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Kamitani Y, Kurumi H, Kanda T, Ikebuchi Y, Yoshida A, Kawaguchi K, Yashima K, Umekita Y, Isomoto H. Comparative study between histochemical mucus volume, histopathological findings, and endocytoscopic scores in patients with ulcerative colitis. Medicine (Baltimore) 2023; 102:e33033. [PMID: 36862904 PMCID: PMC9981389 DOI: 10.1097/md.0000000000033033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/04/2023] Open
Abstract
Ulcerative colitis (UC) causes a reduction in goblet cells. However, there have been few reports on the relationship between endoscopic and pathological findings and mucus volume. In this study, we quantitatively evaluated histochemical colonic mucus volume by fixing biopsied tissue sections taken from patients with UC in Carnoy's solution and compared it with endoscopic and pathological findings to determine whether there is a correlation between them. Observational study. A single-center, university hospital in Japan. Twenty-seven patients with UC (male/female, 16/11; mean age, 48.4 years; disease median duration, 9 years) were included in the study. The colonic mucosa of the most inflamed area and the surrounding less inflamed area were evaluated separately by local MES and endocytoscopic (EC) classification. Two biopsies were taken from each area; one was fixed with formalin for histopathological evaluation, and the other was fixed with Carnoy's solution for the quantitative evaluation of mucus via histochemical Periodic Acid Schiff and Alcian Blue staining. The relative mucus volume was significantly reduced in the local MES 1-3 groups, with worsening findings in EC-A/B/C and in groups with severe mucosal inflammation, crypt abscess, and severe reduction in goblet cells. The severity of inflammatory findings in UC by EC classification correlated with the relative mucus volume suggesting functional mucosal healing. We found a correlation between the colonic mucus volume and endoscopic and histopathological findings in patients with UC, and a stepwise correlation with disease severity, particularly in EC classification.
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Affiliation(s)
- Yu Kamitani
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Hiroki Kurumi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
- * Correspondence: Hiroki Kurumi, Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan (e-mail: )
| | - Tsutomu Kanda
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Yuichiro Ikebuchi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Akira Yoshida
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Koichiro Kawaguchi
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Kazuo Yashima
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Yoshihisa Umekita
- Department of Pathology, Faculty of Medicine, Tottori University, Tottori, Japan
| | - Hajime Isomoto
- Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori, Japan
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Chen P, Li Y, Zhang X, Zhang Y. Systematic review with meta-analysis: effectiveness of hyperbaric oxygenation therapy for ulcerative colitis. Therap Adv Gastroenterol 2021; 14:17562848211023394. [PMID: 34349835 PMCID: PMC8290506 DOI: 10.1177/17562848211023394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 05/18/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND AIMS Hyperbaric oxygenation therapy has been used in the treatment of ulcerative colitis in the past few years. However, its efficacy still remains unclear. The aim of the study was to investigate the efficacy of hyperbaric oxygen combination therapy in patients with ulcerative colitis. METHODS We conducted a comprehensive study search up to September 2020, from the online databases Embase, PubMed, Cochrane Library, China National Knowledge Infrastructure, WanFang and VIP. RESULTS Thirteen studies comprising 780 patients were included. We found that compared with conventional therapy, hyperbaric oxygen combination therapy was superior in reaching clinical remission [risk ratio (RR)=1.62; 95% confidence interval (CI) 1.42 to 1.84; p < 0.001] and clinical response (RR=1.29; 95% CI 1.21 to 1.38; p < 0.001), with lower disease activity scores [standard mean difference (SMD)= -1.19; 95%CI -1.74 to -0.65; p < 0.001]. An obvious reduction of serum levels of tumor necrosis factor-α (SMD= -1.96; 95%CI -2.50 to -1.41; p < 0.001) and interleukin (IL)-6 (SMD= -2.49; 95% CI -2.84 to -2.15; p < 0.001), and elevation of IL-10 level (SMD=2.40; 95% CI 0.68 to 4.12; p = 0.006) were also observed. CONCLUSION Hyperbaric oxygen combination therapy was effective in patients with ulcerative colitis, and has potential as a complementary method for its treatment.
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Gutierrez Becker B, Arcadu F, Thalhammer A, Gamez Serna C, Feehan O, Drawnel F, Oh YS, Prunotto M. Training and deploying a deep learning model for endoscopic severity grading in ulcerative colitis using multicenter clinical trial data. Ther Adv Gastrointest Endosc 2021; 14:2631774521990623. [PMID: 33718871 PMCID: PMC7917417 DOI: 10.1177/2631774521990623] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/03/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: The Mayo Clinic Endoscopic Subscore is a commonly used grading system to assess the severity of ulcerative colitis. Correctly grading colonoscopies using the Mayo Clinic Endoscopic Subscore is a challenging task, with suboptimal rates of interrater and intrarater variability observed even among experienced and sufficiently trained experts. In recent years, several machine learning algorithms have been proposed in an effort to improve the standardization and reproducibility of Mayo Clinic Endoscopic Subscore grading. Methods: Here we propose an end-to-end fully automated system based on deep learning to predict a binary version of the Mayo Clinic Endoscopic Subscore directly from raw colonoscopy videos. Differently from previous studies, the proposed method mimics the assessment done in practice by a gastroenterologist, that is, traversing the whole colonoscopy video, identifying visually informative regions and computing an overall Mayo Clinic Endoscopic Subscore. The proposed deep learning–based system has been trained and deployed on raw colonoscopies using Mayo Clinic Endoscopic Subscore ground truth provided only at the colon section level, without manually selecting frames driving the severity scoring of ulcerative colitis. Results and Conclusion: Our evaluation on 1672 endoscopic videos obtained from a multisite data set obtained from the etrolizumab Phase II Eucalyptus and Phase III Hickory and Laurel clinical trials, show that our proposed methodology can grade endoscopic videos with a high degree of accuracy and robustness (Area Under the Receiver Operating Characteristic Curve = 0.84 for Mayo Clinic Endoscopic Subscore ⩾ 1, 0.85 for Mayo Clinic Endoscopic Subscore ⩾ 2 and 0.85 for Mayo Clinic Endoscopic Subscore ⩾ 3) and reduced amounts of manual annotation. Plain language summary Patient, caregiver and provider thoughts on educational materials about prescribing and medication safety Artificial intelligence can be used to automatically assess full endoscopic videos and estimate the severity of ulcerative colitis. In this work, we present an artificial intelligence algorithm for the automatic grading of ulcerative colitis in full endoscopic videos. Our artificial intelligence models were trained and evaluated on a large and diverse set of colonoscopy videos obtained from concluded clinical trials. We demonstrate not only that artificial intelligence is able to accurately grade full endoscopic videos, but also that using diverse data sets obtained from multiple sites is critical to train robust AI models that could potentially be deployed on real-world data.
