Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005), pp. 581–586 ( C© 2005)DOI: 10.1007/s10620-005-2478-z

Efficacy of Mesalazine in the Treatment ofSymptomatic Diverticular Disease

FRANCESCO DI MARIO, MD,* GIOVANNI ARAGONA, MD,* GIOACCHINO LEANDRO, MD,†GIUSEPPE COMPARATO, MD,* LIBERA FANIGLIULO, MD,* LUCAS G. CAVALLARO, MD,*

GIULIA M. CAVESTRO, MD,* VERONICA IORI, MD,* MARTA MAINO, MD,* ALI M. MOUSSA, MD,*ALESSANDRO GNOCCHI, MD,‡ GIANCARLO MAZZOCCHI, MD,§ and ANGELO FRANZE, MD‡

We aimed to improve symptoms by means of mesalazine in symptomatic colonic diverticular diseasepatients. One hundred seventy outpatients (98 M, 72 F; age, 67.1 years; range, 39–84 years) wereassigned to four different schedules: rifaximin, 200 mg bid (Group R1: 39 pts), rifaximin, 400 mgbid (Group R2: 43 pts), mesalazine, 400 mg bid (Group M1: 40 pts), and mesalazine, 800 mg bid(Group M2: 48 pts), for 10 days per month. At baseline and after 3 months we recorded 11 clinicalvariables (upper/lower abdominal pain/discomfort, bloating, tenesmus, diarrhea, abdominal tender-ness, fever, general illness, nausea, emesis, dysuria), scored from 0 = no symptoms to 3 = severe.The global symptomatic score was the sum of all symptom scores. After 3 months in all schedulesbut Group R1, 3 of the 11 symptoms improved (P < 0.03); the global score decreased in all groupsbut Group R1 (P < 0.0001). Mesalazine-treated patients had the lowest global score at 3 months(P < 0.001). Mesalazine is as effective as rifaximin (higher dosage schedule) for diminishing somesymptoms, but it appears to be better than rifaximin for improving the global score in those patients.

KEY WORDS: mesalazine; diverticular disease; diverticula; rifaximin.

Acquired diverticular disease (DD) of the colon is verycommon in developed countries and its prevalence in-creases with age, varying from less than 10% of subjectsunder 40 years to an estimated 50–66% of patients over age80 (1). According to a recent report by the American Gas-troenterological Association on the burden of digestiveillnesses in the United States, DD represents, in terms ofdirect and indirect costs, the fifth most important gastroin-testinal disease, with a mortality rate of 2.5 per 100,000per year (2).

Manuscript received July 2, 2004; accepted September 9, 2004.From the *Chair of Gastroenterology, University of Parma, Parma,

†Gastroenterological Hospital “S. De Bellis,” IRCCS, Castellana Grotte,Bari, ‡Gastroenterology and Endoscopy Unit, Az. Ospedaliera, Parma,and §U.O. Chirurgia Borgovalditaro, AUSL, Parma, Italy.

This work was carried out under the auspices of the Roberto FariniFoundation for Gastroenterological Research.

Address for reprint requests: Prof. Francesco Di Mario, Uni-versita degli Studi di Parma, Dipartimento di Scienze Cliniche,sezione di Gastroenterologia, Via Gramsci 14, 43100 Parma, Italy;francesco.dimario@unipr.it.

To refer to an acquired alteration present in about two-thirds of the elderly as a “ disease” seems inaccurate, par-ticularly as, in the majority of patients, colonic divertic-ula are asymptomatic (diverticulosis) (1). Nevertheless,an estimated 20% of affected individuals develop symp-toms in their lifetime, such as abdominal pain and/ordiscomfort, bloating, and disturbance of bowel habits.This clinical condition is termed DD (3), which may besymptomatic uncomplicated, recurrent symptomatic, orcomplicated (4–6).

Inflammation of the bowel surface leads to a conditioncalled uncomplicated diverticulitis. Some authors empha-size that clinical diverticulitis virtually always representsa micro perforation, even if the colonic mucosa appearsmacro- and microscopically normal, despite considerableinflammation of the pericolonic tissue (7). The presenceof free perforation, fistula, abscesses, or obstruction istermed complicated acute diverticulitis. Lower gastroin-testinal tract bleeding from diverticula is not associatedwith underlying acute inflammation; rather, the presumed

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DI MARIO ET AL.

cause of this complication is erosion of submucosal bloodvessels by impacted stool at the neck of a diverticulum (7).

