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5-Aminosalicylic acid (PENTASA) in the maintenance of remission of Crohn's disease
A924
•
AGA ABSTRACTS
LACTOFERRIN AS A MARKER FOR DISEASE ACTIVITY IN INFLAMMATORY BOWEL DISEASE: COMPARISON WITH OTHER NEUTROPHIL GRANULE- DERIVED PROTEINS. K.Sugi, O.Saitoh, R.Matsuse, K.Uchida, K.Nakagawa, M.Yoshizurei, K.Takada, I.Hirata, K.Katsu. 2nd Dept. of Int. Med., Osaka Medical College, Osaka, Japan and Kyoto Medical Laboratory,Kyolo, Japan AIM: 1) To examine whether the fecal levels of neutrophil granule-derived proteins could reflect disease activity in inflammatory bowel disease. 2) To examine the extracellular release of these proteitls from activated nentrophils and their stability in feces by an in vitro study. METHODS: We studied 41 patients(99 samples) with ulcerative colitis(UCL 34 patients(106 samples) with Crohn's disesse(CD), and .25 control subjects. The stool samples were collected at 4 "(3 over a period of 48 hours and were homogenized. The fecal levels of lactoferrin(Lf), polymorphonuclear neutrophil elastase(PMN-E), myeloperoxidase(MPO), and iysozyme(Lys) were measured by ELISA. We also measured fecal hemoglobin(Hb) and a 1-antitrypsin(AT), which are useful markers for disease activity in UC and CD patients, respectively. UC was defined active if the patient showed clinical symptoms and/or inflamed colonic mucosa at colonescopy. CD was defined as active if the CDAI was above 150. For the in vitro study, neutrophils were incubated for 15 minutes with latex beads or phorbol myristate acetate. For the assessment of stability, homogenized stool samples were stored at 4 "C , 25 "C , and 37 13 for 0, 24, 48, and 72 hours. RESULTS: 1) Fecal If, PMN-E, MPO, Lys concentrations were significantly increased in both active UC (medians 213.6 tt g/g, 31,5, 98.7, 20.0/ and active CD (62,1 /z g/g, 15.0, 114.7, 7,1) compared to inactive I.IC (17.6//g/g, 4.6, 1,5.4, 8.6) and inactive CD (11.2 tt g/g, 4.3, 21.8, 2.7), respectively. 2) Fecal If, PMN-E, MPO concentrations correlated with the fecal Hb concentration in the UC or AT concentration in CD, whereas the fecal Lys concentration did not. In UC, fecal Lf, P M N - E and MPO concentrations were high in 13, 10, and 10 among 33 samples with a normal Hb concentration, respectively. In CD, fecal Lf, PMN-E. and MPO concentrations were high in 9, 5, and S among the 49 samples with a normal AT concentration. 3) Lf was released extraeellularly most efficiently of all (Lf>Lys>PMN-E>MPO). 4) Lf was the most stable in the feces of all (Lf> MPO>PMN-E>Lys). CONCLUSIONS: The measurement of neutrophil gnanule-derived proteins in feces is useful for monitoring the disease activity of UC and CD, especially when evaluating th e presence of minimal intestinal iullammation. Since Lf Was released from activated neutrophils most efficiently and was the most stable in feces, Lf may be the most suitable as a fecal marker of inflammation for clinical application. FECAL
• 5-AMINOSALICYLIC ACID (PENTASA) IN THE MAINTENANCE OF REMISSION OF CROHN'S DISEASE. LR Sutherland. F Martin, RJ Bailey, R Fedorak, C Dallaire, R Rossman, M Poleski, W Harvey, L Lariviere for the Canadian Study of Pentasa for Remission of Crohn's Disease. Studies of the use of 5-ASA containing compounds such as Pentasa® for the maintenance of remission in Crohn's disease (CD) have been conflicting. We conducted a double-blind, randomized, placebo controlled study of the efficacy of Pentasa (750 mg qid) in maintaining remission in 293 patients with CD. Entry criteria included at least two episodes of active disease within the last four years, one within the last 18 months or a recent resection. Patients were stratified according to whether remission had been induced medically (5-ASA or corticosteroids) or surgically. Patients had to complete four weeks of therapy in order to be included in the final analysis. All patients were assessed at 12 week intervals for a total follow-up of 48 weeks. The primary outcome measure was relapse, defined as a CDAI of > 150 ( + 60 points over baseline). The study had a statistical power of 80% to detect a 50% difference in relapse rates. Patients were enrolled between 90/1/23 and 93/1/20; 246 patients completed at least four weeks of therapy. One hundred and forty (56%) were female, 122 had only ileal disease, 122 had ileocecal or colonic involvement and in two the site was not specified. One hundred and eighty (73%) entered remission via medical treatment. Thirty-five percent were current smokers. By life table analysis, 31% of Pentasa and 46% of placebo treated patients relapsed (Log Rank p = 0 . 0 5 4 , Wilcoxon p =0.049). An unexpected finding was that only 19% of Pentasa treated women relapsed compared to 41% of those on placebo (p = 0.003). Using Cox regression, significant prognos¼ic variables for recurrence were current smoking regression coefficient (RC) 0.817, Relative Risk (RR) 2.26 (CI95 1.29-3.97) and surgically induced remission (RC -1.020, RR 0.36, CI95 0.19-0.69). Funded by Nordic Merrell Dew Research Inc.
GASTROENTEROLOGY, Vol. 108, No. 4
CLINICAL COURSE OF uLCERATIVE COLITIS PATIENTS. L Sutherland, AM Walker, PSzneke, LA Bianchi, L Field. Epidemiology Resources Inc. Newton Lower Falls, MA Much of the choice between 5-ASA drugs depends on questions of tolerance of drum therapy and the occurrence of adverse effects. We have attempted to identify indicators of the progress of ulcerative colitis in a large population of patients managed by general practitioners in the United Kingdom. We reviewed computerized patient records of 2894 patients in the UK who were diagnosed by thei~ general practitioners as havingulcerative colitis and were receiving ongoin~ medical therapy specific to ulcerative colitis. Patient histories were categorized into distinct periods according to dose of 5-ASA products, steroids and immunosuppressants, and were further separated by a variety of markers of the severity and activity of ulcerative colitis. Within these categories, w e e x a m i n e d the incidence of new hospitalizations for ulcerative colitis, new diagnostic interventions, changes in drug therapy, and clinical mentions of hematologic, hepatic, pancreatic and renal events. There were 6122 patient years of experience. Patients treated with mesalamine appeared to be somewhat siekee than patients treated with sulfasalazine, as evidenced by a ~reater utilization of mesalamine following hospitalization. N e w clinical mentions of hepatic, pancreatic, renal and hematologic events other than anemia were similar across the 5-ASAs. The incidence of new pancreatic disease was 0.1, 0, and 0.2 cases per 100 patient years for'low dose users of sulfasalazine, mesalamine (delayed-release tablets), and other mesalamines respectively, and 0, O, and 0.5 for high dose users. The corresponding rates for new renal events were zero for all low dose users, and 0.4 for high dose mesalamine (delayed-release tablets) users, based on a single case. Anemias were identified less frequently in conjunction with meselamines, than with sulfasalazine. ~)espite bein~ used for the treatment of more severely ill patients in the UK, mesalamines appear to have a safety profile similar to that of sul~asalazine. Renal and pancreatic complications of 5-ASA therapy are rare. Patients using mesalamines may experience less megaloblastic, macrocytic and hemolytic anemia than do patients using sulfasalazine. This research was funded by Procter & Gamble Pharmaceuticals, Cincinnati. Ohio.
