ava i l ab l e a t www.sc i enced i r ec t . com

Journal of Crohn's and Colitis (2010) 4, 629–636

Usefulness of oral beclometasone dipropionate in thetreatment of active ulcerative colitis in clinicalpractice: The RECLICU Study☆

Tiago Nunes a,1, Manuel Barreiro-de Acosta b, Pilar Nos c,1,Ignacio Marin-Jiménez d, Fernando Bermejo e, Daniel Ceballos f,Eva Iglesias g, Silvia Gomez-Senent h, Yolanda Torres i, Angel Ponferrada j,José A. Arevalo k, Vicent Hernandez l, Xavier Calvet m,1, Daniel Ginard n,David Monfort o, Maria Chaparro p,1, Noemi Manceñido q,Mercedes Domínguez-Antonaya r, César Villalón s, José L. Perez-Calle t,Carmen Muñoz u, Henar Nuñez v, Daniel Carpio w, Roberto Aramendiz x,Luis Bujanda y,1, Silvia Estrada-Oncins z, Carlos Hermida aa, Jesus Barrio ab,Mª Begoña Casis ac, Ma Carmen Dueñas-Sadornil ad, Luis Fernández ae,Mª Mar Calvo-Cenizo af, Belen Botella ag, Ruth de Francisco ah,Edgar Ayala a,1, Miquel Sans a,⁎,1

for the RECLICU Study Group of GETECCU2

a Hospital Clínic i Provincial/IDIBAPS, Barcelona, Spainb Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spainc Hospital La Fe, Valencia, Spaind Hospital Gregorio Marañón, Madrid, Spaine Hospital Universitario de Fuenlabrada, Madrid, Spainf Hospital Universitario Dr Negrín, Las Palmas, Spaing Hospital Universitario Reina Sofía, Córdoba, Spainh Hospital La Paz, Madrid, Spaini Hospital San Juan de Dios del Aljarafe, Bormujos, Spainj Hospital Infanta Leonor, Madrid, Spaink Hospital Galdakano, Bilbao, Spainl Complexo Hospitalario Universitario de Vigo, Vigo, Spainm Hospital de Sabadell, Sabadell, Spain

Abbreviations: BDP, Beclomethasone dipropionate; UC, Ulcerative colitis; pMS, Partial Mayo score.☆ This study has been presented at the following conferences: Digestive Disease Week, New Orleans, USA, 2010, European Crohn's and ColitisOrganisation annual congress, Prague, Czech Republic, 2010.⁎ Corresponding author. Department of Gastroenterology, Hospital Clínic i Provincial/IDIBAPS, 170 Villarroel, 08036 Barcelona, Spain. Tel.:

+34 932275418/+34 649189146; fax: +34 93 2279387.E-mail address: msans@clinic.ub.es (M. Sans).

1 CIBEREHD: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas.2 Spanish Working Group in Crohn's Disease and Ulcerative Colitis.

1873-9946/$ - see front matter © 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.doi:10.1016/j.crohns.2010.07.003

630 T. Nunes et al.

n Hospital Son Dureta, Palma de Mallorca, Spaino Hospital Terrassa, Terrassa, Spainp Hospital Universitario de La Princesa, Madrid, Spainq Hospital Infanta Sofia, Madrid, Spainr Hospital Universitario Móstoles, Móstoles, Spains Hospital Comarcal Medina del Campo, Valladolid, Spaint Hospital Universitario Fundación Alcorcon, Madrid, Spainu Hospital Basurto, Bilbao, Spainv Hospital Rio Carrión, Palencia, Spainw Complejo Hospitalario Pontevedra, Spainx Consorcio Aragones de Salud, Zaragoza, Spainy Hospital Donostia, Universidad del Pais Vasco, San Sebastián, Spainz Hospital Txagorritxu,Vitoria, Spainaa Clínica Universidad de Navarra, Madrid, Spainab Hospital Rio Hortega, Valladolid, Spainac Hospital 12 de octubre, Madrid, Spainad Hospital Gral S.Pedro Alcántara, Cáceres, Spainae Hospital Clinico, Valladolid, Spainaf Hospital Alto Deba de Mondragón, Guipúzcoa, Spainag Hospital Infanta Cristina, Parla, Spainah Hospital Central de Asturias, Asturias, Spain

Received 5 June 2010; received in revised form 5 July 2010; accepted 5 July 2010

KEYWORDSBeclometasonedipropionate;Steroids;Ulcerative colitis

Abstract

Background: Beclometasone dipropionate (BDP) is a relatively new topically acting oral steroidto treat mild to moderately active ulcerative colitis (UC). We estimate that 20,000 patients havereceived oral BDP in Spain in the last two years. Our aim was to evaluate the efficacy and safetyof oral BDP in clinical practice.

