Glucocorticosteroids in the treatment of inflammatory bowel disease and approaches to minimizing systemic activity

Abstract

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions characterized by chronic, uncontrolled inflammation of the gastrointestinal tract. Reported prevalence is high in the United States and northern Europe, while the incidence varies greatly across the rest of Europe. Glucocorticosteroids are the standard treatment for IBD, but due to adverse events their use can be limited. However, new formulations of glucocorticosteroids have been developed to reduce systemic activation. The aim of this review was to assess and summarize the efficacy and safety of new formulations of glucocorticosteroids. A MEDLINE search identified publications focused on new formulations of nonsystemic steroid-based drugs for IBD and benefits and limitations of each of the new glucocorticosteroid formulations were identified. Budesonide has good efficacy and is an established treatment for Crohn’s disease; it has been shown to be beneficial for the induction of remission in these patients, although it is not recommended for the maintenance of induced remission. Glucocorticosteroids are not recommended for the maintenance of remission in patients with IBD. However, a recent study suggested that beclomethasone dipropionate may be effective for prolonged treatment in patients in the postacute phase of Crohn’s disease who were treated with a short course of systemic steroids. The efficacy of fluticasone propionate and prednisolone metasulphobenzoate in IBD is not well established given the small number of patients enrolled in the few published clinical trials. While the tolerability of these glucocorticosteroids is favourable, more research comparing these new agents with traditional systemic glucocorticosteroids is warranted.

Introduction

Inflammatory bowel diseases (IBDs) are inflammatory conditions characterized by chronic, uncontrolled inflammation of the gastrointestinal tract [Papadakis and Targan, 2000]. Crohn’s disease and ulcerative colitis are the two primary types of IBD [Hanauer, 2006], while unclassified colitis (IBDU) is a form of colitis with clinical and pathological characteristics that do not meet the criteria for classification as either ulcerative colitis or Crohn’s disease [Burakoff, 2004]. The term indeterminate colitis is used for IBDU when classification is impossible even after examination of a surgical specimen. Other rarer cases include collagenous colitis [Fernandez-Banares et al. 2003], lymphocytic colitis [Fernandez-Banares et al. 2003], ischaemic colitis [Green and Tendler, 2005], diversion colitis [Geraghty and Talbot, 1991], colitis associated with diverticular disease and Behçet’s colitis [Akpek and Weinberg, 2003].

Many regions, such as North America [Hanauer, 2006] and the UK [Montgomery et al. 1998], have reported a high prevalence of IBD – approximately 100 people per 100,000 people in the USA are diagnosed with the disease [Crohn’s and Colitis Foundation of America, 2012]. The incidence of IBD varies greatly across Europe, with a much higher incidence reported in northern compared with southern countries [Shivananda et al. 1996].

IBD can be difficult to manage clinically. Currently, treatment can result in recovery and sometimes mucosal healing, but there is no cure. Disease flares can range from mild to severe and involve symptoms such as diarrhoea, abdominal pain, fever and rectal bleeding [Carter et al. 2004; Bernstein et al. 2010]. Current treatment guidelines recommend a variety of therapeutic options depending on disease activity, which tract of the intestine is involved, complications and symptoms of the disease [Carter et al. 2004; Travis et al. 2006; Bernstein et al. 2010]. Such treatments include glucocorticosteroids, aminosalicylates (such as sulfasalazine or mesalamine (5-aminosalicylic acid)], immunosuppressors (such as thiopurines or methotrexate) and biological therapies [such as tumour necrosis factor α (TNFα) inhibitors] [Carter et al. 2004, Bernstein et al. 2010]. In patients with ulcerative colitis with a flare that does not respond to intensive medical therapy, including intravenous steroids, cyclosporine and anti-TNF, surgery is recommended; however, surgery is only recommended for complications of Crohn’s disease and, reluctantly, for treatment failure [Carter et al. 2004].

Overview of glucocorticosteroids in inflammatory bowel disease: use and limitations

Glucocorticosteroids are the standard treatment for IBD as they result in rapid remission of disease activity [Carter et al. 2004, Travis et al. 2006]. Longstanding treatment with glucocorticosteroids is limited because of adverse events associated with their use (such as hypothalamic pituitary adrenal axis suppression) [Stein and Hanauer, 2000] and the possible development of steroid-dependent disease [Aceituno et al. 2007]. As a result, maintenance treatment with systemic glucocorticosteroids is not advised. New formulations of glucocorticosteroids have been developed with the aim of limiting systemic activity and reducing glucocorticosteroid adverse events. The pharmacokinetic profiles of the second-generation topical oral or rectal preparations are such that the agents have high local efficacy in the gut, but minimal systemic bioavailability due to highly efficient first-pass hepatic inactivation, thus minimizing any adverse systemic effects [Campieri, 2002; Mulder and Tytgat, 1993; Girlich and Scholmerich, 2012].

Glucocorticosteroids for which new formulations have been developed include budesonide, beclomethasone dipropionate (BDP), fluticasone propionate and prednisolone metasulphobenzoate.

Recent reviews have highlighted the safety and efficacy of second-generation glucocorticosteroids, particularly budesonide and BDP, in the treatment of Crohn’s disease and ulcerative colitis [De Cassan et al. 2012; Nunes et al. 2012]. This review was undertaken to extend the discussion and report the safety and efficacy of these and other second-generation glucocorticosteroids (fluticasone and prednisolone metasulphobenzoate) in the treatment of IBD, including pouchitis and lymphocytic colitis.

Search methods

To identify publications reporting the efficacy and tolerability of new formulations of nonsystemic steroid-based drugs for the treatment of IBD, a literature search was conducted on the online database Medline using the Ovid interface. The search was conducted on 11 May 2011 using the terms ‘inflammatory bowel disease’, ‘Crohn’s disease’, ‘ulcerative colitis’, ‘indeterminate colitis’, ‘unclassified colitis’, ‘beclomethasone’, ‘fluticasone’, ‘prednisolone’ and ‘budesonide’. Only studies conducted in humans and published in English were included; data were not limited by date. Papers were manually searched and relevant articles were selected. Papers that discussed glucocorticosteroid drugs which had inherent limited systemic activity or discussed formulations designed to reduce systemic activity were included. Additional articles were identified from the reference lists of reviews and from the author’s own experience in the field.

Advances in therapeutic approaches to glucocorticosteroid therapy

Budesonide

Budesonide is a glucocorticosteroid which was originally designed as an inhaled formulation for the treatment of asthma and noninfectious rhinitis. Budesonide is regularly used for the treatment of Crohn’s disease and, to a lesser extent, for the treatment of ulcerative colitis. There are two formulations of oral budesonide regularly employed in Crohn’s disease: Entocort (AstraZeneca, London, UK), a controlled-ileal release formulation using a gelatine capsule containing acid-stable microgranules (http://www1.astrazeneca-us. com/pi/entocortec.pdf), and Budenofalk (Dr Falk Pharma GmbH, Freiburg im Breisgau, Germany), a pH-dependent release tablet which dissolves at pH less than 6.0 (http://www.medicines.org.uk/emc/medicine/16908/SPC/Budenofalk+3mg+gastro-resistant+capsules/). Also, a once-daily oral controlled-release formulation of budesonide that extends release throughout the colon using multimatrix (MMX) technology (budesonide MMX) has completed phase III development with Cosmo Pharmaceuticals (Lainate, Italy) and is currently in the regulatory preregistration phase for the treatment of ulcerative colitis in the USA and Europe (http://www.cosmopharmaceuticals.com/activities/pipeline/budesonide.aspx).

Other budesonide formulations have been investigated and are now used for the treatment of IBD outside the USA. These include a topical budesonide enema [Löfberg et al. 1994; Lemann et al. 1995] and budesonide foam enema [Brunner et al. 2005].

Efficacy in Crohn’s disease

Many trials have been conducted to establish the efficacy of oral budesonide as induction therapy in patients with Crohn’s disease. Two randomized, double-blind, placebo-controlled studies investigated the treatment of flare in patients with mild-to-moderate active Crohn’s disease of the ileum or ascending colon, and showed that controlled-ileal-release budesonide capsules were more effective than placebo for induction of remission (Table 1) [Greenberg et al. 1994; Tremaine et al. 2002]. A controlled-ileal-release formulation of budesonide more effectively induced remission than a slow-release formulation of mesalamine in patients with active Crohn’s disease [Thomsen et al. 1998]. Also, an oral pH-modified budesonide was as effective as mesalamine in patients with mildly to moderately active Crohn’s disease (Table 1) [Tromm et al. 2011]. However, these results should be interpreted cautiously because of mesalamine’s limited efficacy in Crohn’s disease [Travis et al. 2006].

Table 1.

Summary of randomized, double-blind clinical studies investigating glucocorticosteroids in patients with Crohn’s disease.

Study	Study design, patient population and characteristics	Dosage/formulation	Comparator (compound, dosage)	Treatment duration	Primary endpoint		Safety summary
					Definition	Outcome
Budesonide
Greenberg et al. [1994]	R, DB, MC, PC trial in patients with active disease (n = 258)	Oral CIR budesonide 3, 9 or 15 mg/day	Pbo	8 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, budesonide 9 and 15 mg/day were associated with significantly higher remission rates than pbo (51% and 43% versus 20% respectively; p < 0.001 and p = 0.009)	AEs were similar with budesonide 3, 9 and 15 mg/day and pbo, with 81%, 90%, 88% and 76% of patients reporting AEs respectively
Rutgeerts et al. [1994]	R, DB, AC trial in patients with active disease (n = 176)	Oral CIR budesonide 9 mg for 8 weeks then 6 mg for 2 weeks	Prednisolone 40 mg for 2 weeks then tapered gradually to 5 mg in the last week (week 10)	10 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, CIR budesonide and prednisolone were associated with similar rates of remission (53% and 66% of patients respectively; p = 0.12)	Corticosteroid-associated AEs were reported in significantly fewer patients receiving budesonide (29% versus 48% of patients; p = 0.003)
Greenberg et al. [1996]	R, DB, MC, PC trial of maintenance treatment (n = 105)	Oral CIR budesonide 3 or 6 mg	Pbo	1 year	Relapse rates, defined as a CDAI >150	At 1 year, relapse rates were similar between budesonide (3 and 6 mg) and pbo recipients (70% and 61% versus 67% respectively); median time to relapse was 178, 121 and 37 days for budesonide 6 mg, budesonide 3 mg and pbo respectively	AEs were reported in 70%, 78% and 89% of patients receiving 3 mg budesonide, 6 mg budesonide and pbo respectively
Löfberg et al. [1996]	R, DB, MC, PC trial of maintenance treatment (n = 32)	Oral CIR budesonide 3 or 6 mg	Pbo	1 year	Relapse rates, defined as a CDAI >150	At 1 year, relapse rates were similar between budesonide (3 and 6 mg) and pbo recipients (74% and 59% versus 63% respectively); median time to relapse was 258, 139 and 92 days for budesonide 6 mg, budesonide 3 mg and pbo respectively	Acne and moon face were reported in slightly more budesonide than pbo recipients
Campieri et al. [1997]	R, DB, AC trial in patients with active disease (n = 178)	Oral CIR budesonide 9 mg once daily or 4.5 mg twice daily	Prednisolone 40 mg twice daily	12 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, CIR budesonide once daily or twice daily and prednisolone were associated with similar rates of remission (60%, 42% and 60% of patients respectively)	Glucocorticosteroid AEs were similar between CIR budesonide once daily or twice daily and prednisolone patients; however, moon face and impaired adrenal function reported in more prednisolone patients (p = 0.005 and 0.0023 respectively)
Bar-Meir et al. [1998]	R, DB, AC trial in patients with active mild-to-moderate disease (n = 201)	Oral pH-dependent budesonide 9 mg once daily	Prednisolone 40 mg for 2 weeks then tapered to 5 mg/day by week 8	8 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, budesonide and prednisolone were associated with similar remission rates (51% and 52.5% respectively)	Prednisolone was associated with significantly more AEs than budesonide (67% versus 44%; p = 0.0018)
Ferguson et al. [1998]	R, DB, MC, PC trial of maintenance treatment (n = 75)	Oral CIR budesonide 3 or 6 mg	Pbo	1 year	Relapse rates, defined as a CDAI >150	At 1 year, relapse rates were similar between budesonide (3 and 6 mg) and pbo recipients (46% and 48% versus 60% respectively); no significant difference in relapse rates was observed at any time point in this study	Both budesonide and pbo were well tolerated; however more patients receiving budesonide 3 and 6 mg experienced suppressed adrenal function compared with those on pbo (26% and 50% versus 17% of patients; p = 0.096)
Gross et al. [1998]	R, DB, MC, PC trial of maintenance treatment (n = 179)	Oral pH modified release budesonide 3 mg	Pbo	1 year	Relapse rates, defined as a CDAI >150	At 1 year, relapse rates were similar between budesonide and pbo recipients (67% versus 65% of patients respectively)	Budesonide and pbo were similarly well tolerated with 55.2% and 51.5% of patients receiving budesonide and pbo reporting AEs respectively
Thomsen et al. [1998]	R, DB, MC, AC trial in patients with active disease (n = 182)	Oral pH-dependent CIR budesonide 9 mg once daily	Mesalamine controlled release 2 g twice daily	8 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, remission was achieved by significantly more patients receiving budesonide compared with patients receiving mesalamine (69% versus 45%; p = 0.001)	Budesonide and mesalamine patients reported similar frequencies of AEs; however serious and severe AEs were reported in more patients receiving mesalamine (p = 0.16 and 0.04 respectively)
Cortot et al. [2001]	R, DB, MC, PC trial in patients with inactive steroid-dependent disease undergoing prednisolone tapering (n = 120)	Oral CIR budesonide 6 mg once daily	Pbo	13 weeks	Relapse rates, defined as a CDAI >200 and an increase of CDAI by at least 60	Relapse rates were significantly lower with budesonide than pbo after 13 weeks of prednisolone tapering (65% versus 65%; p < 0.001)	AEs were similar between treatment groups
Tremaine et al. [2002]	R, DB, MC, PC trial in patients with active disease (n = 200)	Oral CIR budesonide 9 mg once daily or 4.5 mg twice daily	Pbo	8 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, remission was achieved in 48%, 53% and 33% of patients receiving 9 mg budesonide once daily, 4.5 mg budesonide twice daily and pbo respectively	AEs were reported in 91%, 94% and 93% of patients receiving 9 mg budesonide once daily, 4.5 mg budesonide twice daily and pbo respectively The frequency of steroid-related AEs was similar between treatment groups
Hanauer et al. [2005]	R, DB, MC, PC trial of maintenance treatment (n = 110)	Oral CIR budesonide 9 mg	Pbo	1 year	Time to relapse, defined as a CDAI >150 and an increase of CDAI by at least 60	Median time to relapse was not significantly different between budesonide and pbo recipients (360 versus 169 days respectively)	Budesonide and pbo were similarly well tolerated with 26% and 27% of patients receiving budesonide and pbo reporting treatment-related AEs respectively
Tromm et al. [2011]	R, DB, MC, AC trial in patients with active mild-to-moderate disease (n = 309)	Oral pH dependent budesonide 3 mg three times daily or 9 mg once daily	Eudragit-L-coated oral mesalamine 4.5 g/day	8 weeks	Clinical remission, defined as a CDAI ≤150	After 8 weeks, budesonide and mesalamine were associated with similar remission rates (69.5% and 62.1% respectively)	3% and 5% of patients receiving budesonide and mesalamine discontinuation treatment due to AEs
Beclomethasone dipropionate
Prantera et al. [2011]	R, DB, PC, MC trial in patients with Crohn’s ileitis who achieved remission with 2 weeks of prednisone (n = 84)	Oral BDP 15 mg/day for 2 weeks then 10 mg/day for 22 weeks	Pbo	24 weeks	Relapse rate (CDAI score>150 and an increase of ≥60 from baseline)	23.3% relapse rate with BDP versus 53.8% relapse rate with pbo	51.4% of patients receiving BDP versus 58.4% of patients receiving pbo experienced AEs, 6.0% of patients receiving BDP versus 1.7% of patients receiving pbo experienced HPA axis effects The most commonly reported AEs were GI-related events (20.0% and 36.2%), moon face, hyperthyroidism and Cushing’s syndrome

