Anti-inflammatory drugs called 5-aminosalicylic acids (5-ASAs) do not prevent relapses of Crohn’s disease when compared to placebo at one year.
Crohn’s disease is a long-term inflammatory condition which can affect any part of the gastrointestinal tract, causing pain, diarrhoea and weight loss. It is characterised by recurring bouts of inflammation which can be severe.
Once an attack has been treated through use of corticosteroids and other medication, options to prevent relapses are limited to immunosuppressants, but each can cause serious side effects.
As 5-ASAs are an effective treatment when corticosteroids are unsuitable, it was hoped that they might also be a preventive option with fewer side effects. Biological drugs such as infliximab, adalimumab and vedolizumab are usually reserved in the UK for people with severe disease who respond poorly to other drug treatment.
This study confirms NICE guidance and strengthens the case for using immunosuppressants such as azathioprine, mercaptopurine or methotrexate, and not 5-ASAs, for prevention of flare-ups of Crohn’s disease after medical treatment.
Why was this study needed?
About 115,000 people in the UK have Crohn’s disease. The mainstay of treatment for active disease is corticosteroid drugs, which calm inflammation and reduce symptoms in mild cases. However, the long term aim is to keep the condition under control (in remission) and steroids can cause side effects if used long term.
5-ASAs are anti-inflammatory drugs, usually taken by mouth. They are usually well tolerated and inexpensive and have been used to try to keep Crohn’s disease in remission once a flare-up has settled. Studies of their effectiveness had shown mixed results, however, and a 2012 NICE guideline called for further research to clarify this question.
Other drugs, including immunosuppressants, are more often used to induce and maintain remission in Crohn’s disease, but these have their own limitations. The purpose of the study was to update a previous summary of research, to pool the findings and to ascertain whether oral 5-ASAs are effective in this situation.
What did this study do?
Researchers did a systematic review and meta-analysis of trials which randomly allocated people in remission from Crohn’s disease to take either oral 5-ASA drugs or placebo. They only included trials with a follow up time of at least 12 months and looked at the rate of relapse.
They included 12 studies with a total of 2,146 participants. One study included only children. Participants came from Europe, Canada, South Africa and Israel. Drug doses varied between trials.
The overall quality of the studies for the main outcome was moderate and there was a low risk of publication bias. High drop-out rates were considered to indicate relapse, but this may have been an overestimate. Despite these minor limitations, the results are reliable.
What did it find?
- There was no difference between the proportion of adults treated with 5-ASAs who had a relapse within 12 months (52.5%) and those who took a placebo (53.5%). Evidence for this conclusion was based on 2,014 adults in 11 studies (relative risk [RR] 0.98, 95% confidence interval [CI] 0.91 to 1.07). The studies had a moderate GRADE level of evidence.
- Similarly, there was no difference in relapse within 24 months between adults who took 5-ASAs and those who took placebo, (67.2% versus 67.9%). Evidence for this was based on lower GRADE of evidence from one study of 161 adults (RR 0.99, 95% CI 0.8 to 1.23).
- There was no difference in relapse rates in the trial which included only children over 12 months. Of those taking 5-ASAs, 73.6% relapsed compared to 68.8% taking placebo (RR 1.07, 95% CI 0.86 to 1.33).
- There was no difference between the treatment and placebo groups in adverse events, serious adverse events or withdrawals due to adverse events.
What does current guidance say on this issue?
The NICE guideline updated in 2016 recommends against using 5-ASAs for maintenance treatment during remission. It only includes them as an option in the following circumstances:
- Treatment of a first presentation or single inflammatory episode, for people who decline, cannot tolerate or have a contraindication to corticosteroid treatment.
- To maintain remission after surgery.
These circumstances are not included in the current evidence review, which looks only at maintenance of medically-induced remission.
What are the implications?
This review confirms that 5-ASAs should no longer be used as maintenance treatment for patients in remission after medical treatment for Crohn’s disease. Alternative treatments are already available as recommended by NICE including the immunosuppressants azathioprine, mercaptopurine or methotrexate. Biologics, such as infliximab, adalimumab or vedolizumab are only recommended in certain situations.
These drugs may have more frequent and serious side effects than 5-ASAs, and may cost more. This may impact on budgets and challenge clinicians to find drugs that are most suitable for each of their patients.
Citation and Funding
Akobeng AK, Zhang D, Gordon M, MacDonald JK. Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's disease. Cochrane Database Syst Rev. 2016;(9):CD003715.
Partial funding for the Cochrane IBD Group (April 1, 2016 - March 31, 2018) has been provided by Crohn's and Colitis Canada.
NICE. Crohn’s disease: management. CG152. London: National Institute for Health and Care Excellence; 2012, updated 2016. Updated version NG129; 2019.
NHS Choices. Crohn’s disease. London: Department of Health; 2015.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre