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Budesonide in inflammatory bowel disease
The Netherlands
JOURNAL OF MEDICINE ELSEVIER
Netherlands Journal of Medicine 48 (1996) 60-63
Budesonide in inflammatory bowel disease C.B.H.W.
Lamers
*, M . J . W a g t m a n s , A . v a n d e r S l u y s V e e r , R . A . v a n H o g e z a n d , G. Griffioen
Department of Gastroenterology-Hepatology, University Hospital Leiden, Building 1, C4 POI5, P.O. Box 9600, 2300 RC Leiden, Netherlands
Abstract
Due to its immunomodulatory and anti-inflammatory properties glucocorticosteroids have proved to be highly efficacious in patients with inflammatory bowel disease. However, because of the risk of side-effects, the dose and duration of therapy with systemically acting glucocorticosteroids have to be restricted. Recently the use of topically acting glucocorticosteroids has attracted great interest. Among the various topically acting glucocorticosteroids budesonide has emerged as the most promising. Budesonide is highly potent, is readily water-soluble and has low systemic bioavailability, thus reducing the risk of corticosteroid-related side-effects. When given as enema to patients with proctitis or proctosigmoiditis, the efficacy of budesonide is greater than that of placebo and equal to that of prednisolone or 5-aminosalicylic acid enemas. In an enteric-coated formulation budesonide is more effective than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. Although corticosteroidrelated side-effects are rare, some suppression of the hypothalamic-pituitary-adrenal axis may occur. Keywords: Budesonide; Ulcerative colitis; Crohn's disease; Glucocorticosteroid; Inflammatory bowel disease
1. Introduction
Since the mid-fifties, glucocorticosteroids are one of the mainstays of therapy of active inflammatory bowel disease [1,2]. However, this therapy may provoke serious adverse effects, such as emotional disturbances, Cushing's syndrome, osteoporosis, etc, hampering long-term or high-dose use. In recent years active glucocorticosteroids with fewer systemic side-effects have been developed [3-5]. To obtain high topical efficacy with low risk for systemic steroid side-effects, theoretically sev-
Tel.: (+31-71) 263507; fax: (+31-71) 248115.
eral approaches can be taken [3]. First, to search for subtypes of the glucocorticosteroid receptor separating the various actions of these drugs. Unfortunately this approach does not appear to be very promising because the glucocorticosteroid receptor seems to be uniform throughout the human body, indicating that the same receptor type can mediate therapeutic as well as adverse reactions. Another approach is to use larger prednisolone preparations that give slower release of prednisolone. Prednisolone metasulphobenzoate is the best-known representative of these larger prednisolone molecules. When rectally administered, the drug gives higher rectal tissue levels than rapidly absorbed systemic steroids. However, the conjugate may induce sul-
0300-2977/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0300-2977(95)00090-9
C.B.H.W. Lamers et al. / Netherlands Journal of Medicine 48 (1996) 60-63
pha-like side-effects and when given as a foam preparation it suppresses the hypothalamic-pituitary-adrenal axis. A third more promising approach is to administer glucocorticosteroid derivates with high topical potency, rapid absorption and fast inactivation through biotransformation by liver enzymes. Some of these drugs with topical activity and low systemic availability have been on the market for several years for the treatment of asthma and rhinitis. In fact, the conditions for topical enema treatment of distal ulcerative colitis are even better than for asthma and rhinitis, since after absorption nearly all of the drug will directly reach the liver by the portal circulation, whereas inhaled drugs have to pass the heart first and only one-third will have first pass to the liver. There is a number of such drugs as enema on the market or under investigation, including budesonide, beclomethasone dipropionate, tixocortol pivalate and fluticasone propionate [3-5]. Budesonide is the most thoroughly studied and probably most promising of these drugs. Budesonide has been shown to be effective not only as an enema in distal ulcerative colitis but also as a slow-release oral preparation in ileocecal Crohn's disease [6,7]. Budesonide has a high receptor affinity, indicating a high intrinsic activity of about 2~2 times that of beclomethasone dipropionate, 200 times that of tixocortol pivalate and 15 times that of prednisolone [3]. Furthermore, budesonide has a 100 times higher water solubility than beclomethasone dipropionate and fluticasone propionate, facilitating its dissolution and transport into the bowel. Budesonide is effectively absorbed after rectal application, dwells in the bowel wall for one to a few hours to trigger its anti-inflammatory action, and is subsequently transported via the portal circulation to the liver, where it is rapidly biotransformed by oxidative enzymes into metabolites which have at least 100 times lower intrinsic glucocorticosteroid potencies than that of the parent compound [3]. Pharmacologically there are however discrete differences among the various topically acting glucocorticosteroids. For example, one of the metabolites of beclomethasone dipropionate retains clear glucocorticosteroid activity, tixocortol pivalate is rapidly metabolised by extrahepatic mechanisms
61
which may result in partial inactivation within the bowel wall, and fluticasone propionate is poorly absorbed [3].
