Aminosalicylates. Giovanni Barbara. Department of Medical and Surgical Sciences Alma Mater Studiorum, University of Bologna, Italy ( )

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1 Aminosalicylates Giovanni Barbara Department of Medical and Surgical Sciences Alma Mater Studiorum, University of Bologna, Italy ( )

2 Colonic Diverticula, a Painless Ageing Change? 20% develop symptoms or complications Parks et al, Br Med J 1969;4:639-45

3 Long Term Risk of Acute Diverticulitis Among 2222 Patients With Diverticulosis 4.3 developed diverticulitis over 11 years Shahedi K et al., Clin Gastroenterol Hepatol 2013;11:

4 Acute Diverticulitis is the Third Most Common Inpatient GI Diagnosis in USA Peery AF et al., Gastroenterology 2012;143:

5 Microbiota, Inflammation and Diverticular Disease colonic pouch Fecal entrapment Bacterial translocation Mucosal inflammation ENS Smooth Muscle

6 Macrophage counts (% over lamina propria area) Macrophages in Symptomatic Diverticular Disease Distant site Diverticular region *P<0.05 vs HC **P<0.001 vs HC 10 8 * ** * ** Distant site Diverticular HC Div. SUDD Cremon C et al., Gastroenterology 2015;148 (Suppl 1):S38

7 Mast cell counts (% over lamina propria area) % mastociti/ area lamina propria Mast Cells in Symptomatic Diverticular Disease 88 D *P<0.05 D 66 * HC IBS No IBS 0 IBS NON-IBS SUDD Cremon C et al., Gastroenterology 2015;148 (Suppl 1):S38

8 Inflammation and Diverticular Disease MACROSCOPIC MICROSCOPIC Acute Mild SUDD IBS Control Diverticulitis The clinical scenariors characterized by colonic inflammation are multiple and include complicated and uncomplicated acute diverticulitis, SUDD and post-diverticulitis IBS These scenarios change over time and may shift from one to the other

9 Mesalazine Mechanism of Action Anti-inflammatory mechanisms exerted through the activation of the PPAR-g receptor and inhibition of NF-kB pathway Inhibition of production of proinflammatory cytokines (eg, IL-1, TNF-a) Inhibition of COX, TX, PAF, LT and free radical production Desreumaux P and Gosh S Aliment Pharmacol Ther 2006;24:S1:2-9 Barbara G et al., Dig Dis 2009;27S1:115-21

10 Antimicrobial effect of Mesalazine Andrew CN et al., Aliment Pharmacol Ther 2011; 34:

11 Top 5 Reasons Why is Difficult Interpret the Current Literature on Diverticular Disease 1. Sample heterogeneity 2. Huge number of outcomes 3. Small sample size 4. Low number of events 5. Numerous therapies often used in combination and open design Maconi G et al., Dis Colon Rectum 2011;54:

12 Primary Prevention 6.3 years follow up Diverticulosis Diverticulosis 5-ASA Five randomized open label trials in > 400 patients Diverticulitis Mesalazine alone or in combination with probiotics vs. probiotics alone did not show significant differences among treatments However, the number of diverticulitis episodes was limited (year incidence 2%) Tursi A et al., Aliment Pharmacol Ther 2015;42:664-84

13 Secondary Prevention previous current 6.3 years follow up Diverticulitis Remission 5-ASA Remission Data from 7 double blind, placebo controlled studies Dose range: 0.8 g (for 10 days/month) to 4.8 g daily Most trials failed to find significant differences between mesalazine and placebo However, mesalazine was found to be better than placebo in reducing abdominal symptoms (DIVA trial: P=0.045; DIV/4 trial P=0.021) Diverticulitis Tursi A et al., Aliment Pharmacol Ther 2015;42:664-84

14 Mesalazine in the Prevention of Recurrent Diverticulitis (PREVENT1 & PREVENT2) Multicenter double blind, phase 3, placebo controlled study 590 patients (PREVENT1) and 592 patients (PREVENT2) with >1 episodes of acute diverticulitis in the previous 24 months Randomly assigned to 4 treatment arms Mesalazine (1.2 g/day) Mesalazine (2.4 g/day) Mesalazine (4.8 g/day) Group P (placebo) Follwed for 2 years Primary endpoint was the recurrence of diverticulitis (surgery and or CT scan proven recurrence) Raskin JB, Kamm MA et al., Gastroenterology 2014;147:

15 Mesalazine in the Prevention of Recurrent Diverticulitis (PREVENT1 & PREVENT2) 80 PREVENT1 - % patients without recurrence at week P=0.047 * Placebo Mesalamine 1.2 g/d Mesalamine 2.4 g/d Mesalamine 4.8 g/d Raskin JB, Kamm MA et al., Gastroenterology 2014;147:

16 AGA Technical Review on the Management of Acute Diverticulitis Strate LL, et al. Gastroenterology 2015;149:

17 Mesalazine and SUUD

18 RCT of Mesalazine in Maintaining Remission in Symptomatic Uncomplicated Diverticular Disease Multicenter double blind, placebo controlled study 210 patients randomly enrolled and assigned to 4 treatment arms Group M (mesalazine 1.6 g/day plus L. casei) Group L (L. casei 24 billion/day) Group LM (L. casei plus mesalazine) Group P (placebo) Treatment for 10 days/month for 12 months Recurrence of SUDD was defined as the reappearance of abdominal pain during follow-up Tursi A et al., Aliment Pharmacol Ther 2013;38:741-51

19 Symptomatic Uncomplicated Diverticular Disease RCT of Mesalazine in Maintaining Remission Mesalazine + L.casei (0%) Mesalazine (13%) L.Casei (14%) Placebo (46%) Tursi A et al., Aliment Pharmacol Ther 2013;38:741-51

20 RCT of Mesalazine in SUDD Double blind, placebo controlled, multicenter, 6- weeks 123 patients randomized to receive Mesalazine 1 g tid Placebo Primary efficacy endpoint was change in lower abdominal pain to week 4 Kruis W et al., Aliment Pharmacol Ther 2013;37:680-90

21 RCT of Mesalazine in SUDD Abdominal Pain Reduction with Mesalazine or Placebo Median change in abdominal pain with mesalazine versus placebo was not significant in the ITT analysis and borderline significant in the PP analysis Kruis W et al., Aliment Pharmacol Ther 2013;37:680-90

22 Conclusions Recommendations from several recent consensus conference reports, guidelines and technical reviews indicate that: There is some, although limited evidence suggesting that mesalazine may improve symptoms in patients with symptomatic uncomplicated diverticular disease There is no adequate evidence to recommend mesalazine treatment in the prevention of diverticulitis recurrence Cuomo R et al; United European Gastroenterol J. 2014;2: Tursi A et al; Aliment Pharmacol Ther 2015;42: Strate L et al., Gastroenterology 2015;149:

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