AC, active control; AE, adverse event; BDP, beclomethasone dipropionate; CDAI, Crohn’s Disease Activity Index; CIR, controlled ileal release; DB, double blind; GI, gastrointestinal; HPA, hypothalamic pituitary adrenal; MC, multicenter; pbo, placebo; PC, placebo controlled; R, randomized.

Compared with other glucocorticosteroids, budesonide administered as an oral, controlled- ileal-release capsule [Rutgeerts et al. 1994; Campieri et al. 1997] or as a pH-modified release tablet [Bar-Meir et al. 1998] has been shown to be as effective as prednisone for the treatment of active Crohn’s disease involving the terminal ileum or the right colon (Table 1). Furthermore, oral controlled-ileal-release budesonide capsules were associated with similar toxicity to placebo, with no increase in glucocorticosteroid adverse events in treatment-refractory patients with steroid-dependent Crohn’s disease undergoing prednisolone tapering (Table 1) [Cortot et al. 2001].

There is debate about whether budesonide is effective for the maintenance of clinical remission in patients with Crohn’s disease. Two randomized, double-blind studies suggested that controlled-ileal-release budesonide significantly prolongs remission in patients with ileal or ileo-caecal Crohn’s disease [Greenberg et al. 1996; Löfberg et al. 1996], although relapse rates in the budesonide and placebo groups were similar (Table 1). Another study of comparable design suggested otherwise, showing no difference between budesonide and placebo in terms of relapse rate and time to relapse [Ferguson et al. 1998]. A further trial investigating oral pH-modified-release budesonide also found that budesonide was not effective for maintaining steroid-induced remission compared with placebo (Table 1) [Gross et al. 1998]. Finally, a trial investigating modified-release budesonide showed that budesonide and placebo had similar relapse rates after 1 year of treatment (Table 1) [Hanauer et al. 2005].

A Cochrane review evaluating the efficacy and safety of short-term oral budesonide for the induction of remission in Crohn’s disease [Seow et al. 2008] demonstrated that it was more effective than placebo or mesalamine, and less effective but better tolerated than conventional systemic steroids. Another Cochrane review investigating the efficacy of oral budesonide for the maintenance of remission in Crohn’s disease was published in 2009, and concluded that budesonide is not recommended for the prevention of clinical relapse [Benchimol et al. 2009].

Efficacy in ulcerative colitis

Only a few double-blind, randomized controlled trials have investigated the efficacy of budesonide in patients with ulcerative colitis. These showed that a budesonide enema was effective and safe for the treatment of active distal ulcerative colitis and ulcerative proctitis compared with placebo [Hanauer et al. 1998]; however, it was not shown to be effective in maintaining remission in these patients (Table 2) [Lindgren et al. 2002]. Furthermore, an oral extended-release formulation of budesonide (budesonide MMX) appeared to be effective in patients with active left-sided ulcerative colitis; it induced significant clinical improvement in these patients compared with placebo (Table 2) [D’Haens et al. 2010]. Only one trial compared budesonide with another corticosteroid. This trial showed that oral sustained-release budesonide was as effective and well tolerated as prednisolone in patients with active distal ulcerative colitis (Table 2) [Löfberg et al. 1996].

Table 2.

Summary of randomized, double-blind clinical studies investigating glucocorticosteroids in patients with ulcerative colitis.

Study	Study design, patient population and characteristics	Dosage/formulation	Comparator (compound, dosage)	Treatment duration	Primary endpoint		Safety summary
					Definition	Outcome
Budesonide
Löfberg et al. [1996]	R, DB, AC trial in patients with active mild-to-moderate disease (n = 72)	Budesonide 10 mg CR capsule	Prednisolone 40 mg orally	9 weeks	Clinical response, assessed by endoscopic and histopathological scores	After 9 weeks, budesonide and prednisolone similarly improved endoscopic scores; however, prednisolone appeared to improve histopathological scores to a greater extent than budesonide	AEs were similar between treatment groups; two patients receiving budesonide and one patient receiving prednisolone discontinued treatment due to AEs
Hanauer et al. [1998]	R, DB, PC trial in patients with active distal disease (n = 233)	Budesonide 0.5 mg in 100 ml, 2.0 mg in 100 ml or 8.0 mg in 100 ml enema	Pbo	6 weeks	Clinical response, assessed using sigmoidoscopic, and histopathological scale scores	Budesonide significantly improved sigmoidoscopic inflammation and histopathology scores compared with pbo (p ≤ 0.001) After 6 weeks, remission rates were 7%, 19% and 27% of patients achieving remission with budesonide 0.5, 2.0 and 8.0 mg in 100 ml respectively versus 4% of patients receiving pbo achieving remission	AEs were similar between treatment groups
Lindgren et al [2002]	R, DB, MC, PC trial in patients with active distal UC and proctitis (n = 149)	Budesonide 2 mg in 100 ml enema once daily or twice daily	Pbo	8 weeks induction then a further 6 months maintenance	Remission at 8 weeks and maintenance of remission after 6 months	After 8 weeks, remission rates were 51% and 54% for budesonide once daily and twice daily respectively; in the 77 patients who entered the maintenance phase of the study, relapse after 24 weeks was evident in 41% of patients receiving budesonide versus 51% of patients receiving pbo	AEs were similar between treatment groups
D’Haens et al. [2010]	R, DB, PC trial in patients with active moderate left-sided disease (n = 32)	Budesonide CR tablet 9 mg	Pbo	4 weeks	Proportion of patients achieving clinical improvement (defined as remission or a reduction of CAI by at least 50%) after 4 weeks of treatment	After 4 weeks, 47.1% of patients receiving budesonide achieved clinical improvement compared with 33.3% of patients receiving pbo	The most frequently reported AEs with budesonide were headache (11.86%), abdominal pain (8.47%), common cold (6.77%), diarrhoea, flatulence and influenza (5.08%)
Sandborn et al. [2012]	R, DB, PC, MC trial in patients with mild-to-moderate active UC (n = 509)	Budesonide MMX 9 mg or 6 mg once daily	Pbo	8 weeks	Proportion of patients achieving remission (UC-DAI score ≤1 at week 8, with a 0 score for rectal bleeding and stool frequency; no mucosal friability; and a ≥1 point reduction from baseline in endoscopy score)	After 8 weeks, 17.3% of patients receiving budesonide MMX 9 mg achieved remission compared with 7.0% of patients receiving pbo (p = 0.0119; ITT). However, there was no significant difference in the remission rate between the budesonide MMX 6 mg and placebo groups	AEs were similar between the treatment groups
Travis et al. [2011]	R, DB, PC, MC trial in patients with mild-to-moderate active UC (n = 511)	Budesonide MMX 9 mg or 6 mg once daily	Pbo	8 weeks	Proportion of patients achieving remission (UC-DAI score ≤1 at week 8, with a 0 score for rectal bleeding and stool frequency; no mucosal friability; and a ≥1 point reduction from baseline in endoscopy score)	After 8 weeks, 15.0% of patients receiving budesonide MMX 9 mg achieved remission compared with 3.8% of patients receiving pbo (p = 0.0022; ITT). However, there was no significant difference in the remission rate between the budesonide MMX 6 mg and placebo groups	AEs were similar between the treatment groups
Beclomethasone dipropionate
Bansky et al. [1987]	R, DB, AC trial in patients with distal disease (n = 16)	BDP 0.5 mg in 100 ml enema once daily	Betamethasone phosphate 5 mg in 100 ml enema once daily	20 days	Response, assessed using patient assessments, sigmoidoscopic and histological findings	Clinical remission or improvement was achieved in 89% of patients receiving BDP and 78% of patients receiving betamethasone phosphate Improvement in clinical, endoscopic and histological scores were similar between treatment groups	HPA axis suppression (assessed by measuring adrenocorticol function) was observed in 7 patients receiving betamethasone phosphate and 0 patients receiving BDP (p < 0.01)
Van der Heide et al. [1988]	R, DB, AC trial in patients with active, distal disease (n = 18)	BDP 1 mg in 40 ml enema	Prednisolone disodium phosphate 30 mg in 40 ml enema	4 weeks	Clinical, endoscopic and histological activity	After 4 weeks, prednisolone disodium phosphate significantly improved clinical and endoscopic parameters compared with BDP (both 100% of patients versus 40% of patients; p = 0.01). There was no difference between treatments in terms of histological improvements (75% versus 5% of patients)	Prednisolone disodium phosphate significantly reduced morning plasma cortisol levels and urinary free cortisol excretion indicating reduced HPA axis function; BDP appeared to have no effect on these parameters
Mulder et al. [1989]	R, DB, AC trial in patients with idiopathic disease (n = 25)	BDP 2 mg or 3 mg in 40 ml enema	Prednisolone sodium phosphate 30 mg in 40 ml enema	4 weeks	Clinical response	Overall improvement in clinical, endoscopic and histological scores were similar between treatment groups	No steroidal AEs were observed in patients receiving BDP
Halpern et al. [1991]	R, DB, AC trial in patients with distal disease (n = 32)	BDP 0.5 mg in 100 ml enema once daily	Betamethasone phosphate 5 mg in 100 ml enema once daily	28 days	Clinical response	Clinical response was similar in both BDP and betamethasone phosphate recipients	Fasting plasma cortisol levels were significantly reduced in betamethasone phosphate recipients but not BDP recipients Commonly reported AEs with betamethasone phosphate were moon face (n=7) and leg oedema (n=4) and with BDP severe acne (n=1)
Mulder et al. [1996]	R, MC, DB, AC trial in patients with active distal disease (n = 60)	BDP 3 mg in 100 ml enema or BDP 3 mg in 100 ml + 5-ASA 2 g in 100 ml enema	5-ASA 2 g in 100 ml enema	4 weeks	Clinical response, assessed using DAI scores, endoscopic and histological assessments	Clinical improvement (assessed by DAI) was observed in 100% of patients receiving BDP/5-ASA, 70% receiving BDP and 76% receiving 5-ASA; endoscopic improvement 100%, 75% and 71% respectively; histological improvement 100%, 50% and 48% respectively After 4 weeks, BDP + 5-ASA was associated with significantly better clinical response than BDP or 5-ASA alone (p < 0.01)	No AEs were noted in this study
Campieri et al. [1998]	R, DB, MC, AC trial in patients with distal disease (n = 157)	BDP 3 mg in 60 ml enema	Prednisolone sodium phosphate 30 mg in 60 ml enema	4 weeks	Clinical, endoscopic and histological activity	After 4 weeks, statistically significant improvements in clinical, histological and endoscopic parameters were observed in both treatment groups	Neither BDP nor prednisolone sodium phosphate had reduced HPA axis function AEs were similar between treatment groups: 3 patients receiving BDP and 1 patient receiving prednisolone sodium phosphate discontinued treatment due to an AE
Rizzello et al. [2002]	R, DB, PC trial in patients with mild-to-moderate active disease also receiving oral 5-ASA (n = 119)	Oral BDP 5 mg once daily	Pbo	4 weeks	Clinical response, assessed by DAI scores	After 4 weeks, BDP significantly reduced DAI scores compared with pbo (p = 0.014) Clinical response was achieved by 17.2% of patients receiving BDP and 16.4% receiving pbo	AEs were similar between BDP and pbo patients (3.4% and 6.5% respectively); serum cortisol levels were significantly decreased in BDP patients versus baseline (p = 0.001), however this was not associated with signs of decreased HPA axis function
Gionchetti et al. [2005]	R, SB, AC in patients with active UC (n = 217)	BDP enema 3 g once daily	5-ASA enema 5 g	6 weeks	Decrease in DAI	A significant decrease in the DAI score (p < 0.05) was observed in both treatment groups; clinical remission rate 36.7% with BDP and 29.2% with 5-ASA	Both treatments were well tolerated
Biancone et al. [2007]	R, MC, DB, AC trial in patients with mild-to-moderate distal disease (n = 99)	BDP 3 mg enema or BDP 3 mg foam	Mesalazine (5-ASA) 2 g enema or 5-ASA 2 g foam	8 weeks	Remission rate at 4 weeks; defined as a DAI score less than 3	Both BDP (enema or foam) and 5-ASA (enema or foam) had similar remission rates after 4 weeks (24% versus 28%); these were significant versus baseline (p < 0.0001) Patients receiving BDP (enema or foam) or 5-ASA (enema or foam) had similar response rates after 4 and 8 weeks of treatment (78% and 84% versus 79% and 90% respectively)	AEs were reported in 33% and 25% of patients receiving BDP and 5-ASA respectively; 6% and 7.5% of patients discontinued therapy due to AEs respectively
Fluticasone propionate
Angus et al. [1992]	R, DB, PC trial in patients with active distal disease (n = 60)	Oral FP 5 mg four times a day	Pbo	4 weeks	Clinical, sigmoidoscopic and histological response	After 4 weeks, the clinical, sigmoidoscopic and histological responses were similar between FP and pbo recipients After 4 weeks, 47% (14 out of 30) of patients receiving FP and 45% of patients receiving pbo had improved or gone into remission	AEs were similar between FP and pbo recipients 2 patients receiving FP experienced an AE (rash, tension headache) compared with 3 patients receiving pbo (herpes labialis and light headedness)
Hawthorne et al. [1993]	R, DB, MC, AC trial in patients with active disease (n = 205)	Oral FP 5 mg four times a day	Prednisolone 40 mg for week 1, 30 mg for week 2 then tapered until week 4	4 weeks	Investigators overall assessment of response at day 28	At 2 weeks prednisolone significantly improved response compared with FP (58% versus 49% of patients; p = 0.007); however, after 4 weeks of treatment the difference was no longer significant (48% versus 37% of patients; p = 0.087)	More patients receiving prednisolone reported glucocorticosteroid-associated AEs: 7 had facial swelling, 4 had facial flushing, 1 had confusion and 1 had increased hair growth. No HPA axis associated AEs were reported with FP
Prednisolone metasulphobenzoate
McIntyre et al. [1985]	R, DB, AC trial in patients with active distal disease (n = 40)	PM enema 20 mg	Prednosolone-21-phosphate enema 20 mg	2 weeks	Symptoms, stool frequency, sigmoidoscopic score, histological appearance	Treatments were similarly effective at improving symptoms, stool frequency and sigmoidoscopy scores Both treatments improved symptoms and sigmoidoscopic scores in more than 70% of the patients treated	Not described
Riley et al. [1989]	R, DB, AC trial in patients with mild-to-moderate disease (n = 44)	PM enema 20 mg once daily	Sucralfate enema once daily	4 weeks	Response rates, defined by changes in rectal bleeding, stool frequency and sigmoidoscopic and histologic grades	Patients receiving PM showed greater resolution of rectal bleeding and histologic grade compared with sucralfate Significant improvements in rectal bleeding and sigmoidoscopic grade were observed with PM and sucralfate treatment	Tolerability was similar between treatment groups; 2 cases of constipation were reported in patients receiving sucralfate and 2 patients receiving PM reported transient anal soreness and transient abdominal colic respectively
Rhodes et al. [2008]	R, DB, AC trial in patients with active disease (n = 181)	Oral PM 40 or 60 mg	Oral prednisolone 40 mg for 2 weeks, tapered to week 8 then pbo	6 months	VAS assessment of symptoms at 2 and 6 months	7.4 cm and 6.3 cm mean VAS scores for PM 40 and 60 mg respectively versus VAS of 6.9 cm for tapering prednisolone at 2 months Remission rates at 2 months were 46%, 28% and 41% for patients receiving PM 40 and 60 mg and tapering prednisolone respectively	Steroid-related effects (as measured by VAS) were fewer with PM 40 and 60 mg (both 8.1 cm) compared with tapering prednisolone (6.7 cm) Moon face, hirsutism, flushing, fluid retention, mood changes, sleep changes, acne, insomnia and palpitations were commonly reported AEs

