For David.
Budesonide Is Effective in Treating Lymphocytic Colitis: A Randomized Double-Blind Placebo-Controlled Study
Stephan Miehlke; Ahmed Madisch; Diana Karimi; Susann Wonschik; Eberhard Kuhlisch; Renate Beckmann; Andrea Morgner; Ralph Mueller; Roland Greinwald; Gerhard Seitz; Gustavo Baretton; Manfred Stolte
Gastroenterology. 2009;136(6):2092–2100 © 2009 AGA Institute
Abstract and Introduction
Abstract
Background and Aims: Budesonide is effective in treating collagenous colitis, but no treatment is established for lymphocytic colitis. We performed a randomized, double-blind, placebo-controlled study to evaluate the effects of budesonide in patients with lymphocytic colitis.
Methods: Forty-two patients (median age, 61 years) with lymphocytic colitis and chronic diarrhea were randomly assigned to groups that were given oral doses of budesonide (9 mg/d) or placebo for 6 weeks. Nonresponders at week 6 were given open-label budesonide (9 mg/d) for 6 additional weeks. A complete colonoscopy and histologic and quality-of-life analyses were performed at baseline and at week 6. The primary end point was clinical remission at 6 weeks, with last observation carried forward (LOCF). All patients who left the study in clinical remission were followed for relapse.
Results: At week 6, 86% of patients given budesonide were in clinical remission (with LOCF) compared with 48% of patients given placebo (P = .010). Furthermore, open-label budesonide therapy induced clinical remission in 7 of 8 patients given placebo. Histologic remission was observed in 73% of patients given budesonide compared with 31% given placebo (P = .030). Only 1 patient discontinued budesonide therapy prematurely. During a mean follow-up period of 14 months, 15 patients (44.1%) experienced a clinical relapse (after a mean of 2 months); 8 of the relapsing patients were retreated with and responded again to budesonide.
Conclusions: Budesonide effectively induces clinical remission in patients with lymphocytic colitis and significantly improves histology results after 6 weeks. Clinical relapses occur but can be treated again with budesonide.
Introduction
Lymphocytic colitis is a distinct form of microscopic colitis, characterized by chronic or recurrent nonbloody watery diarrhea, normal radiologic and endoscopic findings, and microscopic abnormalities in the colon. In addition to lymphocytic colitis the entity microscopic colitis includes collagenous colitis. Both diseases cannot be distinguished clinically and differ only by specific histopathologic features of the colon mucosa: lymphocytic colitis shows a characteristic increase of intraepithelial lymphocytes (IELs; ≥20 IEL/100 epithelial cells) and a chronic inflammation in the lamina propria.[1] In contrast to collagenous colitis, the subepithelial collagenous layer is normal (<10 µm) in lymphocytic colitis.
The cause of lymphocytic colitis remains unclear. Mucosal responses to noxious luminal agents or associations with coexistent autoimmune disorders are discussed.[1,2] Some cases might be associated with celiac disease, the use of drugs (eg, lansoprazole, nonsteroidal anti-inflammatory drugs [NSAIDs], ticlopidine, ranitidine, carbamazepine, simvastatin) or with infections (eg, immune responses after infectious triggers).[1,3,4] A seasonal incidence patterns has been reported.[5]
Epidemiologic investigations showed a much higher incidence of lymphocytic colitis than previously presumed. The incidence and prevalence are likely to be underestimated because microscopic colitis might be the underlying disease in some cases diagnosed as irritable bowel syndrome[6,7] or as chronic diarrhea.[8] A recent US study found a mean annual incidence of 5.5 per 100,000 inhabitants together with a pronounced increase during the past 10-15 years and calculated a prevalence rate of 64/100,000 at the end of 2001.[9] Similar incidence rates have been reported from Europe.[10,11]
Currently, no established treatment of lymphocytic colitis exists. A recent Cochrane review identified only one randomized placebo-controlled trial investigating bismuth subsalicylate in 5 patients with lymphocytic colitis and 9 patients with collagenous colitis.[12,13] Because of the small number of patients with lymphocytic colitis, no conclusions about the efficacy of bismuth subsalicylate in lymphocytic colitis can be drawn from this trial. Retrospective and uncontrolled case series reported response rates between 37% and 94% with various drugs, including antidiarrheals, aminosalicylates, and corticosteroids.[14] However, retrospective or uncontrolled studies might be inappropriate for efficacy assessment of pharmacologic treatment options because of the variable course of disease, including spontaneous remissions.[15]
The hypothesis of the presented study was based on the treatment data in collagenous colitis. A recent Cochrane analysis identified 7 randomized placebo-controlled trials: 3 trials studied budesonide, 1 study each investigated bismuth subsalicylate, Boswellia serrata extract, probiotics, and prednisolone.[16] Budesonide showed the most promising results, with clinical responses in 73%-100% of patients with collagenous colitis.[17-19] Histologic improvements were reported in 54%-100% of patients. Each study showed a statistically superior treatment effect of budesonide compared with placebo.
Budesonide is a locally acting anti-inflammatory substance. Its systematic activity is very limited because ≤90% are metabolized during the first pass effect in the liver.[20] On the basis of the experiences in collagenous colitis, we considered it important to investigate the effect of budesonide in the treatment of lymphocytic colitis and conducted a double-blind placebo-controlled study. Our primary objective was to investigate whether oral budesonide 9 mg/d for 6 weeks is effective for the induction of clinical remission in lymphocytic colitis.
Materials and Methods
This study was designed as a randomized, double-blind, placebo-controlled, multicenter clinical study. It was performed in various centers throughout Germany which submitted their biopsy specimen to one of the study pathologists. The study was approved by the independent ethics committee of the Dresden University Hospital. All study participants were given a detailed description of the study, and their written informed consent was obtained. The study was conducted in accordance with good clinical practice and the Declaration of Helsinki. The study was registered at www.clinicaltrials.gov (Identifier: NCT00180050).
Patients
Men and women between 18 and 80 years of age with histologically confirmed lymphocytic colitis (>20 IEL/100 epithelial cells), and >3 watery or loose stools/d within 7 days before random assignment were eligible for inclusion into this trial. Patients with the following conditions were not allowed to participate: Other types of bowel disease, eg, infectious colitis (proved by stool culture or rectal biopsy), collagenous colitis, Crohn's disease, ulcerative colitis or ischemic colitis, celiac disease (ruled out by duodenal biopsy or serum antibodies or both), malignancy or any severe concomitant disease, partial colonic resection, intolerance to budesonide, as well as pregnancy and lactation. In addition, patients treated with budesonide, aminosalicylates, steroids, or antibiotics during the past 4 weeks before random assignment were excluded.
Treatment
Patients with lymphocytic colitis were randomly assigned centrally by a computer-generated random list to receive either budesonide (Budenofalk) at a dose of 9 mg/d (3 capsules) orally or matching placebo (3 capsules/d). Budesonide was supplied as enteric-coated, pH-dependent release granules in capsules and packed in neutral blisters and boxes. Each capsule contained 3 mg budesonide or placebo. Placebo was supplied and formulated in the same way as budesonide except it contained no budesonide. The study medication was manufactured by Dr Falk Pharma GmbH, Freiburg, Germany. All capsules were swallowed whole without chewing and with plenty of fluid. The study treatment period lasted for 6 weeks. Patients evaluated as nonresponders at the end of the 6-week treatment were treated with open-label budesonide 9 mg/d for a further 6 weeks.
Clinic visits were scheduled for 3 and 6 weeks after the start of treatment. If patients discontinued from the study prematurely, a full final visit was performed if possible. Documentation of all assessments occurred at all visits. Patients regarded as nonresponders after 6 weeks of treatment had a further visit after 12 weeks.
Concomitant medications involved in the treatment of inflammatory bowel diseases, including aminosalicylates (eg, mesalamine), antidiarrheals, antibiotics, immunosuppressants, NSAIDs, and all steroids (eg, budesonide, prednisolone) were not allowed. In the case of abdominal pain, butylscopolaminbromid was allowed. Loperamide was allowed during the first 2 weeks of the study. To prevent interactions between loperamide and the efficacy evaluation at the end of the treatment period, loperamide was not allowed thereafter.