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Affiliation(s)
- Benjamin Gutierrez Becker
- Roche Pharma Research and Early Development Informatics, Roche Innovation Center Basel, Basel, Switzerland
| | - Filippo Arcadu
- Roche Pharma Research and Early Development Informatics, Roche Innovation Center Basel, Basel, Switzerland
| | - Andreas Thalhammer
- Roche Pharma Research and Early Development Informatics, Roche Innovation Center Basel, Basel, Switzerland
| | - Citlalli Gamez Serna
- Roche Pharma Research and Early Development Informatics, Roche Innovation Center Basel, Basel, Switzerland
| | - Owen Feehan
- Roche Pharma Research and Early Development Informatics, Roche Innovation Center Basel, Basel, Switzerland
| | - Faye Drawnel
- Roche Personalized Healthcare, Genentech, Inc., South San Francisco, CA, USA
| | - Young S Oh
- Product Development, Genentech, Inc., 1 DNA Way, South San Francisco, CA, USA
| | - Marco Prunotto
- School of Pharmaceutical Sciences, Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, 1211 Geneva 4, Switzerland. Immunology, Infectious Disease & Ophthalmology, Roche, Basel, Switzerland
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Rodrigues BL, Mazzaro MC, Nagasako CK, Ayrizono MDLS, Fagundes JJ, Leal RF. Assessment of disease activity in inflammatory bowel diseases: Non-invasive biomarkers and endoscopic scores. World J Gastrointest Endosc 2020; 12:504-520. [PMID: 33362904 PMCID: PMC7739141 DOI: 10.4253/wjge.v12.i12.504] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/06/2020] [Accepted: 11/05/2020] [Indexed: 02/05/2023] Open
Abstract
Inflammatory bowel diseases (IBD) comprise two major forms: Crohn's disease and ulcerative colitis. The diagnosis of IBD is based on clinical symptoms combined with results found in endoscopic and radiological examinations. In addition, the discovery of biomarkers has significantly improved the diagnosis and management of IBD. Several potential genetic, serological, fecal, microbial, histological and immunological biomarkers have been proposed for IBD, and they have been evaluated for clinical routine and clinical trials. Ileocolonoscopy, especially with biopsy collection, has been considered the standard method to diagnose IBD and to assess clinical activity of the disease, but it is limited to the colon and terminal ileum and is considered invasive. For this reason, non-invasive biomarkers are necessary for this type of chronic inflammatory disease, which affects mostly young individuals, as they are expected to have a long follow-up.
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Affiliation(s)
- Bruno Lima Rodrigues
- Inflammatory Bowel Disease Research Laboratory, Gastrocenter, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
| | - Márcia Carolina Mazzaro
- Inflammatory Bowel Disease Research Laboratory, Gastrocenter, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
| | - Cristiane Kibune Nagasako
- Department of Gastroenterology, Gastrocenter, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory, Gastrocenter, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
| | - João José Fagundes
- Inflammatory Bowel Disease Research Laboratory, Gastrocenter, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory, Gastrocenter, Colorectal Surgery Unit, Department of Surgery, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-878, São Paulo, Brazil
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Dang XF, Qing-Xi Wang, Yin Z, Sun L, Yang WH. Recurrence of moderate to severe ulcerative colitis after fecal microbiota transplantation treatment and the efficacy of re-FMT: a case series. BMC Gastroenterol 2020; 20:401. [PMID: 33243141 PMCID: PMC7691068 DOI: 10.1186/s12876-020-01548-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 11/18/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), the pathogenesis of which is complicated, and it is difficult to treat. In recent years, the emerging fecal microbiota transplantation (FMT) has shown good effects in UC treatment and is therefore accepted by increasing numbers of patients. Our hospital has carried out FMT since 2017, and has achieved good results in UC treatment. We have found in our clinical work that the efficacy of re-FMT after recurrence decreased. This is difference from reported literatures. In order to attract clinical attention, here we selected typical cases for analysis. METHODS Among all UC patients who received FMT in our hospital, 12 patients with moderate to severe UC were selected. They all received multiple FMT and were followed up for 52 weeks. Besides, none of them had other underlying diseases. Colonoscopy images of patients were presentated, SCCAI and UCDAI were used assess the effect of FMT. RESULTS On the whole, FMT has a significant effect on moderate to severe UC. Of the 12 patients, 11 (91.7%) achieved a clinical response, 9 (75.0%) achieved clinical remission, and only one patient did not respond to FMT treatment. However, 6 patients relapsed within 52 weeks after remission, with a recurrence rate of 54.5%. Four of the six relapsed patients received FMT again, but the efficacy of FMT after relapse was significantly lower than that of the initial FMT. Fortunately, compared to before the initial FMT treatment, the severity of the disease after relapse was significantly reduced. CONCLUSION FMT has a good effect on the relief of moderate to severe UC. However, the effect of FMT treatment after relapse is reduced. For patients who relapse after remission, the efficacy of FMT reapplication requires more experiments to verify.
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Affiliation(s)
- Xiao-Fei Dang
- Department of Clinical Microbiology, Medical Research & Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, Shandong, China
| | - Qing-Xi Wang
- Department of Clinical Microbiology, Medical Research & Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, Shandong, China
| | - Zhao Yin
- Gastroenterology, Jinan Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, China
| | - Lin Sun
- Department of Clinical Microbiology, Medical Research & Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, Shandong, China
| | - Wei-Hua Yang
- Department of Clinical Microbiology, Medical Research & Laboratory Diagnostic Center, Jinan Central Hospital Affiliated to Shandong First Medical University, 105 Jiefang Road, Jinan, Shandong, China.
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Battat R, Dulai PS, Ma C, Jairath V, Feagan BG, Sandborn WJ, Khanna R. Current Endpoints of Clinical Trials in Ulcerative Colitis: Are They Valid? CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2020; 18:15-32. [PMID: 31902071 DOI: 10.1007/s11938-019-00259-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, CA, USA
- Robarts Clinical Trials, Inc., 100 Dundas Street, Suite, London, Ontario, Canada
| | - Parambir S Dulai
- Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, CA, USA
| | - Christopher Ma
- Robarts Clinical Trials, Inc., 100 Dundas Street, Suite, London, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Vipul Jairath
- Robarts Clinical Trials, Inc., 100 Dundas Street, Suite, London, Ontario, Canada
- Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada
| | - Brian G Feagan
- Robarts Clinical Trials, Inc., 100 Dundas Street, Suite, London, Ontario, Canada
- Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada
| | - William J Sandborn
- Division of Gastroenterology and Hepatology, University of California San Diego, La Jolla, CA, USA
- Robarts Clinical Trials, Inc., 100 Dundas Street, Suite, London, Ontario, Canada
| | - Reena Khanna
- Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada.
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Ma C, Panaccione R, Fedorak RN, Parker CE, Nguyen TM, Khanna R, Siegel CA, Peyrin-Biroulet L, D'Haens G, Sandborn WJ, Feagan BG, Jairath V. Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set. Clin Gastroenterol Hepatol 2018; 16:637-647.e13. [PMID: 28843356 DOI: 10.1016/j.cgh.2017.08.025] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 07/26/2017] [Accepted: 08/04/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo-controlled randomized controlled trials of patients with UC. METHODS We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo-controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication. RESULTS We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite-clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient-reported efficacy and quality-of-life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%). CONCLUSION In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials.
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Affiliation(s)
- Christopher Ma
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Remo Panaccione
- Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta, Canada
| | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada
| | - Claire E Parker
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Tran M Nguyen
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Reena Khanna
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada
| | - Corey A Siegel
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm U954, Nancy University Hospital, Lorraine University, Nancy, France
| | - Geert D'Haens
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, the Netherlands
| | - William J Sandborn
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Division of Gastroenterology, University of California, San Diego, La Jolla, California
| | - Brian G Feagan
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Vipul Jairath
- Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada.
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Jairath V, Zou GY, Parker CE, MacDonald JK, AlAmeel T, Al Beshir M, Almadi MA, Al‐Taweel T, Atkinson NSS, Biswas S, Chapman T, Dulai PS, Glaire MA, Hoekman DR, Koutsoumpas A, Minas E, Mosli MH, Samaan M, Khanna R, Travis S, D'Haens G, Sandborn WJ, Feagan BG. Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis. Cochrane Database Syst Rev 2017; 9:CD011572. [PMID: 28886205 PMCID: PMC6483671 DOI: 10.1002/14651858.cd011572.pub2] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.
