Preventing Diverticulitis Recurrence by Selecting the Right Therapy for a Complex Disease
2014; Elsevier BV; Volume: 147; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2014.08.022
ISSN1528-0012
Autores Tópico(s)Urinary and Genital Oncology Studies
ResumoSee “Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials,” by Raskin JB, Kamm MA, Jamal MM, et al, on page 793.Diverticulosis of the colon is an anatomic alteration commonly found in those residing in developed countries, slightly more frequent in the United States than in Europe.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar Diverticulitis is the most common complication of diverticulosis: The majority of patients suffer from an “uncomplicated” form of the disease, generally undergoing outpatient medical management, whereas the “complicated” form is generally managed with inpatient medical-surgical treatment.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar It has been thought that diverticulitis affects ≤15% of patients with symptomatic diverticular disease.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar However, a colonoscopy-based study hypothesized that the actual rate of diverticulitis occurrence is lower, occurring in only 5% of patients harboring simple diverticulosis.2Shahedi K. Fuller G. Bolus R. et al.Long-term risk of acute diverticulitis among patients with incidental diverticulosis found during colonoscopy.Clin Gastroenterol Hepatol. 2013; 11: 1609-1613Abstract Full Text Full Text PDF PubMed Scopus (243) Google ScholarThere is little evidence regarding appropriate management of diverticulitis after an acute episode, even though the long-term recurrence rate of diverticulitis is ≤20%.3Binda G.A. Arezzo A. Serventi A. et al.Multicentre observational study on the natural history of left-sided acute diverticulitis.Br J Surg. 2012; 99: 276-285Crossref PubMed Scopus (72) Google Scholar In this issue of Gastroenterology, Raskin et al present the results of 2 phase III, randomized, double-blind, placebo-controlled studies (PREVENT 1 and PREVENT 2) conducted to examine role of mesalamine in preventing recurrence of diverticulitis. More than 1,000 adult patients (590 in PREVENT1and 592 in PREVENT2) with ≥1 episode of acute diverticulitis in the previous 24 months that resolved without surgery were randomised to receive 1 of 3 dose regimens of MMX mesalamine (1.2, 2.4, or 4.8 g/d) or placebo.4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The primary endpoint was the proportion of patients free of recurrent diverticulitis, defined as surgical intervention at any time for diverticular disease or presence of computed tomography (CT) results demonstrating bowel wall thickening (>5 mm) and/or fat stranding consistent with diverticulitis. The authors found that any dose of MMX mesalamine was not better than placebo for reducing diverticulitis recurrence at week 104 by using a CT-only definition of recurrent diverticulitis (recurrence-free rates for PREVENT1: Mesalamine, 53%–63% vs placebo, 65%; recurrence-free rates for PREVENT2: Mesalamine 59%–69% vs placebo 68%).4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Thus, mesalamine does not seem to be effective in preventing diverticulitis recurrence.Given that these controlled trials suggest that mesalamine does not work, how can we prevent diverticulitis recurrence in clinical practice?Once the acute episode has resolved, patients are generally advised to maintain a high-fiber diet to optimize their bowel movements.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar However, the collective literature investigating the role of dietary modification in preventing diverticular disease or a recurrence of diverticulitis is inconsistent, with conflicting results, and does not provide consistent support for recommending a high-fiber diet.5Ünlü C. Daniels L. Vrouenraets B.C. et al.A systematic review of high-fibre dietary therapy in diverticular disease.Int J Colorectal Dis. 2012; 27: 419-427Crossref PubMed Scopus (84) Google Scholar Another interesting point is related to the typical advice to avoid consuming seeds, popcorn, and nuts, which is based on the assumption that such substances could theoretically enter, block, or irritate a