Maintenance of Symptomatic Remission in Patients With Crohn's Disease
1993; Elsevier BV; Volume: 68; Issue: 12 Linguagem: Inglês
10.1016/s0025-6196(12)60070-6
ISSN1942-5546
AutoresMark E. Stark, William J. Tremaine,
Tópico(s)Eosinophilic Esophagitis
ResumoCrohn's disease is a chronic inflammatory intestinal disorder characterized in most patients by repeated episodes of diminished and exacerbated symptoms. Recent controlled trials demonstrated that oral preparations of 5-aminosalicylic acid decrease recurrence rates by approximately 40% when administered long-term to patients with quiescent Crohn's disease. Orally administered corticosteroids, sulfasalazine, metronidazole, azathioprine, and cyclosporine have not proved of benefit in the prevention of recurrences of Crohn's disease. Nonetheless, corticosteroids, metronidazole, and azathioprine can control chronically active disease. Methotrexate may have some benefit in the treatment of active Crohn's disease, but its role in maintenance of remission has not been investigated. Elimination diets seem to prolong periods of symptomatic remission. Further studies are needed to define subgroups of patients who are most likely to benefit from preventive therapy. Crohn's disease is a chronic inflammatory intestinal disorder characterized in most patients by repeated episodes of diminished and exacerbated symptoms. Recent controlled trials demonstrated that oral preparations of 5-aminosalicylic acid decrease recurrence rates by approximately 40% when administered long-term to patients with quiescent Crohn's disease. Orally administered corticosteroids, sulfasalazine, metronidazole, azathioprine, and cyclosporine have not proved of benefit in the prevention of recurrences of Crohn's disease. Nonetheless, corticosteroids, metronidazole, and azathioprine can control chronically active disease. Methotrexate may have some benefit in the treatment of active Crohn's disease, but its role in maintenance of remission has not been investigated. Elimination diets seem to prolong periods of symptomatic remission. Further studies are needed to define subgroups of patients who are most likely to benefit from preventive therapy. Of patients with Crohn's disease who have not previously undergone surgical treatment and who are in symptomatic remission, 25 to 50% will experience symptomatic recurrences after 1 year, and 40 to 65% will have recurrences by 2 years.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar Of patients who have undergone surgical resection of intestinal segments involved with Crohn's disease, 30 to 50% will have symptomatic recurrences during the first 5 postoperative years, and 50 to 80% will have symptomatic recurrences by 10 years postoperatively.3Williams JG Wong WD Rothenberger DA Goldberg SM Recurrence of Crohn's disease after resection.Br J Surg. 1991; 78: 10-19Crossref PubMed Scopus (156) Google Scholar Increasing the length of the margins of normal intestine removed at the time of resection does not decrease the frequency of recurrent disease.3Williams JG Wong WD Rothenberger DA Goldberg SM Recurrence of Crohn's disease after resection.Br J Surg. 1991; 78: 10-19Crossref PubMed Scopus (156) Google Scholar, 4Sachar DB Wolfson DM Greenstein AJ Goldberg J Styczynski R Janowitz HD Risk factors for postoperative recurrence of Crohn's disease.Gastroenterology. 1983; 85: 917-921PubMed Scopus (126) Google Scholar, 5Trnka YM Glotzer DJ Kasdon EJ Goldman H Steer ML Goldman LD The long-term outcome of restorative operation in Crohn's disease: influence of location, prognostic factors and surgical guidelines.Ann Surg. 1982; 196: 345-354Crossref PubMed Scopus (90) Google Scholar, 6Cooper JC Williams NS The influence of microscopic disease at the margin of resection on recurrence rates in Crohn's disease.Ann R Coll Surg Engl. 1986; 68: 23-26PubMed Google Scholar, 7Pennington L Hamilton SR Bayless TM Cameron JL Surgical management of Crohn's disease: influence of disease at margin of resection.Ann Surg. 1980; 192: 311-317Crossref PubMed Scopus (144) Google Scholar Because of the high rate of recurrence, a safe and effective regimen has long been sought for maintaining remission in patients with Crohn's disease. More than 30 clinical trials have examined the role of medical therapy in the prevention of recurrent Crohn's disease that has become inactive spontaneously after medical therapy or surgical resection. Several problems complicate the interpretation and application of these data to clinical practice. First, definitions of recurrence and remission vary among studies. Clinical or symptom-related definitions of recurrence are based on a scoring system such as the Crohn's Disease Activity Index,8Best WR Becktel JM Singleton JW Kern Jr, FJ Development of a Crohn's Disease Activity Index: National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3020) Google Scholar in which eight factors are used to obtain an overall clinical rating of disease activity. With use of the Crohn's Disease Activity Index, remission is usually defined as a score of less than 150 and relapse as a score of more than 150 in conjunction with a more than 100-point increase over the initial score.9Prantera C Pallone F Brunetti G Cottone M Miglioli M Italian IBD Study Group Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease.Gastroenterology. 1992; 103: 363-368PubMed Google Scholar In some clinical trials, endoscopic, pathologic, or surgical data are used to determine recurrence or remission, and the criteria are not standardized.10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar, 11Caprilli R Andreoli A Capurso L D'Albasio G D'Agostino L Ferretti P et al.5-ASA in the prevention of Crohn's disease postoperative recurrence: an interim report of the Italian Study Group of the Colon (GISC) [abstract].Gastroenterology. 1992; 102: A601Google Scholar, 12Florent C Cortot A Quandale P Modigliani R Sarfati E Valleur P et al.Placebo-controlled trial of Claversal® (C) in the prevention of early endoscopic relapse after "curative" resection for Crohn's disease (CD) [abstract].Gastroenterology. 1992; 102: A623Google Scholar Crude recurrence rates (percentage of all patients in whom Crohn's disease has redeveloped, regardless of duration of follow-up) may be misleading because the actual recurrence rate is often underestimated. Actuarial or life-table analysis of cumulative recurrence rates is an appropriate method for studying Crohn's disease. In order to account for the variable times to recurrence and the varied durations of follow-up, the cumulative recurrence rate is calculated for each year of follow-up on the basis of the number of patients at risk for recurrence that year.13Greenstein AJ Sachar DB Pasternack BS Janowitz HD Reoperation and recurrence in Crohn's colitis and ileocolitis: crude and cumulative rates.N Engl J Med. 1975; 293: 685-690Crossref PubMed Scopus (233) Google Scholar, 14Peto R Pike MC Armitage P Breslow NE Cox DR Howard SV et al.Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples.Br J Cancer. 1977; 35: 1-39Crossref PubMed Scopus (7006) Google Scholar Second, definitions of disease activity are imprecise. In most studies, "maintenance of remission" refers to therapy for preventing symptomatic recurrence in patients who are already asymptomatic and who are not receiving treatment.9Prantera C Pallone F Brunetti G Cottone M Miglioli M Italian IBD Study Group Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease.Gastroenterology. 1992; 103: 363-368PubMed Google Scholar In some studies, however, maintenance of remission refers to medical therapy that induces active disease into symptomatic remission and then is continued indefinitely.15Bello C Goldstein F Thornton JJ Alternate-day prednisone treatment and treatment maintenance in Crohn's disease.Am J Gastroenterol. 1991; 86: 460-466PubMed Google Scholar The latter approach is actually long-term suppression of active disease. This distinction is important because treatments that suppress chronic disease activity are not necessarily effective in maintenance of remission. For example, corticosteroids can control active disease, but they have no proven benefit in preventing recurrence in patients in remission.