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Affiliation(s)
- Vipul Jairath
- University of Western OntarioDepartment of MedicineLondonONCanada
- Robarts Clinical TrialsLondonONCanada
- University of Western OntarioDepartment of Epidemiology and BiostatisticsLondonONCanada
| | - GY Zou
- Robarts Clinical TrialsLondonONCanada
- University of Western OntarioDepartment of Epidemiology and BiostatisticsLondonONCanada
| | | | - John K MacDonald
- University of Western OntarioDepartment of MedicineLondonONCanada
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
| | - Turki AlAmeel
- King Fahad Specialist Hospital‐DammamDepartment of MedicineP.O Box 15215DammamSaudi Arabia31444
| | - Mohammad Al Beshir
- King Fahad Specialist Hospital‐DammamDepartment of MedicineP.O Box 15215DammamSaudi Arabia31444
| | - Majid A Almadi
- King Khalid University HospitalDivision of GastroenterologyRiyadhSaudi Arabia
- King Saud UniversityRiyadhSaudi Arabia
| | | | | | - Sujata Biswas
- Wellcome Trust Centre for Human GeneticsTranslational Gastroenterology UnitRoosevelt DriveOxfordUKOX3 7BN
| | - Thomas Chapman
- John Radcliffe HospitalTranslational Gastroenterology UnitHeadley WayOxfordUKOX3 9DU
| | | | | | - Daniël R Hoekman
- Academic Medical CenterMeibergdreef 9AmsterdamNetherlands1105 AZ
| | | | | | - Mahmoud H Mosli
- King Abdulaziz UniversityKing Abdulaziz University HospitalJeddahSaudi Arabia
| | - Mark Samaan
- Academic Medical CenterMeibergdreef 9AmsterdamNetherlands1105 AZ
| | - Reena Khanna
- University of Western OntarioDepartment of MedicineLondonONCanada
- Robarts Clinical TrialsLondonONCanada
| | - Simon Travis
- University of OxfordTranslational Gastroenterology Unit, Nuffield Department of MedicineOxfordUK
| | - Geert D'Haens
- Academic Medical CenterMeibergdreef 9AmsterdamNetherlands1105 AZ
- Robarts Clinical TrialsAmsterdamNetherlands
| | - William J Sandborn
- University of California San DiegoDivision of GastroenterologyLa JollaCAUSA
- Robarts Clinical TrialsSan DiegoCAUSA
| | - Brian G Feagan
- University of Western OntarioDepartment of MedicineLondonONCanada
- Robarts Clinical TrialsLondonONCanada
- University of Western OntarioDepartment of Epidemiology and BiostatisticsLondonONCanada
- Robarts Clinical TrialsCochrane IBD Group100 Dundas Street, Suite 200LondonONCanadaN6A 5B6
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Zhao X, Zhou C, Ma J, Zhu Y, Sun M, Wang P, Zhang Y, Ma H, Zhang H. Efficacy and safety of rectal 5-aminosalicylic acid versus corticosteroids in active distal ulcerative colitis: a systematic review and network meta-analysis. Sci Rep 2017; 7:46693. [PMID: 28440311 PMCID: PMC5404224 DOI: 10.1038/srep46693] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/24/2017] [Indexed: 12/14/2022] Open
Abstract
Topical 5-aminosalicylic acid (5-ASA) and corticosteroids are used frequently in the treatment of active distal ulcerative colitis (UC). Our study aimed to determine the efficacy and safety of different topical drugs used to treat active distal UC. A random-effects model within a Bayesian framework was utilized to compare treatment effects and safety as odds ratios (ORs) with corresponding 95% credible intervals (CrI). The surface under the cumulative ranking area (SUCRA) and median rank (MR) with corresponding 95% CrI were calculated to rank the treatment outcomes. In the induction of clinical and endoscopic remission, most regimens showed significant advantages over placebo except topical budesonide 0.5 mg/d and hydrocortisone 100 mg/d. According to SUCRA and MR values, rectal 5-ASA 1.5 to 2.0 g/d + Beclomethasone dipropionate (BDP) 3 mg/d rendered the highest probability of being the best regimen to achieve clinical and endoscopic remission, followed by the separate use of 5-ASA 4 g/d and BDP 3 mg/d. The occurrence of adverse events was not significantly different between each treatments and placebo. In conclusion, the combined use of topical 5-ASA and BDP proved to be the best choice for active distal UC and further well-designed researches are warranted to assess its efficacy and safety.
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Affiliation(s)
- Xiaojing Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, Jiangsu 210006, China
| | - Jingjing Ma
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yunjuan Zhu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Min Sun
- Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
| | - Peixue Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Yi Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Haiqin Ma
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Hongjie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
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10
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Bojic D, Bodger K, Travis S. Patient Reported Outcome Measures (PROMs) in Inflammatory Bowel Disease: New Data. J Crohns Colitis 2017; 11:S576-S585. [PMID: 27797917 DOI: 10.1093/ecco-jcc/jjw187] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 10/19/2016] [Indexed: 12/13/2022]
Abstract
Patient reported outcome measures [PROMs] are standardized, validated questionnaires intended for completion by patients in order to measure their perceptions of their own health condition or its treatment without interpretation of the patient's response by a clinician or anyone else. Mayo Clinic Score [MCS] or Crohn's Disease Activity Index [CDAI], most frequently used as end points in conventional clinical trials, are composite instruments that are not fully objective nor capture the impact of disease from the patient's perspective. They are difficult to apply to routine clinical practice because they are complex and time consuming. The European Medicines Agency and Food and Drug Administration are re-evaluating composite indices in clinical trials and product development guidelines. The ultimate goal is to support labelling claims to improve safety and effectiveness of medical products through PROMs allied to an objective measure of inflammation, as happens informally in clinical practice. PROMs, developed and validated according to rigorous criteria, are set to become a co-primary end point for clinical trials of therapy, together with objective measure[s] of inflammation. This will affect future trials' design and their results. To find a place in routine care, PROMs should be easy to use, acceptable to patients and healthcare teams, and able to demonstrate added value to normal practice, supporting decision-making at the level of individual patients. Ideally, the same PROMs should be used in clinical trials and practice, to avoid the current disconnect when interpreting the results of clinical trials and translating them into routine clinical practice.
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Affiliation(s)
- Daniela Bojic
- Medical Faculty, University of Belgrade, Belgrade, Serbia.,Tillotts Pharma AG, Rheinfelden, Switzerland
| | - Keith Bodger
- Department of Gastroenterology, Institute of Translational Medicine University of Liverpool, Liverpool, UK.,Digestive Disease Centre, Aintree University Hospital NHS Trust, Liverpool, UK
| | - Simon Travis
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
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11
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Ippolito C, Colucci R, Segnani C, Errede M, Girolamo F, Virgintino D, Dolfi A, Tirotta E, Buccianti P, Di Candio G, Campani D, Castagna M, Bassotti G, Villanacci V, Blandizzi C, Bernardini N. Fibrotic and Vascular Remodelling of Colonic Wall in Patients with Active Ulcerative Colitis. J Crohns Colitis 2016; 10:1194-204. [PMID: 26995183 DOI: 10.1093/ecco-jcc/jjw076] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 03/07/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Intestinal fibrosis is a complication of inflammatory bowel disease [IBD]. Although fibrostenosis is a rare event in ulcerative colitis [UC], there is evidence that a fibrotic rearrangement of the colon occurs in the later stages. This is a retrospective study aimed at examining the histopathological features of the colonic wall in both short-lasting [SL] and long-lasting [LL] UC. METHODS Surgical samples of left colon from non-stenotic SL [≤ 3 years, n = 9] and LL [≥ 10 years, n = 10] UC patients with active disease were compared with control colonic tissues from cancer patients without UC [n = 12] to assess: collagen and elastic fibres by histochemistry; vascular networks [CD31/CD105/nestin] by immunofluorescence; parameters of fibrosis [types I and III collagen, fibronectin, RhoA, alpha-smooth muscle actin [α-SMA], desmin, vimentin], and proliferation [proliferating nuclear antigen [PCNA]] by western blot and/or immunolabelling. RESULTS Colonic tissue from both SL-UC and LL-UC showed tunica muscularis thickening and transmural activated neovessels [displaying both proliferating CD105-positive endothelial cells and activated nestin-positive pericytes], as compared with controls. In LL-UC, the increased collagen deposition was associated with an up-regulation of tissue fibrotic markers [collagen I and III, fibronectin, vimentin, RhoA], an enhancement of proliferation [PCNA] and, along with a loss of elastic fibres, a rearrangement of the tunica muscularis towards a fibrotic phenotype. CONCLUSIONS A significant transmural fibrotic thickening occurs in colonic tissue from LL-UC, together with a cellular fibrotic switch in the tunica muscularis. A full-thickness angiogenesis is also evident in both SL- and LL-UC with active disease, as compared with controls.
