Oral locally active steroids in inflammatory bowel disease

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1 Journal of Crohn's and Colitis (2013) 7, Available online at REVIEW ARTICLE Oral locally active steroids in inflammatory bowel disease Tiago Nunes a, Manuel Barreiro-de Acosta b, Ignácio Marin-Jiménez c, Pilar Nos d, Miquel Sans e, a Chair for Biofunctionality, Research Center for Nutition and Food Science (ZIEL), Technische Universität München, Freising, Germany b Hospital Clinico Universitário de Santiago de Compostela, Spain c Hospital Gregório Marañon, Madrid, Spain d Hospital La Fe, Valencia, Spain e Department of Digestive Diseases, Centro Medico Teknon, Barcelona, Spain Received 22 March 2012; received in revised form 1 June 2012; accepted 10 June 2012 KEYWORDS Budesonide; Beclomethasone; Steroids; Ulcerative colitis; Crohn's disease; Microscopic colitis Abstract IBD is a chronic and relapsing inflammatory disorder of the gut that demands long-lasting treatment targeting both flare-up periods and maintenance of remission. Oral systemic steroids have been used to induce remission in patients with active IBD for over 50 years due to their potent antiinflammatory effects. The efficacy of systemic steroids in this setting has been largely demonstrated. However, the wide range of adverse events associated with these drugs has prompted the development of equally effective but less toxic steroid compounds. Currently, topically acting oral steroids are an important therapeutic option for Crohn's disease, ulcerative colitis and microscopic colitis, being oral budesonide and oral beclomethasone established elements of the IBD armamentarium. At present, oral budesonide is the first-line therapy to induce remission in microscopic colitis and mild to moderate ileocaecal CD patients and oral beclomethasone is effective treating mild to moderate UC patients with left-sided or extensive disease. This review aims at evaluating the current role of these compounds in IBD clinical practice European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. Contents 1. Introduction Budesonide Abbreviations: IBD, inflammatory bowel disease; CD, Crohn's disease; MC, microscopic colitis; UC, Ulcerative colitis. Corresponding author at: Department of Digestive Diseases, Centro Medico Teknon, 12 Vilana, 08022, Barcelona, Spain. address: sans@dr.teknon.es (M. Sans) /$ - see front matter 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi: /j.crohns

2 184 T. Nunes et al Efficacy of budesonide for induction of remission in CD Budesonide vs. placebo Budesonide vs. mesalamine Budesonide vs. other corticosteroids Efficacy of budesonide in maintenance of remission in CD Efficacy of budesonide for prevention of postsurgical recurrence in CD Budesonide in pregnancy and paediatric CD Budesonide for induction of remission in ulcerative colitis (UC) Budesonide for maintenance of remission in ulcerative colitis (UC) Budesonide in chronic refractory pouchitis Budesonide in microscopic colitis (MC) Beclomethasone Beclomethasone vs. mesalamine in UC Beclomethasone in UC patients not responding to mesalamine Beclomethasone vs. conventional steroids in UC Beclomethasone as induction therapy for Ileal CD Beclomethasone as maintenance therapy for Ileal CD Conclusion Conflict of interest statement Acknowledgements References Introduction After antibiotics, most gastroenterologists would choose corticosteroid treatment as the second major advance in drug therapy during the first half of the twentieth century. 1 Following the demonstration of their therapeutic effects in rheumatoid arthritis in the late 1940s, 2 corticosteroids were rapidly introduced in inflammatory bowel disease (IBD) armamentarium. Although advances in general medical care could have contributed to the mortality decline of an acute attack of ulcerative colitis (UC) after the 1950s, the introduction of corticosteroid therapy in IBD undoubtedly played a major role in improving UC mortality. 