Oral 5-aminosalicylic acid drugs for maintenance of medically-induced remission in Crohn's disease

What is Crohn's disease?

Crohn's disease is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. It can affect people of any age. When people have active Crohn's disease they experience symptoms such as abdominal pain, diarrhoea and weight loss. When symptoms stop, people are considered to be in remission. Active Crohn's disease can be treated by medical therapy (e.g. drugs such as steroids, immunosuppressives or biologics) or by surgery to removed the diseased portions of the intestine. The goal of medical therapy of Crohn's disease is to induce remission and to maintain this remission for as long as possible.

What are 5-aminosalicylic acid (5-ASA) drugs?

5-ASA drugs are a group of compounds that are thought to treat Crohn's disease by reducing inflammation in the gastrointestinal tract. These drugs are often taken orally (i.e. by mouth).

What did the researchers investigate?

We studied whether oral 5-ASA maintains remission in patients with Crohn's disease and whether it causes any harms (side effects). We searched the medical literature extensively up to 8 June 2016.

What did the researchers find?

We found 12 studies that included a total of 2146 participants. Eleven studies including 2014 adult participants compared oral 5-ASA to a placebo (i.e. inactive pills or tablets). One study including 132 children compared oral 5-ASA to a placebo. Eleven studies were conducted for 12 months and one study was conducted for 24 months. Seven studies were judged to be of high quality and the other studies were judged to be of unclear quality because insufficient details were reported to allow for a judgement about quality. The studies with insufficient details were generally older studies that were published 20 or more years ago. A combined analysis of eleven studies including 2014 adult participants found no difference between oral 5-ASA (at daily doses between 1.6 g to 4 g) and placebo in the proportion of participants who remained in remission at 12 months. Similarly, a study including 161 adult participants found no difference between oral 5-ASA (at a dose of 2 g per day) and placebo in the proportion of participants who remained in remission at 24 months. The study involving children found no difference between oral 5-ASA (at a daily dose of 50 mg/kg) and placebo in the proportion of participants who remained in remission at 12 months. There does not appear to be an increased risk of side effects in people who take oral 5-ASA compared to placebo. Common adverse events reported in the studies included diarrhoea, nausea and vomiting, abdominal pain, headache and skin rash.

In conclusion, there is no evidence that oral 5-ASA is superior to placebo for helping people with Crohn's disease remain in remission that was achieved by medical therapy.

Authors' 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.

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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.

Objectives: 

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.

Search strategy: 

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.

Selection criteria: 

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.

Data collection and analysis: 

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.

Main 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.

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