2. Clinical studies with b u d e s o n i d e e n e m a s
Since budesonide is by far the best studied topical steroid, not only pharmacologically but also clinically, this section will mainly focus on this drug. The optimal dose of budesonide for distal ulcerative colitis has been found to be 2 m g / 1 0 0 ml enema [8]. Several studies have compared budesonide enemas once daily at night with various prednisolone enema preparations and hydrocortisone foam [5,8-12]. Symptoms, endoscopy, rectal biopsies and side-effects were usually assessed at 2 and 4 weeks. Although in most studies the number of patients was relatively low, the results were clearcut. Budesonide enema was at least equally efficacious as prednisolone enema with regard to symptoms, endoscopy and rectal histology, while plasma cortisol levels were clearly depressed during prednisolone but less so during budesonide therapy. Significant side-effects were few on budesonide enema therapy and only 2% of patients had to be withdrawn from the clinical studies. Although symptoms, endoscopy and histology were significantly improved both with budesonide and prednisolone enemas, a relatively large proportion of patients was not fully healed after 4 weeks, suggesting that a prolonged treatment period may be required in some of them. This has been investigated in only a few studies which showed that another 4 weeks budesonide enema treatment gives further improvement even in patients with a low response to prednisolone [10-12]. In one of the studies, Bianchi Porro et al. reported that a further 4 weeks budesonide treatment in 37 patients who were not healed after 4 weeks resulted in 65% symptomatic remission and 47% mucosal healing or substantial improvement at endoscopy [12]. Budesonide enemas have also been compared with retention enemas containing 1 and 4 g of 5-aminosalicylic acid (5-ASA) [13,14]. In both studies enemas containing 2 mg of budesonide
62
C.B.H.W. Lamers et al. /Netherlands Journal of Medicine 48 (1996) 60-63
were equally effective as the 5-ASA enemas with regard to symptoms, endoscopy, histology and side-effects. In pilot studies, budesonide enemas have also been evaluated in therapy-resistant distal ulcerative colitis and colonic Crohn's disease [5]. In both studies, budesonide produced remission or improvement in approximately 75% of the patients. In an open study Belluzzi et al. treated 10 patients with pouchitis with budesonide suppositories 0.5 mg t.d.s, for 4 weeks [15]. All 10 patients showed clinical and endoscopic improvement, but 6 of them relapsed within 4 weeks after stopping the treatment.