Budesonide Is Effective in Treating Lymphocytic Colitis: A Randomized Double-Blind Placebo-Controlled Study
Stephan Miehlke; Ahmed Madisch; Diana Karimi; Susann Wonschik; Eberhard Kuhlisch; Renate Beckmann; Andrea Morgner; Ralph Mueller; Roland Greinwald; Gerhard Seitz; Gustavo Baretton; Manfred Stolte
Gastroenterology. 2009;136(6):2092–2100 © 2009 AGA Institute
Abstract and Introduction
Abstract
Background and Aims: Budesonide is effective in treating collagenous colitis, but no treatment is established for lymphocytic colitis. We performed a randomized, double-blind, placebo-controlled study to evaluate the effects of budesonide in patients with lymphocytic colitis.
Methods: Forty-two patients (median age, 61 years) with lymphocytic colitis and chronic diarrhea were randomly assigned to groups that were given oral doses of budesonide (9 mg/d) or placebo for 6 weeks. Nonresponders at week 6 were given open-label budesonide (9 mg/d) for 6 additional weeks. A complete colonoscopy and histologic and quality-of-life analyses were performed at baseline and at week 6. The primary end point was clinical remission at 6 weeks, with last observation carried forward (LOCF). All patients who left the study in clinical remission were followed for relapse.
Results: At week 6, 86% of patients given budesonide were in clinical remission (with LOCF) compared with 48% of patients given placebo (P = .010). Furthermore, open-label budesonide therapy induced clinical remission in 7 of 8 patients given placebo. Histologic remission was observed in 73% of patients given budesonide compared with 31% given placebo (P = .030). Only 1 patient discontinued budesonide therapy prematurely. During a mean follow-up period of 14 months, 15 patients (44.1%) experienced a clinical relapse (after a mean of 2 months); 8 of the relapsing patients were retreated with and responded again to budesonide.
Conclusions: Budesonide effectively induces clinical remission in patients with lymphocytic colitis and significantly improves histology results after 6 weeks. Clinical relapses occur but can be treated again with budesonide.
Introduction
Lymphocytic colitis is a distinct form of microscopic colitis, characterized by chronic or recurrent nonbloody watery diarrhea, normal radiologic and endoscopic findings, and microscopic abnormalities in the colon. In addition to lymphocytic colitis the entity microscopic colitis includes collagenous colitis. Both diseases cannot be distinguished clinically and differ only by specific histopathologic features of the colon mucosa: lymphocytic colitis shows a characteristic increase of intraepithelial lymphocytes (IELs; ≥20 IEL/100 epithelial cells) and a chronic inflammation in the lamina propria.[1] In contrast to collagenous colitis, the subepithelial collagenous layer is normal (<10 µm) in lymphocytic colitis.
The cause of lymphocytic colitis remains unclear. Mucosal responses to noxious luminal agents or associations with coexistent autoimmune disorders are discussed.[1,2] Some cases might be associated with celiac disease, the use of drugs (eg, lansoprazole, nonsteroidal anti-inflammatory drugs [NSAIDs], ticlopidine, ranitidine, carbamazepine, simvastatin) or with infections (eg, immune responses after infectious triggers).[1,3,4] A seasonal incidence patterns has been reported.[5]
Epidemiologic investigations showed a much higher incidence of lymphocytic colitis than previously presumed. The incidence and prevalence are likely to be underestimated because microscopic colitis might be the underlying disease in some cases diagnosed as irritable bowel syndrome[6,7] or as chronic diarrhea.[8] A recent US study found a mean annual incidence of 5.5 per 100,000 inhabitants together with a pronounced increase during the past 10-15 years and calculated a prevalence rate of 64/100,000 at the end of 2001.[9] Similar incidence rates have been reported from Europe.[10,11]
Currently, no established treatment of lymphocytic colitis exists. A recent Cochrane review identified only one randomized placebo-controlled trial investigating bismuth subsalicylate in 5 patients with lymphocytic colitis and 9 patients with collagenous colitis.[12,13] Because of the small number of patients with lymphocytic colitis, no conclusions about the efficacy of bismuth subsalicylate in lymphocytic colitis can be drawn from this trial. Retrospective and uncontrolled case series reported response rates between 37% and 94% with various drugs, including antidiarrheals, aminosalicylates, and corticosteroids.[14] However, retrospective or uncontrolled studies might be inappropriate for efficacy assessment of pharmacologic treatment options because of the variable course of disease, including spontaneous remissions.[15]
The hypothesis of the presented study was based on the treatment data in collagenous colitis. A recent Cochrane analysis identified 7 randomized placebo-controlled trials: 3 trials studied budesonide, 1 study each investigated bismuth subsalicylate, Boswellia serrata extract, probiotics, and prednisolone.[16] Budesonide showed the most promising results, with clinical responses in 73%-100% of patients with collagenous colitis.[17-19] Histologic improvements were reported in 54%-100% of patients. Each study showed a statistically superior treatment effect of budesonide compared with placebo.