Methods: Retrospective and multicenter study that included 434 patients with active UC treatedwith BDP. The partial Mayo Clinic score (pMS, 0–9) was used to measure disease activity.Remission was defined as post-treatment pMS of 0 or 1; response as a decrease in pMS of 3 pointsor 2 points and N30%, and failure as lack of remission or response.Results: BDP dose was 5 mg/day in 88% of patients and mean treatment duration was 6.2 weeks.BDP achieved remission in 44.4%, response in 22.3% and failed in 33.2% of patients. Mean pMSdecreased from 4.9±1.3 to 2.4±2.3 (pb0.0001). Remission rate was higher in mild and moderatethan in severe UC (pb0.043) and tended to be higher in left-sided and extensive UC than inproctitis (pb0.06). Failure was less frequent in patients treated for N4 weeks (pb0.02). Mildadverse events were reported in 7.6% of patients.Conclusion: BDP induces response or remission in two thirds of active UC patients, with a goodsafety profile. Patients with mild to moderate, left-sided or extensive UC, receiving BDP for morethan 4 weeks are most likely to benefit from this treatment.© 2010 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

1. Introduction

Ulcerative colitis (UC) is a chronic and relapsing inflammatorydisorder of the gut that demands long-lasting treatmenttargeting both flare-up periods and maintenance of remission.Oral systemic steroids have been used to induce remission inpatients with active UC for over 50 years due to their potentanti-inflammatory effects.1 The efficacy of systemic steroidsin this setting has been largely demonstrated, becoming thefirst choice therapy to treat moderate to severely active UCpatients.2–4 However, the wide range of adverse events

associated to these drugs has prompted the search of equallyeffective but less toxic steroid compounds. The so-calledtopically acting oral steroids are a groupof drugs characterizedby a low systemic bioavailability due to an important first-passliver metabolism aimed at minimizing the amount of drug thatreaches the systemic circulation.5 One of these compounds isoral budesonide which has become the first-line therapy toinduce remission inmild tomoderate ileo-cecal Crohn's diseasepatients.6–8 Beclometasone dipropionate (BDP) is anotherexample of topically acting steroid. It was first introduced intothe UC armamentarium as a rectal suspension enema for thetreatment of distal UCwith good efficacywhen compared to 5-

631Oral beclometasone in the treatment of ulcerative colitis

ASA enemas9–12 or topic conventional steroids.13–15 Morerecently, BDP was formulated as an oral enteric coatedcompound to be released in the distal small bowel andthroughout the colon. Using gamma scintigraphy, Steed et al.described that complete BDP tablet (5 mg) disintegrationoccurred mostly in the proximal colon with no evidence of theactive drug in either plasma or urine.16 Later on, Rizzello et al.undertook a dose-finding study comparing doses of 5 and10 mg. Oral BDP was associated to a significant clinical,endoscopic and histological benefit after 4 weeks of treat-ment. In addition, the 5 mg dose was better tolerated andinduced a lower reduction of plasma cortisol levels, beingequivalent to the 10 mg dose in terms of clinical efficacy.17

Subsequently, Campieri et al. compared oral BDP 5 mg and 5-ASA 2.4 g in a 4-week multicentre, randomized, single-blindstudy. Both groups of treatment achieved similar globalremission rates but remission was more frequently obtainedwith BDP than 5-ASA in the subgroup of extensive UCpatients.18 Rizzello et al. also published a 4-week, double-blind, placebo controlled study in which patients with left-sided or extensive UC were randomized to receive oral 5-ASA(3.2 g/d) along with BDP (5 mg/d) or placebo. The combina-tion of oral BDP with 5-ASA was significantly more effectivethan 5-ASA alone with no inhibition of pituitary–adrenalfunction.19 Recently, Papi et al. studied the role of BDP inpatients with mild to moderately active UC not responding to5-ASA. A 4-week course of oral 10 mg/day BDPwas followed bya 4-week administration of 5 mg/day in 64UCpatients inwhich5-ASA had previously failed. The authors found a remission rateof 75% with most patients achieving 1-year maintenance ofremission with no need of further steroid treatment.20 Finally,Balzano et al. evaluated the efficacy of oral BDP and oralprednisone in a mild tomoderately active UC population, in an8-week, multicentre, randomized, double-blind study. Bothdrugs achieved comparable clinical and endoscopic efficacy,with oral BDP presenting less steroid-related adverseeffects.21

Based on the mentioned body of evidence, BDP (5 mg/day) was recently released for marketing in Spain to treatmild to moderately active UC. In the last 2 years, approxi-mately 20,000 UC patients have been treated with BDP in ourcountry. Our purpose was to study the efficacy and safety oforal BDP in the treatment of active UC patients, in clinicalpractice.

2. Materials and methods

2.1. Study design and definitions

This is a retrospective, multicentre study that included 434patients with active UC treated with BDP (Clipper™; ChiesiFarmaceutici SpA, Parma, Italy), recruited at 34 Spanishhospitals. Since endoscopy had not been performed beforeand after BDP treatment in most patients, the partial MayoClinic score (pMS, 0–9), including number of bowel move-ments (0–3), presence of blood in stools (0–3) and physicianglobal assessment (0–3) was used to measure diseaseactivity.22,23 20 patients in whom pre- and/or post-treat-ment pMS could not be calculated were excluded. Other 20patients with pre-treatment pMSb3 were also excluded dueto lack of clinically relevant activity, leaving a total of 394

evaluable patients. Disease activity was defined as mild(pMSb5), moderate (pMS 5 to 7) and severe (pMSN7).Remission was defined as post-treatment pMS of 0 or 1 andresponse as a decrease in pMS of 3 points or 2 points with apMS reduction greater than 30%. Failure was assumed inpatients not achieving remission or response. UC diseaseextension was defined as E1, E2 and E3, according to theMontreal Classification.24 Data regarding demographics,disease description, flare-up severity, dose and duration ofBDP treatment, other previous, concomitant or rescuetherapy and clinical outcome was collected from patient'scharts.

2.2. Ethical issues and study support

The RECLICU Study was approved by the Ethics Committee ofHospital Clinic i Provincial of Barcelona, Spain. Data wasanonymously analysed to preserve patient's confidentiality.This study has been exclusively planned and undertaken bythe RECLICU Study Investigators Working Group, which hasbeen fully supported by GETECCU†. Chiesi España (thecompany that commercialises oral BDP in Spain) was notinvolved in the study design, data analysis or resultsinterpretation.

2.3. Statistical analysis

Qualitative variables were expressed using frequencies.Continuous variables were expressed using mean±standarddeviation. Fisher and Chi-square tests were used to comparequalitative variables. The Student's t-test was used tocompare quantitative variables. All tests were two-tailedwith a significance level set at b0.05. Analyses wereperformed using Stata 10 (Stata Corp., College Station,TX). The Statistical analysis was carried out by theinvestigators of Hospital Clinic, Barcelona (TN, EA and MS).

3. Results

3.1. Patient characteristics and BDP treatment

Patient characteristics are summarized in Table 1. There were394 evaluable patients, 197 men and 197 women. Mostpatients presented left-sided or extensive colitis and almostall patients were on some type of maintenance therapy whenBDP was started, being oral or rectal 5-ASA compounds themost frequently used (Table 1). BDP dose was 5 mg/day in 88%and 10 mg/day in 10% of patients (Fig. 1A). The subgroups ofpatients treated with 5 mg/day and 10 mg/day differed ondisease severity and length of treatment but not on othercharacteristics. A higher proportion of moderate or severe UCwas found in the 10 mg/day group (75%) than in the 5 mg/daygroup (53%, pb0.007) and patients receiving BDP 10 mg/daywere treated for a longer period of time (9.7±6.7 weeks) thanpatients receiving BDP 5 mg/day (6.2±3 weeks; pb0.003).Globalmean BDP treatment durationwas 6.2±3.8 weeks. Onlyfew patients received BDP for less than 4 weeks, being theirtreatment duration 1 or 2 weeks in most of the cases.Approximately half of patients was treated for 4 weeks,which is the regime recommended in the drug label,

Table 1 Patients characteristics and treatment at studyinclusion.

Characteristics N %

GenderM 197 50%F 197 50%

Age at diagnosis (years) 37.4 a 15.3 b

Disease duration (months) 72.27 a 72.86 b

E1 45 11.4%E2 189 48%E3 160 40.6%

Disease severityMILD 167 42.4%MODERATE 211 53.5%SEVERE 16 4%

Treatment at inclusionOral 5-ASA 322 81.7%Topic 5-ASA 157 39.8%Azathioprine 74 18.8%Prednisone 15 3.8%Topic steroids 37 9.4%Biological 11 2.8%Methotrexate 3 0.76%Others 12 3%a Mean.b SD.

632 T. Nunes et al.

and the rest of patients received BDP for more than 4 weeks(5–18 weeks) (Fig. 1B). Apart from the already mentioneddifference on BDP dose, the subgroups of 4 weeks and morethan 4 weeks of treatment did not differ on any other

Figure 1 BDP dose and treatment duration. A) Percentage ofpatients treated with each BDP dose. B) Percentage of patientsaccording to duration of BDP treatment.

characteristic. At the time of starting BDP, other treatmentmodifications were done in a significant proportion ofpatients, being the addition of oral or topic 5-ASA or anincrease in the dose of oral 5-ASA the most commonly found(Fig. 2).

3.2. Efficacy of BDP

BDP was associated with remission in 175 patients (44.4%),response in 88 patients (22.3%) and failed in 131 patients(33.2%) (Fig. 3A). Mean pMS decreased from 4.9±1.3 beforeBDP treatment to 2.4±2.3 after BDP treatment, (pb0.0001)(Fig. 3B). When considering the efficacy of BDP in differentsubgroups of UC patients, we found that remission rate wassignificantly higher in mild and moderate than in severe UC(pb0.04) (Fig. 4A). In addition, a trend towards a higherremission rate in left-sided and extensive UC than in proctitiswas observed (pb0.06) (Fig. 4B). Patients under immuno-suppressive and/or biological maintenance treatmentshowed a lower remission rate compared to patients underother maintenance treatments or no treatment (pb0.006)(Fig. 4C). In respect to other changes introduced in patient'streatment when BDP was started, there was no significantdifference in remission rates depending on other addedtreatment (pb0.4) (Fig. 4D). Patients under BDP treatmentwith 5 and 10 mg achieved comparable remission rates(pb0.9) (Fig. 5A). Finally, patients treated with BDP for morethan 4 weeks presented less failure than patients treatedduring 4 weeks (pb0.02) (Fig. 5B). As shown in Table 2, thiseffect was independent of BDP dose.

3.3. Safety of BDP

Mild adverse effects were reported in 7.6% of patients,Table 3. Cushing like symptoms were only present in 7patients (1.1%), being the most common adverse effectfound, followed by cephalea (1.3%), nausea/vomiting(0.76%) and menstrual disturbances (0.76%). Mild infections(oral candidiasis and upper respiratory infection) werereported in only 2 cases (0.5%). In respect to drug safety indifferent BDP dose groups, we found that 6% of patients (22individuals) on 5 mg/day and 20% of patients (7 individuals)on 10 mg/day dosage reported an adverse effect. Althoughthe presence of an adverse effect was significantly morefrequent in the 10 mg/day group (pb0,01), it´s difficult todraw any conclusion on dose safety due to the low number ofreported adverse events in the series. Finally, there was nodifference in safety regarding patients on 4-week-treatmentregime compared to patients with more than 4 weeks of BDPtherapy.

3.4. Rescue therapy

Systemic steroids were introduced as rescue therapy inmost patients failing BDP treatment (31.7%). In addition,cyclosporine (2.3%) or infliximab (3.6%) were also used in afew patients. Only 6.6% of UC patients required hospital-ization and 1% underwent colectomy after BDP treatment(Fig. 6).

Figure 2 Other treatment changes at BDP start. Each bar represents the percentage of patients in which treatment was modifiedwhen BDP was started.

633Oral beclometasone in the treatment of ulcerative colitis

4. Discussion

This is the first study reporting on the efficacy and safety oforal BDP in the treatment of active UC patients in clinicalpractice. In this study, more than 40% of patients achievedclinical remission and two thirds of them presented clinicalresponse upon oral BDP treatment. Both figures are slightlysmaller than those reported previously. The reasons forthese differences are multiple. First, and probably the mostimportant, the criteria used to define remission andresponse. In our study we used pMS, which is based on

Figure 3 BDP efficacy. A) Global efficacy of BDP treatment:each bar represents the percentage of patients achievingremission, response or failure under BDP treatment; B) Mayoscore pre/post BDP treatment: box plot graphic displays thedistribution of pMS before and after BDP treatment.