3. Studies with oral budesonide
Since the risk of adverse events of glucocorticosteroids is greater with oral than with enema therapy, there is great interest in studies into the efficacy and safety of orally administered budesonide in patients with inflammatory bowel disease. One of the major problems encountered with the oral use of topically acting drugs in inflammatory bowel disease is the difficulty of obtaining maximal availability of the compound at the site of inflammation. This goal is especially hard to achieve in Crohn's disease, where the inflammatory process may be present anywhere in the gastrointestinal tract, often extends beyond the mucosa, and may lead to small bowel resections interfering with intestinal transit and drug disposition. To obtain optimal availability of budesonide at the ileum and the proximal colon, delayed-release coatings have been applied to prevent absorption in the upper gastrointestinal tract. Enteric-coated budesonide has been studied in patients with Crohn's disease of the ileocecal region [6,7]. In a placebo-controlled dose finding study using enteric-coated budesonide, 9 mg/day appeared to be the optimal dose. After 8 weeks of therapy clinical remission was achieved in 51% of the patients on budesonide in a dose of 9 mg/day, in 43% of those on the 15 rag/day dose, 33% of those on 3 mg/day budesonide and 20% of those receiving placebo [6]. However, although corticosteroid-related side-effects were
rare, the plasma cortisol level was significantly reduced in the patients on 9 mg/day budesonide [6]. In another study, budesonide in a daily dose of 9 mg was compared with prednisolone in a dose of 40 mg/day for 2 weeks, after which it was gradually reduced to 5 m g/ day during the last week [7]. At 10 weeks 53% of the patients treated with budesonide were in remission as compared with 66% of those treated with prednisolone. As expected, plasma eortisol concentrations were less reduced and corticosteroid-associated side-effects occurred less frequently in the patients treated with budesonide. In a subsequent study budesonide in doses of 3 and 6 mg were compared with placebo in those patients who had achieved a clinical remission in the previous study [16]. Orally administered budesonide in the dose of 6 m g/ day was significantly better than placebo in maintaining the patients in remission while corticosteroid-related side-effects were rare [16]. Thus, oral budesonide is better than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. However, budesonide is not a panacea for patients with inflammatory bowel disease since no remission was achieved in almost half of the target group of patients with ileocecal Crohn's disease.
References [1] Peppercorn MA. Advances in drug therapy for inflammatory bowel disease. Ann Intern Med 1990;112:50-60. [2] Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. Gastroenterology 1992;102:1647-1653. [3] Brattsand R. Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Can J Gastroenterol 1990;4:407-414. [4] Mulder CJJ, Tytgat GNJ. Topical corticosteroids in inflammatory bowel disease. Aliment Pharmacol Ther 1993;7:125-130. [5] Lamers CBHW. Future of topical steroid enemas. Eur J Gastroenterol Hepatol 1994;6:121-123. [6] Greenberg GR, Feagan BG, Martin F, et al. Oral budesouide for active Crohn's disease. N Engl J Med 1994;331:836-841. [7] Rutgeerts P, L6fberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med 1994;331:842-845. [8] Danish Budesonide Study Group. Budesonide enema in
C.B.H.W. Lamers et al. / Netherlands Journal of Medicine 48 (1996) 60-63
[9]
[10]
[11]
[12]
distal ulcerative colitis: a randomized dose-response trial with prednisolone enema as positive control. Scand J Gastroenterol 1991;26:1225-1230. o Danielsson A, Hellers G, Lyrenfis E, et al. A controlled randomized trial of budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Scand J Gastroenterol 1987;22:987-992. L6fberg R, Ostergaard-Thomson O, Langholz E, et al. Budesonide versus prednisolone enema in active distal ulcerative colitis. A comparative eight week study. Gut 1993;34(suppl 1):T62. Thomsen O, Anderssen T, Langholz E, et al. Lack of adrenal gland suppression with budesonide enema treatment in active distal ulcerative colitis. A prednisolone controlled eight week study. Gut 1993;34:$27. Bianehi Porro G, Prantera C, Campieri M., et al. Comparative trial of budesonide and methylprednisolone enemas in active distal ulcerative colitis. Eur J Gastroenterol Hepatol 1994;6:125-130.
63
[13] Lamers CBHW, Meijer JL, Engels L, et al. Comparative study of the topically acting glucocorticosteroid budesonide and 5-aminosalicylic acid enema therapy of proctitis and proctosigmoiditis. Gastroenterology 1991;100: A223. [14] Lemann M, Rutgeers P, Van Heuverzwijn R, et al. Comparison of budesonide enema and 5-ASA enema in the treatment of active distal ulcerative colitis. Hell J Gastroenterol 1992;5(suppl):A776. [15] Belluzzi A, Campieri M, Miglioli M, et al. Evaluation of phlogistic pattern in pouchitis before and after treatment with budesonide suppositories. Gastroenterology 1992; 102:A593. [16] L6fberg R, Rutgeerts P, Malchow H, et al. Budesonide CVR for maintenance of remission in ileocecal Crohn's disease. A European multicenter placebo controlled trial for 12 months. Gastroenterology 1994;106:A722.
