Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease.
BACKGROUND
The prevention of relapse is a major issue in the management of Crohn's disease. Corticosteroids, the mainstay of treatment of acute exacerbations, are not effective for maintenance of remission and its chronic use is limited by numerous adverse events. Randomised controlled trials assessing the efficacy of oral 5-aminosalicylic acid (5-ASA) agents for maintenance of medically-induced remission in Crohn's disease have produced conflicting results.


OBJECTIVE
To conduct a systematic review to evaluate the efficacy and safety of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn's disease.


METHODS
We searched MEDLINE, EMBASE, CENTRAL and the IBD Group Specialized Register from inception to 8 June 2016. We also searched reference lists and conference proceedings.


METHODS
We included randomised controlled trials that compared oral 5-ASA agents to either placebo or sulphasalazine in patients with quiescent Crohn's disease. The trials had to have a treatment duration of at least six months.


METHODS
Two authors independently extracted data and performed the risk of bias assessment. Any disagreements were resolved by discussion and consensus. The primary outcome measure was the occurrence of relapse as defined by the primary studies. Secondary outcomes included time to relapse, adverse events, withdrawal due to adverse events and serious adverse events. We calculated the pooled risk ratio (RR) and corresponding 95% confidence interval (95% CI) using a fixed-effect model. All data were analysed on an intention-to-treat basis and drop-outs were considered to be relapses. Sensitivity analyses included an available case analysis where drop-outs were ignored and using a random-effects model. We evaluated the overall quality of the evidence supporting the outcomes using the GRADE criteria.


RESULTS
Twelve studies (2146 participants) that compared 5-ASA to placebo were included. We did not identify any studies that compared sulphasalazine to placebo. Seven studies were judged to be at low risk of bias. The other studies were judged to have an unclear risk of bias for various items due to insufficient details to allow for a judgement. There was no statistically significant difference in relapse rates at 12 months. Fifty-three per cent (526/998) of 5-ASA patients (dose 1.6 g to 4 g/day) relapsed at 12 months compared to 54% (544/1016) of placebo patients (RR 0.98, 95% CI 0.91 to 1.07; 11 studies; 2014 patients; moderate-quality evidence). Sensitivity analyses based on an available case analysis and a random-effects model had no impact on the results. One study found no difference in relapse rates at 24 months. Fifty-four per cent (31/57) of 5-ASA patients (dose 2 g/day) relapsed at 24 months compared to 58% (36/62) of placebo patients (RR 0.94, 95% CI 0.68 to 1.29, 119 patients; low-quality evidence). One paediatric study found no statistically significant difference in relapse rates at 12 months. Sixty-two per cent (29/47) of paediatric 5-ASA patients (dose 50 mg/kg/day) relapsed at 12 months compared to 64% (35/55) of paediatric placebo patients (RR 0.97, 95% CI 0.72 to 1.31; 102 patients; moderate-quality evidence). There was no statistically significant difference in the proportion of patients who experienced an adverse event, withdrawal due to adverse events or serious adverse events. Thirty-four per cent (307/900) of 5-ASA patients had at least one adverse event compared to 33% (301/914) of placebo patients (RR 1.05, 95% CI 0.95 to 1.17; 10 studies; 1814 patients). Fourteen per cent (127/917) of 5-ASA patients withdrew due to adverse events compared to 13% (119/916) of placebo patients (RR 1.11, 95% CI 0.88 to 1.38; 9 studies; 1833 patients). One per cent (3/293) of 5-ASA patients had a serious adverse event compared to 0.7% (2/283) of placebo patients (RR 1.43, 95% CI 0.24 to 2.83; 3 studies; 576 patients). Common adverse events reported in the studies included diarrhoea, nausea and vomiting, abdominal pain, headache and skin rash.


CONCLUSIONS
We found no evidence in this review to suggest that oral 5-ASA preparations are superior to placebo for the maintenance of medically-induced remission in patients with Crohn's disease. Additional randomised trials may not be justified.
Sidra Medical & Research Center, PO Box 26999, Doha, Qatar.
Anthony K
AK
Akobeng
Dongni
D
Zhang
Morris
M
Gordon
John K
JK
MacDonald
Lancet. 1977 Oct 29;2(8044):892-5
72239
Postgrad Med J. 1992 Mar;68(797):189-91
1350343
Am J Gastroenterol. 2003 Dec;98(12 Suppl):S1-5
14697912
Int J Clin Pharmacol Res. 1994;14(4):133-8
7607786
N Engl J Med. 2004 Feb 26;350(9):876-85
14985485
Gut. 1994 Aug;35(8):1081-5
7926910
Aliment Pharmacol Ther. 1997 Oct;11(5):845-52
9354191
Gut. 2001 Oct;49(4):552-6
11559654
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD008414
21249709
Gastroenterology. 1993 Feb;104(2):435-9
8425685
N Engl J Med. 1973 Sep 6;289(10):491-5
4146729
Gastroenterology. 1997 Apr;112(4):1069-77
9097988
Am J Gastroenterol. 1994 Dec;89(12):2116-24
7977225
Ann Gastroenterol Hepatol (Paris). 1993 Oct;29(5):251-6
8250520
Scand J Gastroenterol. 1974;9(6):549-54
4153646
Gastroenterology. 1996 Mar;110(3):688-93
8608877
Gastroenterology. 1992 Aug;103(2):363-8
1634054
Dig Dis Sci. 1992 Jan;37(1):29-32
1728527
Int J Clin Pharmacol Res. 1991;11(4):200-2
1813439
Gastroenterology. 1979 Oct;77(4 Pt 2):847-69
38176
BMJ. 2008 Apr 26;336(7650):924-6
18436948
ACP J Club. 2002 May-Jun;136(3):92
11985433
Aliment Pharmacol Ther. 1990 Feb;4(1):55-64
2104074
Gut. 1972 Apr;13(4):278-84
4402420
Z Gastroenterol Verh. 1981 Jun;19:45-9
6168135
Am J Gastroenterol. 2003 Dec;98(12 Suppl):S6-S17
14697913
Am J Gastroenterol. 1994 May;89(5):692-8
8172139
Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003715
15674913
Gut. 1980 Jul;21(7):632-5
6107263
Gastroenterol Clin Biol. 2009 Jan;33(1 Pt 1):31-40
19118966
Cochrane Database Syst Rev. 2016 May 09;(5):CD000544
27158764
Verh Dtsch Ges Inn Med. 1976;82 Pt 1:930-2
18856
J Clin Gastroenterol. 1995 Apr;20(3):203-6
7797827
Am J Gastroenterol. 2004 Jan;99(1):91-6
14687148
Gut. 1977 Jan;18(1):69-72
14057
Gut. 1987 Feb;28(2):196-200
3557190
Gastroenterology. 1997 Nov;113(5):1465-73
9352848
Lancet. 2002 May 4;359(9317):1541-9
12047962
N Engl J Med. 2000 Jun 1;342(22):1627-32
10833208
Aliment Pharmacol Ther. 1995 Dec;9(6):673-83
8824656
Z Gastroenterol Verh. 1981 Jun;19:38-40
6168133
Gastroenterology. 1984 Feb;86(2):249-66
6140202
N Engl J Med. 1980 Dec 25;303(26):1499-502
6107853
Cochrane Database Syst Rev. 2003;(4):CD000301
14583917
Aliment Pharmacol Ther. 2003 Jun;17 Suppl 2:31-7
12786610
Aliment Pharmacol Ther. 2004 Oct;20 Suppl 4:60-5
15352896
Ugeskr Laeger. 1974 Aug 5;136(32):1798-802
4153180
Am J Gastroenterol. 1993 Sep;88(9):1343-51
8362827
Gastroenterology. 1999 Oct;117(4):761-9
10500056