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Affiliation(s)
| | - Rocchina Colucci
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Mariella Errede
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Francesco Girolamo
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | - Daniela Virgintino
- Unit of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sensory Organs, School of Medicine, University of Bari, Bari, Italy
| | | | - Erika Tirotta
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | | | | | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine, University of Perugia, Perugia, Italy
| | | | - Corrado Blandizzi
- Division of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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12
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Jairath V, Zou G, Parker CE, Macdonald JK, Mosli MH, Khanna R, Shackelton LM, Vandervoort MK, AlAmeel T, Al Beshir M, AlMadi M, Al-Taweel T, Atkinson NSS, Biswas S, Chapman TP, Dulai PS, Glaire MA, Hoekman D, Koutsoumpas A, Minas E, Samaan MA, Travis S, D’Haens G, Levesque BG, Sandborn WJ, Feagan BG. Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis. J Crohns Colitis 2016; 10:607-18. [PMID: 26746169 PMCID: PMC4957452 DOI: 10.1093/ecco-jcc/jjw004] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 12/14/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. RESULTS In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. CONCLUSIONS Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.
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Affiliation(s)
- Vipul Jairath
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK,Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Guangyong Zou
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - Claire E. Parker
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - John K. Macdonald
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Mahmoud H. Mosli
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada,Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Reena Khanna
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Lisa M. Shackelton
- Robarts Research Institute, University of Western Ontario, London, ON, Canada
| | | | - Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Mohammad Al Beshir
- Department of Medicine, King Fahad Specialist Hospital-Dammam, Dammam, Saudi Arabia
| | - Majid AlMadi
- Division of Gastroenterology, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Talal Al-Taweel
- Haya Al-Habeeb Gastroenterology Center, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait
| | - Nathan S. S. Atkinson
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK
| | - Sujata Biswas
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK
| | - Thomas P. Chapman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK
| | - Parambir S. Dulai
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Mark A. Glaire
- Division of Medical Sciences, University of Oxford, Oxford, UK
| | - Daniel Hoekman
- Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
| | - Andreas Koutsoumpas
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK
| | - Elizabeth Minas
- Department of Geratology, Oxford University Hospitals NHS Trust, Oxford, UK
| | - Mark A. Samaan
- Department of Gastroenterology, Guy’s and St Thomas’ Hospital NHS Trust, London, UK
| | - Simon Travis
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, UK
| | - Geert D’Haens
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
| | - Barrett G. Levesque
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - William J. Sandborn
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
| | - Brian G. Feagan
- Robarts Research Institute, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada,Department of Medicine, University of Western Ontario, London, ON, Canada
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13
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Cintolo M, Costantino G, Pallio S, Fries W. Mucosal healing in inflammatory bowel disease: Maintain or de-escalate therapy. World J Gastrointest Pathophysiol 2016; 7:1-16. [PMID: 26909224 PMCID: PMC4753175 DOI: 10.4291/wjgp.v7.i1.1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 11/16/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
In the past decade, thanks to the introduction of biologic therapies, a new therapeutic goal, mucosal healing (MH), has been introduced. MH is the expression of an arrest of disease progression, resulting in minor hospitalizations, surgeries, and prolonged clinical remission. MH may be achieved with several therapeutic strategies reaching success rates up to 80% for both, ulcerative colitis (UC) and Crohn’s disease (CD). Various scoring systems for UC and for the transmural CD, have been proposed to standardize the definition of MH. Several attempts have been undertaken to de-escalate therapy once MH is achieved, thus, reducing the risk of adverse events. In this review, we analysed the available studies regarding the achievement of MH and the subsequent treatment de-escalation according to disease type and administered therapy, together with non-invasive markers proposed as predictors for relapse. The available data are not encouraging since de-escalation after the achievement of MH is followed by a high number of clinical relapses reaching up to 50% within one year. Unclear is also another question, in case of combination therapies, which drug is more appropriate to stop, in order to guarantee a durable remission. Predictors of unfavourable outcome such as disease extension, perianal disease, or early onset disease appear to be inadequate to foresee behaviour of disease. Further studies are warranted to investigate the role of histologic healing for the further course of disease.
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14
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Jairath V, Khanna R, Zou GY, Stitt L, Mosli M, Vandervoort MK, D'Haens G, Sandborn WJ, Feagan BG, Levesque BG. Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials. Aliment Pharmacol Ther 2015; 42:1200-10. [PMID: 26388424 DOI: 10.1111/apt.13408] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 07/08/2015] [Accepted: 08/28/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. AIM To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. METHODS Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4β7 integrin in patients with UC. RESULTS A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. CONCLUSION Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.
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Affiliation(s)
- V Jairath
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Oxford Clinical Trials Research Unit, Oxford, UK
| | - R Khanna
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada
| | - G Y Zou
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - L Stitt
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada
| | - M Mosli
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada.,Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - M K Vandervoort
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada
| | - G D'Haens
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands
| | - W J Sandborn
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Division of Gastroenterology, University of California, San Diego, La Jolla, CA, USA
| | - B G Feagan
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Department of Medicine, University of Western Ontario, London, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - B G Levesque
- Robarts Clinical Trials, University of Western Ontario, London, ON, Canada.,Division of Gastroenterology, University of California, San Diego, La Jolla, CA, USA
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15
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Abstract
BACKGROUND Many therapeutic options are available for patients with distal forms of ulcerative colitis (UC). Rectal therapies (e.g., suppositories, foams, gels, and enemas) may be recommended either alone or in combination with oral treatment. Compared with oral therapies, rectal therapies are underused in patients with distal forms of UC, although rectal therapies have favorable efficacy and safety profiles. METHODS This systematic review identified 48 articles for inclusion after a comprehensive PubMed search and the identification of additional relevant articles through other sources. Inclusion criteria were clinical studies examining efficacy and safety of 5-aminosalicylic acid, corticosteroid, and non-5-aminosalicylic acid rectal therapies (suppositories, foams, gels, and enemas) that induce or maintain remission in patients with ulcerative proctitis, ulcerative proctosigmoiditis, or left-sided colitis (i.e., distal forms of UC). The quality of the evidence presented was evaluated using the GRADE system. RESULTS Overall, a greater percentage of patients with distal forms of UC receiving 5-aminosalicylic acids or corticosteroid rectal formulations derived greater therapeutic benefit after treatment compared with patients receiving placebo. Furthermore, most uncontrolled studies of rectal therapies reported that patients with distal forms of UC had marked improvement from baseline after treatment. The overall safety profile of rectal therapies was favorable. Treatment with second-generation corticosteroids, such as budesonide and beclomethasone dipropionate, did not increase the incidence of steroid-related adverse effects. CONCLUSIONS The current literature supports the use of rectal therapies for both induction and maintenance of remission in patients with distal forms of UC.