JOURNAL OF MEDICINE ELSEVIER
Netherlands Journal of Medicine 48 (1996) 60-63
Budesonide in inflammatory bowel disease C.B.H.W.
Lamers
*, M . J . W a g t m a n s , A . v a n d e r S l u y s V e e r , R . A . v a n H o g e z a n d , G. Griffioen
Department of Gastroenterology-Hepatology, University Hospital Leiden, Building 1, C4 POI5, P.O. Box 9600, 2300 RC Leiden, Netherlands
Abstract
Due to its immunomodulatory and anti-inflammatory properties glucocorticosteroids have proved to be highly efficacious in patients with inflammatory bowel disease. However, because of the risk of side-effects, the dose and duration of therapy with systemically acting glucocorticosteroids have to be restricted. Recently the use of topically acting glucocorticosteroids has attracted great interest. Among the various topically acting glucocorticosteroids budesonide has emerged as the most promising. Budesonide is highly potent, is readily water-soluble and has low systemic bioavailability, thus reducing the risk of corticosteroid-related side-effects. When given as enema to patients with proctitis or proctosigmoiditis, the efficacy of budesonide is greater than that of placebo and equal to that of prednisolone or 5-aminosalicylic acid enemas. In an enteric-coated formulation budesonide is more effective than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. Although corticosteroidrelated side-effects are rare, some suppression of the hypothalamic-pituitary-adrenal axis may occur. Keywords: Budesonide; Ulcerative colitis; Crohn's disease; Glucocorticosteroid; Inflammatory bowel disease
1. Introduction
Since the mid-fifties, glucocorticosteroids are one of the mainstays of therapy of active inflammatory bowel disease [1,2]. However, this therapy may provoke serious adverse effects, such as emotional disturbances, Cushing's syndrome, osteoporosis, etc, hampering long-term or high-dose use. In recent years active glucocorticosteroids with fewer systemic side-effects have been developed [3-5]. To obtain high topical efficacy with low risk for systemic steroid side-effects, theoretically sev-
Tel.: (+31-71) 263507; fax: (+31-71) 248115.
eral approaches can be taken [3]. First, to search for subtypes of the glucocorticosteroid receptor separating the various actions of these drugs. Unfortunately this approach does not appear to be very promising because the glucocorticosteroid receptor seems to be uniform throughout the human body, indicating that the same receptor type can mediate therapeutic as well as adverse reactions. Another approach is to use larger prednisolone preparations that give slower release of prednisolone. Prednisolone metasulphobenzoate is the best-known representative of these larger prednisolone molecules. When rectally administered, the drug gives higher rectal tissue levels than rapidly absorbed systemic steroids. However, the conjugate may induce sul-
0300-2977/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0300-2977(95)00090-9
C.B.H.W. Lamers et al. / Netherlands Journal of Medicine 48 (1996) 60-63
pha-like side-effects and when given as a foam preparation it suppresses the hypothalamic-pituitary-adrenal axis. A third more promising approach is to administer glucocorticosteroid derivates with high topical potency, rapid absorption and fast inactivation through biotransformation by liver enzymes. Some of these drugs with topical activity and low systemic availability have been on the market for several years for the treatment of asthma and rhinitis. In fact, the conditions for topical enema treatment of distal ulcerative colitis are even better than for asthma and rhinitis, since after absorption nearly all of the drug will directly reach the liver by the portal circulation, whereas inhaled drugs have to pass the heart first and only one-third will have first pass to the liver. There is a number of such drugs as enema on the market or under investigation, including budesonide, beclomethasone dipropionate, tixocortol pivalate and fluticasone propionate [3-5]. Budesonide is the most thoroughly studied and probably most promising of these drugs. Budesonide has been shown to be effective not only as an enema in distal ulcerative colitis but also as a slow-release oral preparation in ileocecal Crohn's disease [6,7]. Budesonide has a high receptor affinity, indicating a high intrinsic activity of about 2~2 times that of beclomethasone dipropionate, 200 times that of tixocortol pivalate and 15 times that of prednisolone [3]. Furthermore, budesonide has a 100 times higher water solubility than beclomethasone dipropionate and fluticasone propionate, facilitating its dissolution and transport into the bowel. Budesonide is effectively absorbed after rectal application, dwells in the bowel wall for one to a few hours to trigger its anti-inflammatory action, and is subsequently transported via the portal circulation to the liver, where it is rapidly biotransformed by oxidative enzymes into metabolites which have at least 100 times lower intrinsic glucocorticosteroid potencies than that of the parent compound [3]. Pharmacologically there are however discrete differences among the various topically acting glucocorticosteroids. For example, one of the metabolites of beclomethasone dipropionate retains clear glucocorticosteroid activity, tixocortol pivalate is rapidly metabolised by extrahepatic mechanisms
61
which may result in partial inactivation within the bowel wall, and fluticasone propionate is poorly absorbed [3].
