Long-term follow-up of collagenous colitis after induction of clinical remission with budesonide

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1 Aliment Pharmacol Ther 2005; 22: doi: /j x Long-term follow-up of collagenous colitis after induction of clinical remission with budesonide S. MIEHLKE*, A. MADISCH*, C. VOSS*, A. MORGNER*, P. HEYMER*, E. KUHLISCH, B.BETHKEà & M. STOLTEà *Medical Department I, Technical University Hospital, Dresden; Institute for Medical Statistics & Biometry, Technical University Hospital, Dresden; àinstitute for Pathology, Klinikum Bayreuth, Bayreuth, Germany Accepted for publication 15 September 2005 SUMMARY Background: Budesonide (Entocort) is effective for the treatment of collagenous colitis. Aim: To assess the long-term outcome of patients after induction of clinical remission by budesonide treatment. Methods: Fifty-one patients with chronic diarrhoea and histologically proven collagenous colitis were enrolled in randomized, placebo-controlled crossover trial using budesonide 9 mg daily for 6 weeks. Patients in clinical remission after either initial or crossover budesonide treatment were followed using standardized questionaires. Clinical relapse was defined as five or more loose stools/day for at least 4 consecutive days. Results: A total of 33 patients achieved clinical remission (85% per-protocol). During a median follow-up of 16 months, clinical relapse occurred in 20 patients (61%), after a median time of 2 weeks (range: 1 104, mean: 10 weeks). Patient age <60 years was identified as a significant risk factor for clinical relapse (OR ¼ 7.4, P ¼ 0.048). Budesonide was used for treatment of clinical relapse in 80% of patients achieving clinical response in all of them. Conclusions: Budesonide is effective in the treatment of collagenous colitis. Clinical relapses may occur in a considerable number of patients, particularly in those <60 years. Treatment of clinical relapse with budesonide appears to be an effective option. INTRODUCTION Collagenous colitis is an idiopathic microscopic colitis characterized by chronic watery diarrhoea and few or no endoscopic abnormalities. 1 Typical histological features include increased mononuclear inflammation in the colonic lamina propria and a thickened subepithelial collagen layer. 2 The aetiology of collagenous colitis is largely unknown; however, a variety of factors have been implicated including genetic factors, infectious agents, bile salts and drugs. 1, 3 Recent data from Sweden suggest that the incidence of collagenous colitis is higher than previously considered and similar to the Correspondence to: Dr S. Miehlke, Medical Department I, Technical University Hospital, Fetscherstr. 74, Dresden, Germany. stephan.miehlke@uniklinikum-dresden.de incidence of Crohn s disease. 4 Recent data from the US (Olmsted County, MN, USA) suggest a significant increase in the incidence of microscopic colitis over the last decades, and a significantly higher incidence and prevalence compared with Europe. 5 As in other inflammatory bowel diseases, quality of life is severely reduced in patients with collagenous colitis. 6 The natural history of collagenous colitis appears to vary considerably with a wide range of clinical and histological remission rates reported in the literature. 1, 7 9 Interpretation of these data are further complicated by differences in study designs, variable histological diagnoses and definitions of clinical response or remission, and whether maintenance therapies has been applied or not. Budesonide, a topical acting steroid, has recently been proven effective for induction of remission and improvement of histopathology in collagenous colitis Ó 2005 The Authors 1115

2 1116 S. MIEHLKE et al. by three randomized placebo-controlled trials It has further been shown that budesonide rapidly achieves clinical remission in the majority of patients, and significantly improves quality of life. 6, 13 Recent literature reviews and meta-analyses have concluded that budesonide is currently the only intervention for which strong evidence exists for clinical improvement in collagenous colitis. 14, 15 However, the long-term outcome of patients with collagenous colitis after successful short-term budesonide therapy is largely unknown. Therefore, the aim of our study was to assess the clinical course of a large cohort of patients with collagenous colitis who have participated in a prospective randomized trial and in whom clinical remission has been achieved by a 6-week therapy with budesonide. MATERIAL AND METHODS Study design and patients Patients between 18 and 80 years of age with histologically confirmed collagenous colitis and with at least five loose stools per day on average per week were enrolled in a randomized, double-blind, placebo-controlled multicentre trial conducted between April 1999 and December The full methods and primary efficacy and safety results have been reported previously. 11 Briefly, eligible patients were randomized to receive 9 mg (three capsules of 3 mg) budesonide controlled-release capsules (Entocort, AstraZeneca, Sodertalje, Sweden) given once daily in the morning, or to receive identically looking placebos. The treatment was given orally in a double-blind fashion for a period of 6 weeks. Patients of the placebo group with persisting diarrhoea at the end of the double-blind treatment phase subsequently received open-label crossover therapy with 9 mg (three capsules of 3 mg) budesonide controlled-release capsules for further 6 weeks. Clinical symptoms were assessed by standardized questionnaires at baseline and after 6 weeks of double-blind treatment and if applicable at the end of 6 weeks of subsequent open-label therapy. Colonoscopy including histology from the entire colon was performed at baseline and at the end of the respective treatment periods. All histopathological examinations were performed by two experienced pathologists (B.B. and M.S.) using haematoxylin and eosin (H & E) and van Gieson stain. Histological criteria and definitions for diagnosis and treatment response have been previously described. 