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16
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Peng H, Poovaiah N, Forrester M, Cochran E, Wang Q. Ex Vivo Culture of Primary Intestinal Stem Cells in Collagen Gels and Foams. ACS Biomater Sci Eng 2014; 1:37-42. [DOI: 10.1021/ab500041d] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Haisheng Peng
- Department
of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States
- Department
of Pharmaceutics, Daqing Campus, Harbin Medical University, Daqing 163319, China
| | - Nitya Poovaiah
- Department
of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States
| | - Michael Forrester
- Department
of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States
| | - Eric Cochran
- Department
of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States
| | - Qun Wang
- Department
of Chemical and Biological Engineering, Iowa State University, Ames, Iowa 50011, United States
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17
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Safety and efficacy of sodium hyaluronate (IBD98E) in the induction of clinical and endoscopic remission in subjects with distal ulcerative colitis. Dig Liver Dis 2014; 46:330-4. [PMID: 24462118 DOI: 10.1016/j.dld.2013.12.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Revised: 11/28/2013] [Accepted: 12/04/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Sodium hyaluronate can contribute to the hydration and maintenance of the integrity of the intestinal mucosa. Restoration of the protective layer with sodium hyaluronate may contribute to the induction of remission of active ulcerative colitis. METHODS We investigated the safety and efficacy of sodium hyaluronate enema (IBD98E) in distal active ulcerative colitis, in a prospective, uncontrolled, open-label pilot trial. Subjects with active distal ulcerative colitis (UCDAI ≥ 4 and sigmoidoscopy score ≥ 1) received IBD98E 60 mL enema once a day. Primary endpoints were safety and clinical response rate at Day 28. Secondary endpoints included clinical remission, endoscopic remission, and tolerability of IBD98E. Paired Student's t-test was performed to assess statistically significant differences in subjects between baseline and Day 28. RESULTS Twenty-one subjects were enrolled. The overall safety profile was good; no serious adverse events were recorded. At Day 28, 9 subjects (42.9%) were clinical responders, and 10 subjects (47.6%) had an endoscopic response. Eight subjects (38.1%) achieved clinical remission, and 10 subjects (47.6%) achieved endoscopic remission. The mean average UCDAI score decreased from 6.10 to 3.81 at Day 28 (p=0.001), and average endoscopic score decreased from 1.57 to 1.10 (p=0.004). CONCLUSION IBD98E seems to be safe and effective for the induction of clinical and endoscopic remission. Placebo-controlled studies are warranted.
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18
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Gionchetti P, Praticò C, Rizzello F, Calafiore A, Capozzi N, Campieri M, Calabrese C. The role of Budesonide-MMX in active ulcerative colitis. Expert Rev Gastroenterol Hepatol 2014; 8:215-22. [PMID: 24502535 DOI: 10.1586/17474124.2014.887437] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Traditional corticosteroids represent a well-established and effective treatment for active ulcerative colitis (UC). However, the severity of their systemic side effects, led in recent years to look for new steroid molecules that could reduce them, maximizing the anti-inflammatory activity. Budesonide has been one of the most studied steroid compounds and it has been approved for the treatment of mild to moderate active Crohn's disease (CD). In order to extend the release until the distally located inflammation, budesonide has been coupled with a controlled delivery system, called Multi-Matrix system (MMX), already successfully tested with oral mesalazine for the treatment of distal UC. After in vitro and in vivo models, the efficacy of Budesonide-MMX has been investigated in active UC with a first small phase II study, and partially encouraging results. This article will review the evidences on the use of budesonide in inflammatory bowel diseases and will discuss the role of Budesonide-MMX in active UC nowadays.
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19
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Shiotani A, Kusunoki H, Kimura Y, Ishii M, Imamura H, Tarumi KI, Manabe N, Kamada T, Hata J, Haruma K. S100A expression and interleukin-10 polymorphisms are associated with ulcerative colitis and diarrhea predominant irritable bowel syndrome. Dig Dis Sci 2013; 58:2314-23. [PMID: 23595519 DOI: 10.1007/s10620-013-2677-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 03/27/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Both ulcerative colitis (UC) and diarrhea-predominant irritable bowel syndrome (IBS-D) are associated with alterations in enteric serotonin (5-HT) signaling. AIMS The purpose of this study was to compare the rectal and sigmoid colonic mucosal expression of S100A proteins and functional polymorphisms of the 5-HT transporter (5HTT) and interleukin-10 genes in patients with IBS-D or UC with healthy controls. METHODS mRNA expression of S100 proteins was measured in sigmoid and rectal biopsies and in rectal epithelium isolated by laser-captured microdissection. Leucocyte DNA was analyzed by PCR-based reaction fragment length polymorphisms and direct sequencing. Clinical symptoms were assessed by the self-rating depression scale and by the gastrointestinal symptom rating scale. RESULTS Fifty patients with IBS-D, 56 with UC and 50 healthy controls were studied. Colonic mucosal expression of S100A8 and S100A9 in UC was significantly higher than in IBS or controls and correlated with the UC disease activity index (r = 0.65, p < 0.001). S100A10 expression in the rectal epithelium of the IBS patients was significantly higher (0.643 vs. 0.402, p = 0.01) than in controls and correlated with the SDS scores (r = 0.41, p = 0.002). The frequency of IL10-819 CC genotype was significantly higher in IBS-D (10.7 vs. 0 %, p = 0.047) and UC (16 vs. 0 %, p = 0.007) than that in controls. CONCLUSION Overexpression of S100A10 in the rectum may play a role in IBS as it is involved in modulating 5-HT1B receptors. The IL10-819 CC is a candidate genotype for both IBS and UC in Japanese.
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Affiliation(s)
- Akiko Shiotani
- Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan.
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20
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Allen PB, Kamm MA, Peyrin-Biroulet L, Studd C, McDowell C, Allen BCM, Connell WR, De Cruz PP, Bell SJ, Elliot RP, Brown S, Desmond PV, Lemann M, Colombel JF. Development and validation of a patient-reported disability measurement tool for patients with inflammatory bowel disease. Aliment Pharmacol Ther 2013; 37:438-44. [PMID: 23278192 DOI: 10.1111/apt.12187] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2012] [Revised: 10/16/2012] [Accepted: 11/29/2012] [Indexed: 01/07/2023]
Abstract
BACKGROUND Inflammatory bowel disease can impact on a patient's ability to maintain normal physical and mental function, and fulfil their social, family and work roles. Aspects of disability in IBD have received little attention. AIM To develop, validate and apply a questionnaire directed towards evaluating these disease aspects. METHODS A literature review on disability in IBD was undertaken, and opinion about aspects of disability to measure was sought from six IBD-specialised gastroenterologists. A questionnaire was developed, and IBD patients completed the new disability questionnaire, the SF-36 and the short-IBD (SIBDQ - 10 point). A subgroup of patients completed the questionnaire again 4 weeks later. Healthy volunteers were studied as a control group. RESULTS A total of 116 IBD out-patients were approached, of whom 81 (52 Crohn's disease and 28 ulcerative colitis) participated. Nineteen patients were re-evaluated at 4 weeks. Twenty-five controls were studied. All subscales demonstrated good Cronbach's alpha reliability and reproducibility. There was a significant inverse correlation between the disability score and the SIBDQ and between the disability score and the SF36 and a positive correlation with the Crohn's Disease Activity Index (CDAI) (all P < 0.001). Disability differed between ulcerative colitis and controls, but not between active and inactive disease. CONCLUSIONS The new disability questionnaire is sensitive for detecting disability, is reliable and reproducible, and correlates with disease activity in Crohn's disease, but not ulcerative colitis. Further prospective testing is now needed in the longer term, larger patient populations and in different countries and ethnicities.
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Affiliation(s)
- P B Allen
- St Vincent's Hospital, Melbourne, Australia
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21
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Choi CH, Kim YH, Kim YS, Ye BD, Lee KM, Lee BI, Jung SA, Kim WH, Lee H. [Guidelines for the management of ulcerative colitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2012; 59:118-40. [PMID: 22387836 DOI: 10.4166/kjg.2012.59.2.118] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disorder characterized by a relapsing and remitting course. The quality of life can decreases significantly during exacerbations of the disease. The incidence and prevalence of UC in Korea are still lower than those of Western countries, but have been rapidly increasing during the past decades. Various medical and surgical therapies are currently used for the management of UC. However, many challenging issues exist and sometimes these lead to differences in practice between clinicians. Therefore, Inflammatory Bowel Diseases (IBD) Study Group of Korean Association for the Study of Intestinal Diseases (KASID) set out the Korean guidelines for the management of UC. These guidelines are made by the adaptation using several foreign guidelines and encompass treatment of active colitis, maintenance of remission and indication for surgery in UC. The specific recommendations are presented with the quality of evidence. These are the first Korean treatment guidelines for UC and will be revised with new evidences on treatment of UC.