Budesonide is a locally acting anti-inflammatory substance. Its systematic activity is very limited because ≤90% are metabolized during the first pass effect in the liver.[20] On the basis of the experiences in collagenous colitis, we considered it important to investigate the effect of budesonide in the treatment of lymphocytic colitis and conducted a double-blind placebo-controlled study. Our primary objective was to investigate whether oral budesonide 9 mg/d for 6 weeks is effective for the induction of clinical remission in lymphocytic colitis.
Materials and Methods
This study was designed as a randomized, double-blind, placebo-controlled, multicenter clinical study. It was performed in various centers throughout Germany which submitted their biopsy specimen to one of the study pathologists. The study was approved by the independent ethics committee of the Dresden University Hospital. All study participants were given a detailed description of the study, and their written informed consent was obtained. The study was conducted in accordance with good clinical practice and the Declaration of Helsinki. The study was registered at www.clinicaltrials.gov (Identifier: NCT00180050).
Patients
Men and women between 18 and 80 years of age with histologically confirmed lymphocytic colitis (>20 IEL/100 epithelial cells), and >3 watery or loose stools/d within 7 days before random assignment were eligible for inclusion into this trial. Patients with the following conditions were not allowed to participate: Other types of bowel disease, eg, infectious colitis (proved by stool culture or rectal biopsy), collagenous colitis, Crohn's disease, ulcerative colitis or ischemic colitis, celiac disease (ruled out by duodenal biopsy or serum antibodies or both), malignancy or any severe concomitant disease, partial colonic resection, intolerance to budesonide, as well as pregnancy and lactation. In addition, patients treated with budesonide, aminosalicylates, steroids, or antibiotics during the past 4 weeks before random assignment were excluded.
Treatment
Patients with lymphocytic colitis were randomly assigned centrally by a computer-generated random list to receive either budesonide (Budenofalk) at a dose of 9 mg/d (3 capsules) orally or matching placebo (3 capsules/d). Budesonide was supplied as enteric-coated, pH-dependent release granules in capsules and packed in neutral blisters and boxes. Each capsule contained 3 mg budesonide or placebo. Placebo was supplied and formulated in the same way as budesonide except it contained no budesonide. The study medication was manufactured by Dr Falk Pharma GmbH, Freiburg, Germany. All capsules were swallowed whole without chewing and with plenty of fluid. The study treatment period lasted for 6 weeks. Patients evaluated as nonresponders at the end of the 6-week treatment were treated with open-label budesonide 9 mg/d for a further 6 weeks.
Clinic visits were scheduled for 3 and 6 weeks after the start of treatment. If patients discontinued from the study prematurely, a full final visit was performed if possible. Documentation of all assessments occurred at all visits. Patients regarded as nonresponders after 6 weeks of treatment had a further visit after 12 weeks.
Concomitant medications involved in the treatment of inflammatory bowel diseases, including aminosalicylates (eg, mesalamine), antidiarrheals, antibiotics, immunosuppressants, NSAIDs, and all steroids (eg, budesonide, prednisolone) were not allowed. In the case of abdominal pain, butylscopolaminbromid was allowed. Loperamide was allowed during the first 2 weeks of the study. To prevent interactions between loperamide and the efficacy evaluation at the end of the treatment period, loperamide was not allowed thereafter.