11 Baseline serology was obtained for analysis of Yersinia enterocolitica and Y. pseudotuberculosis immunoglobulin (Ig)G, IgA and IgM using enzyme-linked immunosorbent assay (ELISA; recomwell, Mikrogen, Munich, Germany) performed at the Central Institute for Medical Microbiology, Munich. 16 Long-term follow-up Patients who achieved clinical remission after budesonide treatment, either after the initial double-blind treatment phase or after the crossover open-label treatment phase were eligible for the follow-up evaluation. Patients were retrospectively contacted by mail or telephone between October 2001 and April 2004 using standardized questionnaires. The questionnaires included evaluation of stool frequency and consistency, abdominal pain, weight loss, treatment with antidiarrhoeals or anti-inflammatory drugs, demand for continuous maintenance therapy and further colonoscopies. In addition, the local general practitioner and/or gastroenterologist was contacted for further data collection. In accordance with the initial inclusion criteria of the primary trial, clinical relapse was defined as five or more soft or watery stools per day on at least 4 consecutive days. Reports of colonoscopies including histology were obtained from the local gastroenterologists. Histological evaluations during the follow-up period were performed by the same pathologist in identical manner. Statistical analysis Median follow-up time and relapse-free interval and its 95% confidence interval (CI) were calculated by Kaplan Meier estimated survival functions. Patients were compared by Breslow test with respect to budesonide exposure (double-blind phase vs. open-label crossover phase). Unconditional logistic regression models were used to elucidate the importance of budesonide treatment on higher inflammation level of several colonic regions. The following variables were included in the multivariate analysis to identify predictive factors for clinical relapse: age, gender, body weight, history of diarrhoea, onset of diarrhoea, stool frequency at baseline, time to clinical remission (days), histopathology (thickness of the collagen band, active inflammation of the lamina propria) in all parts of the colon at baseline and after 6 weeks of treatment, and

3 BUDESONIDE IN COLLAGENOUS COLITIS 1117 Yersinia IgG and IgA serum antibody titres. Odds ratios (OR) and their 95% CI are presented. P-values of <5% are considered statistically significant. All analyses were performed using spss 11.5 (SPSS, Inc., Chicago, IL, USA). RESULTS Fifty-one patients were enrolled in the initial clinical trial. The detailed demographic characteristics of the entire patient population have been described previously. 11 During this trial, a total of 39 patients have been exposed to active treatment with budesonide (perprotocol), 23 patients within the double-blind treatment phase and 16 patients within the open-label crossover treatment phase. After 6 weeks of treatment, a total of 33 patients (85%) achieved clinical remission, 20 patients (87%) within the double-blind treatment phase and 13 patients (81%) within the open-label crossover treatment phase. The demographic and clinical characteristics of these patients are summarized in Table 1. None of the patients used non-steroidal anti-inflammatory drugs (NSAID), as NSAID use was an exclusion criterion. None of the patients suffered from concomitant coeliac disease, which was ruled out by upper endoscopy and histology prior to enrolment in the original trial. At the end of the follow-up assessment, the median follow-up period of these 33 patients was 16 months (range: ). One patient in continuous clinical remission died 4 months after cessation of treatment as a result of pulmonary embolism unrelated to the treatment of collagenous colitis, as confirmed by the local practitioner. A total of 32 questionnaires answered Relapse-free survival Weeks 100 Figure 1. Cumulative probability of clinical remission of collagenous colitis after budesonide therapy. 120 by patients and 22 questionnaires answered by doctors were available for the analysis. Within the follow-up period, a total of 20 patients (16 females) suffered from clinical relapse giving a cumulative relapse rate of 61%. In 18 cases there was agreement between patient and doctor to confirm clinical relapse of collagenous colitis. Based on clinical symptomatology and diagnostic assessment by the local practitioner/gastroenterologist, including colonoscopy in nine cases, infectious causes for diarrhoea were ruled out. In two cases, confirmation of clinical relapse was based on the questionnaire returned by the patient reporting symptoms identical to previous ones with typical watery diarrhoea and absence of systemic symptoms. The remaining 12 patients achieved stable clinical remission without treatment over a period of at least 12 months after budesonide therapy (Figure 1). 80 Table 1. Demographic and clinical characteristics of patients in clinical remission at baseline, i.e. at the end of budesonide therapy Variables Group A Group B Age (years; median) Females/males 16/4 10/3 Months between onset of diarrhoea and 8 (1 84) 6 (1 60) diagnosis, median (range) Thickness of collagen band [lm; median (range)] At baseline 25 (10 60) 40 (15 95) At the end of budesonide therapy 18 (0 50) 25 (10 60) Inflammatory score, median (range) At baseline 2 (1 3) 2 (1 3) At the end of budesonide therapy 1 (0 2) 1 (1 3) Days until clinical remission (median) 10 7,5 Group A, budesonide therapy during the double-blind treatment phase (n ¼ 20); group B, budesonide therapy during the open-label crossover treatment phase (n ¼ 13).