Treatment of DD is aimed to relieve symptoms and toprevent major complications (8). Bran and bulking agentsare commonly used in the treatment of symptomatic DDbut their real efficacy is still controversial. Although somecontrolled clinical trials have shown a benefit of high-fiberdiets in obtaining symptomatic relief (9, 10), other stud-ies have failed to show positive results (11, 12). However,there is no evidence that such diets prevent diverticuli-tis (3). Anticholinergic drugs and spasmolytic agents arewidely used in the treatment of symptomatic DD. The ob-served hypermotility of the sigmoid colon in many symp-tomatic patients provides the rationale for using thesedrugs (13). However, the efficacy of spasmolytic agentshas never been clearly documented (3). Antibiotics arewidely used in the treatment of diverticulitis (3), andin a subset of patients with symptomatic DD where aninflammatory component may be clinically suspected, acourse of antibiotics is advisable (8). Rifaximin (a broad-spectrum, poorly absorbable antibiotic) appeared to be ofsome advantage in obtaining symptom relief in uncom-plicated DD (14, 15) and in reducing the incidence of themain complications of this disease (16, 17). The rationalefor antibiotic therapy in these patients is the role of intesti-nal microflora in determining symptoms by fiber degra-dation and gas production (18). Nevertheless, an Italianstudy has reported an increase in pulmonary hydrogen ex-cretion in DD and the therapeutic effect of rifaximin doesnot seem to be due to a persistent correction of this alter-ation. In addition, this drug appears to cause no significantimbalance in the intestinal ecosystem (19).

Mucosal inflammation seems to play an important rolein the etiophatogenesis of diverticulitis by an imbalanceamong proinflammatory (IL-1, TNF) and antinflammatory(IL-1 ra, IL-4, IL-10, IL-11) cytokines (20), with a conse-quent increase in the intramucosal secretion of NO (21).Luminal mucosal inflammation may also occur, not onlyin acute attacks of diverticulitis and peridiverticulitis, butalso, although unusually, in uncomplicated DD (22, 23).This kind of diverticular colitis is wholly confined to thesegment affected by DD and may closely mimic inflam-matory bowel disease (IBD), with its complex flogisticcharacteristics (24). Many of these cases of diverticularcolitis seem to respond favorably to treatment similar tothat given for IBD (22).

Two clinical studies reported that supplementary treat-ment with mesalazine in patients with colonic DD or withrecurrence diverticulitis proved to be well tolerated andpromising for the management of these diseases (25, 26).

The aim of our study was to compare the efficacy ofcyclic administration of rifaximin versus mesalazine in

obtaining symptom relief in patients with symptomaticuncomplicated colonic DD.

MATERIALS AND METHODS

The study was structured as a monocentric, prospective, ran-domized, open trial. Over a period of 2 years a total of 170consecutive outpatients with uncomplicated DD of the colon, di-agnosed by double-contrast barium enema and/or colonoscopy,were screened at our Gastroenterological Unit and randomly as-signed to four different treatment regimens: 39 patients receivedrifaximin, 200 mg bid (Group R1), and 43 patients received ri-faximin, 400 mg bid (Group R2), for 10 days during the firstpart of every month; 40 patients received mesalazine, 400 mgbid (Group M1), and 48 patients received mesalazine, 800 mgbid (Group M2), for 10 days every month. No selective dietaryregimen was prescribed at entry except the recommendation forall patients to follow a high-fiber diet.

Some main criteria had to be fulfilled to enter the trial: agebetween 18 and 85 years, endoscopic and/or radiologic evidenceof DD (with the presence of more than five diverticula) of the leftcolon and the presence of symptoms attributable to the DD ofthe colon such as upper and/or lower abdominal pain/discomfort,bloating, tenesmus, diarrhea, abdominal tenderness, fever, anddysuria. Only patients who experienced two or more symptomsfor at least 1 month before enrolment entered the study.

Exclusion criteria were solitary diverticulum of the colon,signs of diverticulitis, previous colonic surgery, concomitantcolonic or extracolonic cancer, use of antibiotics in the previ-ous 4 weeks, chronic hematological and/or hepatic and/or renaldiseases, immunodeficiency, pregnancy or lactation, proven in-tolerability to rifaximin or mesalazine, and questionable abilityto cooperate. All criteria were assessed by means of a com-plete history, physical examination, endoscopy/double-contrastX-ray, and analysis of biochemical blood samples. Diverticuli-tis was excluded on the basis of clinical and laboratory signs(absence of rebound tenderness or other signs of peritoneal in-flammation and normal values of body temperature, leukocytes,and erythrocyte sedimentation rate) with radiographic or endo-scopic examinations (plain abdominal film, barium enema orcolonoscopy, ultrasonography or computed tomography, specif-ically performed on the basis of clinical findings) excluding thelocal inflammatory process of the colonic wall, perforation, ab-scesses, or stenosis (3, 5).