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar, 16Smith RC Rhodes J Heatley RV Hughes LE Crosby DL Rees BI et al.Low dose steroids and clinical relapse in Crohn's disease: a controlled trial.Gut. 1978; 19: 606-610Crossref PubMed Scopus (74) Google Scholar Third, enlisting a homogeneous group of patients for study is difficult because of the variability in the anatomic sites of bowel involvement, the clinical course, and prior therapy. For example, the National Cooperative Crohn's Disease Study and the European Cooperative Crohn's Disease Study included patients with prior disease at any site, those with quiescent disease who had not undergone surgical intervention, and those with quiescent disease after resection of all diseased bowel.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar For each of these factors, patients should be randomly assigned or stratified into comparable treatment and placebo groups. In addition, the results of studies in patients with quiescent disease after resection, such as the Inter-Nordic Cooperative Study,17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar may be inapplicable to patients with medically induced or spontaneous remission. Fourth, the risk of a type II statistical error has plagued many studies of remission maintenance in patients with Crohn's disease. For instance, Crohn's disease may remain asymptomatic for years without treatment; therefore, even in studies that have a follow-up period of at least 1 year, a risk exists of not detecting therapeutic benefit in comparison with placebo. The problem can be worse in studies of only 6 months or less.12Florent C Cortot A Quandale P Modigliani R Sarfati E Valleur P et al.Placebo-controlled trial of Claversal® (C) in the prevention of early endoscopic relapse after "curative" resection for Crohn's disease (CD) [abstract].Gastroenterology. 1992; 102: A623Google Scholar, 18Brignola C Campieri M Farruggia P Tragnone A Pasquali S Iannone P et al.The possible utility of steroids in the prevention of relapses of Crohn's disease in remission.J Clin Gastroenterol. 1988; 10: 631-634Crossref PubMed Scopus (30) Google Scholar Because relapse rates in patients with Crohn's disease may be as low as 25% at 1 year, studies should be designed with sufficient numbers of patients to detect a difference in outcome. Unfortunately, some studies have had small numbers or high dropout rates (or both).10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar, 17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 19Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial.Gut. 1977; 18: 69-72Crossref PubMed Scopus (69) Google Scholar In four controlled trials, each of 2 to 3 years' duration (Table 1), long-term low-dose corticosteroid therapy, in dosages ranging from 7.5 to 15 mg of prednisone daily, was no better than placebo in preventing recurrence of Crohn's disease.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar, 16Smith RC Rhodes J Heatley RV Hughes LE Crosby DL Rees BI et al.Low dose steroids and clinical relapse in Crohn's disease: a controlled trial.Gut. 1978; 19: 606-610Crossref PubMed Scopus (74) Google Scholar, 20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar In one of these trials, prednisolone was administered in combination with sulfasalazine; however, this was not an actual maintenance study because patients were treated for only 8 months but underwent follow-up for 3 years for relapse.20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar In the one controlled trial that had positive results, 18 patients with quiescent Crohn's disease, considered at high risk for symptomatic recurrence on the basis of increased laboratory markers of inflammation, were randomly assigned to receive methylprednisolone (0.25 mg/kg daily) or placebo.18Brignola C Campieri M Farruggia P Tragnone A Pasquali S Iannone P et al.The possible utility of steroids in the prevention of relapses of Crohn's disease in remission.J Clin Gastroenterol. 