4 1118 S. MIEHLKE et al. There was no significant difference in the clinical relapse rates between patients who received active budesonide within the double-blind treatment phase (n ¼ 12) and those who received budesonide within the open-label crossover treatment phase (n ¼ 8). The median time until occurrence of clinical relapse was 2 weeks (range: 1 104, mean: 10 weeks) after cessation of treatment. Thus, the majority of clinical relapses (88%) occurred within 3 months after cessation of treatment. The median stool frequency at the time of clinical relapse was five stools/per day (mean: 6.7). Five patients (25%) reported abdominal pain in conjunction with recurrence of diarrhoea. Multivariate analysis revealed that patient age <60 years was a risk factor for clinical relapse (OR ¼ 7.4, 95% CI: , P ¼ 0.048). In addition, there was a trend to a higher risk for clinical relapse in patients with a high activity of inflammation in the sigmoid colon at the end of budesonide therapy (OR ¼ 6.2, P ¼ 0.075). In nine of the 20 patients (45%) who experienced clinical relapse, colonoscopy was repeated at the discretion of the local general practitioner and/or the local gastroenterologist after a mean follow-up time of 65 weeks. In all nine patients, the endoscopic findings were normal, particularly without any evidence for infectious diarrhoea. On histology, the mean inflammatory score of the colonic lamina propria was mild in two patients, moderate in five patients and severe in two patients. Compared with the previous examination, i.e. at the end of budesonide treatment, four patients showed histological improvement, four patients showed histological deterioration and one patient showed no change on histology. Valid information about the retreatment of patients with clinical relapse was available in 16 cases (80%). Of those, 13 patients (80%) were retreated at the discretion of the local general practitioner and/or the local gastroenterologist with oral budesonide at dosages ranging from 3 to 9 mg/day depending on the severity of symptoms. All of these patients were reported to have responded to treatment. The remaining patients were treated with mesalazine (n ¼ 1), bismuth (n ¼ 1) or antidiarrhoeals (n ¼ 1). DISCUSSION At present, there are three prospective, randomized placebo-controlled studies which have consistently shown that budesonide is highly effective in inducing clinical remission in patients with collagenous colitis Follow-up of these homogenous patient populations is valuable to gain more insight in the longterm outcome of patients after successful short-term budesonide therapy. Our present study demonstrates that a substantial proportion of patients may suffer from clinical relapse after cessation of successful budesonide treatment with the majority of relapses occurring within the first 3 months after cessation. On the contrary, patients, who do not suffer from early relapse after cessation of treatment appear to stay in prolonged clinical remission. Similar findings have been reported by Baert et al. who found short-term clinical relapses in 12 of 19 patients (63%) after cessation of successful budesonide therapy. 10 Similarly, Bonderup et al. observed clinical relapses in eight of 10 patients within 8 weeks after cessation of budesonide treatment. 12 The available amount of data about the long-term course of collagenous colitis is rather limited. Fernandez-Banares et al. recently reported a prospective study including 37 patients with collagenous colitis. 17 Overall, clinical relapses were observed in 11 patients (30%) within a follow-up period of 3 years. In this study, budesonide was initially effective in eight of nine patients. In six of these patients diarrhoea recurred during follow-up and was successfully retreated with budesonide at daily doses of 3 6 mg/day. 18 Similar to that, the majority of patients in our study presenting with clinical relapse have been successfully retreated with budesonide at similar dosages. In a study by Bonner et al., 15 patients with confirmed collagenous colitis and 10 patients with confirmed lymphocytic colitis were followed by telephonic interviews over a period of 47 months. 9 In the majority of these patients, partially being under treatment with loperamide or 5-aminosalicylates, improvement of diarrhoea was reported, while 29% of patients required continuous maintenance therapy for symptom control. Of interest, among those patients who had a longer duration of symptoms before diagnosis, maintenance therapy was required in up to 50% of cases. 9 Data on the histological evolution of collagenous colitis are limited and difficult to compare due to variable or missing criteria for histological abnormalities. In general, available data suggest a rather poor correlation between clinical and histological remission

