Aliment. Pharmacol. Tkerap. (1991) 5 , 513-522.
Is topical therapy necessary in acute distal colitis? Double- blind comparison of high-dose oral mesalazine versus steroid enemas in the treatment of active distal ulcerative colitis
I. COBDEN", H. AL-MARDINIt, A. Z A I T O U N t & C. 0.R E C O R D t "Gastroenterology Unit, Preston Hospital, North Shields, Tyne & Wear and t Gastroenterology Unit, Royal Victoria Infirmay, Newcastle upon Tyne, UK Accepted for publication 5 April 1991
SUMMARY
Thirty-seven patients suffering an attack of acute distal ulcerative colitis of mild or moderate severity were randomized in a double-blind, doubledummy fashion to receive either 800 mg oral mesalazine four times daily (18 patients) or steroid enemas twice daily (19 patients) for 4 weeks. Both treatments were well tolerated with no adverse effects. Three patients in each group were withdrawn because of clinical deterioration but both treatments produced significant clinical improvement with decreases in stool frequency and scores for urgency, bleeding and tenesmus. There were no significant differences between the treatments although there was a slight trend in favour of the enemas for reduction in rectal bleeding. Activity of the colitis as graded at sigmoidoscopy also decreased significantly with both treatments and there were corresponding improvements in histological parameters of inflammatory activity assessed with the aid of a computerized morphometric system. Little correlation was seen between clinical, sigmoidoscopic and histological changes. Correspondence to: Dr I. Cobden, Gastroenterology Unit, Preston Hospital, North Shields, Tyne & Wear, UK. 35-2 5 13
514
L C O B D E N ek a).
INTRODUCTION Acute relapses of ulcerative colitis of mild or moderate severity are most commonly treated with topical steroid therapies, often in combination with oral sulphasalazine. However, some patients find the therapy unpleasant. Adverse reactions to sulphasalazine, in particular to the sulphonamide moiety, may affect up to 38 % of people taking a standard dose of 4 g per day' and others may reject the prospect or practice of rectal enema or foam treatment. Mesalazine (Asacol, SmithKline & French Laboratories, Welwyn Garden City, UK) is an oral preparation of 5-aminosalicylic acid coated with Eudragit-S in a formulation designed to release the active drug in the colon and prevent more proximal absorption.'^^ Because it lacks the sulphonamide component of sulphasalazine it has a lower incidence of adverse reactions4 and may be tolerated by patients who cannot take sulphasalazine. In corresponding dosage (400 mg mesalazine is equivalent to 1 g sulphasalazine) it appears to be at least as effective in maintaining remission of colitis5 and in acute exacerbation^.^. Higher equivalent doses than generally used with sulphasalazine appear to be safe and well tolerated'-' but there is little information on the use of high-dose oral mesalazine as mono therapy for acute distal ulcerative colitis. The aim of the present study was to assess the safety and eficacy of high-dose oral mesalazine (3.2 g daily) and to compare it with topical steroid therapy in patients with acute attacks of distal ulcerative colitis. PATIENTS A N D M E T H O D S The study protocol was approved by the Newcastle and North Tyneside ethics committees. All patients aged 18-75 years presenting to one of two gastrointestinal clinics with a mild or moderate attack of acute ulcerative colitis distal to the splenic flexure were eligible for the study. Fully informed consent was obtained. Patients were excluded for the following reasons. (a) Severe disease requiring systemic steroids or evidence of involvement proximal to the splenic flexure. (b) Pregnancy. (c) Positive stool culture for pathogens or evidence of parasites. fd) Known allergy to salicylates. (e) Continuing treatment with sulphasalazine or steroids. (f) Significant renal or hepatic impairment. Patients entering the study (Day 0 ) were assessed clinically for severity of symptoms, a sigmoidoscopy was performed and a rectal biopsy taken. Blood samples were taken for full blood count, sedimentation rate, urea and electrolytes and liver function tests. Daily stool frequency was recorded and a score for severity of rectal bleeding was derived (0 = no bleeding, 1 = occasional streaking, 2 = blood with each motion, 3 = blood alone passed), the values taken for Day 0