3 Corticosteroids offer a high rate of clinical response and remission in both UC and Crohn's disease (CD), but their introduction is often associated with severe adverse effects that limit their long-term use. 4 6 The administration of corticosteroids induces a variety of changes in the normal metabolism. Clinicians must always bear in mind that the choice of dose, route and duration of therapy impacts clinical efficacy but also determines the severity of the subsequent side-effects. In the individual level, many factors also influence the safety profile of steroids such as the genetic background, the endocrine and nutritional status and the disease itself or other concomitant comorbidities. 7 The most noticeable side-effects associated with systemic steroids use include glaucoma, fluid retention, increased blood pressure, weight gain, diabetes, loss of bone calcium and an increased risk for infections. 8 In this context, an ideal corticosteroid therapy theoretically should be as potent as classical systemic corticosteroids, but with an improved safety profile. In recent years, new corticosteroid molecules have been developed for IBD management combining three major characteristics: an oral controlled-release formulation that can reach different bowel segments, high affinity for the corticosteroid receptor affording potent local efficacy and an important first-pass liver metabolism. 9 These so-called topically acting oral steroids are characterized by a low systemic bioavailability aimed at minimizing the amount of drug that reaches the systemic circulation. As a result, these relatively new drugs manage to achieve an enhanced safety profile without significant loss of therapeutic effectiveness. 9,10 Oral budesonide and beclomethasone are two fine examples of oral locally acting steroids used in IBD clinical practice. Oral budesonide has become first-line therapy to induce remission in mild to moderate ileocaecal CD patients and oral beclomethasone has its role in treating mild to moderate UC activity. This review aims at evaluating the current role of these compounds in IBD clinical practice. 2. Budesonide Budesonide is a synthetic steroid that has high topical glucocorticoid activity with low systemic bioavailability caused by a high first-pass hepatic metabolism. Budesonide has a superior side-effect profile to conventional steroid therapy because of its relatively low bioavailability, and is better able to preserve adrenal function and bone mass. Superior tolerability might be attributed to extensive first-pass metabolism of budesonide by cytochrome P450 3A (CYP3A) enzymes and to gastrointestinal efflux mediated by P-glycoprotein, a product of the multidrug resistance 1 gene (MDR1). 11, Efficacy of budesonide for induction of remission in CD Budesonide vs. placebo Greenberg et al. in a double-blind, multicentre trial with 258 patients compared the efficacy of budesonide 3, 9, or 15 mg daily with placebo. 13 After eight weeks of treatment, remission occurred in 51% of patients receiving 9 mg of budesonide (43% and 33% with 15 and 3 mg, respectively) as compared to 20% of those receiving placebo (P b 0.001). Subsequently, Tremaine et al. published a multicentre, double blind, randomized trial with 200 patients with mild to

3 Oral locally active steroids in inflammatory bowel disease 185 Table 1 Studies comparing oral budesonide with conventional steroids for induction of remission at 8 weeks. Author n Drugs Remission (%) Main conclusions Rutgeerts (19) 176 Budesonide (9mg) Prednisolone (40mg) Bar-Meir (20) 201 Budesonide (9mg) Prednisone (40mg) Gross (21) 67 Budesonide (9mg) Methylprednisolone (48mg) Campieri (22) 178 Budesonide (9mg) Prednisone (40mg) Escher (23) 48 Budesonide (9mg) Prednisolone (1mg/kg/day) Van Ierssel (24) 18 Budesonide (9mg) Prednisolone (40mg) Levine (26) 33 Budesonide (9mg) Prednisone (40mg) Seow a (15) 