5-ASA, 5-aminosalicylic acid (mesalazine); AC, active control; AE, adverse event; BDP, beclomethasone dipropionate; CAI, Colitis Activity Index; CR, controlled release; DAI, Disease Activity Index score; DB, double blind; FP, fluticasone propionate; HPA, hypothalamic pituitary adrenal; ITT, intent to treat; MC, multicenter; pbo, placebo; MMX, multimatrix; PC, placebo controlled; PM, prednisolone metasulphobenzoate; R, randomized; UC, ulcerative colitis; VAS, visual analogue scale.

A Cochrane review investigating the efficacy of oral budesonide for the induction of remission in ulcerative colitis was published in 2010 and concluded that there was no evidence to suggest that oral budesonide is effective for the induction of remission in ulcerative colitis [Sherlock et al. 2010]. Conversely, data from two randomized, double-blind trials reported in 2011 and 2012 showed that oral budesonide MMX 9 mg, but not 6 mg, once daily was significantly more effective than placebo for the induction of remission (Table 2) [Sandborn et al. 2012; Travis et al. 2011]. However, two slow-release delivery systems were developed for budesonide which are presently on the market. Both agents use enteric-coated (Eudragit, Evonik Industries, Essen, Germany) pellets with a rate-limiting polymer containing the active drug. These time-dependent and pH-dependent delivery systems (controlled ileal release, Entocort CIR, AstraZeneca; and Budenofalk, Dr Falk Pharma GmbH) release the drug in the distal ileum and the cecum, where approximately 70% of the total absorption takes place, making it effective for treatment of active distal ileal and right-sided colonic Crohn’s disease.

A new controlled release system, MMX extended-release tablets, characterized by a multimatrix structure, has recently been developed for 5-aminosalicylic acid preparations and marketed under the trade name of Lialda (Cosmo Pharmaceuticals, Lainate, Italy) or Mezavant (Shire, Dublin, Ireland). Data from two randomized, double-blind trials reported in 2011 and 2012 showed that oral budesonide MMX 9 mg, but not 6 mg, once daily was significantly more effective than placebo for the induction of remission (Table 2) [Sandborn et al. 2011; Travis et al. 2011].

The most recent study, an 8-week, randomized, double-blind trial to evaluate the efficacy of budesonide MMX for induction of remission in 509 patients with active, mild-to-moderate UC – showed that not only was remission induction greater with the 9mg dose, but so was endoscopic improvement. Moreover, both doses of budesonide MMX and mesalamine resulted in greater clinical improvement and symptom resolution compared with placebo, and tolerability was similar in all groups.[Sandborn et al. 2012]

Further trials investigating budesonide in patients with ulcerative colitis are consequently required.

Efficacy in pouchitis

Two trials have investigated the efficacy of budesonide in patients with pouchitis (Table 3); one was an open-label observational study investigating the efficacy and tolerability of oral, controlled-ileal-release budesonide [Gionchetti et al. 2007] and one was a randomized, double-blind study comparing a budesonide enema with metronidazole [Sambuelli et al. 2002]. These trials showed that oral budesonide is effective in inducing remission in patients with active refractory pouchitis [Gionchetti et al. 2007], and that the budesonide enema was as effective as oral metronidazole in patients with pouchitis, but with improved tolerability [Sambuelli et al. 2002]. These results indicated that budesonide may be a valuable treatment option for patients with pouchitis; however, both studies suggested that more randomized controlled trials are warranted.

Table 3.

Summary of prospective clinical studies investigating glucocorticosteroids in patients with pouchitis and lymphocytic colitis.

Study	Study design, patient population and characteristics	Dosage/formulation	Comparator (compound, dosage)	Treatment duration	Primary endpoint		Safety summary
					Definition	Outcome
Budesonide
Gionchetti et al. [2007]	P, OL in patients with active pouchitis (n = 20)	Budesonide 9 mg/day, controlled ileal release	None	8 weeks	Remission (PDAI clinical score ≤2, endoscopic score ≤1 and total PDAI score ≤4)	75% achieved remission Median total PDAI reduced from 14 to 3 (p < 0.001)	NR
Sambuelli et al. [2002]	R, DB, AC in patients with active pouchitis (n = 26)	Budesonide enema 2 mg/100 ml	Pbo Oral metronidazole 0.5 g twice daily	6 weeks	Disease activity	Significant improve in disease activity with active treatments (p < 0.01 versus baseline)	AEs in 57% of patients with metronidazole and 25% with budesonide
Miehlke et al. [2009]	R, DB, PC trial in patients with lymphocytic colitis (n = 42)	Budesonide 9 mg/day oral	Pbo	6 weeks	Clinical remission	Budesonide provided significantly greater remission versus pbo (86% versus 48%; p = 0.01)	Only 1 patient discontinued budesonide prematurely

AC, active control; AE, adverse event; DB, double blind; OL, open label; pbo, placebo; P, prospective; PC, placebo controlled; PDAI, Pouchitis Disease Activity Index; R, randomized.

Efficacy in lymphocytic colitis

Only one clinical trial has investigated the efficacy of budesonide in patients with lymphocytic colitis (Table 3). In a 6-week, randomized, double-blind placebo-controlled study [Miehlke et al. 2009] in 42 patients with lymphocytic colitis and chronic diarrhoea, 86% of patients achieved clinical remission with budesonide 9 mg/day versus 48% with placebo (p = 0.01).

Evidence from a retrospective study of patients with lymphocytic colitis [Simondi et al. 2010] showed that approximately 80% of patients improved on treatment with oral topical steroids (including budesonide) which is a similar rate to that achieved with mesalamine.

Tolerability

The tolerability of budesonide is well established: compared with conventional glucocorticosteroids it is associated with less glucocorticosteroid-related adverse events. A pooled safety analysis investigating the long-term effects of oral, controlled-release budesonide capsules showed that budesonide was generally well tolerated in patients with Crohn’s disease. The most common adverse events associated with budesonide capsules are gastrointestinal and endocrine system related events, with only rare occurrences of the clinically severe adverse events associated with traditional systemic glucocorticosteroids [Lichtenstein et al. 2009].

The most debilitating adverse events associated with glucocorticosteroids are osteopenia and bone fractures [D’Haens et al. 1998]. A few trials have been conducted to investigate the bone-related adverse events associated with budesonide; however, the results of these are conflicting. Short-term therapy with controlled-ileal-release budesonide did not impair osteoblast activity compared with oral methylprednisolone [D’Haens et al. 1998], and was associated with better preserved bone mass compared with prednisolone in corticosteroid-naïve patients [Schoon et al. 2005]. However, it has been shown that maintenance treatment with oral budesonide may be associated with lumbar spine and femoral neck bone loss [Cino and Greenberg, 2002].

Beclomethasone dipropionate

BDP is a second-generation glucocorticosteroid with topical effects and minimal systemic activity. There are many formulations of BDP available for the treatment of IBD, including a topical formulation and an oral, enteric-coated, controlled-release tablet (Clipper, Chiesi Ltd, Cheadle, UK; http://www.medicines.org.uk/emc/medicine/21329/SPC/Clipper+5mg+sustained+release+tablets/). This controlled-release tablet permits local delivery of BDP at the site of the inflammatory process in the mucosa of the distal ileum and proximal colon. These tablets have been launched in Belgium, Italy, Spain and the UK as a once-daily treatment, in combination with mesalamine, for mild-to-moderate, active ulcerative colitis. Controlled-release tablets are also being investigated for the treatment of Crohn’s disease [Tursi et al. 2006, Prantera et al. 2011].

Efficacy in Crohn’s disease

No double-blind, randomized trials have investigated the induction of remission with BDP in Crohn’s disease. However, results from a randomized, open-label trial indicated that BDP seems to be less effective than budesonide for the treatment of flares in patients with mild-to-moderate active Crohn’s disease [Tursi et al. 2006]. A recently published trial of 6 months’ maintenance therapy showed that oral, controlled-release BDP was well tolerated and significantly reduced the relapse rate in patients with postactive Crohn’s ileitis compared with placebo, after induction of remission with a short course of systemic glucocorticosteroids (Table 1) [Prantera et al. 2011]. Long-term steroid use is currently not recommended in patients with Crohn’s disease and further studies to establish the efficacy of BDP as a maintenance therapy in patients with Crohn’s disease are recommended.

Efficacy in ulcerative colitis

The efficacy of BDP in patients with ulcerative colitis has been well established; eight double-blind randomized trials have been published. These trials showed that topical administration of a BDP enema was as effective as first-generation beclomethasone phosphate and was preferable in terms of tolerability, as it did not affect adrenocortical function in patients with distal ulcerative colitis (Table 2) [Bansky et al. 1987; Halpern et al. 1991]. Furthermore, topical BDP enema was as effective as mesalamine foam in patients with mild-to-moderate distal ulcerative colitis (Table 2) [Biancone et al. 2007].

While BDP is effective in ulcerative colitis, the degree of efficacy compared with other glucocorticosteroids is not well defined. There is conflicting evidence regarding the efficacy of a BDP enema compared with a prednisolone sodium enema. Two studies, one in patients with distal ulcerative colitis and one in patients with more extensive ulcerative colitis, suggested that topical administration of BDP is as effective as a prednisolone sodium enema and does not affect the hypothalamic–pituitary–adrenal axis function [Mulder et al. 1989; Campieri et al. 1998]. On the contrary, another trial in patients with ulcerative proctitis suggested that a BDP enema was less effective than prednisolone 21-phosphate enema in ulcerative proctitis (Table 2) [Van der Heide et al. 1988]. Finally, three studies compared the efficacy of BDP, mesalamine and a combination of both drugs: one investigated topical mesalamine and a BDP enema [Mulder et al. 1996], one investigated oral, controlled-release BDP with mesalamine [Rizzello et al. 2002], and another compared topical BDP (36.7%) and topical mesalamine (29.2%) in 217 patients with distal active ulcerative colitis and demonstrated similar clinical remission rates between the two treatments [Gionchetti et al. 2005].

These trials showed that BDP alone was more effective than mesalamine alone in patients with extensive or left-sided ulcerative colitis, and that the combination of BDP and mesalamine was more effective than either BDP or mesalamine alone (Table 2).

Efficacy in pouchitis and lymphocytic colitis

There are no published randomized clinical trials of BDP in pouchitis or lymphocytic colitis. One retrospective study in patients with lymphocytic colitis found that 39% of patients were treated with oral topical steroids (including beclomethasone) and the clinical response rates achieved (approximately 80%) were similar to those achieved with mesalamine [Simondi et al. 2010].

Tolerability

The tolerability of BDP is well documented (Tables 1 and 2). As a second-generation glucocorticosteroid with much lower systemic absorption, it is associated with significantly fewer glucocorticosteroid adverse events than first-generation betamethasone phosphate, particularly with respect to hypothalamic–pituitary–adrenal axis suppression [Bansky et al. 1987; Halpern et al. 1991]. The most commonly reported adverse events associated with 6 months’ administration of BDP, however, were gastrointestinal related, including moon face, hyperthyroidism and Cushing’s syndrome [Prantera et al. 2011].

Other glucocorticosteroids

Fluticasone

Fluticasone propionate is an oral glucocorticosteroid that is used in the management of IBD.

Currently, no randomized, controlled trials have been conducted to investigate the efficacy of fluticasone propionate in patients with Crohn’s disease. However, an observational study which investigated the efficacy of oral fluticasone propionate in 12 patients with Crohn’s disease suggested that it may be an effective treatment for this disease. After 3 weeks of treatment, fluticasone propionate significantly reduced Crohn’s Disease Activity Index scores without inducing typical systemic corticosteroid side effects [De Kaski et al. 1991].

Two double-blind, randomized controlled trials have explored the efficacy and tolerability of oral fluticasone propionate in patients with ulcerative colitis (Table 2). Their negative results do not support the use of fluticasone propionate in this patient population. In the first placebo-controlled trial, fluticasone propionate was not found to be effective for the treatment of distal ulcerative colitis in 60 patients with active disease [Angus et al. 1992]. After 4 weeks of treatment, there was no difference between the clinical response observed in patients receiving fluticasone propionate or placebo. Furthermore, in the second study, fluticasone propionate appeared less effective than tapering of prednisolone in a study of 250 patients with active ulcerative colitis [Hawthorne et al. 1993]. After 2 weeks, the treatment response was significantly greater with prednisolone than fluticasone propionate; this difference was no longer significant by the end of the 4-week treatment period, possibly due to rapid tapering of the prednisolone dose, but there remained a trend towards significance (Table 2). However, fluticasone propionate was associated with very few of the adverse events typical of glucocorticosteroids in this study, with minimal suppression of the hypothalamic–pituitary–adrenal axis. This suggested that fluticasone propionate may be of use for short-term treatment in this patient population (Table 2).