diverticulum and result in diverticulitis, and possibly increase the risk of perforation. However, there is no evidence to date to support this practice.6Strate L.L. Liu Y.L. Syngal S. et al.Nut, corn, and popcorn consumption and the incidence of diverticular disease.JAMA. 2008; 300: 907-914Crossref PubMed Scopus (193) Google ScholarSeveral treatments have been proposed and are used in clinical practice (Figure 1). Given the potential involvement of microbial imbalance in the pathogenesis of diverticular disease,1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar 1 option to prevent recurrence after an acute episode may be to use a single, broad-spectrum antibiotic that has activity against both Gram-negative and anaerobic bacteria. Recently, an open-label, pilot study found cyclic administration of rifaximin (800 mg/d for 10 days every month) to be effective for improving symptoms, but not for prevention of acute diverticulitis.7Lanas A. Ponce J. Bignamini A. et al.One year intermittent rifaximin plus fibre supplementation vs. fibre supplementation alone to prevent diverticulitis recurrence: a proof-of-concept study.Dig Liver Dis. 2013; 45: 104-109Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar However, the lack of a placebo-controlled arm is a limitation; therefore, the role of rifaximin in preventing diverticulitis recurrence needs definitive confirmation.Surgery is considered a therapeutic option after an attack of diverticulitis. According to the current guidelines,8Rafferty J. Shellito P. Hyman N.H. et al.Practice parameters for sigmoid diverticulitis.Dis Colon Rectum. 2006; 49: 939-944Crossref PubMed Scopus (564) Google Scholar, 9Andeweg C.S. Mulder I.M. Felt-Bersma R.J. et al.Guidelines of diagnostics and treatment of acute left-sided colonic diverticulitis.Dig Surg. 2013; 30: 278-292Crossref PubMed Scopus (141) Google Scholar elective resection should be considered after 1 or 2 well-documented attacks of diverticulitis, depending on the severity of the attack and age and medical fitness of the patient. However, abdominal symptoms persist in up to 25% of patients after elective surgery for diverticulitis,10Egger B. Peter M.K. Candinas D. Persistent symptoms after elective sigmoid resection for diverticulitis.Dis Colon Rectum. 2008; 51: 1044-1048Crossref PubMed Scopus (97) Google Scholar although the recurrence rate of diverticulitis after surgery is currently considered quite low.3Binda G.A. Arezzo A. Serventi A. et al.Multicentre observational study on the natural history of left-sided acute diverticulitis.Br J Surg. 2012; 99: 276-285Crossref PubMed Scopus (72) Google Scholar Neither the stage of disease (complicated or uncomplicated) nor the surgical technique (laparotomy or laparoscopy) were significantly related to the occurrence of symptoms after surgery.10Egger B. Peter M.K. Candinas D. Persistent symptoms after elective sigmoid resection for diverticulitis.Dis Colon Rectum. 2008; 51: 1044-1048Crossref PubMed Scopus (97) Google ScholarBecause diverticulitis pathogenesis is driven by inflammation, it seems logical that control of inflammation could be a relevant therapeutic option. Indeed, in diverticular disease there is a significant microscopic inflammatory infiltrate,11Tursi A. Brandimarte G. Elisei W. et al.Assessment and grading of mucosal inflammation in colonic diverticular disease.J Clin Gastroenterol. 2008; 42: 699-703Crossref PubMed Scopus (85) Google Scholar overexpression of fecal calprotectin (relative to the disease severity),12Tursi A. Brandimarte G. Elisei W. et al.Faecal calprotectin in colonic diverticular disease: a case-control study.Int J Colorectal Dis. 2009; 24: 49-55Crossref PubMed Scopus (95) Google Scholar and an enhanced expression of proinflammatory cytokines as tumor necrosis factor-α at mucosal sites.13Tursi A. Elisei W. Brandimarte G. et al.Mucosal tumour necrosis factor-alpha in diverticular disease of the colon is overexpressed with disease severity.Colorectal Dis. 2012; 14: e258-e263Crossref PubMed Scopus (38) Google ScholarTherefore, diverticular disease may be considered as a chronic inflammatory process ranging from low-grade inflammation that is localized within the colonic mucosa to a full-blown acute diverticulitis resulting in expanding inflammation to the colonic wall. In this way, mesalamine may be an interesting therapeutic tool. Two recent double-blind, placebo-controlled studies found mesalamine effective in treating symptomatic uncomplicated diverticular disease (SUDD). The first trial, conducted in Germany, found that mesalamine is better than placebo in improving abdominal pain in SUDD patients.14Kruis W. Meier E. Schumacher M. et al.German SAG-20 Study GroupRandomised clinical trial: mesalazine (Salofalk granules) for uncomplicated diverticular disease of the colon–a placebo-controlled study.Aliment Pharmacol Ther. 2013; 37: 680-690Crossref PubMed Scopus (80) Google Scholar The second trial, conducted in Italy, found that mesalamine alone or in combination with probiotic strain Lactobacillus casei subsp. DG is superior to placebo not only in preventing SUDD recurrence, but also in preventing the occurrence of diverticulitis.15Tursi A. Brandimarte G. Elisei W. et al.Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease–a double-blind, randomised, placebo-controlled study.Aliment Pharmacol Ther. 2013; 38: 741-751Crossref PubMed Scopus (121) Google ScholarBecause mesalamine was effective in controlling SUDD and in preventing the occurrence of diverticulitis from SUDD, it was considered that it may be a useful therapeutic option for preventing recurrence of diverticulitis. Several double-blind, placebo-controlled studies have recently been completed to assess the role of mesalamine in preventing recurrence of diverticulitis. Unfortunately, most did not find mesalamine to be superior to placebo in preventing diverticulitis recurrence.16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar On the other hand, in the DIVA and DIV/4 trials mesalamine was found significantly better than placebo in reducing abdominal symptoms after acute diverticulitis (DIVA trial: P = .045; DIV/04 trial: P = .021).16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar, 17Stollman N. Magowan S. Shanahan F. et al.DIVA Investigator GroupA randomized controlled study of mesalamine after acute diverticulitis: results of the DIVA trial.J Clin Gastroenterol. 2013; 47: 621-629Crossref PubMed Scopus (114) Google Scholar Only a trial conducted in Romania found mesalamine superior to placebo in reducing the risk of developing diverticulitis as well as the number of diverticulitis flares and the need for surgery. The relative risk of developing diverticulitis was 2.47 times higher (95% CI, 1.38-4.43) in the placebo group than in the mesalamine group.18Gaman A. Teodorescu R. Georhescu E.F. et al.Prophylactic effects of mesalamine in diverticular disease.Falk Symposium. 2011; 178: 13Google ScholarThese conflicting results raise some key questions. First of all, are all the patients enrolled in the studies similar, or has the placebo effect altered the results? Heterogeneity in the population enrolled, the different endpoint used, and heterogeneity in the type of mesalamine investigated suggest that the studies are quite different. But the question of why mesalamine seems to be effective in treating SUDD and in preventing diverticulitis occurrence, but not in preventing diverticulitis recurrence, remains. A potential explanation is that SUDD and diverticulitis are 2 different diseases. SUDD is characterized by mucosal inflammation, whereas acute diverticulitis is characterized by transmural inflammation, leading to fibrosis. Fibrosis may be the key point explaining mesalamine effectiveness in SUDD but not in diverticulitis.19Tursi A. Elisei W. Brandimarte G. et al.Mucosal expression of basic fibroblastic growth factor, Syndecan 1 and tumor necrosis factor-alpha in diverticular disease of the colon: a case-control study.Neurogastroenterol Motil. 2012; 24 (836–e396)Crossref PubMed Scopus (23) Google Scholar We can speculate that, if the patients are at the first episode of diverticulitis, it is probable that the disease still has lower levels of fibrosis and greater inflammation: In those patients, mesalamine is still able to control inflammation and therefore symptoms and recurrence of the disease. On the contrary, >2 attacks are able to cause fibrosis, limiting the mesalamine absorption across the colonic wall, and therefore mesalamine is ineffective.20Tursi A. Elisei W. Inchingolo C.D. et al.Chronic diverticulitis and Crohn's disease share the same expression of basic fibroblastic growth factor, syndecan 1 and tumour necrosis factor-α.J Clin Pathol. 2014 Jun 26; ([Epub ahead of print])Crossref PubMed Scopus (8) Google Scholar Disease history, and the number of previous attacks with potential different degrees of fibrosis, could therefore help to explain in part the difference across trials. Parente et al16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar enrolled only patients at the first attack of diverticulitis and the vast majority of patients enrolled in the Stollman et al17Stollman N. Magowan S. Shanahan F. et al.DIVA Investigator GroupA randomized controlled study of mesalamine after acute diverticulitis: results of the DIVA trial.J Clin Gastroenterol. 2013; 47: 621-629Crossref PubMed Scopus (114) Google Scholar trial were at the first or second attack of diverticulitis. Although most of patients enrolled in the PREVENT 1 and PREVENT 2 were at the first or second attack of diverticulitis, about 15% of the enrolled patients suffered from multiple attacks of diverticulitis and, unfortunately, the authors did not assess whether there was a difference in preventing diverticulitis recurrence according to the number of prior attack of diverticulitis.4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarAnother key point is in relation to the potential differences among mesalamine formulations. Indeed, the mechanism of mesalamine discharging through the colon, both from distal to proximal colon both transmural discharging (Eudragit L, granules, MMX),21Sandborn W.J. Hanauer S.B. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis.Aliment Pharmacol Ther. 2003; 17: 29-42Crossref PubMed Scopus (217) Google Scholar could in part explain the differences in the literature for symptom control.Further studies are therefore needed to overcome these limits, for example, enrolling patients with the same endoscopic and/or radiologic finding of the disease. However, objective measures of diverticular disease are still lacking in terms of inflammation or grading. For this purpose, the first endoscopic classification of diverticular disease of the colon, the Diverticular Inflammation and Complication Assessment (DICA) classification, has been developed and validated.22Tursi A. Brandimarte G. Di Mario F. et al.Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification.Dig Dis. 2014; (in press)PubMed Google Scholar This classification considers 4 endoscopic items on which classify the patients: (a) Diverticulosis extension, (b) number of diverticula (≤15, grade I; >15, grade II), (c) presence of inflammatory signs (edema/hyperemia, erosions, segmental colitis associated with diverticulosis), and (d) presence of complications (rigidity of the colon, stenosis, pus, bleeding). Points in constructing final DICA were assigned according to the severity of the anatomic/inflammatory findings and patients are therefore classified as DICA 1, DICA 2, and DICA 3. Preliminary data found DICA classification able to predict patient outcomes during a 1-year follow-up, as well as found higher DICA scores at higher risk of developing diverticulitis occurrence/recurrence.22Tursi A. Brandimarte G. Di Mario F. et al.Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification.Dig Dis. 2014; (in press)PubMed Google ScholarIt is advisable that in the future trials will enroll homogeneous populations to define a correct therapeutic strategy for this complex disease. See “Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials,” by Raskin JB, Kamm MA, Jamal MM, et al, on page 793. See “Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials,” by Raskin JB, Kamm MA, Jamal MM, et al, on page 793. See “Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials,” by Raskin JB, Kamm MA, Jamal MM, et al, on page 793. Diverticulosis of the colon is an anatomic alteration commonly found in those residing in developed countries, slightly more frequent in the United States than in Europe.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar Diverticulitis is the most common complication of diverticulosis: The majority of patients suffer from an “uncomplicated” form of the disease, generally undergoing outpatient medical management, whereas the “complicated” form is generally managed with inpatient medical-surgical treatment.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar It has been thought that diverticulitis affects ≤15% of patients with symptomatic diverticular disease.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar However, a colonoscopy-based study hypothesized that the actual rate of diverticulitis occurrence is lower, occurring in only 5% of patients harboring simple diverticulosis.2Shahedi K. Fuller G. Bolus R. et al.Long-term risk of acute diverticulitis among patients with incidental diverticulosis found during colonoscopy.Clin Gastroenterol Hepatol. 2013; 11: 1609-1613Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar There is little evidence regarding appropriate management of diverticulitis after an acute episode, even though the long-term recurrence rate of diverticulitis is ≤20%.3Binda G.A. Arezzo A. Serventi A. et al.Multicentre observational study on the natural history of left-sided acute diverticulitis.Br J Surg. 2012; 99: 276-285Crossref PubMed Scopus (72) Google Scholar In this issue of Gastroenterology, Raskin et al present the results of 2 phase III, randomized, double-blind, placebo-controlled studies (PREVENT 1 and PREVENT 2) conducted to examine role of mesalamine in preventing recurrence of diverticulitis. More than 1,000 adult patients (590 in PREVENT1and 592 in PREVENT2) with ≥1 episode of acute diverticulitis in the previous 24 months that resolved without surgery were randomised to receive 1 of 3 dose regimens of MMX mesalamine (1.2, 2.4, or 4.8 g/d) or placebo.4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar The primary endpoint was the proportion of patients free of recurrent diverticulitis, defined as surgical intervention at any time for diverticular disease or presence of computed tomography (CT) results demonstrating bowel wall thickening (>5 mm) and/or fat stranding consistent with diverticulitis. The authors found that any dose of MMX mesalamine was not better than placebo for reducing diverticulitis recurrence at week 104 by using a CT-only definition of recurrent diverticulitis (recurrence-free rates for PREVENT1: Mesalamine, 53%–63% vs placebo, 65%; recurrence-free rates for PREVENT2: Mesalamine 59%–69% vs placebo 68%).4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Thus, mesalamine does not seem to be effective in preventing diverticulitis recurrence. Given that these controlled trials suggest that mesalamine does not work, how can we prevent diverticulitis recurrence in clinical practice? Once the acute episode has resolved, patients are generally advised to maintain a high-fiber diet to optimize their bowel movements.1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar However, the collective literature investigating the role of dietary modification in preventing diverticular disease or a recurrence of diverticulitis is inconsistent, with conflicting results, and does not provide consistent support for recommending a high-fiber diet.5Ünlü C. Daniels L. Vrouenraets B.C. et al.A systematic review of high-fibre dietary therapy in diverticular disease.Int J Colorectal Dis. 2012; 27: 419-427Crossref PubMed Scopus (84) Google Scholar Another interesting point is related to the typical advice to avoid consuming seeds, popcorn, and nuts, which is based on the assumption that such substances could theoretically enter, block, or irritate a diverticulum and result in diverticulitis, and possibly increase the risk of perforation. However, there is no evidence to date to support this practice.6Strate L.L. Liu Y.L. Syngal S. et al.Nut, corn, and popcorn consumption and the incidence of diverticular disease.JAMA. 2008; 300: 907-914Crossref PubMed Scopus (193) Google Scholar Several treatments have been proposed and are used in clinical practice (Figure 1). Given the potential involvement of microbial imbalance in the pathogenesis of diverticular disease,1Tursi A. New physiopathological and therapeutic approaches to diverticular disease: an update.Expert Opin Pharmacother. 2014; 15: 1005-1017Crossref PubMed Scopus (23) Google Scholar 1 option to prevent recurrence after an acute episode may be to use a single, broad-spectrum antibiotic that has activity against both Gram-negative and anaerobic bacteria. Recently, an open-label, pilot study found cyclic administration of rifaximin (800 mg/d for 10 days every month) to be effective for improving symptoms, but not for prevention of acute diverticulitis.7Lanas A. Ponce J. Bignamini A. et al.One year intermittent rifaximin plus fibre supplementation vs. fibre supplementation alone to prevent diverticulitis recurrence: a proof-of-concept study.Dig Liver Dis. 2013; 45: 104-109Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar However, the lack of a placebo-controlled arm is a limitation; therefore, the role of rifaximin in preventing diverticulitis recurrence needs definitive confirmation. Surgery is considered a therapeutic option after an attack of diverticulitis. According to the current guidelines,8Rafferty J. Shellito P. Hyman N.H. et al.Practice parameters for sigmoid diverticulitis.Dis Colon Rectum. 2006; 49: 939-944Crossref PubMed Scopus (564) Google Scholar, 9Andeweg C.S. Mulder I.M. Felt-Bersma R.J. et al.Guidelines of diagnostics and treatment of acute left-sided colonic diverticulitis.Dig Surg. 2013; 30: 278-292Crossref PubMed Scopus (141) Google Scholar elective resection should be considered after 1 or 2 well-documented attacks of diverticulitis, depending on the severity of the attack and age and medical fitness of the patient. However, abdominal symptoms persist in up to 25% of patients after elective surgery for diverticulitis,10Egger B. Peter M.K. Candinas D. Persistent symptoms after elective sigmoid resection for diverticulitis.Dis Colon Rectum. 2008; 51: 1044-1048Crossref PubMed Scopus (97) Google Scholar although the recurrence rate of diverticulitis after surgery is currently considered quite low.3Binda G.A. Arezzo A. Serventi A. et al.Multicentre observational study on the natural history of left-sided acute diverticulitis.Br J Surg. 2012; 99: 276-285Crossref PubMed Scopus (72) Google Scholar Neither the stage of disease (complicated or uncomplicated) nor the surgical technique (laparotomy or laparoscopy) were significantly related to the occurrence of symptoms after surgery.10Egger B. Peter M.K. Candinas D. Persistent symptoms after elective sigmoid resection for diverticulitis.Dis Colon Rectum. 2008; 51: 1044-1048Crossref PubMed Scopus (97) Google Scholar Because diverticulitis pathogenesis is driven by inflammation, it seems logical that control of inflammation could be a relevant therapeutic option. Indeed, in diverticular disease there is a significant microscopic inflammatory infiltrate,11Tursi A. Brandimarte G. Elisei W. et al.Assessment and grading of mucosal inflammation in colonic diverticular disease.J Clin Gastroenterol. 2008; 42: 699-703Crossref PubMed Scopus (85) Google Scholar overexpression of fecal calprotectin (relative to the disease severity),12Tursi A. Brandimarte G. Elisei W. et al.Faecal calprotectin in colonic diverticular disease: a case-control study.Int J Colorectal Dis. 2009; 24: 49-55Crossref PubMed Scopus (95) Google Scholar and an enhanced expression of proinflammatory cytokines as tumor necrosis factor-α at mucosal sites.13Tursi A. Elisei W. Brandimarte G. et al.Mucosal tumour necrosis factor-alpha in diverticular disease of the colon is overexpressed with disease severity.Colorectal Dis. 2012; 14: e258-e263Crossref PubMed Scopus (38) Google Scholar Therefore, diverticular disease may be considered as a chronic inflammatory process ranging from low-grade inflammation that is localized within the colonic mucosa to a full-blown acute diverticulitis resulting in expanding inflammation to the colonic wall. In this way, mesalamine may be an interesting therapeutic tool. Two recent double-blind, placebo-controlled studies found mesalamine effective in treating symptomatic uncomplicated diverticular disease (SUDD). The first trial, conducted in Germany, found that mesalamine is better than placebo in improving abdominal pain in SUDD patients.14Kruis W. Meier E. Schumacher M. et al.German SAG-20 Study GroupRandomised clinical trial: mesalazine (Salofalk granules) for uncomplicated diverticular