sign in sign up
<<
Home , Betamethasone, Budesonide, Hydrocortisone, Suppository, Tixocortol

Gut 1997; 40: 775-781 775

Rectal versus alternative treatments in : a meta-analysis Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from

J K Marshall, E J Irvine

Abstract consistently to the splenic Background-Clear strategies to optimise flexure,49 and a larger volume seems to allow the use of corticosteroids in ulcerative more proximal delivery.10 11 Rectal foam dis- colitis are lacking. seminates medication to the rectum and distal Aim-A meta-analysis was undertaken to descending colon,'2-16 whereas suppositories examine critically the role of rectal corti- coat only the rectum.'7 18 costeroids in the management of active Although studies of rectally administered distal ulcerative colitis. corticosteroids have reported fewer systemic Methods-AJl reported randomised con- adverse effects than with oral preparations, trolled trials were retrieved by searching plasma concentrations of were the Medline and EMBASE databases and similar after administration of identical oral or the bibliographies of relevant studies. rectal doses.'9 20 Suppression of the hypo- Trials which met inclusion criteria were thalamic-pituitary-adrenal axis in association assessed for scientific rigour. Data were with rectal therapy has also been shown.2' 26 extracted by two independent observers Newer topically active corticosteroids such according to predetermined criteria. as , beclomethasone, prednisolone Results-Of 83 trials retrieved, 33 met metasulphabenzoate, and , with inclusion criteria. Pooled odds ratios restricted absorption or rapid hepatic metab- (POR) showed conventional rectal corti- olism have been developed to reduce the costeroids and rectal budesonide to be adverse effects associated with conventional clearly superior to placebo. In seven trials, corticosteroids.27 28 rectal 5-aminosalicylic acid (5-ASA) was To examine critically the role of rectal corti- significantly better than conventional costeroids in the treatment of active distal rectal corticosteroids for inducing re- ulcerative colitis, we performed a meta-analysis mission of symptoms, endoscopy, and of all reported randomised controlled trials.

histology with POR of 2-42 (95% confi- http://gut.bmj.com/ dence interval (CI) 1-72-3-41), 1.89 (95% CI 1.29-2*76), and 2*03 (95% CI 1.28-3*20), Methods respectively. Rectal budesonide was of Relevant clinical trials were identified by comparable efficacy to conventional corti- searching the Medline database from 1966 to costeroids but produced less endogenous 1996 and the EMBASE database from 1985 to suppression. Side effects, 1996, using the MeSH terms "inflammatory

although inconsistently reported, were bowel disease", "therapy", and "topical ad- on September 23, 2021 by guest. Protected copyright. generally minor. A cost comparison of ministration", "", or "suppository". rectal preparations showed 5-ASA to be Bibliographies of all relevant studies and recent less expensive than corticosteroids. review articles were scanned to identify further Conclusions-Rectal 5-ASA is superior to citations. Each paper was assessed by two rectal corticosteroids in the management independent observers (JKM, EJI) according ofdistal ulcerative colitis. to predetermined inclusion criteria. Studies (Gut 1997; 40: 775-781) were accepted if patients had active ulcerative colitis with a documented disease margin distal Keywords: ulcerative colitis, corticosteroids, therapy, to the splenic flexure on radiographic studies topical administration, enema, suppository. or less than 60 cm from the anal verge at flexible or colonoscopy. We required that patients had been randomly Oral corticosteroids have been a well-accepted assigned to two or more treatment groups, with treatment for active ulcerative colitis since rectal corticosteroids in at least one treatment Division of Gastroenterology and Truelove et al reported the efficacy of oral arm and a symptom score as one of the main Intestinal Disease over 40 years ago.' However, outcome criteria. The minimum duration of Research Programme, their long term use may be limited and patient therapy permitted was two weeks. McMaster University, Hamilton, Ontario, compliance diminished by potential adverse Trials which met the inclusion criteria were Canada effects. Administration of a then evaluated quantitatively for scientific J K Marshall enema was first suggested to be effi- rigour using a 30 point scoring system.29 Dis- E J Irvine cacious in distal ulcerative colitis in 1956.2 The agreements in scoring between the two Correspondence to: Dr E Jan Irvine, proven efficacy of direct delivery to the observers were settled by consensus. Division of Gastroenterology, site of inflammation has since led to wide- Data were extracted from each report using Room 4W8, McMaster University Medical Center, spread acceptance of rectal corticosteroid a predefined format. Recorded data points 1200 Main Street West, therapy.3 included the number of patients enrolled, Hamilton, Ontario L8N 3Z5, Canada. The ability of a rectal preparation to achieve number completing the study, sex, and disease Accepted for publication a proximal distribution is determined by the distribution. The proportion of patients that 23 December 1996 type of vehicle. Liquid can deliver improved or attained remission, or both, by 776 MarshaUl, Irvine

symptomatic, endoscopic, and histological remission. When corticosteroid doses were criteria were recorded from each trial using an converted to their hydrocortisone equivalent,30 intention to treat principle. The dose, no dose response relation was observed for frequency, duration, and formulation (enema, either conventional or topical formulations.