MESALAZINE F O R ACUTE DISTAL COLITIS
515
being the mean of the previous 3 days. Urgency and tenesmus were each evaluated with the aid of a patient-recorded mark on a 100 mm standard scale. Sigmoidoscopic appearances were graded 0-3 on the basis of the worst abnormalities seen at any level as follows. Grade 0. Intact vascular pattern, no friability or granularity. Grade 1.Erythema, loss of vascular marking. Minimal friability. Grade 2. Friability with contact bleeding. Marked erythema. No ulceration. Grade 3 . Ulceration, spontaneous bleeding, luminal pus. Rectal biopsies were assessed blind with the aid of a MOP-Videoplan semiautomated image analysis system (Carl-Zeiss Ltd) as previously described,’ allowing quantitative measurements of surface areas, heights and cell counts in different regions of interest of the tissue biopsy. Four parameters which have previously been shown to differ significantly in untreated active colitis from controls and treated patients were assessed, namely the surface epithelium/lamina propria area ratio (Ep/LP), the ratio of surface to crypt epithelial cell height (S/C), the number of intraepithelial polymorphs in crypt epithelium per unit muscularis length (IEP/crypt) and the ratio of goblet cells to epithelial cells (GCR). Each patient was provided with medication comprising rectal and oral therapy by the pharmacy. Treatment was allocated according to a previously randomized code, the patient receiving either active predenemas (Pharmax Ltd, 20 mg prednisolone metabenzoate in 100 ml) rectally, morning and night as instructed, with placebo capsules orally or alternatively, placebo enemas with active mesalazine, 2 capsules to be taken four times daily (3.2 g mesalazine daily). Patients were instructed to return with a completed diary card at 2 and 4 weeks and to avoid using any medication on the morning of the clinic visit. Assessments were made similar to those at Day 0 except that a blood sample was also taken for trough levels of 5-aminosalicylic acid and metabolites3 and the rectal biopsy was omitted at Week 2. Scores for stool frequency and rectal bleeding were calculated as the mean for the previous 7 days. Statistical comparisons were tested using the Mann-Whitney U test, Wilcoxon signed Rank, Fisher’s exact and Siege1 sign tests as appropriate. RESULTS Thirty-seven patients entered the study. Eighteen were randomized to receive active oral mesalazine and 19 active steroid enemas each with corresponding dummy therapy. The pre-treatment patient characteristics are summarized in Table I.
Withdrawals and adverse effects There were no adverse clinical effects but three patients in each group were withdrawn at two weeks because of symptomatic deterioration (i.e. worsening of bleeding, diarrhoea or pain).
516
I. COBDEN et al.
Table 1. Pre-treatment characteristics of patients entering the study
Mean age (years) Age range (years) Male/female First attack/relapse Distribution of activity: proctitis/ sigmoid/ left -sided
+
Mesalazine
Steroid enemas
38.3 f11.5 21-61 6/12 7/11 7/10/1
3 9 . 6 k 10.9 21-61 1019 12/7 71913
Trough levels of 5-aminosalicylic acid plus metabolites were 11.3& 6.6 pmol. L in the mesalazine group. Serum creatinine levels did not change with treatment, that is, there was no evidence of any adverse effect on renal function, nor were there any changes in blood indices or liver function tests.
Clinical responses to treatment The results for 2 weeks of treatment showed trends similar to those observed after 4 weeks, with no evidence of any difference in speed of onset of remission between the groups. The data presented therefore relate to the 4-week values only.
Stool frequency (see Figure I ) Mean stool frequency was 3.8 & 2.5 at outset in the mesalazine group and 5.6 & 5.1 in the enema group. Corresponding median values were 3,0/day in the mesalazine group and 3.3/day respectively, falling significantly with treatment in both groups (mesalazine-median decrease = 1.2, 95 % confidence intervals (CI) 0.3-2.2, P < 0.01; enemas-median decrease = 1.5,95% CI 0.4-5.4, P < 0.01). The number of subjects experiencing fewer than two bowel actions per day increased from 3/18 to 8/18 in the mesalazine group (P = 0.06, Fisher's exact test) and from 4/19 to 10/19 in the enema group ( P = 0.04). There were no significant differences between the groups.
Urgency (see Figure 2 ) The mean urgency score was 53.6+31 in the mesalazine group and 59.6 +35 in the enema group. Corresponding median values were 46 and 74, respectively. There was a significant reduction in urgency in both groups at 4 weeks (mesalazine-median reduction = 35, 95% CI 0.1-63.0, P < 0.02; enemas-median reduction = 39, 95 % CI 14.0-74.0, P < 0.01). The number of subjects experiencing an urgency score of less than 10 mm increased from 1/18 to 9/18 in the mesalazine group ( P < 0.005) and from 1/19 to 9/19 in the enema group (P < 0.005). There were no significant differences between the groups.
MESALAZINE F O R ACUTE DISTAL COLITIS
517
Stool Frequency Mesalazine
Week 0
Enemas
Week4
o
Week 0
Week 4
Withdrawn at 2 weeks
Figure 1. Mean daily stool frequencies before and after 4 weeks of treatment for patients receiving either active oral mesalazine or active steroid enemas (mean standard error at 0 and 4 weeks is shown).
Urgency Score Mesalazine
0 week 0
Enemas
w6&
Week 0
4
0
week 4
Withdrawn a1 2 weeks
Figure 2. Mean urgency scores before and after 4 weeks of treatment for patients receiving either active oral mesalazine group or active steroid enemas (mean & standard error at O and 4 weeks is shown).
I. COBDEN et al.
518
-
Enema bleeding
Mesalazine bleeding
E2
~
Week0 Week4
10 -
17
n $
Week4
ia
6
E
2
4 2 0
0
Is topical therapy necessary in acute distal colitis? Double- blind comparison of high-dose oral mesalazine versus steroid enemas in the treatment of active distal ulcerative colitis
I. COBDEN", H. AL-MARDINIt, A. Z A I T O U N t & C. 0.R E C O R D t "Gastroenterology Unit, Preston Hospital, North Shields, Tyne & Wear and t Gastroenterology Unit, Royal Victoria Infirmay, Newcastle upon Tyne, UK Accepted for publication 5 April 1991
SUMMARY
Thirty-seven patients suffering an attack of acute distal ulcerative colitis of mild or moderate severity were randomized in a double-blind, doubledummy fashion to receive either 800 mg oral mesalazine four times daily (18 patients) or steroid enemas twice daily (19 patients) for 4 weeks. Both treatments were well tolerated with no adverse effects. Three patients in each group were withdrawn because of clinical deterioration but both treatments produced significant clinical improvement with decreases in stool frequency and scores for urgency, bleeding and tenesmus. There were no significant differences between the treatments although there was a slight trend in favour of the enemas for reduction in rectal bleeding. Activity of the colitis as graded at sigmoidoscopy also decreased significantly with both treatments and there were corresponding improvements in histological parameters of inflammatory activity assessed with the aid of a computerized morphometric system. Little correlation was seen between clinical, sigmoidoscopic and histological changes. Correspondence to: Dr I. Cobden, Gastroenterology Unit, Preston Hospital, North Shields, Tyne & Wear, UK. 35-2 5 13
514
L C O B D E N ek a).
INTRODUCTION Acute relapses of ulcerative colitis of mild or moderate severity are most commonly treated with topical steroid therapies, often in combination with oral sulphasalazine. However, some patients find the therapy unpleasant. Adverse reactions to sulphasalazine, in particular to the sulphonamide moiety, may affect up to 38 % of people taking a standard dose of 4 g per day' and others may reject the prospect or practice of rectal enema or foam treatment. Mesalazine (Asacol, SmithKline & French Laboratories, Welwyn Garden City, UK) is an oral preparation of 5-aminosalicylic acid coated with Eudragit-S in a formulation designed to release the active drug in the colon and prevent more proximal absorption.'^^ Because it lacks the sulphonamide component of sulphasalazine it has a lower incidence of adverse reactions4 and may be tolerated by patients who cannot take sulphasalazine. In corresponding dosage (400 mg mesalazine is equivalent to 1 g sulphasalazine) it appears to be at least as effective in maintaining remission of colitis5 and in acute exacerbation^.^. Higher equivalent doses than generally used with sulphasalazine appear to be safe and well tolerated'-' but there is little information on the use of high-dose oral mesalazine as mono therapy for acute distal ulcerative colitis. The aim of the present study was to assess the safety and eficacy of high-dose oral mesalazine (3.2 g daily) and to compare it with topical steroid therapy in patients with acute attacks of distal ulcerative colitis. PATIENTS A N D M E T H O D S The study protocol was approved by the Newcastle and North Tyneside ethics committees. All patients aged 18-75 years presenting to one of two gastrointestinal clinics with a mild or moderate attack of acute ulcerative colitis distal to the splenic flexure were eligible for the study. Fully informed consent was obtained. Patients were excluded for the following reasons. (a) Severe disease requiring systemic steroids or evidence of involvement proximal to the splenic flexure. (b) Pregnancy. (c) Positive stool culture for pathogens or evidence of parasites. fd) Known allergy to salicylates. (e) Continuing treatment with sulphasalazine or steroids. (f) Significant renal or hepatic impairment. Patients entering the study (Day 0 ) were assessed clinically for severity of symptoms, a sigmoidoscopy was performed and a rectal biopsy taken. Blood samples were taken for full blood count, sedimentation rate, urea and electrolytes and liver function tests. Daily stool frequency was recorded and a score for severity of rectal bleeding was derived (0 = no bleeding, 1 = occasional streaking, 2 = blood with each motion, 3 = blood alone passed), the values taken for Day 0
MESALAZINE F O R ACUTE DISTAL COLITIS
515
being the mean of the previous 3 days. Urgency and tenesmus were each evaluated with the aid of a patient-recorded mark on a 100 mm standard scale. Sigmoidoscopic appearances were graded 0-3 on the basis of the worst abnormalities seen at any level as follows. Grade 0. Intact vascular pattern, no friability or granularity. Grade 1.Erythema, loss of vascular marking. Minimal friability. Grade 2. Friability with contact bleeding. Marked erythema. No ulceration. Grade 3 . Ulceration, spontaneous bleeding, luminal pus. Rectal biopsies were assessed blind with the aid of a MOP-Videoplan semiautomated image analysis system (Carl-Zeiss Ltd) as previously described,’ allowing quantitative measurements of surface areas, heights and cell counts in different regions of interest of the tissue biopsy. Four parameters which have previously been shown to differ significantly in untreated active colitis from controls and treated patients were assessed, namely the surface epithelium/lamina propria area ratio (Ep/LP), the ratio of surface to crypt epithelial cell height (S/C), the number of intraepithelial polymorphs in crypt epithelium per unit muscularis length (IEP/crypt) and the ratio of goblet cells to epithelial cells (GCR). Each patient was provided with medication comprising rectal and oral therapy by the pharmacy. Treatment was allocated according to a previously randomized code, the patient receiving either active predenemas (Pharmax Ltd, 20 mg prednisolone metabenzoate in 100 ml) rectally, morning and night as instructed, with placebo capsules orally or alternatively, placebo enemas with active mesalazine, 2 capsules to be taken four times daily (3.2 g mesalazine daily). Patients were instructed to return with a completed diary card at 2 and 4 weeks and to avoid using any medication on the morning of the clinic visit. Assessments were made similar to those at Day 0 except that a blood sample was also taken for trough levels of 5-aminosalicylic acid and metabolites3 and the rectal biopsy was omitted at Week 2. Scores for stool frequency and rectal bleeding were calculated as the mean for the previous 7 days. Statistical comparisons were tested using the Mann-Whitney U test, Wilcoxon signed Rank, Fisher’s exact and Siege1 sign tests as appropriate. RESULTS Thirty-seven patients entered the study. Eighteen were randomized to receive active oral mesalazine and 19 active steroid enemas each with corresponding dummy therapy. The pre-treatment patient characteristics are summarized in Table I.
Withdrawals and adverse effects There were no adverse clinical effects but three patients in each group were withdrawn at two weeks because of symptomatic deterioration (i.e. worsening of bleeding, diarrhoea or pain).
516
I. COBDEN et al.
Table 1. Pre-treatment characteristics of patients entering the study
Mean age (years) Age range (years) Male/female First attack/relapse Distribution of activity: proctitis/ sigmoid/ left -sided
+
Mesalazine
Steroid enemas
38.3 f11.5 21-61 6/12 7/11 7/10/1
3 9 . 6 k 10.9 21-61 1019 12/7 71913
Trough levels of 5-aminosalicylic acid plus metabolites were 11.3& 6.6 pmol. L in the mesalazine group. Serum creatinine levels did not change with treatment, that is, there was no evidence of any adverse effect on renal function, nor were there any changes in blood indices or liver function tests.
Clinical responses to treatment The results for 2 weeks of treatment showed trends similar to those observed after 4 weeks, with no evidence of any difference in speed of onset of remission between the groups. The data presented therefore relate to the 4-week values only.
Stool frequency (see Figure I ) Mean stool frequency was 3.8 & 2.5 at outset in the mesalazine group and 5.6 & 5.1 in the enema group. Corresponding median values were 3,0/day in the mesalazine group and 3.3/day respectively, falling significantly with treatment in both groups (mesalazine-median decrease = 1.2, 95 % confidence intervals (CI) 0.3-2.2, P < 0.01; enemas-median decrease = 1.5,95% CI 0.4-5.4, P < 0.01). The number of subjects experiencing fewer than two bowel actions per day increased from 3/18 to 8/18 in the mesalazine group (P = 0.06, Fisher's exact test) and from 4/19 to 10/19 in the enema group ( P = 0.04). There were no significant differences between the groups.
Urgency (see Figure 2 ) The mean urgency score was 53.6+31 in the mesalazine group and 59.6 +35 in the enema group. Corresponding median values were 46 and 74, respectively. There was a significant reduction in urgency in both groups at 4 weeks (mesalazine-median reduction = 35, 95% CI 0.1-63.0, P < 0.02; enemas-median reduction = 39, 95 % CI 14.0-74.0, P < 0.01). The number of subjects experiencing an urgency score of less than 10 mm increased from 1/18 to 9/18 in the mesalazine group ( P < 0.005) and from 1/19 to 9/19 in the enema group (P < 0.005). There were no significant differences between the groups.
MESALAZINE F O R ACUTE DISTAL COLITIS
517
Stool Frequency Mesalazine
Week 0
Enemas
Week4
o
Week 0
Week 4
Withdrawn at 2 weeks
Figure 1. Mean daily stool frequencies before and after 4 weeks of treatment for patients receiving either active oral mesalazine or active steroid enemas (mean standard error at 0 and 4 weeks is shown).
Urgency Score Mesalazine
0 week 0
Enemas
w6&
Week 0
4
0
week 4
Withdrawn a1 2 weeks
Figure 2. Mean urgency scores before and after 4 weeks of treatment for patients receiving either active oral mesalazine group or active steroid enemas (mean & standard error at O and 4 weeks is shown).
I. COBDEN et al.
518
-
Enema bleeding
Mesalazine bleeding
E2
~
Week0 Week4
10 -
17
n $
Week4
ia
6
E
2
4 2 0
0