number of bowel movements, presence of blood in stools andphysician global assessment (0–9), because endoscopy hadnot been performed before and after BDP treatment in mostpatients. We defined remission as pMS of 0 or 1 after BDPtreatment, a criteria more stringent than that used in mostpreviously published studies, in which remission was definedby a pMS of 0, 1 or 2, in a 0–12 scale.17–21 Another reasoncontributing to the mentioned differences between our workand previous studies is the criteria applied for patientselection. Whereas in our study all UC patients treated withBDP were included in the analysis, to obtain a more completepicture of the efficacy and safety of oral BPD in clinical

Figure 4 Factors influencing BDP-induced remission. Barsrepresent the percentage of patients that achieved remissionunder BDP treatment, according to UC severity (A), extension (B),maintenance treatment (C) and changes in treatment (D).

Figure 5 Efficacy of BDP treatment according to dose andtherapy duration. Bars represent the percentage of patients thatachieved remission, response or failure according to A) BDP doseand B) treatment duration.

Table 3 Adverse events.

Adverse events Frequency Percent

Cushing like symptoms 7 1.77%Cephalea 5 1.27%Nausea/vomiting 3 0.76%Menstrual disturbances 3 0.76%Infection 2 0.5%Asthenia 2 0.5%Anxiety 1 0.25%Dry mouth 1 0.25%Insomnia 1 0.25%Abdominal pain 1 0.25%Muscular cramps 1 0.25%Skin lesions 1 0.25%Malaise 1 0.25%Total 29 7.3%

634 T. Nunes et al.

practice, previous studies selected the UC patients accordingto age (18–70 years), disease extension (left-sided orextensive UC), disease activity (mild to moderate), absenceof concomitant serious diseases, and other requirements onconcomitant treatment at study inclusion.

In addition to defining the global efficacy of oral BDP inclinical practice, we were also able to evaluate the efficacyof this drug in different subgroups of UC patients. Theremission rate was significantly higher in mild and moderatethan in severe UC. Few patients with severe UC were treatedwith BDP in our study, since BDP has been specificallylaunched to treat mild to moderate UC, as disclosed in thedrug label. However, the very low remission rate found in ourfew severe UC patients clearly support the notion thatsystemic steroids, and not oral BDP, are the appropriatetreatment in this potentially life-threatening situation, asrecently recommended in the ECCO guidelines.3 The factthat patients under immunosuppressive or biological main-tenance treatment had a lower remission rate than patientsreceiving mesalazine or no maintenance treatment alsosupports this concept, since the need of immunosuppressiveor biologic therapy undoubtedly identifies a subgroup ofmore severe and more difficult to manage UC patients.

Table 2 BDP duration, and not dose, influences BDP efficacy.

4 weeks N4 weeks

5 mg dose N: 176 N: 148Failure: 59 (33.5%) Failure: 33 (22.2%)

10 mg dose N: 11 N: 26Failure: 6 (55%) Failure: 6 (23%)

In respect to disease extension, there was a trend towardsa higher remission rate in left-sided and extensive colitisthan in proctitis. In fact, oral BDP has been designed to reachthe proximal colon and, for that reason, all previouslypublished studies evaluating oral BDP considered proctitis anexclusion criteria. As discussed for severe UC, although thenumber of patients with proctitis included in our study wasrelatively low, our results clearly demonstrate that patientswith proctitis should not be treated with oral BDP.

Conversely to a previously published clinical trial,19 wewere unable to demonstrate the superiority of combined oralBDP. In fact, none of the treatment changes introduced atthe time of BDP start significantly influenced remission ratesto the BDP therapy. The most likely explanation is the factthat more than 80% of our UC patients already were on oral 5-ASA maintenance treatment when BDP was introduced.

As expected, close to 90% of patients were treated withBDP 5 mg/day, the recommended dose in the drug label,whereas 10% of them received 10 mg/day. We found nodifferences between both doses in respect to BDP efficacy.Our results are in keeping with the first, BDP dose-findingstudy, conducted by Rizzello et al., in which both doses wereequally effective. In that study the 10 mg/day dose caused agreater inhibition of the pituitary–adrenal axis,17 providingthe rational to use the 5 mg/day dose, which was chosen inmost subsequently published BDP clinical trials.18,19 We

Figure 6 Rescue therapy after BDP treatment. Each barrepresents the percentage of patients receiving differentmedical rescue therapies or requiring colectomy.

635Oral beclometasone in the treatment of ulcerative colitis

found a higher proportion of moderate and severe disease inpatients treated with 10 mg/day, which might have influ-enced the efficacy in this subgroup of patients. Thisdifference in respect to disease severity in addition to thelow number of patients treated with 10 mg/day in the seriesmakes BDP efficacy comparisons between the two BDP dosegroups difficult in our study.

One of the most relevant findings of our study was the factthat patients treated for more than 4 weeks failed BDPtherapy less frequently than patients treated for 4 weeks.Differences seemed to be truly dependent on duration of BDPtreatment, since disease extension and severity werecomparable in the two groups and the potential confoundinginfluence of BDP dose was specifically ruled out. Our resultstherefore suggest that duration of BDP treatment should belonger than 4 weeks, which is the recommended length ofBDP treatment in the drug label. The fact that all previouslypublished clinical trials only used 4 weeks of BDP treatmentis really surprising if we take into account that other wellestablished treatment options for mild to moderate UC, suchas oral 5-ASA and systemic steroids, are used in this settingfor a minimum of 8 to 12 weeks. In that regard, a veryrecently published, non-controlled study, using for the firsttime a 8-week course of BDP in mild to moderately active UCpatients previously not responding to 5-ASA has reported thehighest response and remission rates published so far,20

which might also support the notion that more than 4 weeksof treatment are required to successfully manage mild tomoderately active UC with BDP. Although encouraging, theseresults require to be confirmed due to the uncontrollednature of the study and the relatively small number ofpatients included in it.

Systemic steroids were introduced as rescue therapy inmost patients failing BDP treatment. We can assume that thistreatment had a high efficacy after BDP failure, based on therelatively low proportion of patients that required additionaltreatment with cyclosporine or infliximab. Consideredtogether, these results suggest that the failure of BDP,which occurs in one third of UC patients, can be successfullymanaged introducing systemic steroids, leaving the colect-omy rate as low as 1%.

Finally, our study also provides interesting data regardingoral BDP safety. Although the retrospective nature of ourstudy is an obvious limitation to address this issue, the factthat no serious adverse events were identified and mildadverse events were only found in 7.6% of the cases in thiscohort of 394 UC patients, points towards an excellent safetyprofile of this drug. Our results are in keeping with those of adouble-blind trial, very recently presented at the ECCO 2010Meeting, in which patients receiving BDP experienced lesssteroid-related side effects than patients treated with oralprednisone.21

In conclusion, our study is the first aimed at defining theusefulness of oral BDP in clinical practice, a scenario inwhich BDP is more frequently used associated with sometype of maintenance therapy. It demonstrates that thisdrug is efficacious and safe in the treatment of active UC.Oral BDP induces remission in more than 40% and responsein two thirds of UC patients. Patients with left-sided orextensive, mild or moderately active UC that are treatedfor more than 4 weeks present the best outcome inresponse to oral BDP.

Acknowledgements

Grant support:This Study has been supported by GETECCU, the Spanish

Working Group in Crohn's Disease and Ulcerative Colitis.El Centro de Investigación Biomédica en Red de Enferme-

dades Hepáticas y Digestivas (CIBEREHD) is funded by theInstituto de Salud Carlos III.

Statement of authorship:All authors have made substantial contributions to the

conception and design of the study, acquisition, analysis andinterpretation of data, in addition to drafting and revisingthe manuscript.

References

1. Truelove SC, LJ WITTS. Cortisone in ulcerative colitis; finalreport on a therapeutic trial. Br Med J 1955;2:1041–8.

2. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines inadults (update): American College of Gastroenterology, Prac-tice Parameters Committee. Am J Gastroenterol 2004;99:1371–85.

3. Travis SP. European evidence based consensus on the manage-ment of ulcerative colitis: current management. J Crohns Colitis2008;2:24–62.

4. Carter MJ, Lobo AJ, Travis SP. Guidelines for the management ofinflammatory bowel disease in adults. Gut 2004;53(Suppl 5):V1–V16.

5. Harris DM. Some properties of beclomethasone dipropionate andrelated steroids in man. Postgrad Med J 1975;51:20–5.

6. Seow CH, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH.Budesonide for induction of remission in Crohn's disease.Cochrane Database Syst Rev 2008:CD000296.

7. Travis SP, Stange EF, Lemann M, Oresland T, Chowers Y, ForbesA, et al. European evidence based consensus on the diagnosisand management of Crohn's disease: current management. Gut2006;55(Suppl 1):i16–35.

8. Seow CH, Benchimol EI, Steinhart AH, Griffiths AM, Otley AR.Budesonide for Crohn's disease. Expert Opin Drug Metab Toxicol2009;5:971–9.

9. Manguso F, Balzano A. Meta-analysis: the efficacy of rectalbeclomethasone dipropionate vs. 5-aminosalicylic acid in mildto moderate distal ulcerative colitis. Aliment Pharmacol Ther2007;26:21–9.

10. Biancone L, Gionchetti P, Blanco GV, Orlando A, Annese V, PapiC, et al. Beclomethasone dipropionate versus mesalazine indistal ulcerative colitis: a multicenter, randomized, double-blind study. Dig Liver Dis 2007;39:329–37.

11. Gionchetti P, D'Arienzo A, Rizzello F, Manguso F, Maieron R,Lecis PE, et al. Topical treatment of distal active ulcerativecolitis with beclomethasone dipropionate or mesalamine: asingle-blind randomized controlled trial. J Clin Gastroenterol2005;39:291–7.

12. D'Arienzo A, Manguso F, Castiglione GN, Vicinanza G, ScaglioneG, Bennato R, et al. Beclomethasone dipropionate (3 mg)enemas combined with oral 5-ASA (2.4 g) in the treatment ofulcerative colitis not responsive to oral 5-ASA alone. Ital JGastroenterol Hepatol 1998;30:254–7.

13. Campieri M, Cottone M, Miglio F, Manenti F, Astegiano M,D'Arienzo A, et al. Beclomethasone dipropionate enemas versusprednisolone sodium phosphate enemas in the treatment ofdistal ulcerative colitis. Aliment Pharmacol Ther 1998;12:361–6.

14. Halpern Z, Sold O, Baratz M, Konikoff F, Halak A, Gilat T. Acontrolled trial of beclomethasone versus betamethasone

636 T. Nunes et al.

enemas in distal ulcerative colitis. J Clin Gastroenterol1991;13:38–41.

15. van der HH, van dB.-G. V, Tytgat GN, Endert E, Wiltink EH,Schipper ME, et al. Comparison of beclomethasone dipropionateand prednisolone 21-phosphate enemas in the treatment ofulcerative proctitis. J Clin Gastroenterol 1988;10:169–72.

16. Steed KP. The in vivo behavior of a colonic delivery system: apilot study in man. Int J Pharm 1994:199–206.

17. Rizzello F, Gionchetti P, Galeazzi R, Novelli G, Valpiani D,D'Arienzo A, et al. Oral beclomethasone dipropionate in patientswith mild to moderate ulcerative colitis: a dose-finding study.Adv Ther 2001;18:261–71.

18. Campieri M, Adamo S, Valpiani D, D'Arienzo A, D'Albasio G,Pitzalis M, et al. Oral beclometasone dipropionate in thetreatment of extensive and left-sided active ulcerative colitis:a multicentre randomised study. Aliment Pharmacol Ther2003;17:1471–80.

19. Rizzello F, Gionchetti P, D'Arienzo A, Manguso F, Di MG, AnneseV, et al. Oral beclometasone dipropionate in the treatment of

active ulcerative colitis: a double-blind placebo-controlledstudy. Aliment Pharmacol Ther 2002;16:1109–16.

20. Papi C, Aratari A, Moretti A, Mangone M, Margagnoni G, Koch M,et al. Oral beclomethasone dipropionate as an alternative tosystemic steroids in mild to moderate ulcerative colitis notresponding to aminosalicylates. Dig Dis Sci 2009.

21. Balzano A, Manguso F, Alberici M. Abstract4 ed. ; 2010. S53.22. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosa-

licylic acid therapy for mildly to moderately active ulcerativecolitis. A randomized study. N Engl J Med 1987;317:1625–9.

23. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN,Ellenberg JH. Use of the noninvasive components of the Mayoscore to assess clinical response in ulcerative colitis. InflammBowel Dis 2008;14:1660–6.

24. Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN,Brant SR, et al. Toward an integrated clinical, molecular andserological classification of inflammatory bowel disease: reportof a working party of the 2005 Montreal World Congress ofGastroenterology. Can J Gastroenterol 2005;19(Suppl A):5–36.