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Affiliation(s)
- Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Korea
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22
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Lichtenstein GR, Zakko S, Gordon GL, Murthy U, Sedghi S, Pruitt R, Merchant K, Bortey E, Forbes WP. Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials. Aliment Pharmacol Ther 2012; 36:126-34. [PMID: 22617015 DOI: 10.1111/j.1365-2036.2012.05142.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 12/30/2011] [Accepted: 05/01/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. AIM To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. METHODS Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. RESULTS Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P < 0.001). Rectal bleeding, stool frequency and the physician's rating of disease activity remained unchanged after 6 months in a higher percentage of patients using MG compared with those on placebo (P < 0.004 for each endpoint). CONCLUSION Mesalazine granules 1.5 g once-daily is effective for maintenance of remission in UC patients who switch from other 5-ASA formulations. ClinicalTrials.gov identifiers NCT00744016, NCT00767728.
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Affiliation(s)
- G R Lichtenstein
- Gastroenterology Division, Department of Medicine, University of Pennsylvania, Philadelphia, USA
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23
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Marshall JK, Thabane M, Steinhart AH, Newman JR, Anand A, Irvine EJ. Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2010:CD004115. [PMID: 20091560 DOI: 10.1002/14651858.cd004115.pub2] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND 5-Aminosalicylates (5-ASA) are considered a first-line therapy for inducing and maintaining remission of mild to moderately active ulcerative colitis (UC). When inflammation in UC is limited to the distal colon, 5-ASA can also be administered rectally as a suppository, enema or foam. OBJECTIVES A systematic review was undertaken to evaluate the efficacy of rectal 5-ASA for treating active distal UC. SEARCH STRATEGY Electronic searches of the MEDLINE database (1966-2008), the Cochrane Central Register of Controlled Trials and the Cochrane IBD/FBD Group Specialized Trials Register were supplemented by manual reviews of reference listings and conference proceedings. SELECTION CRITERIA Randomized trials comparing rectal 5-ASA to placebo or another active therapy were eligible for inclusion. Eligible trials enrolled patients with a distal disease margin less than 60 cm from the anal verge or distal to the splenic flexure. Trials that enrolled subjects less than 12 years of age were excluded. DATA COLLECTION AND ANALYSIS Eligibility was assessed by three authors. Data were extracted by two authors using standardized forms. Pooled odds ratios (POR) for inducing improvement and remission by symptomatic, endoscopic and histologic criteria were calculated using an intention to treat principle. Fixed effects models were used unless heterogeneity was encountered within groups (P < 0.10), where random effects models were used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, subgroup analyses were performed for disease extent, total daily 5-ASA dose, 5-ASA formulation (enema,suppository, foam) and the type of control intervention (placebo or another active therapy). MAIN RESULTS Thirty-eight studies fulfilled the inclusion criteria. Rectal 5-ASA was superior to placebo for inducing symptomatic, endoscopic and histological improvement and remission, with POR for symptomatic improvement 8.87 (8 trials, 95% CI: 5.30 to 14.83; P < 0.00001), endoscopic improvement 11.18 (5 trials, 95% CI 5.99 to 20.88; P < 0.00001), histologic improvement 7.69 (6 trials, 95% CI 3.26 to 18.12; P < 0.00001), symptomatic remission 8.30 (8 trials, 95% CI 4.28 to 16.12; P < 0.00001), endoscopic remission 5.31 (7 trials, 95% CI 3.15 to 8.92; P < 0.00001), and histologic remission 6.28 (5 trials, 95% CI 2.74 to 14.40; P < 0.0001). Rectal 5-ASA was superior to rectal corticosteroids for inducing symptomatic improvement and remission with POR 1.56 (6 trials, 95% CI 1.15 to 2.11; P = 0.004) and 1.65 (6 trials, 95% CI 1.11 to 2.45; P = 0.01), respectively. Rectal 5-ASA was not superior to oral 5-ASA for symptomatic improvement (POR 2.25; 95% CI 0.53 to 19.54; P = 0.27). Neither total daily dose nor 5-ASA formulation affected treatment response. AUTHORS' CONCLUSIONS Rectal 5-ASA should be considered a first-line therapy for patients with mild to moderately active distal UC. The optimal total daily dose and dose frequency of 5-ASA remain to be determined. Future research should define differences in efficacy among patient subgroups defined by proximal disease margin and disease activity. There is a strong need for consensus standardization of outcome measurements for clinical trials in ulcerative colitis.
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Affiliation(s)
- John K Marshall
- Division of Gastroenterology, McMaster University, 1200 Main Street 2F59, Hamilton, Ontario, Canada, L8N 3Z5
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24
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Garud S, Brown A, Cheifetz A, Levitan EB, Kelly CP. Meta-analysis of the placebo response in ulcerative colitis. Dig Dis Sci 2008; 53:875-91. [PMID: 17934839 DOI: 10.1007/s10620-007-9954-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Accepted: 07/24/2007] [Indexed: 12/14/2022]
Abstract
PURPOSE The placebo response rate in randomized controlled trials (RCTs) in ulcerative colitis (UC) varies from 0 to 76%. The aims of this study were to quantify the pooled placebo response rate and identify the factors affecting it. METHODS We performed a meta-analysis of 110 RCTs carried out between 1955 and 2005 and published in English. Regression analysis was used to identify factors significantly modifying placebo response. RESULTS The pooled placebo remission rate was 23% (95%CI: 18.4-28%) and the pooled placebo improvement rate was 32.1% (95%CI: 28.1-36.3%). Multivariate analysis showed that the country where the study was performed (P = 0.025 for placebo remission and P = 0.0083 for placebo response rates) significantly influenced the placebo remission and response rates. CONCLUSION Placebo remission and response rates in RCTs of UC are highly variable and are significantly influenced by the country in which the RCT is performed.
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Affiliation(s)
- Sagar Garud
- Department of Medicine, Beth Israel Deaconess Medical Center, 300 Deaconess Building, 1 Deaconess Road, Boston, MA 02215, USA.
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25
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Travis SPL, Stange EF, Lémann M, Oresland T, Bemelman WA, Chowers Y, Colombel JF, D'Haens G, Ghosh S, Marteau P, Kruis W, Mortensen NJM, Penninckx F, Gassull M. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis 2008; 2:24-62. [PMID: 21172195 DOI: 10.1016/j.crohns.2007.11.002] [Citation(s) in RCA: 402] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Accepted: 11/23/2007] [Indexed: 02/08/2023]
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26
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Lewis JD, Lichtenstein GR, Deren JJ, Sands BE, Hanauer SB, Katz JA, Lashner B, Present DH, Chuai S, Ellenberg JH, Nessel L, Wu GD. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology 2008; 134:688-95. [PMID: 18325386 PMCID: PMC2276587 DOI: 10.1053/j.gastro.2007.12.012] [Citation(s) in RCA: 169] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2007] [Accepted: 11/29/2007] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Thiazolidinedione ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARgamma), widely used to treat type 2 diabetes mellitus, have been proposed as novel therapies for ulcerative colitis (UC). METHODS This multicenter, randomized, double-blind, placebo-controlled clinical trial compared the efficacy of rosiglitazone (Avandia; GlaxoSmithKline, Philadelphia, PA) 4 mg orally twice daily vs placebo twice daily for 12 weeks in 105 patients with mild to moderately active UC. Disease activity was measured with the Mayo score. The primary end point was clinical response (>/=2-point reduction) at week 12. Clinical remission (Mayo score </=2), endoscopic remission, and quality of life were secondary outcomes. RESULTS After 12 weeks of therapy, 23 patients (44%) treated with rosiglitazone and 12 patients (23%) treated with placebo achieved clinical response (P = .04). Remission was achieved in 9 patients (17%) treated with rosiglitazone and 1 patient (2%) treated with placebo (P = .01). Endoscopic remission was uncommon in either treatment arm (8% rosiglitazone vs 2% placebo; P = .34). Clinical improvement was evident as early as 4 weeks after beginning treatment (P = .049). Quality of life was improved significantly at week 8 (P = .01), but not at week 4 (P = .48) or week 12 (P = .14). Serious adverse events were rare. CONCLUSIONS Rosiglitazone was efficacious in the treatment of mild to moderately active UC.