5 BUDESONIDE IN COLLAGENOUS COLITIS 1119 in collagenous colitis. 19, 20 This lack of correlation is further supported by the limited data of our study. In the present study, patients <60 years of age had an increased risk for clinical relapse suggesting that the course of disease may vary between age groups. In fact, Abdo et al. have shown that spontaneous remissions may be more likely in older patients 20 which would further support this hypothesis. Clearly, this potential risk factor for clinical relapse needs to be confirmed by future prospective studies in order to identify patients for maintenance therapy after induction of clinical remission. In conclusion, budesonide is highly effective in inducing clinical remission in collagenous colitis; however, clinical relapses may occur in a substantial proportion of patients after cessation of therapy, particularly in patients <60 years of age. Treatment of clinical relapse with budesonide appears to be an effective option. The use of budesonide in maintenance therapy of collagenous colitis is currently under investigation in a randomized, placebo-controlled study by our group. ACKNOWLEDGEMENT This study was supported by AstraZeneca. REFERENCES 1 Pardi DS. Microscopic colitis. An update. Inflamm Bowel Dis 2004; 10: Bohr J, Olesen M, Tysk C, Järnerot G. Collagenous and lymphocytic colitis: a clinical and histopathological review. Can J Gastroenterol 2000; 14: Abdo AA, Urbanski SJ, Beck PL. Lymphocytic and collagenous colitis: the emerging entity of microscopic colitis. An update on pathophysiology, diagnosis and management. Can J Gastroenterol 2003; 17: Olesen M, Eriksson S, Bohr J, Jarnerot G, Tysk C. Microscopic colitis: a common diarrheal disease. An epidemiological study in Orebro, Sweden, Gut 2004; 53: Pardi DS, Smyrk TC, Kammer P, et al. The epidemiology of mircroscopic colitis (MC): a population-based study in Olmsted County, MN. Gastroenterology 2004; 126: Madisch A, Heymer P, Voss C, et al. Oral Budesonide therapy improves quality of life in patients with collagenous colitis. Int J Colorectal Dis 2005; 20: Bohr J, Tysk C, Eriksson S, Abrahamson H, Jänerot G. Collagenous colitis: a retrospective study of clinical presentation and treatment in 163 patients. Gut 1996; 39: Bonderup OK, Folkersen BH, Gjersoe P, Teglbjaerg PS. Collagenous colitis: a long-term follow-up study. Eur J Gastroenterol Hepatol 1999; 11: Bonner GF, Petras RE, Cheong DM, Grewal ID, Breno S, Ruderman WB. Short- and long-term follow-up of treatment for lymphocytic and collagenous colitis. Inflamm Bowel Dis 2000; 6: Baert F, Schmit A, D Haens G, et al. Budesonide in collagenous colitis-a double-blind placebo-controlled trial with histological follow-up. Gastroenterology 2002; 122: Miehlke S, Heymer P, Bethke B, et al. Budesonide treatment for collagenous colitis a randomized, double-blind, placebocontrolled, multicenter trial. Gastroenterology 2002; 123: Bonderup OK, Hansen JB, Birket-Smith L, Vestergaard V, Teglbjaerg PS, Fallingborg J. Budesonide treatment of collagenous colitis: a randomised, double blind, placebo controlled trial with morphometric analysis. Gut 2003; 52: Miehlke S, Madisch A, Bethke B, Stolte M. Time to clinical remission with budesonide treatment in collagenous colitis. Aliment Pharmacol Ther 2005; 21: Chande N, McDonald JW, MacDonald JK. Interventions for treating collagenous colitis: a Cochrane Inflammatory Bowel Disease Group systematic review of randomized trials. Am J Gastroenterol 2004; 99: Feyen B, Wall GC, Finnerty EP, DeWitt JE, Reyes RS. Metaanalysis: budesonide treatment for collagenous colitis. Aliment Pharmacol Ther 2004; 20: Miehlke S, Schneider-Brachert W, Madisch A, et al. High prevalence of Yersinia IgG and IgA in patients with collagenous colitis. Gastroenterology 2003; 124: A Fernandez-Banares F, Salas A, Esteve M, Espinos J, Forne M, Viver JM. Collagenous and lymphocytic colitis. Evaluation of clinical and histological features, response to treatment, and long-term follow-up. Am J Gastroenterol 2003; 98: Carpenter HA, Tremaine WJ, Batts KP, Czaja AJ. Sequential histologic evaluations in collagenous colitis. Correlations with disease behavior and sampling strategy. Dig Dis Sci 1992; 37: Shaz BH, Reddy SI, Ayata G, et al. Sequential clinical and histopathological changes in collagenous and lymphocytic colitis over time. Mod Pathol 2004; 17: Abdo A, Raboud J, Freeman HJ, et al. Clinical and histological predictors of response to medical therapy in collagenous colitis. Am J Gastroenterol 2002; 97: