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E V O LV I N G A P P R O A C H E S I N

THE MEDICAL MANAGEMENT OF DIVERTICULAR DISEASE

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E V O LV I N G A P P R O A C H E S I N

THE

MEDICAL MANAGEMENT

OF

DIVERTICULAR DISEASE

INTRODUCTION In the United States (US), it’s estimated that more than 2.5 million people are affected by diverticular disease (DD); though the actual prevalence is difficult to determine precisely as most patients remain asymptomatic.1 The prevalence is generally similar in both men and women, although there is a male predominance in younger patients. While uncommon in people under 40 years of age (less than 10%), up to 65% of people have diverticulosis by age 80.2

By convention, SUDD is defined as suggestive abdominal symptoms affecting patients with diverticulosis, but without overt clinical signs of inflammation.6 However, this definition is obviously imprecise, as many conditions other than DD may cause abdominal symptoms (eg, irritable bowel syndrome [IBS]). Furthermore, there is no consensus on the measures used to define “inflammation” (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], etc).

The disease burden of DD is substantial. In 2004, DD was the fifth most common reason for ambulatory care visits.3 One to two percent of all cases require hospitalization.4 The overall economic burden of DD is estimated to be more than $2.6 billion per year.5

Adding to the confusion is the fact that current classification schemes are based upon clinical, radiologic, or surgical findings (Table 2) which may not adequately reflect advances in imaging and treatment modalities that have implications for clinical practice.8

Despite advances in therapeutic and imaging modalities, the management of patients with diverticular disease remains imprecise due to the debate over classification schema, a lack of understanding of the pathophysiology underlying disease manifestations, and conflicting data in support of emerging medical interventions.

Table 1. Major classification schema currently used to describe the spectrum of diverticular disease

The first section of this monograph summarizes current and proposed classification schemes as well as advances in understanding the potential pathophysiologic roles of inflammation and intestinal microflora in the development and progression of diverticular disease. The second section briefly touches on current standards of care, but focuses on emerging data that may support new therapeutic approaches and treatment options for diverticular disease that are not the current standard of care. During this activity, a case study will illustrate some of the clinical decisions that need to be made to address symptoms as a patient is followed along the spectrum of diverticular disease, and the role emerging strategies might play.

Floch review9

Classification Stage 0 Stage I Stage II

Stage III European Association for Endoscopic Surgeons (EAES) (acute diverticulitis)6

There is no consensus on how to classify the spectrum of DD DR. STOLLMAN: What are the issues surrounding a lack of consensus about how to classify diverticular disease?

Grade 1 Symptomatic, uncomplicated diverticular disease (SUDD) Grade II Recurrent, symptomatic disease Grade III Complicated disease

Buckley Classification10 Mild click on this speaker icon

and listen to Dr. Stollman’s response

Moderate

Currently, there is no universally accepted classification schema for diverticular disease. In clinical practice, DD is usually classified as asymptomatic, symptomatic uncomplicated disease, recurrent symptomatic disease, or complicated disease.6-7 However, when patients with diverticulosis become symptomatic or have complications, they are often diagnosed with “diverticular disease”. The challenges with respect to this apparent misnomer are illustrated by the commonly used term Symptomatic Uncomplicated Diverticular Disease or SUDD (Table 1) by the European Association for Endoscopic Surgeons (EAES).

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Severe

Hinchey Classification (perforated diverticulitis)11

Stage I Stage II Stage III Stage IV

Description Development of diverticular disease Asymptomatic disease Symptomatic disease a. Single episode b. Recurrent c. Chronic (pain, diarrhea, IBD overlap/segmental colitis associated with diverticulosis [SCAD]) Complicated: abscess, phlegmon, obstruction, fistulization, bleeding, sepsis, stricture Clinical description: Fever, crampy abdominal pain

Recurrence of above

Abscess, hemorrhage, stricture, fistula, phlegmon, purulent and fecal peritonitis, perforation, obstruction CT findings: Bowel wall thickening, fat stranding Bowel wall thickening >3 mm, phlegmon or small abscess Bowel wall thickening >5 mm, frank perforation with subdiaphragmatic free air, abscess >5 cm CT findings: Pericolic abscess or phlegmon Pelvic, intra-abdominal or retroperitoneal abscess Generalized purulent peritonitis Generalized fecal peritonitis

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A consensus about the optimal classification scheme for research or clinical purposes is still lacking. Klarenbeek et al recently proposed a three-stage classification model that uses imaging results to integrate the clinical presentation and type and duration of symptoms (Table 2).8 The authors suggest that the three-stage model is more useful than current classifications in that it can better inform clinical decisionmaking and management of diverticular disease.8

Figure 1. Diverticular Disease: Symptomatic and Asymptomatic Spectrum Uncomplicated DD Normal Colon

C3

Massive rectal blood loss

C4

Generalized peritonitis

Imaging CT scan or ultrasound Phlegmon Small abscess in bowel wall

Clinical Relevance

Stenosis Fistula

Stenois Fistula Blood in diverticula

CT scan

Colonoscopy Active diverticular bleeding Colonoscopy

Contrast blush CT scan Pneumoperitoneum Extraluminal contrast Free fluid

C A S E P R E S E N TAT I O N Mr. K. is a 55-year-old male who is found to have diverticulosis during a routine colonoscopy. There are no signs of inflammation and he is not feeling any symptoms.

CLINICAL PERSPECTIVE Based on Mr. K’s colonoscopy findings and lack of symptoms, his diverticulosis is felt to be an incidental finding; no intervention beyond education, and perhaps dietary advice about fiber intake, would be required.

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Common

Uncommon

Rare

No Treatment

Diverticulosis Inflammation

Colonoscopy

CT angio

Very Common

Colonoscopy

CT scan

Large abscess (>5 cm) CT scan Intestinal obstruction

Symptomatic

No Clinical Significance

Table 2. Proposed classification scheme by Klarenbeek8 Clinical Classification Presentation A Uncomplicated disease Pain in lower left quadrant Fever Changes in relief pattern B Chronic complicated disease Impaired passage of stool Presence of fistula Recurrent rectal blood loss Complaints of incapacitation High-risk patients C1 Acute complicated disease Fever Painful mass C2 Ileus

Asymptomatic

Complicated DD

Source: Sopena F, Lanas A. Ther Adv Gastroenterol. 2011;4(6):365.12

New insights into the pathophysiology of DD that have implications for treatment include the role of inflammation in the development of DD and the influence of gastrointestinal microflora on inflammation and colonic microenvironments.

Chronic inflammation may play a role in the etiology of DD We are currently somewhat ignorant about the natural history of inflammation along the spectrum of DD. It’s estimated that up to 20% of all people with diverticulosis will experience an inflammatory complication of the condition.13 The association between inflammation and DD was first suggested by Narayan and Floch who found that most patients with DD had evidence of a chronic inflammatory infiltrate.14 Tursi et al found that the inflammatory infiltrate is related to the severity of the disease15-16; and that inflammation may be detected by fecal calprotectin (FC).17 Cianci et al reported a significant lymphocytic infiltrate in the colonic mucosa harboring diverticula in patients with uncomplicated diverticular disease.18 Several studies suggest that chronic inflammation and its impact on neuromuscular function in the colon may be partially responsible for symptomatic diverticular disease.19-22 A recent study assessed visceral sensitivity and its association with markers of previous inflammation in patients with asymptomatic (n=13) and symptomatic (n=12) diverticular disease. Symptomatic patients had a lower overall pain threshold and a higher median pain rating for stimuli (barostat-mediated rectal distension), as well as a greater relative expression of receptors for proinflammatory molecules (neurokinin 1, tumor necrosis factor-alpha) compared with asymptomatic patients.23 Support for this concept can also be found in reports that patients with “smoldering” diverticular disease experienced symptomatic relief following sigmoid resection and over threefourths remained in remission one year later. Most of the resected specimens exhibited chronic inflammatory changes.24

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Persistent inflammation may be a risk factor for recurrent disease. We know that diverticulitis recurs in many patients despite surgical treatment25 symptoms persist in 25% of patients following sigmoid resection.26 Recent evidence suggests that the detection of inflammation during follow-up is a risk factor for diverticulitis recurrence.27 In a prospective study, patients with acute uncomplicated diverticulitis were treated with mesalamine (1.6 g/day, n=59) or rifaximin (800 mg/day for 7 days every month, n=52) after they achieved remission, defined as the absence of endoscopic histological damage. Clinical, endoscopic and histological follow-up was performed at 6, 12 months, and 24 months after the acute diagnosis. Significantly more patients in the mesalamine group sustained remission compared to the rifaximin group at 24 months.27 Data from studies demonstrating that antiinflammatory agents such as mesalamine improve symptoms in patients with DD also support an association between inflammation and symptoms.28-34 Changes in GI microflora are hypothesized to influence the etiology of DD While we know a fair amount about structural colonic changes in DD, our understanding of changes in the colonic microflora in DD remains rudimentary.35 It is hypothesized that microbial imbalance, associated with colonic bacterial overgrowth, may be a significant factor in the development of DD.36 It is generally accepted that a fiber-deficient diet facilitates diverticula formation; however, it may also bring about a change in the colonic microflora. Increased bran intake, for example, has been shown to alter the ratio of anaerobic to aerobic organisms in healthy subjects.37 This is also seen clearly when comparing Western vs. Japanese populations or United Kingdom (UK) vs. African populations. Finegold et al described differences in fecal flora among American and Japanese diets, with greater bacterial variation (>220 distinct types of bacteria) among subjects who consumed a Japanese diet compared to an American diet (>160 distinct types of bacteria).38 Tomkins et al found greater numbers of bacteroides and clostridia in adults from the UK who consumed more cereal and bread compared to Nigerian adults.39 It has been recently suggested that, as in inflammatory bowel disease, a deficiency in fiber alters the intestinal microecology such that it reduces the microflora’s influence on the host’s immune processes, which may permit chronic inflammation.40 A soluble fiber deficit produces changes that ultimately reduce the bacterial production of short-chain fatty acids (SCFAs). Short-chain fatty acids are an important fuel source for the colon and reduced production may “starve” the colonocytes, thereby reducing the threshold of inflammation.41

Current and Emerging Standards of Care Antibiotic Therapy Antibiotic therapy is appropriate in acute and complicated diverticulitis.42-43 A list of commonly used antibiotics is shown in Table 3. Patients with severe or complicated disease need antibiotic coverage for aerobic, anaerobic, and Gram-negative bacteria. Antibiotics in acute and complicated disease are standard; however, their role in preventing recurrence and complication of DD, in particular the role of cyclic antibiotic therapy, is a matter of discussion. It appears that the role, if any, of cyclic antibiotic therapy may be in treating SUDD or multiply recurrent disease. A recent meta-analysis of pooled data from four prospective, randomized rifaximin studies (N=1660) suggests treatment with rifaximin is effective at 1 year.44-46 Bianchi et al used the calculated rate difference (RD, with 95% CI) and the Number Needed to Treat (NNT) as measures of the therapeutic effect on symptoms and complications. The pooled RD for symptom relief was 29.0% (rifaximin vs. control; 95% CI 24.5-33.6%; P<0.0001; NNT=3). The pooled RD for complication rate was -1.7% in favor of rifaximin (95% CI -3.2 to -0.1%; P=0.03; NNT=59). When considering only acute diverticulitis, the pooled RD in the treatment group was -2% (95% CI -3.4 to -0.6%; P=0.0057; NNT=50).44 Data from more reliable, well-controlled trials are needed to help define the benefits of antibiotics in these situations.

Rifaximin is not absorbed systemically and its use is not associated with serious adverse events. In clinical trials of traveler’s diarrhea and irritable bowel syndrome, adverse events rates were similar to, or lower than, the placebo groups.47 Table 3. Antibiotics that are commonly used to treat acute diverticulitis43 Oral Antibiotics

Intravenous Antibiotics

Amoxicillin + clavulanic acid Sulphametoxazoletrimethoprim + metronidazole Fluoroquinolone + metronidazole

Metronidazole + aminoglycosidic (eg, gentamicin) Clindamycin Aztreonam

DR. STOLLMAN: Could you explain the potential role of cyclic antibiotics in the treatment of SUDD or multiply recurrent disease?. click on this speaker icon

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Second generation cephalosporins Third generation cephalosporins Beta-lactamase inhibitors (eg, ampicillin-sulbactam)

and listen to Dr. Stollman’s response

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C A S E P R E S E N TAT I O N FIRST ATTACK OF ACUTE DIVERTICULITIS: One year after he was diagnosed with incidental diverticular disease, Mr. K complains of abdominal pain that has become progressively severe over 3 days. He reports left lower abdominal cramping, some nausea, and loose stools. On examination, he has tenderness in the left iliac fossa with no signs or symptoms of peritonitis.

CLINICAL PERSPECTIVE Mr. K’s symptoms indicate his diverticular disease has progressed to a more clinically significant stage. At this point, a clinical diagnosis of acute diverticulitis is made and he should be treated with oral antibiotics for 7 to 10 days.

Figure 2. Diverticular Disease: Symptomatic and Asymptomatic Spectrum Uncomplicated DD Normal Colon

Asymptomatic

Complicated DD Symptomatic

Low Clinical Significance Clinical Relevance

Very Common

Common

Uncommon

Rare

Fiber, non-absorbed antibiotics and probiotics Source: Sopena F, Lanas A. Ther Adv Gastroenterol. 2011;4(6):365.12

Dietary modification in diverticulitis The collective literature investigating the role of dietary modification in preventing DD and/or diverticulitis recurrence is somewhat inconsistent. Looking at the more recent data, a prospective study comparing vegetarians (vegetarian or vegan) and non-vegetarians (people who ate meat or fish or both) found that consuming a vegetarian diet and a high intake of dietary fiber were both associated with a lower risk of developing diverticular disease, admission to hospital, or death from DD.48 Vegetarians had a 30% lower risk of developing diverticular disease than non-vegetarians (relative risk 0.69, 95% CI 0.55 to 0.86) and vegans had an even lower risk compared with non-vegetarians (relative risk 0.28, 95% CI 0.10 to 0.74). The cumulative probability of admission to hospital or death from diverticular disease between the ages of 50 and 70 for meat eaters was 4.4% compared with 3.0% for vegetarians.48 Fiber intake was significantly inversely related to the risk of diverticular disease.

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Participants in the highest fifth of dietary fiber intake (≥25.5 g/day for women and ≥26.1 g/day for men) had a 42% lower risk (relative risk 0.58, 0.46 to 0.73, P=0.002) compared with participants with the lowest intake of fiber (<14 g/day for both women and men).48 Non-vegetarians in the highest fifth of dietary fiber intake had a 26% lower risk of developing diverticular disease (0.74, 0.54 to 1.00; P=0.018).48 On the other hand, a recent cross-sectional study49 and a systematic review50 failed to find a consistent level of evidence for recommending a high-fiber diet. In fact, Peery et al suggested that a very high fiber diet might actually increase the risk of developing diverticulosis.49 In the Peery study (N=2104), diverticulosis was more prevalent among patients in the quartile with the highest fiber intake compared to those in the lowest quartile (prevalence ratio = 1.30; 95% CI 1.13-1.50). The risk increased when calculated based on intake of total fiber, fiber from grains, soluble fiber, and insoluble fiber. Compared to individuals with <7 bowel movements per week, individuals with >15 bowel movements per week had a 70% greater risk for diverticulosis (prevalence ratio=1.70; 95% CI, 1.24-2.34). Constipation was not a risk factor and neither physical inactivity nor intake of fat or red meat was associated with diverticulosis.49 Unlü’s review determined that high-quality studies supporting the efficacy of a high-fiber diet to improve symptoms and/or prevent complications in diverticular disease are lacking and data are inconsistent. The researchers were able to identify only 3 moderate-quality, randomized, controlled trials and a case study. One trial found no differences; another trial and the case study reported fiber significantly improved symptomatic diverticular disease. The third trial reported methylcellulose was significantly more effective than placebo; however, there was also a large placebo effect.50

What dietary recommendations do you suggest for patients following an acute episode of diverticulitis?

Dr. Antonio Tursi: The current guidelines still advise that patients eat a high-fiber diet following an episode of acute diverticulitis. Looking at results from recent studies (for example, the Peery data) it’s clear that some of the traditional dietary recommendations might need to be reconsidered.

The classical advice to avoid consuming seeds, popcorn, and nuts 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.

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There is, however, no evidence to date to support this practice. In fact, a recent study of more than 47,000 men without DD found an inverse relationship between nut and popcorn consumption and the risk of diverticulitis.51 Men who participated in the Health Professionals Follow-up Study were followed prospectively from 1986 to 2004 via selfadministered medical (biennial) and dietary (quadrennial) questionnaires; supplemental questionnaires were mailed to men who reported newly diagnosed diverticulosis or diverticulitis. During 18 years of follow-up, there were 801 incident cases of diverticulitis and 383 incident cases of diverticular bleeding. Nut and popcorn consumption were inversely associated with the risk of diverticulitis independent of other known or potential risk factors including age, body mass index, dietary fat, fiber, and red meat, physical activity, cigarette smoking and the use of non-steroidal antiinflammatory drugs and acetaminophen. The multivariable hazard ratios (HR) for men with the highest intake of each food (at least twice per week) compared to men with the lowest intake (less than once per month) were 0.80 (95% CI 0.63-1.01; P=0.04) for nuts, and 0.72 (95% CI 0.56-0.92; P=0.007) for popcorn. No associations were found between nut, corn or popcorn consumption and diverticular bleeding.51

Figure 3. Diverticular Disease: Symptomatic and Asymptomatic Spectrum Uncomplicated DD Normal Colon

Asymptomatic

Complicated DD Symptomatic High Clinical Significance

Clinical Relevance

Very Common

Common

Uncommon

Rare

Mesalamine Source: Sopena F, Lanas A. Ther Adv Gastroenterol. 2011;4(6):365.12

Role of anti-inflammatory agents in disease management DR. STOLLMAN: How do you see anti-inflammatory agents fitting into clinical practice? click on this speaker icon

and listen to Dr. Stollmanâ&#x20AC;&#x2122;s response

C A S E P R E S E N TAT I O N SMOLDERING DISEASE: 6 months after his first attack of diverticulitis, despite normal laboratory values, Mr. K continues to complain of milder, but persistent, abdominal pain and cramping and fluctuations in both the frequency of bowel movements and the consistency of stools.

CLINICAL PERSPECTIVE Mr. K remains symptomatic despite dietary modifications, including increased water and fiber intake, indicating that his diverticular disease remains chronically symptomatic. At this point, he could be advised to consume a higher fiber diet and to take anti-spasmodics as needed for cramps or he could be put on rifaximin for 7 days per month.

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How do you see anti-inflammatory agents fitting into clinical practice?

Dr. Antonio Tursi: Because of its ability to inhibit pro-inflammatory molecules, mesalamine may be particularly useful in preventing disease flares.

The proposition that chronic inflammation plays a role in the pathogenesis of diverticular diseases has led clinical researchers to evaluate anti-inflammatory agents in the treatment of diverticulitis and symptomatic uncomplicated diverticular disease. The rationale for treating DD with antiinflammatory agents is based on the fact that medications such as mesalamine inhibit inflammatory processes and the production of pro-inflammatory molecules (Figure 4).52

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Figure 4. Anti-inflamatory Agents: Mechanism of Action

Altered colonic micro-ecology leads to activation of inflammatory cascade

Mesalasine

Increase of: TNF-α and IFN-γ synthesis Release of free radicals

Inhibition of: IL-1 synthesis COX, TBX, PAF activity Phagocytic and lymphocytic aspecific activity + “Scavenger” effect Inhibition of NO release

Increase diverticula inflammation

Decreases diverticula inflammation

Source: Tursi A, Papagrigoriadis S. Aliment Pharmacol Thera. 2009;30(6):532.52

Studies of 5-aminolsalicylic acid (5-ASA), an antiinflammatory agent that is routinely used to treat inflammatory bowel disease, suggest that patients with diverticulitis and symptomatic diverticular disease improve with treatment. A number of 5-ASA products are currently available (Table 4). They all act directly on the colonic mucosa, but they differ in the way in which they release the drug. Some are pH-controlled, others use inert carriers or various coatings. It’s still unclear exactly how 5-ASAs exert their anti-inflammatory effects.53 Table 4. 5-aminosalicylic acid preparations 5-ASA agent

Product name

Mesalamine

APRISOTM ASACOL®/ASACOL HD LIALDA® PENTASA® COLAZAL® DIPENTUM® AZULFIDINE®

Balsalazide Olsalazine Sulfasalazine

Several open-label studies found 5-ASA and its pro-drug balsalazide effective in the management of DD.54 Recently, results from several, double-blind, placebo controlled trials assessing the role of 5-ASA in treating DD have been presented as abstracts (Table 5).

Kruis et al found that mesalamine was superior to placebo in reducing DD-associated pain. Patients treated with mesalamine had greater improvements in pain intensity scores and visual analogue scale (VAS) combined symptoms. The

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median time to pain relief was shorter in the mesalamine group (8 days) compared to placebo (19 days).55 In the Diverticulitis Assessment (DIVA) trial, Stollman et al found that 3 months of mesalamine treatment (2.4 g/day) after a CT-confirmed episode of acute diverticulitis was superior to placebo in reducing GI symptoms for up to one year, although the study was underpowered to evaluate recurrent diverticulitis.56 Mesalamine reduced global symptomatic score by 2.9 points vs. placebo at 12 weeks (P=0.38) and improved complete symptom response (Likert=0) at 12 weeks vs. placebo (28.1% vs. 13.8%; total N=61, P=0.083), which persisted at 52 weeks (40.7 vs. 18.2%; total N=49, P=0.045). Symptom response rates were higher in rectosigmoid-specific symptoms (urgency, tenesmus, diarrhea, constipation). Complete symptom response rates were 56.3% in the mesalamine group vs. 17.2% in the placebo group at 12 weeks (P=0.001), and 59.3% in the mesalamine group vs.

27.3% in the placebo group at 52 weeks (P=0.013). There were no differences in diverticulitis recurrent rates, surrogate markers, or safety outcomes.56 Parente et al reported similar efficacy results with intermittent mesalamine treatment (mesalamine, 800 mg), as well as a decrease in the relative risk of recurrence after 24 months (P=0.48, 95% CI 0.20-1.15). Physical condition and quality of life improved significantly in the mesalamine group compared to placebo (P=0.021) at 24 months as assessed by the Therapy Impact Questionnaire. They also found that mesalamine-associated improvement resulted in a reduction of the consumption of other gastrointestinal medications.57 In patients with diverticulosis that had been confirmed by colonoscopy, Gaman et al found treatment with mesalamine (514.7 +/- 30.5 mg/day) was better then placebo in reducing the risk of developing diverticulitis, as well as the number of diverticulitis flares and the need for surgery. Thirty-four percent of patients treated with mesalamine had one diverticulitis flare compared to 54% in the placebo group (P=0.044) over a 40-month period. Patients in the mesalamine group had significantly fewer flares (0.9 +/- 0.17) compared to the placebo group (3.25 +/- 0.46; P=0.001) More than 30% of patients in the placebo group (34.6%) required surgery compared to 14.7% in the mesalamine group (P=0.02). The relative risk of developing diverticulitis was 2.47 times higher (95% CI 1.38-4.43) in the placebo group compared to the mesalamine group.58 A large, double-blind, dose-finding, placebo-controlled study comparing multi-matrix system mesalamine vs. placebo in preventing diverticulitis recurrence has been recently concluded (Prevention of Recurrence of Diverticulitis [PREVENT2]).59 While a full reporting of results is pending, a press release in early April 2012, announced that the study did not meet the primary endpoint of reducing the rate of recurrent diverticulitis.

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Results of well-designed, large, placebo-controlled studies are needed to define the optimal role of mesalamine in patients with diverticulosis of the colon.

Table 5. Recent abstracts reporting on studies of 5-ASA for diverticular disease Study/Location

Results

Kruis W et al 2007/EU55

• Mesalamine was superior to placebo in reducing DD-associated pain as measured by pain intensity scores and changes in VAS combined symptoms • Mesalamine significantly improved rectosigmoid-specific symptoms (urgency, tenesmus, diarrhea, constipation) at 12 and 52 weeks • 12 weeks: mesalamine 56.3%; placebo 17.2% (P=0.001) • 52 weeks: mesalamine 59.3%; placebo 27.3% (P=0.013) • Mesalamine significantly improved Therapy Impact Questionnaire scores for physical condition at 24 months (P=0.021 vs. placebo) • Average additional drug consumption was significantly lower (-20.4%, P=0.028) during mesalamine than placebo treatment • Significantly fewer flares with over 40 months with mesalamine treatment: 0.9 +/- 0.17, mesalamine; 3.25 +/- 0.46 placebo; P=0.001 • 1 flare: 34% mesalamine; 54% placebo group (P=0.044) over a 40-month period • Required surgery: 14.7%, mesalamine; 34.6%, placebo, (P=0.02) • Relative risk of developing diverticulitis was 2.47 times higher (95% CI 1.38-4.43) in the placebo group compared to the mesalamine group

Stollman N et al 2010/EU56 (DIVA Trial)

Parente F et al 2011/EU57

Gaman A et al 2011/EU58

The side effect profile of mesalamine in diverticular disease appears to parallel the favorable safety and tolerability profile that has been extensively documented in the setting of IBD.53 Ten to fifteen percent of patients may develop diarrhea as a side effect of treatment with a 5-ASA agent, especially agents with non-absorbable components (olsalazine, balsalazide).53 Acute interstitial nephritis has been reported in a small percentage of patients taking mesalamine (0.26 per patient year) and renal function should be routinely monitored in patients taking mesalamine.60

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Probiotics Probiotics are living microorganisms that can alter gut microflora. Common probiotics include Bifidobacterium spp, Lactobacillus spp, certain strains of E. coli, and the budding yeast Saccharomyces boulardii.43,61 Probiotics have been investigated for the treatment of a variety of digestive disorders as well as the prevention of antibiotic-related gastrointestinal side effects.62-66 Probiotics may exert beneficial effects through a variety of mechanisms—including interference with the ability of a pathogen to adhere to the intestine wall, stimulating immunoglobulin A secretion in Peyer’s patches, and immunomodulating effects that alter the balance of pro- and anti-inflammatory cytokines.65 Probiotics may also interfere with pathogen metabolism (Figure 5).65 Figure 5. Inflammation and Probiotics Cascade Faecal stasis within diverticula causes altered colonic micro-ecology and activation of inflammatory cascade

Probiotics

Increase of: TNF-α and IFN-γ synthesis Intestinal permeability Pathogen translocation

Increase of: IgA production IL-10 synthesis Phagocytic and lymphocytic aspecific activity + “Metabolic competition” with pathogens Anti-bacterial effect

Increase diverticula inflammation

Decreases diverticula inflammation

Source: Tursi A, Papagrigoriadis S. Aliment Pharmacol Thera. 2009;30(6):532.52

Based upon evidence from other therapeutic areas, it has been proposed that probiotics may be beneficial in the treatment of DD. Studies have shown that probiotics (L. acidophilus, Lactobacillus GG, Lactobacillus reuteri) can reduce the severity and duration of acute viral diarrhea in children67-72; as well as the incidence of traveler’s diarrhea and relapses of C. difficile–associated diarrhea.73,74 A study by Gionchetti et al reported that a mixture of different species of lactobacilli prevented pouchitis in patients who underwent colectomy for ulcerative colitis. In that study, 100% of placebo patients relapsed compared to only 15% of patients who received probiotic treatment (P=<0.001).75 A study of patients with irritable bowel syndrome (IBS) showed that Bifidobacterium infantis 35624 alleviated symptoms of IBS including pain/discomfort, bloating/distention and bowel movement difficulty.76 The researchers in that study suggested that the probiotic was acting as an immunomodulator based upon

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changes in the ratio of an anti-inflammatory cytokine interleukin-10 (IL-10) to a proinflammatory cytokine (IL-12).76 While several properties of probiotics may be of benefit in DD, the majority of available data are from lower-quality studies that had methodological limitations including openlabel and uncontrolled design and small sample size.77,78 Three open-label studies have investigated the efficacy of probiotics alone or in combination with a broad-spectrum antibiotic or 5-ASA in preventing recurrence of symptomatic, uncomplicated diverticular disease.

One study compared an antibiotic (dichlorchinolinol)/active charcoal to an antibiotic/active charcoal/probiotic (E. coli, Nissle strain) regimen in patients (N=15) who presented with abdominal pain, irregular defecation, bloating, and excessive flatulence. The addition of the probiotic produced longer intervals of disease quiescence and a greater degree of symptom relief than the antibiotic/absorbent regimen alone.79 The average length of remission after the probiotic regimen was 14.1 months compared to 2.43 months for the antibiotic/active charcoal regimen (P<0.001). All symptoms decreased significantly after treatment with the antibiotic/active charcoal/probiotic regimen (P<0.001).79 The second study investigated the efficacy of Lactobacillus casei DG in combination with mesalamine in patients with SUDD that was in remission.32 Ninety patients (36 men, 54 women, mean age 67.5 years) who were in remission after a rifaximin/mesalamine regimen (rifaximin 800 mg/day plus mesalamine 2.4 g/day for 10 days, followed by mesalamine 1.6 g/day for 8 weeks) were enrolled in a 12-month study.

Patients were randomly assigned to one of 3 groups: mesalamine 1.6 g/day (Group A); L. casei DG 16 billion/day for 15 days/month (Group B); mesalamine 1.6 g/day plus L. casei DG 16 billion/day for 15 days/month (Group C).

A quantitative scale was used to assess constipation, diarrhea, abdominal pain, rectal bleeding, and mucus with the stools.

Of the 85 patients who completed the study, 88% (n=75) were symptom-free (overall symptom score of zero) after 12 months of treatment: 23/27 patients in Group A; 23/29 in Group B, and 29/29 in Group C.32 The third study evaluated a high-potency probiotic (VSL#3 450) in combination with balsalazide in patients with acute, uncomplicated diverticulitis in remission.80 In this pilot study, 30 patients (19 males, 11 females, mean age 60.1 years) were randomly assigned to one of two groups: balsalazide 2.25 g/day for 10 days every month plus VSL#3 450 billion/day for 15 days every month (Group A) or VSL#3 alone 450 billion/day for 15 days every month (Group B). The primary end-point was maintenance of remission throughout a 12month follow-up. At the end of follow-up, 11 patients (73%) in Group A were completely symptom-free; 2 patients complained of only mild, recurrent symptoms. In Group B, 8

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patients (60%) were completely symptom-free; 2 patients complained of mild, recurrent symptoms; 1 patient complained of mild, but continuous symptoms. The differences between the groups were not statistically significant. No side effects were recorded throughout the follow-up in both groups.80

Can you explain the rationale for including probiotics in a treatment regimen for a patient with uncomplicated diverticular disease?

Dr. Antonio Tursi: We know that fecal stasis can alter microflora, not only causing colonic bacterial overgrowth, but also altering the composition of bacterial strains that live in the colon; for example, reducing Bifidobacteria and increasing Bacterioides.

This microbial imbalance can cause microscopic inflammation, resulting in symptoms that are common in patients with uncomplicated diverticular disease. The use of probiotics could potentially break the cycle and help to restore the colonic microecology to a more normal composition.

Preliminary data from the DIVA trial, the only controlled study to date, suggest that probiotic supplementation with Bifidobacterium infantis 35624 does not improve the effectiveness of mesalamine in reducing symptoms after an attack of diverticulitis.54,56,60 Further studies are needed to evaluate the efficacy of probiotics in order to make data-supported recommendations in this setting. Probiotics are not regulated medications, therefore there are no formal clinical trials assessing their safety. In a recent literature review, Whelan et al showed that probiotics had been used safely in immunocompetent hosts in an outpatient setting; however, their safety in debilitated patients or in patients with compromised gut epithelial integrity was unclear.81

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C A S E P R E S E N TAT I O N SECOND ATTACK OF ACUTE DIVERTICULITIS: Mr. K took cyclic rifaximin for one year with improved symptoms and then stopped. Two years later, he again complains of acutely increased abdominal pain that has become more severe over 3 days. He reports cramping, some nausea, and loose stools.

On examination, he has tenderness in the left iliac fossa with no signs or symptoms of peritonitis or systemic illness.

CLINICAL PERSPECTIVE With a second attack of acute diverticulitis and a recently reported difficulty with bowel movements, Mr. Kâ&#x20AC;&#x2122;s clinical status has changed. He is treated with a 10-day course of antibiotics for the acute attack with rapid symptomatic improvement. At follow-up, Mr. K asks if there are any therapeutic options available to diminish his chronic symptoms and/or decrease the likelihood of another recurrence. His physician discusses with him possible surgery or a trial of mesalamine. Mr. K requests more information about both options to make an informed decision.

Figure 6. Diverticular Disease: Symptomatic and Asymptomatic Spectrum Uncomplicated DD Normal Colon

Asymptomatic

Complicated DD Symptomatic High Clinical Significance

Clinical Relevance

Very Common

Common

Uncommon

Rare

led to the characterization of recurrent diverticulitis as a more virulent disease. Clinical practice reflected the belief that patients with recurrent disease were less likely to respond to pharmacologic intervention and more likely to develop complicated disease.86,87 More recent data, however, suggest there are no significant differences in morbidity and mortality in patients with recurrent disease compared to those with 1 or 2 prior episodes.87 A study of more than 300 patients with complicated diverticulitis found that less than half (45.4%) had a history of uncomplicated diverticulitis. Among patients with a prior history of diverticulitis, overall mortality was lower (2.5%) than in patients who presented initially with complicated diverticulitis (10%).

Recent data suggest that the timing of surgery in recurrent diverticulitis should be based on the patientâ&#x20AC;&#x2122;s history as well as clinical and radiologic evaluation. Broderick-Villa et al reported a low rate of recurrence among patients treated nonoperatively, thus arguing against routine colectomy after successful medical management of an initial episode of acute diverticulitis.88 Indications for surgery are evolving generally towards a more conservative approach and later, rather than earlier, prophylactic surgical intervention. The most recent practice guideline for sigmoid diverticulitis endorsed by the American Society of Colon and Rectal Surgeons (ASCR) suggests that the number of attacks of uncomplicated diverticulitis is not necessarily an overriding factor in defining the appropriateness of surgery. A more conservative and individualized approach is suggested.89 The ASCR guidelines reflect more recent data than either the American College of Gastroenterology or the European Union guidelines, which are consistent yet dated and do not reflect newer data and evidence.42 No medical treatments are currently indicated to prevent recurrent diverticulitis; however, mesalamine is being evaluated in several double-blind, placebo-controlled trials.56,57,59

Systemic antibiotics Source: Sopena F, Lanas A. Ther Adv Gastroenterol. 2011;4(6):365.12

Recurrent disease Acute diverticulitis is well characterized. Clinicians can rely upon a robust body of data on the natural history of acute diverticulitis82 to inform their treatment decisions.83-85 Recurrent disease, on the other hand, is more challenging with less well-established data to support the best treatment.

Early studies, including a 1969 study by Parks et al, formed the basis for recommendations for surgery following a second episode of uncomplicated acute diverticulitis. These studies

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Summary The spectrum of diverticular disease presents clinical challenges that change as the disease progresses. Research advances suggest that inflammation plays a role in the development and progression of diverticular disease, opening the door to pharmacologic interventions that target inflammation. Recent clinical evidence challenges commonly held beliefs about surgical and dietary recommendations.

Treatment of acute diverticulitis is well established; however, an individualized approach is most effective in selecting the type and timing of an intervention for symptomatic uncomplicated or recurrent disease.

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What Patient Groups Might Benefit from New Therapeutic Approaches?

References

• Patients with diverticulitis may benefit from treatment with mesalamine

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• Patients with recurrent diverticulitis (after at least two to three episodes) should be carefully evaluated in order to determine if a trial of medical therapy (ie, mesalamine) or elective segmental colectomy should be the next step Key Educational and Practice Points • The incidence of diverticular disease, and diverticulitis in particular, is increasing • Microscopic inflammation likely plays a key role in persistent symptoms and in causing recurrence of diverticulitis • Antibiotic therapy is advised in the acute phase, but not in preventing recurrence of the disease (Level of Evidence III; Grade B)

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• Surgical treatment for recurrent diverticulitis should be considered on an individualized basis (Level of Evidence III; Grade B)

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