suppository or foam) of treatments were noted, Similarly, no correlation was apparent between Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from as were any reported adverse effects of therapy. duration of treatment and response rate. We anticipated that the definitions of (4-ASA or 5-ASA), which "improvement" and "remission" would vary were used most frequently as a comparative considerably among the papers accepted. To treatment, produced improvement in symp- overcome the problems of standardising end- toms, endoscopy, and histology in, respect- points, provided that an adequate definition of ively, 81%, 75%, and 65% of patients. Re- improvement or remission was offered, the mission with these endpoints was induced in authors' criteria for these outcomes were 52%, 410%, and 32% of patients, respectively. respected. All clinical symptom scores Across four trials, 34% of patients taking included stool frequency and rectal bleeding. placebo improved symptomatically, and 38% Studies were grouped for analysis according improved endoscopically. Remission rates by to the type of corticosteroid and control symptomatic and endoscopic criteria were 9% therapies. Corticosteroid doses were also con- and 17%. verted to a hydrocortisone dose equivalent to permit testing for a dose response relation.30 The statistical analysis was conducted using the RECTAL CORTICOSTEROIDS VERSUS PLACEBO method of DerSimonian and Laird.3' An odds Two trials compared conventional rectal corti- ratio for each trial and a common odds ratio for costeroids with placebo.34 The combined each group with 95% confidence intervals (CI) results clearly favoured corticosteroids, with a were calculated according to Mantel-Haenszel. pooled odds ratios (POR) for symptomatic and Unless otherwise stated, odds ratios below 1 endoscopic improvement of 0-21 (95% CI favoured corticosteroid treatment, whereas 0-07-0-71) and 0-27 (95% CI 0-10-0-77), odds radios above 1 favoured the alternative respectively. The PORs for symptomatic and treatment. Continuous data points were pooled endoscopic remission were 0 07 (95% CI and compared using a weighted mean differ- 0-02-0-29) and 0 34 (95% CI 0-10-1-20), ence.32 Homogeneity within groups oftrials was respectively. Histological endpoints were not confirmed using the Breslow-Day test.33 Over- reported in these early trials. all response rates for each drug were calculated One trial reported that 2-3 mg budesonide by dividing the total number of patients enemas were superior to placebo for improve-

reaching an endpoint by the total number of ment of symptoms, endoscopy, and his- http://gut.bmj.com/ patients treated. tology,36 whereas another found 2-0 mg or 8-0 mg daily superior to placebo in inducing com- bined symptomatic and endoscopic remission, Results with higher response rates at the larger dose.37

ACCEPTANCE AND VALIDITY SCORING

In total, 83 relevant trials were identified by the RECTAL VERSUS ORAL CORTICOSTEROIDS on September 23, 2021 by guest. Protected copyright. search, of which 33 met our inclusion criteria. Rectal hydrocortisone 100 mg was compared Reasons for excluding a trial included: lack of with oral prednisolone 60 mg daily in one trial randomisation (36 trials), inclusion of patients which showed oral treatment to be better for with disease proximal to the splenic flexure (29 symptomatic improvement and remission.39 A trials), lack of a predefined symptom score second trial compared low dose oral pred- (nine trials), duplicate reporting of data (three nisolone (7 5 mg daily) with rectal pred- trials), and inclusion of patients with Crohn's nisolone metasulphobenzoate 20 mg, and colitis (one trial). found rectal treatment to be more efficacious Table I summarises the characteristics of the for inducing symptomatic improvement.38 33 trials accepted for analysis. The median Because of substantial differences in oral dose, validity score (out of 30) was 21 (range 9-26). these results were not pooled.

RESPONSE RATES RECTAL CORTICOSTEROIDS VERSUS RECTAL Table II lists the response rates for all treat- 5-ASA ments and placebo. Among patients receiving Seven accepted trials compared rectal corti- conventional rectal corticosteroids (hydro- costeroids with rectal 5-ASA.4"6 The total , prednisolone, or ), daily dose of 5-ASA ranged from 1 to 4 g, pooled improvement rates by symptomatic, whereas the hydrocortisone equivalent dose of endoscopic, and histological criteria were 77%, corticosteroids ranged from 100 to 356 mg. 66%, and 52%, whereas remission rates were One trial compared a hydrocortisone foam 45%, 34%, and 29%, respectively. The pooled with a 5-ASA suppository,43 whereas another response rates for the topically active corti- compared hydrocortisone foam with 5-ASA costeroids (budesonide, beclomethasone, or foam.45 All other trials compared liquid enema prednisolone metasulphobenzoate) were preparations of equal volume. Pooled odds similar: 73% for symptoms, 69% for ratios for symptomatic, endoscopic, and histo- endoscopy, and 55% for histology, whereas logical improvement among the trials reporting 46%, 31%, and 23%, respectively, attained these data were 1-36 (95%/o CI 0 88-2 09), 1 06 Rectal treatment in ulcerative colitis 777

TABLE I Characteristics oftrials acceptedfor meta-analysis

Duration Number of Validity score Reference Author (year) Medication (dose andfrequency)* (days) patients (maximum=30) A Rectal corticosteroids v placebo

