screening tests should not be uniform. For a range of reasonable marginal benefits from additional testing, the number of tests recommended is less than the number of tests done in fixed-interval screening programs. Scheduling screening tests using patient-specific hazard rates to minimize the delay in the diagnosis of cancer reduces the number of colonoscopies, associated cost, and morbidity.
Adolescent↗
Smoking and inflammatory bowel disease in families.
Smoking habits of inflammatory bowel disease (IBD) patients were compared with family members with IBD to determine the effects of cigarette smoking on the development of either ulcerative colitis or Crohn's disease. In a previous study of patients randomly selected from the University of Chicago IBD Registry, 40 patients with IBD were identified as having a confirmed IBD family history. Thirty-one of those probands and relatives were contacted and included in this study. Of the 36 patients in the study with Crohn's disease, 78% were former or current smokers, whereas only 27% of the 26 patients with ulcerative colitis were former or current smokers. Eighty-three percent of all those who had ever smoked, started before the onset of symptoms of their disease. There were high concordance rates for type of IBD (81%) and for smoking habits (65%, when a history of smoking was compared with a history of never having smoked) among the matched pairs. The concordance rates were not significantly different from each other, but the magnitude of concordance of each suggests that both smoking habits and consanguinity may be important factors in the pathogenesis of this disease.
Adult↗