disease of the colon–a placebo-controlled study.Aliment Pharmacol Ther. 2013; 37: 680-690Crossref PubMed Scopus (80) Google Scholar The second trial, conducted in Italy, found that mesalamine alone or in combination with probiotic strain Lactobacillus casei subsp. DG is superior to placebo not only in preventing SUDD recurrence, but also in preventing the occurrence of diverticulitis.15Tursi A. Brandimarte G. Elisei W. et al.Randomised clinical trial: mesalazine and/or probiotics in maintaining remission of symptomatic uncomplicated diverticular disease–a double-blind, randomised, placebo-controlled study.Aliment Pharmacol Ther. 2013; 38: 741-751Crossref PubMed Scopus (121) Google Scholar Because mesalamine was effective in controlling SUDD and in preventing the occurrence of diverticulitis from SUDD, it was considered that it may be a useful therapeutic option for preventing recurrence of diverticulitis. Several double-blind, placebo-controlled studies have recently been completed to assess the role of mesalamine in preventing recurrence of diverticulitis. Unfortunately, most did not find mesalamine to be superior to placebo in preventing diverticulitis recurrence.16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar On the other hand, in the DIVA and DIV/4 trials mesalamine was found significantly better than placebo in reducing abdominal symptoms after acute diverticulitis (DIVA trial: P = .045; DIV/04 trial: P = .021).16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar, 17Stollman N. Magowan S. Shanahan F. et al.DIVA Investigator GroupA randomized controlled study of mesalamine after acute diverticulitis: results of the DIVA trial.J Clin Gastroenterol. 2013; 47: 621-629Crossref PubMed Scopus (114) Google Scholar Only a trial conducted in Romania found mesalamine superior to placebo in reducing the risk of developing diverticulitis as well as the number of diverticulitis flares and the need for surgery. The relative risk of developing diverticulitis was 2.47 times higher (95% CI, 1.38-4.43) in the placebo group than in the mesalamine group.18Gaman A. Teodorescu R. Georhescu E.F. et al.Prophylactic effects of mesalamine in diverticular disease.Falk Symposium. 2011; 178: 13Google Scholar These conflicting results raise some key questions. First of all, are all the patients enrolled in the studies similar, or has the placebo effect altered the results? Heterogeneity in the population enrolled, the different endpoint used, and heterogeneity in the type of mesalamine investigated suggest that the studies are quite different. But the question of why mesalamine seems to be effective in treating SUDD and in preventing diverticulitis occurrence, but not in preventing diverticulitis recurrence, remains. A potential explanation is that SUDD and diverticulitis are 2 different diseases. SUDD is characterized by mucosal inflammation, whereas acute diverticulitis is characterized by transmural inflammation, leading to fibrosis. Fibrosis may be the key point explaining mesalamine effectiveness in SUDD but not in diverticulitis.19Tursi A. Elisei W. Brandimarte G. et al.Mucosal expression of basic fibroblastic growth factor, Syndecan 1 and tumor necrosis factor-alpha in diverticular disease of the colon: a case-control study.Neurogastroenterol Motil. 2012; 24 (836–e396)Crossref PubMed Scopus (23) Google Scholar We can speculate that, if the patients are at the first episode of diverticulitis, it is probable that the disease still has lower levels of fibrosis and greater inflammation: In those patients, mesalamine is still able to control inflammation and therefore symptoms and recurrence of the disease. On the contrary, >2 attacks are able to cause fibrosis, limiting the mesalamine absorption across the colonic wall, and therefore mesalamine is ineffective.20Tursi A. Elisei W. Inchingolo C.D. et al.Chronic diverticulitis and Crohn's disease share the same expression of basic fibroblastic growth factor, syndecan 1 and tumour necrosis factor-α.J Clin Pathol. 2014 Jun 26; ([Epub ahead of print])Crossref PubMed Scopus (8) Google Scholar Disease history, and the number of previous attacks with potential different degrees of fibrosis, could therefore help to explain in part the difference across trials. Parente et al16Parente F. Bargiggia S. Prada A. et al.“Gismi Study Group.”Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration.Int J Colorectal Dis. 2013; 28: 1423-1431Crossref PubMed Scopus (73) Google Scholar enrolled only patients at the first attack of diverticulitis and the vast majority of patients enrolled in the Stollman et al17Stollman N. Magowan S. Shanahan F. et al.DIVA Investigator GroupA randomized controlled study of mesalamine after acute diverticulitis: results of the DIVA trial.J Clin Gastroenterol. 2013; 47: 621-629Crossref PubMed Scopus (114) Google Scholar trial were at the first or second attack of diverticulitis. Although most of patients enrolled in the PREVENT 1 and PREVENT 2 were at the first or second attack of diverticulitis, about 15% of the enrolled patients suffered from multiple attacks of diverticulitis and, unfortunately, the authors did not assess whether there was a difference in preventing diverticulitis recurrence according to the number of prior attack of diverticulitis.4Raskin J.B. Kamm M.A. Jamal M.M. et al.Mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.Gastroenterology. 2014; 147: 793-802Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Another key point is in relation to the potential differences among mesalamine formulations. Indeed, the mechanism of mesalamine discharging through the colon, both from distal to proximal colon both transmural discharging (Eudragit L, granules, MMX),21Sandborn W.J. Hanauer S.B. Systematic review: the pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis.Aliment Pharmacol Ther. 2003; 17: 29-42Crossref PubMed Scopus (217) Google Scholar could in part explain the differences in the literature for symptom control. Further studies are therefore needed to overcome these limits, for example, enrolling patients with the same endoscopic and/or radiologic finding of the disease. However, objective measures of diverticular disease are still lacking in terms of inflammation or grading. For this purpose, the first endoscopic classification of diverticular disease of the colon, the Diverticular Inflammation and Complication Assessment (DICA) classification, has been developed and validated.22Tursi A. Brandimarte G. Di Mario F. et al.Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification.Dig Dis. 2014; (in press)PubMed Google Scholar This classification considers 4 endoscopic items on which classify the patients: (a) Diverticulosis extension, (b) number of diverticula (≤15, grade I; >15, grade II), (c) presence of inflammatory signs (edema/hyperemia, erosions, segmental colitis associated with diverticulosis), and (d) presence of complications (rigidity of the colon, stenosis, pus, bleeding). Points in constructing final DICA were assigned according to the severity of the anatomic/inflammatory findings and patients are therefore classified as DICA 1, DICA 2, and DICA 3. Preliminary data found DICA classification able to predict patient outcomes during a 1-year follow-up, as well as found higher DICA scores at higher risk of developing diverticulitis occurrence/recurrence.22Tursi A. Brandimarte G. Di Mario F. et al.Development and validation of an endoscopic classification of diverticular disease of the colon: the DICA classification.Dig Dis. 2014; (in press)PubMed Google Scholar It is advisable that in the future trials will enroll homogeneous populations to define a correct therapeutic strategy for this complex disease. Preventing Diverticulitis: Mesalamine May Still Be Indicated in the DecisionGastroenterologyVol. 148Issue 4PreviewI read with great interest the excellent editorial written by Drs Tursi and Danese concerning the prevention of diverticulitis recurrence.1 The article was obviously stimulated by the publication by Raskin et al, also in this issue, reporting that mesalamine did not prevent recurrent diverticulitis in phase 3 controlled trials.2 The history of recent interest in diverticulitis was focused in our Yale University Workshop Report published on Diverticulitis: New Concepts and New Therapies in 2006.3 That workshop was attended by the National Diverticulitis Study Group, including Drs. Full-Text PDF
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