1988; 10: 631-634Crossref PubMed Scopus (30) Google Scholar This small group of patients was observed for only 6 months, and the relapse rate was lower with use of corticosteroids than with placebo. Nevertheless, the weight of evidence from these four trials supports the conclusion that corticosteroids do not have a major benefit in the prevention of recurrences of Crohn's disease.Table 1Placebo-Controlled Trials of Corticosteroids to Prevent Recurrent Crohn's Disease*C = colon; ECCDS = European Cooperative Crohn's Disease Study; FU = follow-up; I = ileum; IC = ileocolic area; M = medical remission; NCCDS = National Cooperative Crohn's Disease Study; NS = not significant; R = rectum; Rx = treatment; S = postsurgical remission; SB = small bowel.ReferenceAgent (dosage)No. of patientsType of remissionSite of prior diseaseRelapse (definition)Duration of trial (mo)Relapse rate, corticosteroid vs placebo (P value)Positive results Brignola et al18Brignola C Campieri M Farruggia P Tragnone A Pasquali S Iannone P et al.The possible utility of steroids in the prevention of relapses of Crohn's disease in remission.J Clin Gastroenterol. 1988; 10: 631-634Crossref PubMed Scopus (30) Google ScholarMethylprednisolone (0.25 mg/kg/day)18MSB, SB + C, CClinical66 mo, ll%vs78%(<0.001)Negative results Bergman & Krause20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google ScholarPrednisolone (15 mg/day for 2 wk, 10 mg/day for 14 wk, 5 mg/day for 17 wk) with sulfasalazine97SSB, I, IC, C, IC + RRadiologie8 (Rx); 36 (FU) 12 mo, 14%vsll%(NS)24 mo, 36% vs 26% (NS)36 mo, 47% vs 37% (NS) Smith et al16Smith RC Rhodes J Heatley RV Hughes LE Crosby DL Rees BI et al.Low dose steroids and clinical relapse in Crohn's disease: a controlled trial.Gut. 1978; 19: 606-610Crossref PubMed Scopus (74) Google ScholarPrednisone (7.5 mg/day)64S,MSB, SB + C, CClinical36 12 mo, 0% vs 10% (NS)24 mo, 20% vs 17% (NS)36 mo, 28% vs 31% (NS)Summers et al' (NCCDS)Prednisone (0.25 mg/kg/day)274S, MSB, SB + C,Clinical24 12 mo, 28% vs 28% (NS)24 mo, 31%vs40%(NS)Malchow et al2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar (ECCDS)Methylprednisolone (8 mg/day)237S,MSB, SB + C,Clinical24 12 mo, 38%vs51%(NS)24 mo, 53% vs 66% (NS)* C = colon; ECCDS = European Cooperative Crohn's Disease Study; FU = follow-up; I = ileum; IC = ileocolic area; M = medical remission; NCCDS = National Cooperative Crohn's Disease Study; NS = not significant; R = rectum; Rx = treatment; S = postsurgical remission; SB = small bowel. Open table in a new tab Sulfasalazine, a 5-aminosalicylic acid (5-ASA) linked by an azo bond to sulfapyridine, has been studied in six randomized trials in patients with Crohn's disease in remission. The trials lasted 8 months to 3 years (Table 2),1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar, 10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar, 17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 19Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial.Gut. 1977; 18: 69-72Crossref PubMed Scopus (69) Google Scholar, 20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar and the dosages of sulfasalazine ranged from 1.5 to 3.0 g daily. Three of the studies included only patients who had undergone resection;10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar, 17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar the other three studies included patients who either had undergone surgical treatment or were in medical remission.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar, 19Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial.Gut. 1977; 18: 69-72Crossref PubMed Scopus (69) Google Scholar In five of these trials, sulfasalazine was found no more effective than placebo in preventing symptomatic recurrences.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar, 17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 19Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial.Gut. 1977; 18: 69-72Crossref PubMed Scopus (69) Google Scholar, 20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar Two of these five studies may have had an insufficient number of patients to detect a therapeutic effect,17Wenckert A Kristensen M Eklund AE Barany F Jarnum S Worning H et al.The long-term prophylactic effect of salazosulphapyridine (SalazopyrinR) in primarily resected patients with Crohn's disease: a controlled double-blind trial.Scand J Gastroenterol. 