34 Lennard-Jones et al (1962) Prednisolone (5 mg SUPP od) 21 39 16 Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from Placebo 35 Watkinson (1958) Hydrocortisone (100 mg/100 ml od) 15 19 17 Placebo B Rectal budesonide v placebo 36 Danielsson et al (1992) Budesonide (2-3 mg/i 15 ml od) 28 41 23 Placebo 37 Hanauer and Robinson (1995)t Budesonide (0 5 mg or 2-0 mg or 8 0 mg od) 42 233 12 Placebo C Rectal v oral corticosteroids 38 Hamilton et al (1984) Prednisolone metasulphoenzoate (20 mg od) 14 36 17 Prednisolone (7 5 mg ORAL od) 39 Lennard-Jones et al (1960) Hydrocortisone (100 mg/150 ml) od 21 60 15 (variable dose ORAL od) Salazopyrin (4 g ORAL od) D Rectal corticosteroids v rectal 5-ASA 40 Bianchi Porro etal (1995) Hydrocortisone (100 mg/60 ml od) 21 52 23 5-ASA (1 g/I00 ml od) 41 Campieri et al (1981) Hydrocortisone (100 mg/100 ml od) 15 86 19 5-ASA (4 g/100 ml od) 42 Danish 5-ASA Group (1987) Prednisolone (25 mg/100 ml od) 14 123 25 5-ASA (1 g/100 ml od) 43 Farup et al (1995) Hydrocortisone (178 mg/60 ml FOAM bid) 28 79 23 5-ASA (0-5 g SUPP bid) 44 Friedman et al (1986) Hydrocortisone (100 mg/100 ml od) 21 18 24 5-ASA (4 g/100 ml od) 45 Lee et al (1996) Prednisolone (20 mg/30 ml FOAM od) 28 295 25 5-ASA (2 g/120 ml FOAM od) 46 Mulder et al (1988) Prednisolone (30 mg/40 ml od) 28 29 24 5-ASA (3 g/40 ml od) E Rectal corticosteroids v rectal 4-ASA 47 O'Donnell et al (1992) Prednisolone (20 mg/50 ml od) 42 45 24 4-ASA (2 g/50 ml od) 48 Sharma et al (1992) Prednisolone (20 mg/60 ml od) 28 40 26 4-ASA (2 g/60 ml od) F Rectal corticosteroids v rectal budesonide 24 Bianchi Porro et al (1994) (20 mg/100 ml od) 28 88 21 Budesonide (2 mg/100 ml od) 25 Danielsson et al (1987) Prednisolone (31-25 mg/100 ml od) 28 64 20 Budesonide (2 mg/100 ml od) 26 Danish Budesonide Study Group (1991) Prednisolone (25 mg/100 ml od) 14 139 19 Budesonide (1 or 2 or 4 mg/100 ml od) 49 Lofberg et al (1994) Prednisolone (31-25 mg/125 ml od) 56 100 24 Budesonide (2-3 mg/i 15 ml od) 50 Tarpila et al (1994) Hydrocortisone (125 mg/125 ml od) 28 72 20 http://gut.bmj.com/ Budesonide (2-3 mg/i 15 ml od) G Rectal budesonide v rectal 5-ASA 51 Lamers et al (I991)t Budesonide (2 mg/100 ml od) 28 62 13 5-ASA (4 g/60 ml od) 52 Lemann et al (1995) Budesonide (2 mg/1 15 ml od) 28 92 22 5-ASA (1 g/100 ml od) H Other 53 Cobden et al (1991) Prednisolone metabenzoate (20 mg/100 ml bid) 28 37 26 5-ASA (0-8 g ORAL qid) 54 Grace et al (1987) Prednisolone (20 mg/100 ml od) 56 70 18 on September 23, 2021 by guest. Protected copyright. Sodium cromoglycate (600 mg/100 ml od) 55 Halpemet al (1991)t Beclomethasone dipropionate (0 5 mg/100 ml od) 28 40 22 (5 mg/100 ml od) 56 Hanauer et al (1986)t (250 mg od) 21 125 9 Hydrocortisone (100 mg od) 57 Lennard-Jones (1971) (5 mg/100 ml od) 28 105 17 Prednisolone (20 mg/100 ml od) 58 Mulder et al (1989) Beclomethasone diproprionate (2 or 3 mg/40 ml od) 28 25 23 Prednisolone (30 mg/40 ml od) 59 Mulder et al (1994)t Beclomethasone dipropionate (3 mg/100 ml od) 28 60 13 5-ASA (1 g/100 ml od) Beclomethasone and 5-ASA (3 mg/100 ml and 1 g/100 ml od) 60 Riley et al (1989) Prednisolone metasulphobenzoate (20 mg/100 ml od) 28 44 23 Sucralfate (4 g/100 ml od) 61 Ruddell et al (1980) Hydrocortisone (100 mg/60 ml bid) 14 30 16 Hydrocortisone (100 mg/5 ml FOAM bid) 62 van der Heide et al (1988) Beclomethasone dipropionate (1 mg/40 ml od) 28 18 24 Prednisolone (30 mg/40 ml od) 63 van Outryve et al (1996)t Ridogrel (300 mg/40 ml od) 28 40 17 Prednisolone (30 mg/40 ml od)

*Medication in enema format unless otherwise stated. tAbstract only. tTotal 32 patients with 40 treatment courses. SUPP=suppository; od=once daily; bid=twice daily; qid=four times daily.

(95% CI 0-61-1 85), and 2-27 (95%/o CI analysis, recalculated PORs for remission 1 224-27), with results clearly favouring endpoints still favoured 5-ASA significantly, 5-ASA only for histology (Figs 1 and 3). Using despite wider confidence intervals as a result of the stricter outcome of disease remission, the smaller sample size. 5-ASA was significantly better for all three A single trial compared 5-ASA and beclo- criteria with PORs of 2-42 (95%/o CI 1 -72-3-41) enemas alone versus a combined for symptoms, 1-89 (1-29-2-76) for endos- 5-ASA/beclomethasone enema.59 The com- copy, and 2-03 (95% CI 1-28-3-20) for his- bination surpassed monotherapy in inducing tology (Figs 2 and 3). When the two trials using symptomatic or endoscopic improvement foam preparations43 45 were excluded from the (p<0 05). 778 Marshall, Irznne

TABLE II Pooled response ratesfor rectalpreparations (all trials) Response rate across all trials (ratio, percentage) Improvement Remission Medication Symptomatic Endoscopic Histologic Symptomatic Endoscopic Histological Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from Conventional corticosteroids Hydrocortisone 58/94 (62%) 61/109 (56%) 71/137 (52%) 50/119 (42%) 43/96 (45%) 14/51 (27%) Prednisolone 272/344 (79%) 146/196 (74%) 73/144 (51%) 149/338 (44%) 127/387 (33%) 83/262 (32%) Methylprednisolone 28/44 (59%) 20/44 (45%) 20/44 (45%) 16/44 (36%) 8/44 (18%) 6/44 (14%) Betamethasone 61/71 (86%) 18/20 (90%) 16/20 (80%) 40/71 (56%) 6/20 (30%) 10/20 (500/a) Pooled 428/553 (77%) 245/369 (66%) 180/345 (52%) 255/572 (45%) 184/547 (34%) 113/377 (30%) Topically active corticosteroids Prednisolone metasulphobenzoate 33/40 (83%) 15/22 (68%) 15/22 (68%) 15/22 (68%) 17/41 (41%) 10/22 (45%) Beclomethasone 42/65 (65%) 44/65 (68%) 24/45 (53%) 9/20 (45%) 16/56 (29%) 5/20 (25%) Budesonide 49/64 (77%) 163/237 (69%) 110/205 (54%) 53/137 (39%) 70/237 (30%) 26/137 (19%) Pooled 124/169 (73%) 222/324 (69%) 149/272 (55%) 77/169 (46%) 103/334 (31%) 41/179 (23%) Aminosalicylates 5-ASA 230/282 (82%) 154/212 (73%) 93/141 (66%) 195/368 (53%) 140/384 (36%) 84/251 (33%) 4-ASA 37/47 (79%) 20/20 (100%) 29/47 (62%) 9/27 (33%) 18/20 (90%) 5/27 (19%) Pooled 267/329 (81%) 174/232 (75%) 122/188 (65%) 204/395 (52%) 158/404 (39%) 89/278 (32%) Placebo 18/53 (34%) 12/32 (38%) 3/32 (9%) 5/32 (17%)

RECTAL CORTICOSTEROIDS VERSUS RECTAL budesonide dose ranged from 2-0 to 2-5 mg, 4-ASA whereas the corticosteroid dose ranged from Rectal corticosteroids were compared with 100 to 125 mg of hydrocortisone equivalent. rectal 4-ASA in two trials.4748 Each compared Data from one trial could not be extracted 4-ASA 2 g with prednisolone 20 mg (hydro- adequately for meta-analysis.2" One trial used cortisone dose equivalent 80 mg). POR for a hydrocortisone foam.50 All other symptomatic improvement was 3-88 (95% CI were given as enemas. 1 29-11 64), favouring 4-ASA. The PORs for improvement by sympto- matic, endoscopic, and histological criteria were 2-08 (95% CI 0-84-5 14), 1-40 (95% CI RECTAL CORTICOSTEROIDS VERSUS RECTAL 0 87-2 25), and 1-23 (95°/O CI 080-1L91), BUDESONIDE respectively (Fig 4). PORs for symptomatic, Five trials compared conventional rectal corti- endoscopic, and histological remission were costeroids with rectal budesonide.2F26 4 50The 0-85 (95% CI 0-44-1*63), 1 14 (95% CI

0-69-1-88), and 0-68 (95% CI 0-28-1-67). All http://gut.bmj.com/ confidence intervals included 1.

Friedman et al 44 4 Danish 5-ASA * RECTAL BUDESONIDE VERSUS RECTAL 5-ASA Study Group42 .. .. . A46 Two trials comparing rectal budesonide with Mulder et al -* - rectal 5-ASA were evaluated.51 52 Endoscopic Bianchi Porro et 40 4 al improvement and remission data were re- on September 23, 2021 by guest. Protected copyright. Lee et al 45 4 ported in both trials, with a POR of 0-58 (95% CI 0-27-1'22) and 0 95 (95% CI 0-43-2 10), Pooled respectively, where an OR <1 favoured 5-ASA. In one of the trials 5-ASA exceeded budeso- I. nide for inducing symptomatic remission, with 0.01 0.1 10 100 an OR of 0-41 (95% CI 0-18-0.94).52 The Ocdds ratio other reported similar symptomatic remission (Corticosteroids better) (5-ASA better) rates in both treatment arms, but the data Figure 1: Symptomatic improvemzent: rectal corticosteroids v provided did not permit calculation of an rectal 5-aminosalicylic acid (5-A'SA). OR.5'

Improvement: Campieri et al 41 Symptomatic (n = 5) -_-_ Friedman et al 44 Endoscopic (n = 4) Danish 5-ASA Study Group 42 - Histological (n = 4) Farup et al 43 Remission: Lee et al 45 Symptomatic (n = 5) Endoscopic (n = 4) Pooled Histological (n = 3)

I~~~~~~~~~~~~~~~~~~~~~~I 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Odds ratio Pooled odds ratio (Corticosteroids better) (5-ASA better) (Corticosteroids better) (5-ASA better) Figure 2: Symptomatic remission: rectal corticosteroids v Figure 3: Pooled odds ratiosfor aUl outcomes: rectal rectal 5-aminosalicylic acid (5-ASA). corticosteroids v rectal 5-aminosalicylic acid (5-ASA). Rectal treatment in ulcerative colitis 779

Improvement: on 4-ASA. Other drug related adverse effects Symptomatic (n = 1) such as nausea, abdominal distension, fatigue, Endoscopic (n = 4) __- and perianal irritation were infrequent. Overall, 10 trials reported hypothalamic- Histological (n = 4) .1-__

pituitary-adrenal axis function before and after Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from Remission: treatment. Three of these compared rectal Symptomatic (n = 2) +_ budesonide with conventional rectal corti- Endoscopic (n = 4) U- costeroids, noting mean cortisol concen- Histological (n = 2) trations after four weeks of treatment.25 49 50 Cortisol concentrations were consistently Il higher, indicating lesser suppression, in the 0.01 O.A 1 10 100 budesonide group than in the group receiving Pooled odds ratic conventional corticosteroids (Fig 5). The (Conventional (Budesonide weighted mean difference between pooled corticosteroids better) better) treatment arms was 1 19-1 nmol/l (95% CI Figure 4: Pooled odds ratiosfor all outcomes conventional 70-3-167-9), confirming that this difference rectal corticosteroids v rectal budesonide. was statistically significant. Another trial re- ported similar data using an analog scale which could not be pooled.26 ADVERSE EFFECTS OF RECTAL CORTr-I- COSTEROIDS Adverse effects of treatment Nwere incon- COST COMPARISON sistently reported in the accepted trials. Nine The costs for rectal and 5-ASA enema of the 33 trials made no referencee whatsoever and foam preparations available in Canada, in to adverse effects, whereas a further 11 trials Canadian dollars, were obtained from the reported no drug related adverse e!ffects in any Chedoke-McMaster hospital pharmacy and treatment arm. Among the remaining 13 trials, are shown in Table III. Hydrocortisone 100 mg seven dropouts for drug related effects were and 5-ASA 4 g enemas are comparable in cost, noted: four on 5-ASA, one on conventional whereas 5-ASA 1 g and 2 g enemas cost corticosteroids, one on budesonide, and one considerably less. Budesonide enemas are marginally more expensive than hydro- cortisone liquid enema, and hydrocortisone 550 [ Buidesonide foam costs slightly less. Methylprednisolone T * Ccwrticosteroids enemas currently are not available in Canada. O Weighted mean http://gut.bmj.com/ 450 F T difference 'f-I T Discussion 0 This study confirms that rectal corticosteroids E 350 are an effective treatment for active distal C ulcerative colitis, with a therapeutic gain over ._L7, 250 _- placebo of approximately 30%, but suggests

0 that rectal 5-ASA is significantly more effi- on September 23, 2021 by guest. Protected copyright. 150 H cacious for inducing disease remission. E Placebo controlled data are becoming co Cu increasingly scarce in the recent literature, 50 possibly because of the ethical concerns of treating patients with active ulcerative colitis -50 H with placebo. Two early placebo controlled trials34 63 confirmed the efficacy of con- L ventional rectal corticosteroids for inducing -150 improvement and remission by symptomatic Bianchi Danielsson Tarpila recent Porro et al 25 et al 50 and endoscopic criteria. Two trials36 37 et al 24 also showed the topically acting corticosteroid budesonide to be superior to placebo using Figure 5: Plasma cortisol concentrations and weighted mean difference (with 95% I) after symptomatic, endoscopic, and histological four weeks oftreatment: conventional rectal corticosteroids v rectal budesonide. endpoints. Our pooled placebo data demon- strated symptomatic and endoscopic improve- TABLE m Cost ofavailable rectal treatments (Chedoke-McMaster Hospital Phar, ment in 34% and 38%, and symptomatic and July 1996) endoscopic remission in 9% and 17% of patients, respectively. These findings were Unit cost Cost of 14 day (Can S; USS;/) course (Can S; uSS;I) similar to those of another overview which Medication excluding dispensingfee excluding dispe? isingfee suggested that placebo benefited 30% of Hydrocortisone enema 100 mg (Cortenema) 6-93; 4-89; 3-00 97-02; 68-50 42-01 patients and produced remission in 10%.64 Hydrocortisone foam 80 mg 83-24; 58-77; 36-04 83-24; 58-77 36 04 Our meta-analysis suggests that rectal (Cortifoam 14 dose cannister) Betamethasone enema 5 mg (Betnesol) 8-68; 6-13; 3-76 121-52; 85 79 52-62 5-ASA is as efficacious as rectal corticosteroids Budesonide enema 2-3 mg (Entocort) 9 00; 6-35; 3 90 126-00; 88-96 54-56 for improving disease and is better than rectal Tixocortol 250 mg (Rectovalone) 7-95; 5-61; 3-44 111-30; 78 58 5-ASA enema 4 g (Salofalk) 7-08; 5-00; 3 07 99-12; 69-98 42-9248.19 corticosteroids for inducing remission. Results 5-ASA enema 2 g (Salofalk) 4- 10; 2-89; 1-78 57-40; 40-52 2485 wereweecnittconsistent, with similarly narrow confi- 5-ASA enema 2 g (Quintasa) 4-35; 3 07; 1-88 60-90; 43-00 26-37 5-ASA enema 1 g (Quintasa) 3-97; 2-80; 1-72 55-58; 39 24 dence intervals, for symptomatic, endoscopic, or histological outcomes. The two trials which 780 Marshall, Irvine

compared rectal 5-ASA with budesonide response and remission. The ability to pool suggested that 5-ASA is at least as effective in data effectively from several trials is limited by producing disease improvement and remission. the variability in outcome criteria. As meta- However, not all endpoints were noted. analyses and overviews are updated, it is

Only two studies compared the role of rectal essential that methods of diagnosis, definitions Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from 4-ASA with corticosteroids, but supported a of active or inactive disease, and criteria for therapeutic gain in producing symptomatic symptomatic, endoscopic, and histological improvement for 4-ASA. outcomes are standardised.67 Increased atten- Budesonide is a new topically active corti- tion should also be given to the potential costeroid formulation with a high gluco- confounding influence of proximal disease corticoid receptor affinity, and significant first margin, formulation of delivery vehicle, pass hepatic . The pooled results volume of preparation, and duration of treat- for accepted trials failed to demonstrate signifi- ment. As the potential for adverse reactions cant therapeutic benefit of either budesonide often governs selection among equally effective or conventional corticosteroids. However, agents, adverse effects also must be reported budesonide caused significantly less endo- more rigorously. genous cortisol suppression, based on pooled We conclude that treatment with rectal mean cortisol concentrations. Although these 5-ASA is superior to treatment with rectal data are promising, no data have been reported corticosteroids in the management of active regarding differences in steroid specific adverse distal ulcerative colitis. Rectal budesonide effects, such as osteopenia or Cushingoid seems to be as effective as conventional rectal facies. corticosteroids, but seems to cause less sup- Other factors which may influence the effi- pression of endogenous cortisol production. cacy of a treatment formulation include the Conventional rectal corticosteroids may be proximal extent of the disease. Although our regarded as an alternative rectal treatment for pooled data did not permit subgroup analysis, active distal ulcerative colitis once aminosali- foam and suppositories did produce higher cylates have failed, or in patients allergic to response rates in patients with more distal 5-ASA. disease,43 supporting the findings of radio- logical and radionuclide studies of a more 1 Truelove SC, Witts LJ. Cortisone in ulcerative colitis: preliminary report on a therapeutic trial. BMJ 1954; 2: distal distribution of medication.' 1-8 Patient 375-8. preference for foam or suppository prepar- 2 Truelove SC. Treatment of ulcerative colitis with local hydrocortisone. BMJ7 1956; 2: 1267-72. ations also may augment compliance, and 3 Mulder CJJ, Tytgat GNJ. Topical corticosteroids in inflam- hence the effectiveness of therapy.6" Similarly, matory bowel disease. Aliment Pharmacol Ther 1993; 7: 125-30. the volume of enema or foam http://gut.bmj.com/ preparations may 4 Chapman NJ, Brown ML, Phillips SF, Tremaine WJ, influence treatment distribution and efficacy.'0 Schroeder KW, Dewanjee MK, et al. Distribution of most mesalamine enemas in patients with active distal Although trials used equivalent volumes ulcerative colitis. Mayo Clin Proc 1992; 67: 245-8. in both treatment arms, Lee et a145 compared 5 Tiel-van Buul MMC, Mulder CJJ, van Royen EA, a Wsltink EHH, Tytgat GNJ. Retrograde spread of 30 cc prednisolone foam with a 120 cc 5-ASA (5-aminosalicylic acid)-containing enema in foam, a bias which could favour the efficacy of patients with ulcerative colitis. Clin Pharmacokinet 1991; 20: 247-51. 5-ASA. When these data were excluded from 6 Jay M, Digenis GA, Foster TS, Antonow DR. Retrograde

the pooled results, 5-ASA remained superior to spreading of hydrocortisone enema in inflammatory on September 23, 2021 by guest. Protected copyright. bowel disease. Dig Dis Sci 1986; 31: 139-44. corticosteroids in inducing remission, although 7 Campieri M, Lanfranchi GA, Brignola C, Bazzocchi G, confidence intervals were wider. Gionchetti P, Minguzzi MR, et al. Retrograde spread of An 5-aminosalicylic acid enemas in patients with active important feature which potentially ulcerative colitis. Dis Colon Rectum 1986; 29: 108-10. could confound results of this meta-analysis 8 Kruis W, Bull U, Eisenburg J, Paumgartner G. Retrograde was colonic spread of sulphasalazine enemas. ScandJ3Gastro- duration of treatment, which ranged from enterol 1982; 17: 933-8. 14 to 56 days among the trials accepted. 9 Nymann-Pantelidis M, Nilsson A, Wagner ZG, Borga 0. and retrograde colonic spread of Although pooled results of trial endpoints did budesonide enemas in patients with distal ulcerative not demonstrate a clear relation, individual colitis. Aliment Pharmacol Ther 1994; 8: 617-22. trials 10 Swarbrick ET, Loose H, Lennard-Jones JE. Enema volume which reported interim endpoints at as an important factor in successful topical corticosteroid different time intervals observed higher endos- treatment of colitis. Proc Royal Soc Med 1974; 67: 753-4. 11 Van Bodegraven AA, Boer RO, Lourens J, Tuynman copic and histological remission rates with HARE, Sindram JW. Distribution of mesalazine enemas prolonged treatment.2" 36 42 43 49-51 Although in active and quiescent ulcerative colitis. Aliment Pharmacol Ther 1996; 10: 327-32. longer treatment may potentially increase 12 Farthing MJG, Rutland MD, Clark ML. Retrograde spread adverse effects or diminish compliance, treat- of hydrocortisone containing foam given intrarectally in ment ulcerative colitis. BMJ 1979; 2: 822-4. requiring endoscopic or histological 13 Hay DJ. Spreading characteristics of proprietary rectal remission has been associated with a lower steroid preparations. In: Wilson CG, Hardy JG, eds. Radionuclide imaging in drug research. London: Croom relapse rate.65 66 Helm, 1982: 71-80. Adverse effects for all rectal preparations 14 Wood E, Wilson CG, Hardy JG. The spreading offoam and enemas. InteJPhar,naceut 1985; 25: 191-7. were under-reported, but seemed comparable. 15 Campieri M, Corbelli C, Gionchetti P, Brignola C, Drug costs using a two week treatment Belluzzi A, Di Febo G, et al. Spread and distribution of 5-ASA colonic foam and 5-ASA enemas in patients with regimen were lower for rectal ulcerative colitis. Dig Dis SCi 1992; 37: 1890-7. products than for most corticosteroid prepar- 16 Wilding IR, Kenyon CJ, Chauhan S, Hooper G, Marshall S, McCracken JS, et al. Colonic spreading of a non-chloro- ations. However, longer term studies may be fluorocarbon mesalazine rectal foam enema in patients necessary to evaluate further the median time with quiescent ulcerative colitis. Aliment Pharmacol Ther 1995; 9: 161-6. to remission before it can be concluded that 17 Williams CN, Haber G, Aquino JA. Double-blind, placebo- 5-ASA enemas are more cost effective than controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement ofextent ofspread using corticosteroids. To facilitate our analysis, we 99m-Tc-labelled 5-ASA suppositories. Dig Dis Sci 1987; accepted the authors' definitions of disease 32: 71S-5S. Rectal treatment in ukerative colitis 781

18 Jay M, Beihn RM, Digenis GA, Deland FH, Caldwell L, 44 Friedman LS, Richter JM, Kirkham SE, DeMonaco HJ, Mlodozeniec AR. Disposition of radiolabelled supposi- May RJ. 5-Aminosalicylic acid enemas in refractory distal tories in humans. _J Pharn Pharmacol 1985; 37: 266-8. ulcerative colitis: a randomized controlled trial. Am Jf 19 Powell Tuck J, Lennard-Jones JE, May CS, Wilson CG, Gastroenterol 1986; 81: 412-8. Paterson JW. Plasma prednisolone levels after admin- 45 Lee FI, Jewell DP, Mani V, Keighley MRB, Kingston RD, istration of prednisolone-21-phosphate as a retention Record CO, et al. A randomised trial comparing enema in colitis. BMJ 1976; 1: 193-5. mesalazine and prednisolone foam enemas in patients 20 Lee DAH, Taylor GM, James VHT, Walker G. Plasma with acute distal ulcerative colitis. Gut 1996; 38: 229-33. Gut: first published as 10.1136/gut.40.6.775 on 1 June 1997. Downloaded from prednisolone levels and adrenocortical responsiveness 46 Mulder Cnl, Endert E, Van der Heide H, Houthoff HJ, after administration of prednisolone-2 1-phosphate as a Wiersinga W, Wiltink EHH, et al. Comparison of retention enema. Gut 1979; 20: 349-55. 5-aminosalicylic acid (3g) and prednisolone phosphate 21 Farmer RG, Schumacher OP. Treatment of ulcerative sodium (enemas (30mg) in the treatment of distal colitis with hydrocortisone enemas: relationship of hydro- ulcerative colitis: a prospective, randomized, double-blind cortisone absorption, adrenal suppression, and . ScandJ Gastroenterol 1988; 23: 1005-8. response. Dis Colon Rectum 1970; 13: 355-61. 47 O'Donnell LJD, Arvind AS, Cameron D, Talbot IC, 22 Luman W, Gray RS, Pendek R, Palmer KR. Prednisolone Jewell DP, Lennard-Jones JE, et al. Double blind, metasulphobenzoate foam retention enemas suppress the controlled trials of 4-aminosalicylic acid and prednisolone hypothalamo-pituitary-adrenal axis. Aliment Pharmacol enemas in distal ulcerative colitis. Gut 1992; 33: 947-9. Ther 1994; 8: 255-8. 48 Sharma MP, Duphare HV, Dasarathy S. A prospective 23 Cann PA, Holdsworth CD. Systemic absorption from randomized double blind trial comparing prednisolone hydrocortisone foam enema in ulcerative colitis. Lancet and 4-aminosalicylic acid enemas in acute distal 1987; i: 922-3. ulcerative colitis. J Gastroenterol Hepatol 1992; 7: 173-7. 24 Bianchi Porro G, Prantera C, Campieri M, Petrillo M, 49 Lofberg R, Ostergaard Thomsen 0, Langholz E, Schioler R, Campanini MC, Gionchetti P, et al. Comparative trial of Danielsson A, Suhr 0, et al. Budesonide versus methylprednisolone and budesonide enemas in the treat- prednisolone retention enemas in active distal ulcerative ment of active distal ulcerative colitis. EurJ Gastroenterol colitis. Aliment Pharmacol Ther 1994; 8: 623-9. Hepatol 1994; 6: 125-30. 50 Tarpila S, Turunen U, Seppala K, Aukee S, Pikkarainen P, 25 Danielsson A, Hellers G, Lyrenas E, Lofberg R, Nilsson A, Elomaa I, et al. Budesonide enema in active haemorrhagic Olsson 0, et al. A controlled randomized trial of proctitis: a controlled trial against hydrocortisone foam budesonide versus prednisolone retention enemas in enema. Aliment Pharmacol Ther 1994; 8: 591-5. active distal ulcerative colitis. Scand J Gastroenterol 1987; 51 Lamers C, Meijer J, Engels L, Bos L, Van Hogezand R, 22: 987-92. Driesson W, et al. Comparative study of the topically 26 Danish Budesonide Study Group. Budesonide enema in acting budesonide and 5-aminosalicylic distal ulcerative colitis. Scand 7 Gastroenterol 1991; 26: acid enema therapy of proctitis and proctosigmoiditis 1225-30. [abstract]. Gastroenterology 1991; 100: A223. 27 Spencer CM, McTavish D. Budesonide: a review of its 52 Lemann M, Galian A, Rutgeerts P, van Heuverzwijn R, pharmacological properties and therapeutic efficacy in Cortot A, Viteau JM, et al. Comparison of budesonide inflammatory bowel disease. 1995; 50: 854-72. and 5-aminosalicylic acid enemas in active distal ulcer- 28 Brattsand R. Overview of newer glucocorticosteroid prepar- ative colitis. Aliment Pharmacol Ther 1995; 9: 557-62. ations for inflammatory bowel disease. Can Jf Gastroenterol 53 Cobden I, Al-Mardini H, Zaitoun A, Record CO. Is topical 1990;4: 407-14. therapy necessary in acute distal ulcerative colitis? 29 Marshall JK, Irvine EJ. Rectal aminosalicylate therapy for Double-blind comparison of high-dose oral mesalazine distal ulcerative colitis: a meta-analysis. Aliment Pharmacol versus steroid enemas in the treatment of active distal Ther 1995; 9: 293-300. ulcerative colitis. Aliment Pharmacol Ther 1991; 5: 30 Schimmer BP, Parker KL. Adrenocorticotropic hormone; 513-22. adrenocortical and their synthetic analogs; 54 Grace RH, Gent AE, Hellier MD. Comparative trial of inhibitors of the synthesis and actions of adrenocortical sodium cromoglycate enemas with prednisolone enemas hormones. In: Wonsiewica MJ, McCurdy P, eds. in the treatment of ulcerative colitis. Gut 1987; 28: Goodman and Gilman's The pharmacological basis of 88-92. therapeutics. New York: McGraw Hill, 1996: 466. 55 Halpern Z, Sold 0, Baratz M, KonikoffF, Halak A, Gilat T. 31 DerSimonian R, Laird N. Meta-analysis in clinical trials. A controlled trial of beclomethasone versus betame- Control Clin Trials 1986; 7: 177-80. thasone enemas in distal ulcerative colitis. Jf Clin Gastro- 32 Bracken MB. Statistical methods for analysis of effects of enterol 1991; 13: 38-41. http://gut.bmj.com/ treatment in overviews of randomized trials. In: Sinclair 56 Hanauer SB, Kirsner JB, Barrett WE. The treatment of left- JC, Bracken MB, eds. Effective care of the newborn infant. sided ulcerative colitis with tixocortol pivalate [abstract]. Oxford: Oxford University Press, 1992: 15-6. Gastroenterology 1986; 90: A1449. 33 Breslow NE, Day NE (eds). Statistical methods in cancer 57 Lennard-Jones JE. Betamethasone 17-valerate and pred- research. Lyon: International Agency for Research on nisolone 21-phosphate retention enemas in proctocolitis. Cancer, 1980: 136-46. BMJ 1971; 3: 84-6. 34 Lennard-Jones JE, Baron JH, Connell AM, Avery Jones F. 58 Mulder CJJ, Endert E, Van der Heide H, Houthoff HJ, A double blind controlled trial of prednisolone- Wiersinga W, Wiltink EHH, et al. Comparison of beclo- 21-phosphate suppositories in the treatment of idiopathic methasone diproprionate (2 and 3mg) and prednisolone

proctitis. Gut 1962; 3: 207-10. sodium phosphate enemas (30mg) in the treatment of on September 23, 2021 by guest. Protected copyright. 35 Watkinson G. Treatment of ulcerative colitis with topical ulcerative proctitis: an adrenocortical approach. Neth J hydrocortisone hemisuccinate sodium: a controlled trial Med 1989; 35: 18-24. employing restricted sequential analysis. BMJ 1958; 2: 59 Mulder CJ, Fockens P, Van der Heide H, Tytgat GNJ. A 1077-82. controlled randomized trial of beclomethasone dipro- 36 Danielsson A, Lofberg R, Persson T, Salde L, Schioler R, pionate (3mg) versus 5-ASA (1g) versus the combination Suhr 0, et al. A steroid enema, budesonide, lacking of both (3mg/lg) as retention enemas in active distal systemic effects for the treatment ofdistal ulcerative colitis ulcerative colitis [abstract]. Gastroenterology 1994; 106: or proctitis. ScandJ7 Gastroenterol 1992; 27: 9-12. A739. 37 Hanauer S, Robinson M. Dose ranging study ofbudesonide 60 Riley SA, Gupta I, Mani V. A comparison of sucralfate enemas in active distal ulcerative colitis [abstract]. Gastro- and prednisolone enemas in the treatment of active enterology 1995; 108: A832. distal ulcerative colitis. Scand Jf Gastroenterol 1989; 24: 38 Hamilton I, Pinder IF, Dickinson RJ, Ruddel WSJ, 1014-8. Dixon MF, Axon ATR. A comparison of prednisolone 61 Ruddell WSJ, Dickinson RJ, Dixon MF, Axon ATR. Treat- enemas with low-dose oral prednisolone in the treatment ment of distal ulcerative colitis (proctosigmoiditis) in of acute distal ulcerative colitis. Dis Colon Rectum 1984; relapse: comparsion of hydrocortisone enemas and rectal 27: 701-2. hydrocortisone foam. Gut 1980; 21: 885-9. 39 Lennard-Jones JE, Longmore AJ, Newell AC, Wilson CWE, 62 Van der Heide H, Van den Brandt-Gradel, Tytgat GNJ, Avery Jones F. An assessment of prednisone, salazopyrin, Endert E, Wiltink EHH, Schipper MEI, et al. Com- and topical hydrocortisone hemisuccinate used as out- parison of beclomethasone dipropionate and pred- patient treatment for ulcerative colitis. Gut 1960; 1: nisolone 21-phosphate enemas in the treatment of ulcer- 217-22. ative proctitis. _J Clin Gastroenterol 1988; 10: 169-72. 40 Bianchi Porro G, Ardizzone S, Petrillo M, Fasoli A, 63 Van Outryve M, Huble F, Van Eeghem P, De Vos M. Molteni P, Imbesi V. Low Pentasa dosage versus hydro- Comparison of ridogrel versus prednisolone, both ad- cortisone in the topical treatment of active ulcerative ministered rectally, for the treatment of active ulcerative colitis: a randomized double blind study. Am Jf Gastro- colitis [abstract]. Gastroenterology 1996; 110: A1035. enterol 1995; 90: 736-9. 64 Ilnycki A, Shanahan F, Anton PA, Cheang M, 41 Campieri M, Lanfranchi GA, Bazzocchi G, Brignola C, Bernstein CN. The placebo response in ulcerative colitis Sarti F, Franzin G, et al. Treatment of ulcerative colitis [abstract]. Gastroenterology 1996; 110: A929. with high-dose 5-aminosalicylic acid enemas. Lancet 65 Meyers S, Janowitz HD. The natural history of ulcerative 1981; ii: 270-1. colitis: an analysis of the placebo response. J7 Clin Gastro- 42 Danish 5-ASA Study Group. Topical 5-aminosalicylic acid enterol 1989; 11: 33-7. versus prednisolone in ulcerative proctosigmoiditis. Dig 66 Riley SA, Mani V, Goodman MJ, Dutt 5, Nerd MB. Dis Sci 1987; 32: 598-602. Microscopic activity in ulcerative colitis: what does it 43 Farup PG, Hovde 0, Halvorsen FA, Raknerud N, mean? Gut 1991; 32: 174-8. Brodin U. Mesalazine suppositories versus hydrocorti- 67 Irvine EJ. Assessing outcome in randomized clinical trials: sone foam in patients with distal ulcerative colitis. Scand inflammatory bowel disease. Can J Gastroenterol 1993; 7: Jf Gastroenterol 1995; 30: 164-70. 561-7.