NIHR Signal One group of drugs used to treat Crohn’s disease is unlikely to prevent relapse

Published on 21 December 2016

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.

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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.

Bibliography

NICE. Crohn's disease: management. CG152. London: National Institute for Health and Care Excellence; 2012, updated 2016.

NHS Choices. Crohn’s disease. London: Department of Health; 2015.

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.

Bibliography

NICE. Crohn's disease: management. CG152. London: National Institute for Health and Care Excellence; 2012, updated 2016.

NHS Choices. Crohn’s disease. London: Department of Health; 2015.

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

Published on 30 September 2016

Akobeng, A. K.,Zhang, D.,Gordon, M.,MacDonald, J. K.

Cochrane Database Syst Rev Volume 9 , 2016

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 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. 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. 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.

Expert commentary

The benefit of 5-ASA for Crohn's disease is considered too marginal to recommend it especially given the change in goals of therapy towards more effective treatment that heals mucosa and alters natural history. Some believe there remains a role in pure colonic disease and in relapse prevention after small bowel resection. However, this is also marginal and most people are now abandoning use.

Dr Jeremy Sanderson, Consultant Gastroenterologist, Joint Clinical Director, Gastrointestinal Medicine and Surgery, Guy's & St Thomas' Hospitals NHS Foundation Trust