1978; 13: 161-167Crossref PubMed Scopus (103) Google Scholar, 19Sulphasalazine in asymptomatic Crohn's disease: a multicentre trial.Gut. 1977; 18: 69-72Crossref PubMed Scopus (69) Google Scholar and one was not an actual maintenance study because patients were treated for only 8 months but underwent follow-up for 3 years for relapse.20Bergman L Krause U Postoperative treatment with corticosteroids and salazosulphapyridine (SalazopyrinR) after radical resection for Crohn's disease.Scand J Gastroenterol. 1976; 11: 651-656PubMed Google Scholar Two of the studies that showed no benefit, the National Cooperative Crohn's Disease Study and the European Cooperative Crohn's Disease Study, had large sample sizes, but only modest dosages of sulfasalazine (0.5 g per 15 kg daily and 3.0 g daily, respectively) were administered.1Summers RW Switz DM Sessions Jr, JR Becktel JM Best WR Kern Jr, F et al.National Cooperative Crohn's Disease Study: results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar, 2Malchow H Ewe K Brandes JW Goebell H Ehms H Sommer H et al.European Cooperative Crohn's Disease Study (ECCDS): results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar These dosages of sulfasalazine may have been inadequate because experience in noncontrolled trials suggests that full therapeutic dosages of up to 4 g/day may be necessary for maintenance treatment of Crohn's disease.21Goldstein F Maintenance treatment for Crohn's disease: has the time arrived?.Am J Gastroenterol. 1992; 87: 551-556PubMed Google Scholar The one study that showed some benefit was a German multicenter trial of 232 postoperative patients who were randomly assigned to receive sulfasalazine (3 g/day) or placebo for a 3-year period.10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar The recurrence rate was significantly lower in the sulfasalazine-treated patients after 1 and 2 years, but by the third year, statistically significant differences were not detectable. After the third year, however, only 44 patients remained in the trial, and perhaps a type II statistical error existed. Despite the somewhat encouraging results from this last-mentioned study, sulfasalazine does not seem to prevent Crohn's disease from recurring.Table 2Placebo-Controlled Trials of Sulfasalazine to Prevent Recurrent Crohn's Disease*For explanations of abbreviations, see Table 1.ReferenceDosageNo. of patientsType of remissionSite of prior diseaseRelapse (definition)Duration of trial (mo)Relapse rate, sulfasalazine vs placebo (P value)Positive results Ewe et al10Ewe 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. 1989; 42: 224-232Crossref PubMed Scopus (152) Google Scholar3 g/day232SI,IC,CRadiologie361 yr, 16% vs 28% (<0.01)Endoscopic2 yr, 24% vs 38% ( 7.0Terminal ileum and colonClaversal or SalofalkEudragit-L-coated capsules dissolve to release 5-ASA in pH >5.6Distal jejunum, ileum, and colonPentasaEthyl cellulose-coated 5-ASA microgranules slowly dissolve throughout bowelProximal jejunum and throughout small bowel and colon* 5-ASA = 5-aminosalicylic acid. Open table in a new tab Table 4Placebo-Controlled Trials of Preparations of 5-Aminosalicylic Acid to Prevent Recurrent Crohn's Disease*5-ASA = 5-aminosalicylic acid. For explanations of other abbreviations, see Table 1. See text for discussion of subgroups with benefit.ReferenceAgent (dosage)No. of patientsType of remissionSite of prior diseaseRelapse (definition)Duration of trial (mo)Relapse rate, 5-ASA vs placebo (P value)Positive results Thomson et al22Thomson ABR International Mesalazine Study Group Coated oral 5-aminosalicylic acid versus placebo in maintaining remission of inactive Crohn's disease.Aliment Pharmacol Ther. 1990; 4: 55-64PubMed Google ScholarClaversal (1.5 g/day)209S,MI, IC, CClinical1212 mo, 22.4% vs 36.2% (0.0395) Prantera et al9Prantera C Pallone F Brunetti G Cottone M Miglioli M Italian IBD Study Group Oral 5-aminosalicylic acid (Asacol) in the maintenance treatment of Crohn's disease.Gastroenterology. 1992; 103: 363-368PubMed Google ScholarAsacol (2.4 g/day)125MI, IC, CClinical1212 mo, 34% vs 55% (0.02) Gendre et al23Gendre J-P Mary J-Y Florent C Modigliani R Colombel J-F Soulé J-C et al.Oral mesalamine (Pentasa) as maintenance treatment in Crohn's disease: a multicenter placebo-controlled study.Gastroenterology. 1993; 104: 435-439Abstract PubMed Google S
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