Clinical evaluation was performed by an interview ques-tionnaire and a clinical visit at admission and after 3 months,taking into account 11 clinical variables (upper abdominalpain/discomfort, lower abdominal pain/discomfort, bloating,tenesmus, diarrhea, abdominal tenderness, fever, general illness,nausea, emesis, dysuria) scored as follows: 0 = no symptoms;1 = mild, symptoms easily tolerated; 2 = moderate, symptomssufficient to cause interference with usual daily activities; and3 = severe, incapacitating symptoms with inability to performnormal activities. Furthermore, the patients were invited to returnfor control visits whenever they considered it necessary.

The Global Symptomatic Score (GSS) (15, 16), calculated asthe sum of all symptom scores, was assigned to each patient atevery clinical evaluation (maximum score = 33). It was assessedto evaluate the effect of the administered therapy on the over-all severity of the combined symptoms. It therefore reflects theoverall clinical conditions of the patients during the follow-up.

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TABLE 1. DEMOGRAPHIC AND CLINICAL CHARACTERISTICS OF THE PATIENTS AT BASELINE (ALL DIFFERENCES

NONSIGNIFICANT)

Rifaximin, Rifaximin, Mesalazine, Mesalazine,200 mg bid 400 mg bid 400 mg bid 800 mg bid

Patients 39 43 40 48Males 25 (64.1%) 24 (55.8%) 26 (65%) 23 (47.9%)Females 14 (35.9%) 29 (44.2%) 14 (35%) 25 (52.1%)Age (mean yr ± SD) 66 ± 7.1 66 ± 10.9 67 ± 9.5 67 ± 9.2

Range (53–83) (44–82) (39–83) (44–84)Global Symptomatic Score (mean ± SD) 8.38 ± 4.06 9.81 ± 4.99 11 ± 4.96 8.83 ± 4Occurrence rate of symptoms (%)

A. Upper abdominal pain/discomfort 41.1 58.2 47.5 45.9B. Lower abdominal pain/discomfort 56.5 62.7 67.5 68.7C. Bloating 94.8 93 90 87.2D. Tenesmus 56.4 62.7 75 50E. Diarrhea 43.5 58.1 65 50F. Abdominal tenderness 84.6 65.1 77.5 72.9G. Fever (last 3 months) 25.6 20.9 27.5 29.1H. General illness 43.5 44.1 59 56.2I. Nausea 30.7 37.2 42.5 39.5L. Emesis 17.9 23.2 37.5 16.6M. Dysuria 15.3 18.6 20 31.2

The frequency rate of each symptom was calculated on the basisof symptom presence (yes/no), independently of severity, and itwas evaluated to determine which symptom benefited most frommesalazine and which from rifaximin.

Patients who developed complications or side effects,recorded by means of a structured clinical interview at everyclinical evaluation or at any time required, were withdrawn fromthe study. Patients who voluntarily stopped the treatment or werelost to follow-up were considered dropouts. Noncompliance wasdefined as an interruption of drug intake for more than 4 weeksor as less than 80% of the appropriate dose being taken. Thestudy was performed according to the Declaration of Helsinkiand all patients included in the study gave oral informed consenton entering the study.

Statistical Methods. Demographic and clinical characteris-tics are given as mean ± standard deviation and range for con-tinuous variables or as absolute and percentage frequencies fordiscrete variables. The variation in GSS was analyzed by meansof nonparametric tests: Kruskall–Wallis one-way ANOVA orWilcoxon signed-rank test, when appropriate. For all calcula-

Fig 1. Frequency of symptoms that showed a statistical difference after 3 months of treatment.

tions BioMedical Data Processing (BMDP, dynamic version 7;University of California, Los Angeles) was used. A P value ofless then 0.05 was considered significant.

RESULTS

Demographic and clinical characteristics of patients ad-mitted to the study are shown in Table 1. At admissionthe four groups were homogeneous for age, gender, fre-quency of symptoms, and mean GSS. Compliance wassatisfactory, as all patients took more than 80% of the pre-scribed drugs. All 170 patients admitted to the study werefollowed up for 3 months; none was withdrawn duringtherapy. Results were analyzed by means of an evaluationof GSS in the four treatment groups and by consideringthe frequency of each symptom after follow-up. Figure 1reports symptoms with a significant statistical difference

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Fig 2. Global Symptomatic Score of symptoms at baseline and after 3 months of treatment.

after 3 months of therapy. The analysis of standardizeddeviates showed that all treatments but rifaximin, 200 mgbid (Group R1), were effective in reducing lower abdom-inal pain/discomfort, tenesmus, and diarrhea (P < 0.02,P < 0.01, and P < 0.03 respectively) after 3 months oftherapy; none of the three schedules was better than theothers for reducing symptom frequency; however, patientstreated with mesalazine, 800 mg bid (Group M2), showeda more marked reduction in symptom severity than thosein group R2 and M1 (data not shown). No differences werefound regarding other symptoms studied.

Fig 3. Global Symptomatic Score of symptoms at baseline and after 3 months of treatment.*Mesalazine group showed a more marked reduction in mean GSS at 3 months.

Analysis of the mean GSS is shown in Figure 2. Allgroups but Group R1 had a significantly reduced scoreafter 3 months (P < 0.0001) of therapy. No statisticallysignificant differences were noted among the three effec-tive therapies, although all of them were better than theGroup R1 treatment in diminishing such score (P < 0.05).A further analysis was performed comparing mean GSSof all patients treated with rifaximin (Groups R1 plus R2)vs patients treated with mesalazine (Group M1 plus M2)(Figure 3). After 3 months of therapy both Groups R1 plusR2 and Groups M1 plus M2 showed a highly significant

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reduction of their mean GSS (P < 0.0001), even thoughthe treatment with mesalazine showed better results thanrifaximin in diminishing the mean GSS at 3-monthfollow-up (P < 0.001).

DISCUSSION

In the present study, cyclic administration ofmesalazine, at a lower dosage than that normally usedin the treatment of IBD, has shown promising results forreducing the frequency of some symptoms (lower abdom-inal pain/discomfort, tenesmus, diarrhea) and the meanGSS of patients with symptomatic uncomplicated colonicDD. At 3-month follow-up, all schedules but the Group R1treatment effectively relieved symptoms in these patients,although Group M2, which received mesalazine, 800 mgbid, showed a more marked reduction in symptom sever-ity. Furthermore, mesalazine-based treatments were moreeffective than rifaximin-based treatments at lowering themean GSS.

The favorable effect of mesalazine in DD has previouslybeen observed in two Italian studies. In the first, patientstreated with sulbactam/ampicillin and rifaximin followedby mesalazine showed a lower probability of symptomaticrelapse (P = 0.00005) and microhemorrhagic phenom-ena (P = 0.001) versus a group treated without supple-mentation of mesalazine (25). In the second study, recur-rent diverticulitis attacks benefited from the synergic effectof a poorly absorbable antibiotic, rifaximin, plus an anti-inflammatory drug, mesalazine, to reduce the duration ofsymptoms more rapidly, to improve bowel habits morerapidly, and to restore normal lumen of the colon betterthan rifaximin alone (26). About their study, Tursi and col-leagues concluded that rifaximin plus mesalazine could beconsidered the best medical treatment currently availablefor patients showing recurrent attacks of diverticulitis.

Since inflammation is the main pathogenetic mecha-nism in diverticulitis and DD-associated chronic colitis(22–24), the use of mesalazine in the treatment of suchdiseases is advisable based on its anti-inflammatory prop-erty, as it can reduce mucosal hyperaemia, oedema, ero-sion, and other inflammatory signs observed near and of-ten well away from the diverticular orifices themselves(22–24, 27). DD of the colon could benefit from anti-inflammatory agents not only when inflammation of di-verticula, diverticulitis, and adjacent subserosal tissues,peridiverticulitis, are present, but also when luminal mu-cosal inflammation occurs (22–24). Endoscopically in-tramucosal hemorrhage, congestion, and granularity canaffect the mucosa away from the diverticula (27), espe-cially the crescientic mucosal folds (22). Given its seg-mental localization in the sigmoid colon and histopatho-

logical similarity to idiopathic inflammatory bowel dis-ease, DD-associated chronic colitis must be distinguishedfrom Crohn’s disease (28–33) and ulcerative colitis withrelative sparing of the rectum (34). Crohn’s disease of thesigmoid colon may also induce diverticulitis in patientswith DD (32). Even granulomata cryptitis, a histiocyticand granulomatous reaction to disruptive crypt abscessesin the mucosa, a characteristic feature of Crohn’s disease(35, 36), may accompany the luminal mucosal inflam-matory response that occurs in DD (23). In this light, wethought that a well-known anti-inflammatory drug such asmesalazine could be of some advantage in lessening thetiresome symptoms of symptomatic patients affected byDD. In the present study 3 of 11 symptoms improved withboth the mesalazine schedule and rifaximin at a higherdosage, but mesalazine-treated patients showed a lowerGSS than rifaximin patients. This score represents thesum of all single symptoms recorded and consequentlythe overall clinical condition of every patients and thustheir general well-being; the advantage of intermittent ad-ministration of mesalazine is attested to by the significantreduction in the GSS after 3 months (P < 0.001) com-pared to that in rifaximin-treated patients.

In conclusion, 3 months of cyclic administration ofmesalazine is as effective as rifaximin (higher dosageschedule) in diminishing some symptoms related tocolonic DD, but it appears to be better than rifaximinin improving the GSS in these patients. Larger studieswith a longer follow-up appear to be warranted; a pos-sible synergistic action of the mesalazine in associationwith rifaximin could be verified.

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