750 Budesonide Conventional steroids Prednisolone no superior to budesonide Budesonide is as effective as prednisone Budesonide is as effective as methylprednisolone Budesonide is as effective as prednisone No significant differences between the two groups No significant differences between the two groups Budesonide is as effective as prednisone Budesonide is less effective than conventional steroids a Seow et al. performed a meta-analysis including a total of 750 patients in 8 trials. The global rates are related to remission after 8 weeks. Budesonide was demonstrated to be inferior to conventional steroids for the induction of remission in active CD. moderate CD involving distal ileum and/or ascending colon comparing budesonide 9 mg once daily, 4.5 mg b.i.d. and placebo for 8 weeks. 14 Remission was achieved in 48%, 53%, and 33% of patients with 9 mg, 4.5 mg b.i.d and placebo, respectively. Differences were not significant but the mean change from the baseline Crohn's disease activity index (CDAI) between combined budesonide and placebo groups was significant (p b 0.05). In a recent Cochrane review that included these two previously referred studies, authors showed that, after 8 weeks of treatment, budesonide was significantly more effective than placebo for induction of remission in CD (RR 1.96, 95% CI 1.19 to 3.23) Budesonide vs. mesalamine Budesonide and mesalamine were compared in a doubleblind, multicentre trial with 182 CD patients. 16 Patients were randomized to receive budesonide 9 mg once daily or mesalamine 2 g b.i.d for 16 weeks. Remission rates after 8 weeks of treatment were 69% in the budesonide group and 45% in the mesalamine group (P= 0.001); the respective rates after 16 weeks of treatment were 62% and 36% (Pb0.001). In another publication, the same authors observed that budesonide (9 mg once daily) improves health-related quality of life to a greater extent than mesalamine (2 g b.i.d.) in patients with mild to moderate active CD. 17 In the recent Cochrane review, authors have shown that budesonide was significantly more effective than mesalamine for induction of remission (RR 1.63; 95% CI 1.23 to 2.16). 15 Recently, Tromm et al. performed a randomized, double-blind, 8-week, multicentre study in which 309 patients with mild to moderately active CD received ph-modified-release oral budesonide (9 mg/day once daily or 3 mg/day t.i.d) or Eudragit-L-coated oral mesalamine (4.5 g/day). 18 Clinical remission at the final visit occurred in 69.5% of patients given budesonide vs. 62.1% with placebo, evidencing that budesonide is at least as effective as mesalamine to induce remission in mild to moderate CD. Clinical remission rates did not differ significantly between the two budesonide groups Budesonide vs. other corticosteroids Based on the idea that budesonide presents an improved safety profile compared to conventional steroids, several studies have been performed in order to compare the efficacy of these drugs (Table 1) In the Cochrane review, 9 studies comparing budesonide with conventional corticosteroids were included and it was observed that budesonide was significantly less effective than conventional steroids for induction of remission (RR 0.86, 95% CI 0.76 to 0.98). Conventional steroids Table 2 Studies comparing oral budesonide with conventional steroids for induction of remission in patients with severe activity at 8 weeks. Author n Drugs Remission (%) Gross 67 Budesonide (9mg) 40 (21) Methylprednisolone (48mg) 60 Campieri 178 Budesonide (9mg) 23 (22) Prednisone (40mg) 54 Seow a (15) 48 Budesonide (9mg) Conventional steroids Main conclusions Budesonide is inferior to methylprednisolone in severe activity Budesonide is less effective than prednisone in severe patients Budesonide is clearly less effective than conventional corticosteroids for induction of remission a Seow et al. is a meta-analysis which included both studies evaluating budesonide in severe CD.