2. Clinical studies with b u d e s o n i d e e n e m a s
Since budesonide is by far the best studied topical steroid, not only pharmacologically but also clinically, this section will mainly focus on this drug. The optimal dose of budesonide for distal ulcerative colitis has been found to be 2 m g / 1 0 0 ml enema [8]. Several studies have compared budesonide enemas once daily at night with various prednisolone enema preparations and hydrocortisone foam [5,8-12]. Symptoms, endoscopy, rectal biopsies and side-effects were usually assessed at 2 and 4 weeks. Although in most studies the number of patients was relatively low, the results were clearcut. Budesonide enema was at least equally efficacious as prednisolone enema with regard to symptoms, endoscopy and rectal histology, while plasma cortisol levels were clearly depressed during prednisolone but less so during budesonide therapy. Significant side-effects were few on budesonide enema therapy and only 2% of patients had to be withdrawn from the clinical studies. Although symptoms, endoscopy and histology were significantly improved both with budesonide and prednisolone enemas, a relatively large proportion of patients was not fully healed after 4 weeks, suggesting that a prolonged treatment period may be required in some of them. This has been investigated in only a few studies which showed that another 4 weeks budesonide enema treatment gives further improvement even in patients with a low response to prednisolone [10-12]. In one of the studies, Bianchi Porro et al. reported that a further 4 weeks budesonide treatment in 37 patients who were not healed after 4 weeks resulted in 65% symptomatic remission and 47% mucosal healing or substantial improvement at endoscopy [12]. Budesonide enemas have also been compared with retention enemas containing 1 and 4 g of 5-aminosalicylic acid (5-ASA) [13,14]. In both studies enemas containing 2 mg of budesonide
62
C.B.H.W. Lamers et al. /Netherlands Journal of Medicine 48 (1996) 60-63
were equally effective as the 5-ASA enemas with regard to symptoms, endoscopy, histology and side-effects. In pilot studies, budesonide enemas have also been evaluated in therapy-resistant distal ulcerative colitis and colonic Crohn's disease [5]. In both studies, budesonide produced remission or improvement in approximately 75% of the patients. In an open study Belluzzi et al. treated 10 patients with pouchitis with budesonide suppositories 0.5 mg t.d.s, for 4 weeks [15]. All 10 patients showed clinical and endoscopic improvement, but 6 of them relapsed within 4 weeks after stopping the treatment.
3. Studies with oral budesonide
Since the risk of adverse events of glucocorticosteroids is greater with oral than with enema therapy, there is great interest in studies into the efficacy and safety of orally administered budesonide in patients with inflammatory bowel disease. One of the major problems encountered with the oral use of topically acting drugs in inflammatory bowel disease is the difficulty of obtaining maximal availability of the compound at the site of inflammation. This goal is especially hard to achieve in Crohn's disease, where the inflammatory process may be present anywhere in the gastrointestinal tract, often extends beyond the mucosa, and may lead to small bowel resections interfering with intestinal transit and drug disposition. To obtain optimal availability of budesonide at the ileum and the proximal colon, delayed-release coatings have been applied to prevent absorption in the upper gastrointestinal tract. Enteric-coated budesonide has been studied in patients with Crohn's disease of the ileocecal region [6,7]. In a placebo-controlled dose finding study using enteric-coated budesonide, 9 mg/day appeared to be the optimal dose. After 8 weeks of therapy clinical remission was achieved in 51% of the patients on budesonide in a dose of 9 mg/day, in 43% of those on the 15 rag/day dose, 33% of those on 3 mg/day budesonide and 20% of those receiving placebo [6]. However, although corticosteroid-related side-effects were
rare, the plasma cortisol level was significantly reduced in the patients on 9 mg/day budesonide [6]. In another study, budesonide in a daily dose of 9 mg was compared with prednisolone in a dose of 40 mg/day for 2 weeks, after which it was gradually reduced to 5 m g/ day during the last week [7]. At 10 weeks 53% of the patients treated with budesonide were in remission as compared with 66% of those treated with prednisolone. As expected, plasma eortisol concentrations were less reduced and corticosteroid-associated side-effects occurred less frequently in the patients treated with budesonide. In a subsequent study budesonide in doses of 3 and 6 mg were compared with placebo in those patients who had achieved a clinical remission in the previous study [16]. Orally administered budesonide in the dose of 6 m g/ day was significantly better than placebo in maintaining the patients in remission while corticosteroid-related side-effects were rare [16]. Thus, oral budesonide is better than placebo in achieving and maintaining remission in patients with ileocecal Crohn's disease. However, budesonide is not a panacea for patients with inflammatory bowel disease since no remission was achieved in almost half of the target group of patients with ileocecal Crohn's disease.