ULCEROUS COLITIS AND DISPLASYS F.Svanohi, U.Bonassi, A.Malesci, R.Colombi, S.Signorelli, E.Pelizzati, N.Dioguardi II ^ Scuola di Speciallta In GasU'oenterohigia ed Endoseopia Digestiva, Univemi~ 0i Milano-Italy First study, by Bargen, based on relations between cancer and U.C. dates back to 1928; since then it is currently common knowledge that patients with U.C. have an incremented risk to develop cancer of colon comparated to average population. At the present it seems that risk is related to the duration and the extension of disease and only partially to the activity degree. The increase of the risk is to be considered not before seven years since the outbreak of the disease. The increased risk is particularly high in patients with pancolltis. The objective of this study is to vet,fly the effectiveness of the colonscopic surveillance program to which our patients have been submitted, the above in order to establish a long range management program of patients themselves. 148 patients affected by U.C. have been engaged, 90 males and 58 females, average age 40 years. The following factors have been evaluated for each patients initially and evely six month: family and pathological remote anamnesys, age of disense~s beginning, histological diagnosys, extension, activity clinical indexes, endosco#c aspect and carried out therapies. Wit~a the considered sample the average duration of disease, since the first histological diaga~is, was 71,4 months; 40 of them presented a duration above 84 months; the extension of the disease involved left colon in 114 cases (77%) and whole colon in 34 cases (23%). 14 patients pxesented displasys, out of them we observed 10 slight intensity case and 4 severe; it must be underline that the evidence of displasys has never been verify at the first endescopical exam but only in following controls. Patients with displnsys were 51 years old in average; the average duration of the disease was of 124 months. Displasys econred on 25% of subjects with an increased risk, that is in patients with disease duration above seven years. Malignant degeneration was fonnd in 4 out of 148 cases, 2 males and 2 females, average period between diagnosis and disease degeneration was 17 years. From the analisys of results we deduce the following conclusion: the utility of m u l ~ g colonscopic management for high risk patients, continuing with in evenafter first negative controls; in no risk population, it would be better to have a clinical approach with cohincopic exam only if there's an alteration of symptomatology.
•
AGA ABSTRACTS
LACTOFERRIN AS A MARKER FOR DISEASE ACTIVITY IN INFLAMMATORY BOWEL DISEASE: COMPARISON WITH OTHER NEUTROPHIL GRANULE- DERIVED PROTEINS. K.Sugi, O.Saitoh, R.Matsuse, K.Uchida, K.Nakagawa, M.Yoshizurei, K.Takada, I.Hirata, K.Katsu. 2nd Dept. of Int. Med., Osaka Medical College, Osaka, Japan and Kyoto Medical Laboratory,Kyolo, Japan AIM: 1) To examine whether the fecal levels of neutrophil granule-derived proteins could reflect disease activity in inflammatory bowel disease. 2) To examine the extracellular release of these proteitls from activated nentrophils and their stability in feces by an in vitro study. METHODS: We studied 41 patients(99 samples) with ulcerative colitis(UCL 34 patients(106 samples) with Crohn's disesse(CD), and .25 control subjects. The stool samples were collected at 4 "(3 over a period of 48 hours and were homogenized. The fecal levels of lactoferrin(Lf), polymorphonuclear neutrophil elastase(PMN-E), myeloperoxidase(MPO), and iysozyme(Lys) were measured by ELISA. We also measured fecal hemoglobin(Hb) and a 1-antitrypsin(AT), which are useful markers for disease activity in UC and CD patients, respectively. UC was defined active if the patient showed clinical symptoms and/or inflamed colonic mucosa at colonescopy. CD was defined as active if the CDAI was above 150. For the in vitro study, neutrophils were incubated for 15 minutes with latex beads or phorbol myristate acetate. For the assessment of stability, homogenized stool samples were stored at 4 "C , 25 "C , and 37 13 for 0, 24, 48, and 72 hours. RESULTS: 1) Fecal If, PMN-E, MPO, Lys concentrations were significantly increased in both active UC (medians 213.6 tt g/g, 31,5, 98.7, 20.0/ and active CD (62,1 /z g/g, 15.0, 114.7, 7,1) compared to inactive I.IC (17.6//g/g, 4.6, 1,5.4, 8.6) and inactive CD (11.2 tt g/g, 4.3, 21.8, 2.7), respectively. 2) Fecal If, PMN-E, MPO concentrations correlated with the fecal Hb concentration in the UC or AT concentration in CD, whereas the fecal Lys concentration did not. In UC, fecal Lf, P M N - E and MPO concentrations were high in 13, 10, and 10 among 33 samples with a normal Hb concentration, respectively. In CD, fecal Lf, PMN-E. and MPO concentrations were high in 9, 5, and S among the 49 samples with a normal AT concentration. 3) Lf was released extraeellularly most efficiently of all (Lf>Lys>PMN-E>MPO). 4) Lf was the most stable in the feces of all (Lf> MPO>PMN-E>Lys). CONCLUSIONS: The measurement of neutrophil gnanule-derived proteins in feces is useful for monitoring the disease activity of UC and CD, especially when evaluating th e presence of minimal intestinal iullammation. Since Lf Was released from activated neutrophils most efficiently and was the most stable in feces, Lf may be the most suitable as a fecal marker of inflammation for clinical application. FECAL
• 5-AMINOSALICYLIC ACID (PENTASA) IN THE MAINTENANCE OF REMISSION OF CROHN'S DISEASE. LR Sutherland. F Martin, RJ Bailey, R Fedorak, C Dallaire, R Rossman, M Poleski, W Harvey, L Lariviere for the Canadian Study of Pentasa for Remission of Crohn's Disease. Studies of the use of 5-ASA containing compounds such as Pentasa® for the maintenance of remission in Crohn's disease (CD) have been conflicting. We conducted a double-blind, randomized, placebo controlled study of the efficacy of Pentasa (750 mg qid) in maintaining remission in 293 patients with CD. Entry criteria included at least two episodes of active disease within the last four years, one within the last 18 months or a recent resection. Patients were stratified according to whether remission had been induced medically (5-ASA or corticosteroids) or surgically. Patients had to complete four weeks of therapy in order to be included in the final analysis. All patients were assessed at 12 week intervals for a total follow-up of 48 weeks. The primary outcome measure was relapse, defined as a CDAI of > 150 ( + 60 points over baseline). The study had a statistical power of 80% to detect a 50% difference in relapse rates. Patients were enrolled between 90/1/23 and 93/1/20; 246 patients completed at least four weeks of therapy. One hundred and forty (56%) were female, 122 had only ileal disease, 122 had ileocecal or colonic involvement and in two the site was not specified. One hundred and eighty (73%) entered remission via medical treatment. Thirty-five percent were current smokers. By life table analysis, 31% of Pentasa and 46% of placebo treated patients relapsed (Log Rank p = 0 . 0 5 4 , Wilcoxon p =0.049). An unexpected finding was that only 19% of Pentasa treated women relapsed compared to 41% of those on placebo (p = 0.003). Using Cox regression, significant prognos¼ic variables for recurrence were current smoking regression coefficient (RC) 0.817, Relative Risk (RR) 2.26 (CI95 1.29-3.97) and surgically induced remission (RC -1.020, RR 0.36, CI95 0.19-0.69). Funded by Nordic Merrell Dew Research Inc.