There are no published randomized clinical trials of fluticasone in pouchitis or lymphocytic colitis.

Prednisolone metasulphobenzoate

Prednisolone metasulphobenzoate is a formulation of prednisolone which is not absorbed as extensively as previous formulations, such as prednisolone-21-phosphate. Prednisolone metasulphobenzoate is used for the treatment of ulcerative colitis and can be administered as an oral controlled-release formulation (Predocol, Enterotech Limited, Jersey, UK) [Rhodes et al. 2008]. Additionally, rectal administration of a foam formulation of prednisolone metasulphobenzoate (PredFoam, Forest Laboratories UK Limited, Bexley, UK) has been approved for the treatment of ulcerative colitis and proctitis (http://www.drugs.com/uk/predfoam-spc-1068.html).

Only a few double-blind, randomized controlled trials have been published reporting the efficacy and tolerability of prednisolone metasulphobenzoate in patients with ulcerative colitis. First, Predocol was shown to have similar efficacy to a conventional tapering prednisolone regimen in patients with active ulcerative colitis (Table 2) [Rhodes et al. 2008]. Prednisolone metasulphobenzoate was also shown to be associated with significantly fewer glucocorticosteroid-associated adverse events than the tapered prednisolone regimen (Table 2). In another two studies, a prednisolone metasulphobenzoate enema was shown to be as effective as a prednisolone-21-phosphate enema [McIntyre et al. 1985], and more effective than a sucralfate enema [Riley et al. 1989] in patients with active distal ulcerative colitis and mild-to-moderate ulcerative colitis respectively (Table 2). Furthermore, while the prednisolone metasulphobenzoate enema was shown to be as effective as the prednisolone-21-phosphate enema, peak plasma concentrations and the area under the concentration–time curve of prednisolone were lower after rectal administration of prednisolone metasulphobenzoate compared with prednisolone-21-phosphate. This suggested that the metasulphobenzoate formulation of prednisolone may reduce the systemic adverse effects of prednisolone to a greater extent than the phosphate formulation, which is particularly an advantage when long-term prednisolone treatment is required [McIntyre et al. 1985].

There are no published randomized clinical trials of prednisolone metasulphobenzoate in pouchitis or lymphocytic colitis.

The tolerability of prednisolone metasulphobenzoate has been well established in trials to date. These showed that oral prednisolone metasulphobenzoate is associated with fewer corticosteroid-related adverse events than oral prednisolone, and that the prednisolone metasulphobenzoate enema has a similar tolerability profile to a sucralfate enema (Table 2). A few trials have been conducted to investigate the effects of prednisolone metasulphobenzoate on bone formation or bone mineral density. These found that short-term oral controlled-release prednisolone metasulphobenzoate had no effect on bone formation (measured by osteocalcin levels) or bone mineral density after 4 months of treatment in patients with active ulcerative colitis [Darlow et al. 2004]. However, conflicting results were reported in two studies that investigated the effects of short-course prednisolone metasulphobenzoate foam enemas (20 mg twice daily) on bone formation in patients with distal ulcerative colitis. One observational study showed that prednisolone metasulphobenzoate was associated with a significant reduction in bone-specific alkaline phosphatase activity [Robinson et al. 1997]. In contrast, another randomized, active-controlled trial showed that neither prednisolone metasulphobenzoate nor hydrocortisone acetate enemas were associated with a reduction in serum osteocalcin or bone-specific alkaline phosphatase levels, suggesting no effect of treatment on bone turnover [Robinson et al. 1998]. Due to these conflicting results, no concrete conclusions regarding the effects of prednisolone metasulphobenzoate can be made. It is important for physicians to be aware of the potential bone-related effects associated with prednisolone metasulphobenzoate in patients with ulcerative colitis, and monitoring of such patients is therefore recommended.

Conclusion

Glucocorticosteroids are the most common therapy for the induction of remission in the active phases of IBD. Unfortunately, their use is burdened by important side effects. New formulations of glucocorticosteroids have been introduced with the intention of maintaining the efficacy of systemic steroids, while reducing the number of side effects, and in the case of the latter they have been successful. Nevertheless, compared with systemic administration, the improved tolerability profile of local steroids is accompanied by reduced efficacy.

Budesonide is the first glucocorticosteroid that has been extensively investigated for the treatment of Crohn’s disease. It has been shown to be beneficial for the induction of remission in these patients, but is not recommended for the maintenance of remission in patients with Crohn’s disease. This recommendation is not completely accepted in clinical practice, mainly in the North of Europe, because many patients are treated for periods of over 1 year. Few studies have investigated the efficacy of budesonide in ulcerative colitis and the results of these are conflicting. Further research is warranted to establish the efficacy of budesonide in patients with ulcerative colitis. Furthermore, new formulations of budesonide which release the drug in the colon have been effective therapy for patients with active ulcerative colitis in initial studies. These findings merit more extensive study.

BDP has good efficacy and is an established treatment for patients with ulcerative colitis, but data are not extensive in patients with Crohn’s disease. While glucocorticosteroids are not recommended for the maintenance of remission in patients with IBD, a promising recent study suggested that BDP might maintain the remission induced by a short course of systemic glucocorticosteroids, reducing the number of side effects. Further investigation to confirm the efficacy of BDP in this indication is warranted.

The efficacy of fluticasone propionate and prednisolone metasulphobenzoate for the treatment of IBD is not well established in published clinical trials. While the tolerability profiles of these glucocorticosteroids are favourable, more research investigating their efficacy in these patients is required.

Finally, given that the most important advantage of the new glucocorticosteroids is their improved safety profile, we must mention that there are no studies assessing prolonged treatment (of over 1 year), and it is well known that steroid-related side effects are mainly associated with long-term therapy. It is possible, therefore, that long-term therapy with new glucocorticoid formulations could be associated with the appearance of important side effects, although it is likely that these will be less severe than those seen with traditional systemic steroids.