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Affiliation(s)
- James D. Lewis
- Division of Gastroenterology, University of Pennsylvania School of Medicine Philadelphia, PA,Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine Philadelphia, PA
| | - Gary R. Lichtenstein
- Division of Gastroenterology, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, PA
| | - Julius J Deren
- Division of Gastroenterology, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, PA
| | | | | | | | | | | | - Shaokun Chuai
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine Philadelphia, PA
| | - Jonas H. Ellenberg
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine Philadelphia, PA
| | - Lisa Nessel
- Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine Philadelphia, PA
| | - Gary D. Wu
- Division of Gastroenterology, University of Pennsylvania School of Medicine Philadelphia, PA,Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, PA
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27
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Su C, Lewis JD, Goldberg B, Brensinger C, Lichtenstein GR. A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis. Gastroenterology 2007; 132:516-26. [PMID: 17258720 DOI: 10.1053/j.gastro.2006.12.037] [Citation(s) in RCA: 97] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2006] [Accepted: 10/31/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. METHODS We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. RESULTS Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%-18%; range, 0%-40%; median, 12%) and 28% (95% confidence interval, 23%-33%; range, 0%-67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. CONCLUSIONS Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC.
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Affiliation(s)
- Chinyu Su
- Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania and University of Pennsylvania Presbyterian Medical Center, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
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28
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Lepage P, Seksik P, Sutren M, de la Cochetière MF, Jian R, Marteau P, Doré J. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD. Inflamm Bowel Dis 2005; 11:473-80. [PMID: 15867587 DOI: 10.1097/01.mib.0000159662.62651.06] [Citation(s) in RCA: 189] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The mucosa-associated microbiota, being very close to the inflammatory process associated with inflammatory bowel disease (IBD), may have a pathogenic role. We used a culture-independent method to analyze the mucosa-associated microbiota in IBD patients at various points of the distal digestive tract. METHODS Thirty-five patients (20 with Crohn's disease, 11 with ulcerative colitis, and 4 controls) underwent colonoscopy. Biopsies (n = 126) were taken from 4 sites: the ileum, right colon, left colon, and rectum. Fecal samples were also obtained from 7 individuals. Temporal temperature gradient gel electrophoresis (TTGE) of 16S rDNA was used to evaluate dominant species diversity. TTGE profiles were compared using software that measures the degree of similarity. RESULTS In a given individual, the overall similarity percentage between the 4 segments of the distal digestive tract was 94.7 +/- 4.0%, regardless of clinical status. The average similarity of all profiles for a given segment was 59.3 +/- 18.3% in the overall population. Dendrogram analysis showed that TTGE profiles did not cluster with clinical status. Differences were observed between the dominant fecal microbiota and the mucosa-associated microbiota of all 4 sites, with similarity percentages less than 92%. CONCLUSIONS These results confirm that the dominant species differ between the mucosa-associated and fecal microbiota. They also show that, in a given individual, the microbiota is relatively stable along the distal digestive tract, showing a slight evolution in dominant species diversity from the ileum to the rectum, in both healthy subjects and patients with IBD.
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Affiliation(s)
- Patricia Lepage
- National Institute for Agromonic Research, Digestive Tract Ecology and Physiology Unit, Research Center, Jouy en Josas, France
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29
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Reimund JM, Bonaz B, Gompel M, Michot F, Moreau J, Veyrac M, Wagner Ballon J. [Induction and maintenance of remission in ulcerative colitis]. ACTA ACUST UNITED AC 2005; 28:992-1004. [PMID: 15672571 DOI: 10.1016/s0399-8320(04)95177-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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30
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Marteau P, Beaugerie L, Bouhnik Y, Flourié B, Gambiez L, Reimund JM, Seksik P. [Introduction of the evidence]. ACTA ACUST UNITED AC 2005; 28:961-3. [PMID: 15672567 DOI: 10.1016/s0399-8320(04)95173-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Philippe Marteau
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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31
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Seksik P, Contou JF, Ducrotté P, Faucheron JL, de Parades V. [The treatment of distal ulcerative colitis]. ACTA ACUST UNITED AC 2005; 28:964-73. [PMID: 15672568 DOI: 10.1016/s0399-8320(04)95174-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Philippe Seksik
- Service d'hépato-gastroentérologie, Hôpital Européen Georges Pompidou, 75015 Paris
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32
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Godeberge P. [Management of idiopathic proctitis]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2004; 28:D70-4. [PMID: 15213666 DOI: 10.1016/s0399-8320(04)94990-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Affiliation(s)
- Philippe Godeberge
- Département Médico-Chirurgical de Pathologie Digestive, Institut Mutualiste Montsouris, 42, Boulevard Jourdan, 75014 Paris
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33
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Su C, Salzberg BA, Lewis JD, Deren JJ, Kornbluth A, Katzka DA, Stein RB, Adler DR, Lichtenstein GR. Efficacy of anti-tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002; 97:2577-84. [PMID: 12385442 DOI: 10.1111/j.1572-0241.2002.06026.x] [Citation(s) in RCA: 134] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory bowel disease. The monoclonal antibody to TNF-alpha, infliximab, is effective in treating Crohn's disease. Preclinical studies suggest the importance of TNF-alpha in treating ulcerative colitis (UC). We report the effectiveness of infliximab for UC and examine factors predictive of response to medication. METHODS Data from all UC patients receiving infliximab at four institutions were analyzed. Disease activity was determined by the Disease Activity Index. RESULTS A total of 27 patients with active UC received inpatient (37%) and outpatient (63%) infliximab as single (52%) or multiple (two to 15) infusions (48%). Twelve patients (44%) achieved remission and six patients (22%) had partial response. Nine patients had no response; five subsequently underwent total colectomy. The median time to achieve response and remission was 4 days and the median duration 8 wk. Nine of the 18 patients who responded experienced 19 relapses; 18 of these relapses (95%) were successfully treated with repeat infusions. Steroid-refractory patients were less likely to respond to infliximab therapy than were steroid-responsive patients (33% vs 83%; p = 0.026). No other factors were predictive of response to infliximab. Two patients developed serious adverse events, including death in one case. CONCLUSIONS Preliminary evidence suggest effectiveness of infliximab in the treatment of UC, including medically refractory severe disease. Individuals who are refractory to corticosteroids, however, may be unlikely to respond to infliximab. A randomized controlled trial is necessary to further investigate the efficacy of infliximab in patients with UC.
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Affiliation(s)
- Chinyu Su
- Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-4283, USA
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34
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Banerjee S, Peppercorn MA. Inflammatory bowel disease. Medical therapy of specific clinical presentations. Gastroenterol Clin North Am 2002; 31:185-202, x. [PMID: 12122731 DOI: 10.1016/s0889-8553(01)00012-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ulcerative colitis and Crohn's disease are chronic relapsing inflammatory disorders of the gastrointestinal tracts. The inflammatory process is restricted to the mucosa and submucosa of the colon in ulcerative colitis and is transmural and may occur anywhere in the gastrointestinal tract in Crohn's disease. Clinical presentation of these inflammatory disorders depends on the segments of digestive tract affected and on the extent and aggressiveness of the disease process. The treatment of specific clinical presentations of these disorders is discussed in this article.