GASTROENTEROLOGY, Vol. 108, No. 4
CLINICAL COURSE OF uLCERATIVE COLITIS PATIENTS. L Sutherland, AM Walker, PSzneke, LA Bianchi, L Field. Epidemiology Resources Inc. Newton Lower Falls, MA Much of the choice between 5-ASA drugs depends on questions of tolerance of drum therapy and the occurrence of adverse effects. We have attempted to identify indicators of the progress of ulcerative colitis in a large population of patients managed by general practitioners in the United Kingdom. We reviewed computerized patient records of 2894 patients in the UK who were diagnosed by thei~ general practitioners as havingulcerative colitis and were receiving ongoin~ medical therapy specific to ulcerative colitis. Patient histories were categorized into distinct periods according to dose of 5-ASA products, steroids and immunosuppressants, and were further separated by a variety of markers of the severity and activity of ulcerative colitis. Within these categories, w e e x a m i n e d the incidence of new hospitalizations for ulcerative colitis, new diagnostic interventions, changes in drug therapy, and clinical mentions of hematologic, hepatic, pancreatic and renal events. There were 6122 patient years of experience. Patients treated with mesalamine appeared to be somewhat siekee than patients treated with sulfasalazine, as evidenced by a ~reater utilization of mesalamine following hospitalization. N e w clinical mentions of hepatic, pancreatic, renal and hematologic events other than anemia were similar across the 5-ASAs. The incidence of new pancreatic disease was 0.1, 0, and 0.2 cases per 100 patient years for'low dose users of sulfasalazine, mesalamine (delayed-release tablets), and other mesalamines respectively, and 0, O, and 0.5 for high dose users. The corresponding rates for new renal events were zero for all low dose users, and 0.4 for high dose mesalamine (delayed-release tablets) users, based on a single case. Anemias were identified less frequently in conjunction with meselamines, than with sulfasalazine. ~)espite bein~ used for the treatment of more severely ill patients in the UK, mesalamines appear to have a safety profile similar to that of sul~asalazine. Renal and pancreatic complications of 5-ASA therapy are rare. Patients using mesalamines may experience less megaloblastic, macrocytic and hemolytic anemia than do patients using sulfasalazine. This research was funded by Procter & Gamble Pharmaceuticals, Cincinnati. Ohio.
ULCEROUS COLITIS AND DISPLASYS F.Svanohi, U.Bonassi, A.Malesci, R.Colombi, S.Signorelli, E.Pelizzati, N.Dioguardi II ^ Scuola di Speciallta In GasU'oenterohigia ed Endoseopia Digestiva, Univemi~ 0i Milano-Italy First study, by Bargen, based on relations between cancer and U.C. dates back to 1928; since then it is currently common knowledge that patients with U.C. have an incremented risk to develop cancer of colon comparated to average population. At the present it seems that risk is related to the duration and the extension of disease and only partially to the activity degree. The increase of the risk is to be considered not before seven years since the outbreak of the disease. The increased risk is particularly high in patients with pancolltis. The objective of this study is to vet,fly the effectiveness of the colonscopic surveillance program to which our patients have been submitted, the above in order to establish a long range management program of patients themselves. 148 patients affected by U.C. have been engaged, 90 males and 58 females, average age 40 years. The following factors have been evaluated for each patients initially and evely six month: family and pathological remote anamnesys, age of disense~s beginning, histological diagnosys, extension, activity clinical indexes, endosco#c aspect and carried out therapies. Wit~a the considered sample the average duration of disease, since the first histological diaga~is, was 71,4 months; 40 of them presented a duration above 84 months; the extension of the disease involved left colon in 114 cases (77%) and whole colon in 34 cases (23%). 14 patients pxesented displasys, out of them we observed 10 slight intensity case and 4 severe; it must be underline that the evidence of displasys has never been verify at the first endescopical exam but only in following controls. Patients with displnsys were 51 years old in average; the average duration of the disease was of 124 months. Displasys econred on 25% of subjects with an increased risk, that is in patients with disease duration above seven years. Malignant degeneration was fonnd in 4 out of 148 cases, 2 males and 2 females, average period between diagnosis and disease degeneration was 17 years. From the analisys of results we deduce the following conclusion: the utility of m u l ~ g colonscopic management for high risk patients, continuing with in evenafter first negative controls; in no risk population, it would be better to have a clinical approach with cohincopic exam only if there's an alteration of symptomatology.