References [1] Peppercorn MA. Advances in drug therapy for inflammatory bowel disease. Ann Intern Med 1990;112:50-60. [2] Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn's disease treatment: a prospective, randomized clinical trial. Gastroenterology 1992;102:1647-1653. [3] Brattsand R. Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Can J Gastroenterol 1990;4:407-414. [4] Mulder CJJ, Tytgat GNJ. Topical corticosteroids in inflammatory bowel disease. Aliment Pharmacol Ther 1993;7:125-130. [5] Lamers CBHW. Future of topical steroid enemas. Eur J Gastroenterol Hepatol 1994;6:121-123. [6] Greenberg GR, Feagan BG, Martin F, et al. Oral budesouide for active Crohn's disease. N Engl J Med 1994;331:836-841. [7] Rutgeerts P, L6fberg R, Malchow H, et al. A comparison of budesonide with prednisolone for active Crohn's disease. N Engl J Med 1994;331:842-845. [8] Danish Budesonide Study Group. Budesonide enema in
C.B.H.W. Lamers et al. / Netherlands Journal of Medicine 48 (1996) 60-63
[9]
[10]
[11]
[12]
distal ulcerative colitis: a randomized dose-response trial with prednisolone enema as positive control. Scand J Gastroenterol 1991;26:1225-1230. o Danielsson A, Hellers G, Lyrenfis E, et al. A controlled randomized trial of budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Scand J Gastroenterol 1987;22:987-992. L6fberg R, Ostergaard-Thomson O, Langholz E, et al. Budesonide versus prednisolone enema in active distal ulcerative colitis. A comparative eight week study. Gut 1993;34(suppl 1):T62. Thomsen O, Anderssen T, Langholz E, et al. Lack of adrenal gland suppression with budesonide enema treatment in active distal ulcerative colitis. A prednisolone controlled eight week study. Gut 1993;34:$27. Bianehi Porro G, Prantera C, Campieri M., et al. Comparative trial of budesonide and methylprednisolone enemas in active distal ulcerative colitis. Eur J Gastroenterol Hepatol 1994;6:125-130.
63
[13] Lamers CBHW, Meijer JL, Engels L, et al. Comparative study of the topically acting glucocorticosteroid budesonide and 5-aminosalicylic acid enema therapy of proctitis and proctosigmoiditis. Gastroenterology 1991;100: A223. [14] Lemann M, Rutgeers P, Van Heuverzwijn R, et al. Comparison of budesonide enema and 5-ASA enema in the treatment of active distal ulcerative colitis. Hell J Gastroenterol 1992;5(suppl):A776. [15] Belluzzi A, Campieri M, Miglioli M, et al. Evaluation of phlogistic pattern in pouchitis before and after treatment with budesonide suppositories. Gastroenterology 1992; 102:A593. [16] L6fberg R, Rutgeerts P, Malchow H, et al. Budesonide CVR for maintenance of remission in ileocecal Crohn's disease. A European multicenter placebo controlled trial for 12 months. Gastroenterology 1994;106:A722.