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Affiliation(s)
- Subhas Banerjee
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
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35
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Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt F, Furth EE, Demissie EJ, Hurd LB, Su CG, Keilbaugh SA, Lazar MA, Wu GD. An open-label trial of the PPAR-gamma ligand rosiglitazone for active ulcerative colitis. Am J Gastroenterol 2001; 96:3323-8. [PMID: 11774944 DOI: 10.1111/j.1572-0241.2001.05333.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Previous research has demonstrated that ligands for the gamma subtype of peroxisome proliferator-activated receptors (PPARs) reduce inflammation in two different murine models of colitis. This study was designed to examine the potential efficacy of rosiglitazone, a ligand for the gamma subtype of PPARs, as a therapy for active ulcerative colitis. METHODS Fifteen patients with mild to moderately active ulcerative colitis despite therapy with 5-aminosalicylic acid compounds were enrolled in an open-label study of rosiglitazone (4 mg b.i.d. p.o.) for 12 wk. Thirteen of 15 patients were receiving concomitant therapy with corticosteroids and/or immunomodulator medications. Disease activity was measured with the Disease Activity Index. RESULTS After 12 wk of therapy, four patients (27%) had achieved clinical remission, of whom three (20%) also had an endoscopic remission. Four additional patients (27%) had a clinical response without achieving remission. Two patients were hospitalized with worsened disease activity, and one patient was withdrawn for nephrotic syndrome. CONCLUSIONS These data suggest that ligands for the gamma subtype of PPARs may represent a novel therapy for ulcerative colitis. A double blind, placebo-controlled, randomized trial is warranted.
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Affiliation(s)
- J D Lewis
- Division of Gastroenterology, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA
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Cohen RD, Woseth DM, Thisted RA, Hanauer SB. A meta-analysis and overview of the literature on treatment options for left-sided ulcerative colitis and ulcerative proctitis. Am J Gastroenterol 2000; 95:1263-76. [PMID: 10811338 DOI: 10.1111/j.1572-0241.2000.01940.x] [Citation(s) in RCA: 166] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Therapeutic trials in left-sided ulcerative colitis (L-UC) and ulcerative proctitis (UP) have lacked control for medication type, dose, delivery, and duration of therapy. METHODS All published therapeutic articles and abstracts in L-UC or UP from 1958-1997 were reviewed. Improvement, remission rates, and adverse events were recorded for all (ALL), placebo-controlled (PC) studies, and for PC studies passing quality assessment (QA) scoring. Meta-analysis was used where appropriate. RESULTS Left-sided UC: For active disease, 67 studies (17 PC; 10 QA) were identified. Mesalamine enemas achieved remission in a duration but not a dose response (QA), with higher remission rates than steroid enemas (ALL) and clinical improvement rates superior to oral therapies (QA, ALL). Remission maintenance: 17 (six PC, six QA) studies were identified. Mesalamine therapies had comparable remission rates at 6 months, with a possible dose but not delivery effect. Mesalamine enema dosing intervals between QHS to Q3 days maintained efficacy. Reported adverse events were most common with oral sulfasalazine and dose-independent for mesalamine. Withdrawals from therapy were less than placebo, or < or =3%. Ulcerative proctitis: For active disease, 18 (nine PC, three QA) studies were identified. Mesalamine suppositories achieved clinical improvement and remission in a duration but not dose response, with higher rates of remission than topical steroids (ALL). Remission maintenance: three (three PC, two QA) studies were identified. Remission ranged from 75% to 90% (6 months) and 61-90% (12 months) for mesalamine agents. Reported adverse events were most common for mesalamine foam (8%). Withdrawals from therapy were <2%. CONCLUSIONS In L-UC and UP, the efficacy and side-effect profile of topical mesalamine are dose independent and superior to oral therapies and topical steroids. Economic analysis suggests that use of these agents will also result in an overall decrease in patient costs.
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Affiliation(s)
- R D Cohen
- Department of Medicine, University of Chicago Medical Center, Pritzker School of Medicine, University of Chicago, Illinois 60637, USA
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Abstract
A pluridisciplinary approach that integrates medical therapy with surgery and other aspects of patient care, such as nutritional and psychosocial support, is essential to the management of patients with inflammatory bowel disease (IBD). Despite new medical therapies, such as 5-amino-salicylic acid compounds, steroids, and immunomodulators, the treatment of patients with IBD remains challenging. Success depends on the appropriate use of the available medications in relation to the severity and localization of the disease. The introduction of novel immunomodulating agents such as antitumor necrosis factor alpha is likely to have a major influence on the current therapeutic strategies. This article describes the use of the available medications in the most common clinical presentations of IBD.
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Affiliation(s)
- P Michetti
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Scheppach W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebo-controlled trial. German-Austrian SCFA Study Group. Dig Dis Sci 1996; 41:2254-9. [PMID: 8943981 DOI: 10.1007/bf02071409] [Citation(s) in RCA: 132] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Rectal enemas containing a short-chain fatty acid mixture, butyrate alone, or saline placebo were administered to 47 patients with active distal ulcerative colitis. Enemas were instilled twice daily and the patients' condition was evaluated at entry and after four and eight weeks of local therapy. A disease activity index, chosen as the major end point, decreased significantly after all three modes of treatment with no difference among groups. The endoscopic appearance of the mucosa and the histologic degree of inflammation was not different among groups. After eight weeks, fewer colonic segments were affected endoscopically following butyrate than placebo treatment. This study showed trends towards a beneficial effect of topical short-chain fatty acids in active ulcerative colitis, but more patients are needed to demonstrate this effect with sufficient statistical power.
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Affiliation(s)
- W Scheppach
- Department of Medicine, University of Würzburg, Germany
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Brogden RN, Sorkin EM. Mesalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in chronic inflammatory bowel disease. Drugs 1989; 38:500-23. [PMID: 2684592 DOI: 10.2165/00003495-198938040-00003] [Citation(s) in RCA: 61] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Mesalazine (5-aminosalicylic acid; mesalamine), the active moiety of sulphasalazine (salazosulfapyridine), is available in specially formulated oral and rectal forms for the treatment of active ulcerative colitis of mild to moderate severity and for maintenance therapy during disease remission. Tablets or capsules coated with acrylic-based resin and tablets containing microgranules coated with ethylcellulose deliver mesalazine to the distal small intestine and colon, thus avoiding the need for the carrier, sulphapyridine, which is responsible for many of the adverse effects associated with sulphasalazine. Since mesalazine is released in the small intestine from some coated preparations in contrast to sulphasalazine, these oral formulations have therapeutic potential in Crohn's disease. A limited number of therapeutic trials suggest that orally administered mesalazine 1.5 to 2.4g daily is of similar efficacy to sulphasalazine 2 to 3g daily in patients with mild to moderate ulcerative colitis. The efficacy of mesalazine enemas has been more widely investigated, a dose of 1 to 4g once daily being consistently more effective than placebo and apparently similar to enemas of prednisone 25mg or oral sulphasalazine 3g. Initial results suggest that mesalazine 4g enemas may be more effective than those containing hydrocortisone 100mg. Mesalazine and sulphasalazine in approximately equivalent oral dosages are similarly effective in maintaining remission in ulcerative colitis. Orally administered coated mesalazine is generally well tolerated by about 85% of patients allergic to or intolerant of sulphasalazine, the remainder experiencing similar reactions to both drugs. Adverse effects of mesalazine enemas are confined to local irritation and effects resulting from enema-tip insertion. Thus, orally administered coated mesalazine is a suitable alternative to sulphasalazine in the treatment of patients with mild to moderate active distal ulcerative colitis and for maintaining remission particularly in patients allergic to or intolerant of sulphasalazine. In patients who find enema therapy acceptable, mesalazine enemas are effective and well tolerated.
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Affiliation(s)
- R N Brogden
- ADIS Drug Information Services, Auckland, New Zealand
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