4 186 T. Nunes et al. Table 3 Studies comparing oral budesonide with placebo for maintenance of remission at 12 months. Author Drugs Remission (%) Main conclusions Ferguson (28) Budesonide (6 mg) Relapse rate and time to relapse were similar in the patients treated with budesonide and placebo Greenberg (29) Budesonide (6 mg) 39 Budesonide prolonged remission, but this effect was not sustained at 12 months 33 Hanauer (30) Budesonide (6 mg) 53 Relapse rates were not significantly different at the 1-year end point 42 Hellers (31) Budesonide (6 mg) 68 The frequency of endoscopic recurrence did not differ between the groups 35 Lofberg (32) Budesonide (6 mg) Budesonide did not have any clear impacton the overall relapse rate after 12 months Benchimol a (33) Budesonide (6 mg) Budesonide is no better than placebo at maintaining remission at 12 months a The study by Benchimol et al. is a meta-analysis including previous studies evaluating budesonide as maintenance therapy. are superior to budesonide particularly among patients with severe disease (CDAIN300) (RR 0.52, 95% CI 0.28 to 0.95), suggesting that locally active oral corticoids have limited usefulness in this setting (Table 2). Importantly, fewer adverse effects occurred in patients treated with budesonide compared to those treated with conventional steroids (RR 0.64, 95% CI 0.54 to 0.76). Similarly, budesonide preserved better the adrenal function than conventional steroids (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78) Efficacy of budesonide in maintenance of remission in CD Approximately 50% of patients achieving remission with conventional corticosteroids are not able to maintain remission after 1 year. 27 In addition, conventional steroids are not used as maintenance treatment due to their well-known adverse effects. The more positive safety profile of budesonide has encouraged some investigators to attempt to identify whether budesonide could be effective as CD maintenance treatment, unfortunately achieving poor results (Table 3) A recent Cochrane review evaluating eight studies that compared budesonide with placebo concluded that budesonide 6 mg daily was no more effective than placebo for maintenance of remission at 3 months (RR 1.25; 95% CI 1.00 to 1.58; P=0.05), 6 months (RR 1.15; 95% CI 0.95 to 1.39; P=0.14), or 12 months (RR 1.13; 95% CI 0.94 to 1.35; P=0.19). 33 In contrast, in a prospective, investigator-blind, one year trial that compared efficacy of budesonide and mesalamine as maintenance treatment, Mantzaris et al. observed that the 1-year relapse rate was significantly lower in the budesonide group than in the mesalamine group (55% vs. 82%; 95% CI, 12.4% 41%; P =0.045). Compared with mesalamine, budesonide treatment was also associated with a better quality of life throughout the study (P=0.0001). 34 Tursi et al. in a small prospective study also suggested that budesonide could be a reasonable alternative as maintenance treatment for CD patients. 35 In this study, 14 out of 20 patients maintained remission after a mean follow-up of 25 months without significant side-effects. Nevertheless, in keeping with the Cochrane review, the ECCO guidelines states that budesonide may delay relapse after medically induced remission, but is not effective at maintaining remission for 12 months Efficacy of budesonide for prevention of postsurgical recurrence in CD A double-blind, multicentre, randomized trial evaluating budesonide utility to prevent CD postsurgical recurrence compared budesonide (6 mg) to placebo. 31 The frequency of endoscopic recurrence did not differ between groups at 3 and 12 months. Another multicentre randomized doubleblind placebo-controlled trial was performed comparing 3 mg oral ph-modified release budesonide to placebo. 36 The recurrence rate after 1 year was 57% in the budesonide group and 70% in the placebo group, not reaching statistical significance. Authors concluded that low-dose oral budesonide cannot be recommended for prevention of postoperative relapse in CD Budesonide in pregnancy and paediatric CD There is no standard medical CD management during pregnancy and there is limited data regarding safety and efficacy of budesonide in this scenario. In a recent retrospective study, 6 patients with budesonide 6 mg daily and 2 patients with 9 mg daily were evaluated. 37 The average treatment duration ranged from 1 to 8 months. There were no cases of maternal adrenal suppression, glucose intolerance, ocular side effects, hypertension or fetal congenital abnormalities. Indirect data from inhaled or intranasal budesonide have confirmed that this drug is not associated with adverse fetal outcomes. 38 Conventional steroids side-effects such us osteoporosis and growth retardation are especially detrimental in paediatric patients. Two studies have compared budesonide and conventional steroids for induction of remission in children and they concluded that there were not significant differences in efficacy between both drugs. 23,26 Recently, a randomized, controlled, double-blind study in 70 children with mild or moderately active CD was performed. 39 Authors compared two different budesonide doses (standard dose of 9 mg daily for 7 weeks followed by 6 mg daily for an additional 3 weeks

5 Oral locally active steroids in inflammatory bowel disease 187 and induction with 12 mg daily for the first month followed by the same regimen as the first group). At week 7, clinical response was obtained in 51.4% 9 mg group versus 74.3% in the 12 mg group. There was no significant difference in remission rates, frequency of adverse events or serum cortisol. ECCO guidelines states that budesonide is effective and must be favoured over prednisolone in mild to moderate active ileocaecal paediatric CD Budesonide for induction of remission in ulcerative colitis (UC) Although a first randomized, double-blind, controlled trial comparing budesonide 10 mg and prednisolone 40 mg in left side UC did show differences in remission rates, 41 posterior studies have not been able to reproduce these results. A Cochrane review stated that oral budesonide was significantly less likely to induce clinical remission than oral mesalamine after 8 weeks of therapy (RR 0.72, 95% CI 0.57 to 0.91) and there was no significant benefit from oral budesonide in comparison with placebo for inducing clinical remission after 4 weeks of treatment (RR 1.41, 95% CI 0.59 to 3.39). 42 More recent studies, however, have suggested that budesonide can be useful in the management of UC patients. In a randomized, double-blind, multicentre study comparing 3 g mesalamine with 9 mg budesonide for achieving remission in mild-to-moderately active UC, budesonide was inferior to mesalamine but achieved clinical remission in almost 40% of patients with a rapid onset of resolution. 43 Another study evaluated the efficacy and safety of the newly developed Budesonide-MMX 9 mg tablets (a new oral, extended-release formulation) in 36 left-sided UC patients. 44 After 4 weeks, 47.1% in the budesonide-mmx group achieved remission whereas only 33.3% in the placebo group, nevertheless differences did not reach statistical significance due to the small number of patients included. More recently, in two large multicenter clinical trials comparing once daily budesonide MMX 9 mg and 6 mg tablets to placebo over an 8-week treatment, a significantly greater proportion of patients achieved remission in the 9 mg group compared to placebo. 45,46 Currently the role of budesonide MMX as induction treatment for UC patients is still matter of debate. In this regard, though the compound seems to be more effective than placebo in mild to moderate active UC patients, comparison with effective induction doses of mesalamine is still lacking Budesonide for maintenance of remission in ulcerative colitis (UC) Based on the better results of the newer budesonide MMX as induction treatment for active mild to moderate UC patients in multicenter trials, 45,46 Sandborn et al. evaluated the role of this compound as maintenance treatment in a 12 month placebo-controlled trial. 47 In this study, 122 patients were randomized to either Budesonide-MMX 6 mg or placebo. The probability of clinical relapse at 12 months was reduced and the median time to clinical relapse was longer in the intention-to-treat population with budesonide-mmx 6 mg compared to placebo. Currently, the role of budesonide as maintenance treatment for UC patients requires future further evaluation since there is still very limited data and no comparison with mesalamine is available at this time Budesonide in chronic refractory pouchitis Almost half of the patients who have undergone ileal pouchanal anastomosis surgery for UC will develop at least one episode of pouchitis. Up to 15% of patients with pouchitis experience a chronic course. In that scenario, antibiotics are less effective and maintenance therapy may be required. 48 Combined antibiotic therapy or biologics may be effective but new therapeutic options are needed Oral budesonide was evaluated in two small prospective open-label studies as a treatment alternative for chronic refractory pouchitis, both achieving good remission rates. 51,52 In the largest study, 20 consecutive patients with active pouchitis with no response to antibiotic treatment were treated with oral budesonide 9 mg/day for 8 weeks. In this series, 15 of 20 patients (75%) achieved clinical and endoscopic remission. 51 Currently, 8-week treatment with oral budesonide appears effective in inducing remission in patients with chronic refractory pouchitis but further studies are needed Budesonide in microscopic colitis (MC) There have been relatively few randomised controlled trials assessing treatment options both in induction of remission and maintenance therapy in MC. Budesonide is the most evaluated treatment for MC patients and it has proven efficacy in inducting remission in both collagenous and lymphocytic colitis. Three short-term (6 8 weeks), randomized controlled trials have consistently shown that budesonide 9 mg daily for 6 8 weeks is superior to placebo in collagenous colitis, with most patients (80%) achieving remission within 2 4weeks In a recent Cochrane meta-analysis that included these studies, clinical response occurred in 81% of patients receiving budesonide compared to 17% of patients with placebo (pb ). The pooled odds ratio for clinical response with budesonide treatment was (95% CI 5.53 to 27.46), with a number needed to treat of 2 patients. 56 Recently, in a new large double-blind, randomized, multicenter trial of budesonide in collagenous colitis, budesonide achieved 80% of clinical remission over 60% in the placebo group, suggesting once more that budesonide is highly effective for induction of remission in collagenous colitis, improving both stool frequency and consistency. 57 Few randomized, controlled trials have investigated the efficacy of pharmacological treatment for lymphocytic colitis. Three randomized trials evaluating the role of budesonide treatment in this scenario have shown that this drug is effective for inducing clinical response (OR 9.00; 95% CI ), with an NNT of 3 patients. 56 In addition, a new randomized, placebo-controlled trial in forty-two patients with lymphocytic colitis receiving budesonide 9 mg daily for 6 weeks found that 86% of patients given budesonide were in clinical remission compared with 48% of patients given placebo (p=0.010). 58 Although budesonide is the bestdocumented short-term treatment for lymphocytic colitis, an optimal long-term budesonide therapy in this setting needs further evaluation.

6 188 T. Nunes et al. Doses for MC maintenance therapy are 6 mg per day for six months. It is possible that in some patients doses could be individualized from 3 mg every other day to 9 mg daily. 59 The pooled odds ratio for maintenance of clinical response in clinical trials with 6 mg daily was 8.82 (95% CI ) with an NNT of 2 patients. 56 Time to relapse is usually brief for patients who relapse, approximately two weeks. Longterm maintenance therapy with oral budesonide is effective; nevertheless the risk of relapse after weeks of treatment is similar to that observed after induction treatment Beclomethasone Beclomethasone was first introduced into the UC armamentarium as a rectal suspension enema for the treatment of distal UC with good efficacy when compared to 5-ASA enemas or topic conventional steroids More recently, beclomethasone was formulated as an oral enteric coated compound to be released in the distal small bowel and throughout the colon. Rizzello et al. undertook a dose-finding study comparing doses of 5 and 10 mg. Oral beclomethasone was associated with a significant clinical, endoscopic and histological benefit after 4 weeks of treatment. 67 In addition, the 5 mg dose was better tolerated and induced lower reduction of plasma cortisol levels, being equivalent to the 10 mg dose in terms of clinical efficacy. Therefore, at present, the recommended label dose of oral beclomethasone to induce remission in mild to moderate UC patients is 5 mg/day Beclomethasone vs. mesalamine in UC Three studies have evaluated the effectiveness of oral beclomethasone to treat active UC patients compared to 5-ASA compounds (Table 4). Campieri et al. compared oral beclomethasone 5 mg and 5-ASA 2.4 g in a 4-week multicentre, randomized, single-blind study. Both groups achieved similar global remission rates but remission was more frequently obtained with beclomethasone than 5-ASA in the subgroup of extensive UC patients. 68 Rizzello et al. 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 beclomethasone (5 mg/d) or placebo. 69 The combination of oral beclomethasone with 5-ASA proved to be significantly more effective than 5-ASA alone. Importantly, in this study, beclomethasone presented a good safety profile with no inhibition of pituitaryadrenal function detected. In an open-labeled, randomized study in a pediatric population, 30 patients with active UC (left-sided or pancolitis) were enrolled to receive either oral beclomethasone (5 mg/day) for 8 weeks, followed by maintenance therapy with oral mesalazine or 80 mg.kg of 5-ASA. 70 Patients treated with beclomethasone showed a significant reduced clinical activity within 4 weeks with 80% achieving clinical remission compared with 33% treated with only 5-ASA. Importantly, in 73% of beclomethasone-treated patients colonoscopy showed remission compared to 27% of 5-ASA (Pb 0.025). These studies suggest that beclomethasone is an option as induction therapy for mild to moderate extensive or left-sided colitis. Of note, oral beclomethasone is currently not indicated to treat neither ulcerative proctitis nor severe disease activity because its efficacy in these settings was not evaluated by controlled studies Beclomethasone in UC patients not responding to mesalamine In the scenario when patients do not respond to induction treatment with 5-ASA, oral systemic steroids are usually the next option. The existence of many steroid-related adverse effects prompted the evaluation of oral beclomethasone in the specific setting. In that regard, Papi et al. studied the role of beclomethasone in patients with mild to moderately active UC not responding to 5-ASA. 71 A 4-week course of oral 10 mg/day beclomethasone was followed by a 4-week administration of 5 mg/day in 64 UC patients in which 5-ASA had previously failed. The authors found a remission rate of 75% with most patients achieving 1-year maintenance of remission with no need for further steroid treatment. These data suggest that oral beclomethasone might have a role as an alternative to systemic steroids in patients with a mild to moderate flare that is not responsive to 5-ASA. Importantly, Papi et al. achieved these impressive remission rates using a 4-week course of 10 mg/day at induction which is twice the recommended label dose Beclomethasone vs. conventional steroids in UC Balzano et al. 72 evaluated the efficacy of oral beclomethasone and oral prednisone in a mild to moderately active UC population, in an 8-week, multicentre, randomized, doubleblind study. 72 Both drugs achieved comparable clinical and endoscopic efficacy, with oral beclomethasone presenting less steroid-related adverse effects. Out of the context of controlled clinical trials, data suggests that oral beclomethasone also manages to achieve impressive remission rates. In a very recently published, large retrospective study Table 4 Studies comparing oral beclomethasone (BDP) to oral 5-ASA for induction of clinical remission in UC. Author n Drugs Remission (%) Rizzello (69) ASA (3.2 g/day) plus BDP (5 mg/day) 5-ASA (3.2 g/day) plus placebo Campieri 177 BDP (5 mg/day) 63 (68) 5-ASA (2,4 g/day) 63 Romano (70) 30 BDP (5 mg/day) 80 5-ASA (80 mg. kg. day) 33 Main conclusions Oral BDP+oral 5-ASA is more effective than 5-ASA alone Oral BDP is as effectiveas 5-ASA Oral BDP is more effective than 5-ASA in inducing remission

7 Oral locally active steroids in inflammatory bowel disease 189 aiming at evaluating oral beclomethasone efficacy in the clinical practice scenario, oral beclomethasone induced remission in more than 40% and response in two thirds of UC patients. In addition, patients with left-sided or extensive, mild or moderately active UC treated for more than 4 weeks presented the best outcome Beclomethasone as induction therapy for Ileal CD In an open-label, budesonide-controlled, randomized study, 30 patients with active ileal or right colon non-stricturing nonpenetrating disease was enrolled to receive either budesonide 9 mg/day or oral beclomethasone 10 mg/day for 8 weeks. 74 In the budesonide group, 67% of the patients achieved remission after 8 weeks of treatment compared to 53% of remission rate in the beclomethasone group suggesting that beclomethasone seems to be less effective than budesonide as induction treatment.asthisstudyremainstheonlyprospectiveevaluationof beclomethasone as induction therapy, its role in the management of active ileal CD patients remains uncertain Beclomethasone as maintenance therapy for Ileal CD At present, oral budesonide is the first-line therapy to induce remission in mild to moderate ileocaecal CD, but this topically active agent failed to be effective as an alternative therapy to maintain patients relapse-free at 1 year. This prompted the evaluation of other locally active steroids as maintenance treatment for CD patients. In that regard, Astegiano et al. published a small retrospective study evaluating oral beclomethasone as maintenance therapy in mild to moderate CD patients. 75 In this study, beclomethasone managed to achieve clinical response at 24 weeks in 67% and maintained remission in 94% of the patients who were in remission at baseline. Subsequently, Pratera et al. published the first randomized, double-blind, placebo-controlled, multicentre study assessing the efficacy of beclomethasone in the treatment of ileal Crohn's disease as maintenance therapy. 76 This study included a total of 84 CD patients with active ileitis, ileoceacal disease and right colitis. After having received prednisone, 73 patients who achieved remission were randomized to receive beclomethasone or placebo. In the beclomethasone group, patients received 15 mg/day for 2 weeks and afterwards, 10 mg/day. The placebo group continued prednisone for 2 weeks and then placebo. At 24 weeks, significantly less patients in the beclomethasone group compared to the placebo presented disease activity (23.3% vs. 53.8%). The cumulative probability of relapse was also significantly lower in patients on beclomethasone than on placebo (38% vs. 56%). Due to the small sample size, this study has to be interpreted with caution and further studies are required to establish the effectiveness of oral beclomethasone as an alternative maintenance therapy for CD patients. As stated by Billioud et al., beclomethasone might be used as maintenance therapy in CD patients who are intolerant, refractory or with a contraindication to standard immunosuppressive therapy, as well as to reduce exposure to systemic steroids in case of steroid dependency Conclusion Oral systemic steroids have been used to induce remission in patients with active IBD for over 50 years due to their potent anti-inflammatory effects. Nevertheless, the wide range of adverse events associated with these drugs has prompted the development of less toxic steroid compounds. These oral locally active drugs have improved safety profile and constitute an important alternative to the classic steroids for patients with mild to moderate active CD and UC as induction treatment. In this regard, oral budesonide and beclomethasone can replace systemic corticoids in mild to moderate ileocaecal CD and mild to moderate left-sided or extensive UC, respectively. In addition, oral budesonide has been proven to be highly effective in the management of microscopic colitis. In case of severe disease activity, locally active steroids should not be used. In this scenario, either systemic corticoids aremoreeffectiveortheusefulnessofthesenewercompounds was not properly assessed by clinical trials. Importantly, as maintenance treatment, budesonide is no more effective than placebo in CD at 12 months of follow-up and beclomethasone still has to be evaluated by controlled prospective studies. Conflict of interest statement The author Miquel Sans has acted as medical advisor for Chiesi which detains the rights to commercialize oral beclomethasone in Spain. The remaining authors state to have no conflict of interest. Acknowledgements This work has been partially funded by Fundació Miarnau. References 1. Hodgson H. Systemic corticosteroids in inflammatory bowel disease. In: Bayless TM, Hanauer SB, editors. Advanced Therapy of Inflammatory Bowel Disease. London: BC Decker; p Hench PS, Kendall EC, Slocumb CH, Polley HF. Adrenocortical Hormone in Arthritis : Preliminary Report. Ann Rheum Dis 1949;8: Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 1955;2: Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130: Travis SP, Stange EF, Lemann M, Oresland T, Bemelman WA, Chowers Y, et al. European evidence-based Consensus on the management of ulcerative colitis: Current management. J Crohns Colitis 2008;2: Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, Colombel JF, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Current management. J Crohns Colitis 2010;4: Rutgeerts PJ. Review article: the limitations of corticosteroid therapy in Crohn's disease. Aliment Pharmacol Ther 2001;15:

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