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Literature Review

Literature Review. Peter R. McNally, DO, FACP, FACG University Colorado at Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045. Miehlke S, Madisch A, Bethke B, Morgner A, et al.

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Literature Review

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  1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado at Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

  2. Miehlke S, Madisch A, Bethke B, Morgner A, et al. Oral Budesonide for Maintenance Treatment of Collagenous Colitis: A Randomized, Double-Blind, Placebo-Controlled Trial. Gastroenterology. 2008;135:1510-1516. Dresden, Germany

  3. Introduction • Collagenous colitis is an idiopathic disorder characterized by chronic diarrhea, a normal macroscopic colonoscopy, but characteristic mucosal changes on biopsy. • Incidence “microscopic colitis” 8.6 per 100,000 in US 1985-2001 with secular ↑ 20 per 100,000 @ 2001 • ♀ >> ♂ (ratio 2-4:1) • Incidence increases with age, arthritis, autoimmune disorders, celiac disease and use of NSAID’s Schiller LR. Diagnosis and management of microscopic colitis syndrome. J Clin Gastroenterol. 2004;38(5 Suppl):S27-30. Pardi DS, Loftus EV, Smyrk TC, et al. The epidemiology of microscopic colitis: a population based study in Olmsted County, Minnesota. Gut. 2007;56:504-8.

  4. Introduction Collagenous colitis: thickened sub-epithelial collagen band > 10 μm (normal 0-3 μm). Note: the diameter of an RBC is 6–8 µm. • Collagenous Colitis Treatment • Acute: • Anti-diarrheal agents are helpful for 1/3 of patients. • Bismuth subsalicylate and 5-aminoslaysilates benefit some. • Budesonide is effective acute treatment. • Chronic: • No medical treatment has been tested for safety or efficacy in maintenance trials Courtesy, Leslie Sobin, MD. Armed Forces Institute Pathology. Wash, DC. Chande N, McDonald JW, MacDonald JK. Interventions for treating collagenous colitis. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003575

  5. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Aim To evaluate the efficacy of long-term maintenance therapy with oral budesonide (Entocort CIR capsules, AstraZeneca, Lund, Sweden) for maintenance of clinical remission of collagenous colitis, including effects on histology and HRQOL.

  6. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Study Design: Study Population • Enrollment from 38 centers in Germany • Men and women > 18 yrs • Symptomatic and biopsy proven collagenous colitis • Inclusion Criteria • > 3 watery/loose stool per day • (> 4 of 7 previous days) • Diarrhea symptoms > 4 weeks duration • Exclusion Criteria • Infectious cause for diarrhea • Inflammatory Bowel Disease, Celiac disease, Malignancy • Prior Large bowel surgery • Current Rx: 5-ASA, NSAIDs, >165mg ASA/day • Alcohol/drug abuse or Pregnancy

  7. Study Design Open-Label Induction Phase Double-Blind Maintenance Phase Budesonide (B) 6mg/d for 6 mo Collagenous colitis + Diarrhea Budesonide (B) 9mg/d for 6 weeks Clinical Remission Placebo (P) 6mg/d for 6 mo

  8. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Study Design • Primary End Point: Relapse Rate @ T 6wk & 6 mo • Definition of Relapse: > 3 stools/day on 4 consecutive days • Secondary End Points • Time to relapse • Proportion of patients in remission • Time 6wk, 2, 4, 6 mo • HRQOL outcomes • ∆ Histology

  9. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Study Tools • Health Related Quality of Life(HRQOL) SF-36 • 4 physical health domains (controls > 50.2) • 4 mental health domains (controls > 51.2) • Measurements taken @ T0, 6wk, 2,4,6 mo • Short Inflammatory Bowel Disease Questionaire (sIBDQ) • Safety Assessments (Global Tolerability) • “Very Good,” “Good,” “Moderate,” or “Bad”

  10. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Colonoscopy & Histology Evaluations Colonoscopy and biopsy Time 0 n = 48 Time 6 mo n = 25 (17B, 8P) Only if in remission Histology Evaluation Measurement of subepithelial collagen band Inflammation: absent, mild, moderate, severe Degeneration surface epithelium: absent or present Trichrome stain, blue band of thickened sub-epithelial collagen and mild lympocytic inflammation. Courtesy, Shalini Tayal, MD. Denver Health Med Center. Denver, CO .

  11. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Flow of Patients Through Study

  12. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Demographics & Clinical Characteristics

  13. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Results • HRQOL SF-36 Scores • SF-36 T0 Study Pts Control • Physical domain 39.5 50.2 p<0.05 • Mental Domain 44.1 51.2 p<0.05 • SF-36 T6wk Rx Study Pts = Control

  14. Results: Kaplan-Meier curves of patients with relapse of collagenous colitis during maintenance therapy with Budesonide or Placebo P = .022 Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

  15. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Results: Histologic Findings

  16. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Results: Proportion of patients in clinical remission on maintenance budesonide or placebo P=.007 P=.017 P=.008 % In Remission

  17. Adverse Events

  18. Adverse Events

  19. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Conclusions: • Budesonide 9 mg daily for 6 weeks was effective in inducing remission (46/48, 98%) in most patients with collagenous colitis. • Budesonide 6 mg daily for 6 months was effective in maintaining remission. Clinical relapse rates were much lower in the budesonide group compared to placebo 6/23 (26%) vs. 15/23 (65%), respectfully.

  20. Conclusions: No serious side effects occurred during maintenance treatment with budesonide. Tolerability of budesonide was considered “very good” or “good” in 61% at 6 month. Long term maintenance (6 mo) therapy with budesonide (Entorcort CIR capsules) was well tolerated and prevented clinical relapse in 75% of patients with collagenous colitis. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516.

  21. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Reviewer Comments Dr. Miehlke and colleagues have shown: • Acute treatment with budesonide 9 mg daily is effective in Collagenous Colitis, n= 46/48 or 98% response. • Chronic (6 mo) maintenance with budesonide 6 mg daily is superior to placebo by clinical symptoms and QOL, with 80% vs. 20% (B vs. P) remission at 6 months. • Chronic (6 mo) budesonide is safe and “well” tolerated by most patients with Collagenous Colitis.

  22. Miehlke S, et al. Gastroenterology. 2008;135:1510-1516. Reviewer Comments Miehlke, et al, do not answer the following questions? • Why histologic improvement in inflammation is seen just a commonly in placebo as budesonide treatment groups? • What is the inciting factor of this disorder? • What is the natural history of collagenous colitis? • Does duration of disease impact acute and durable long term response to budesonide?

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