Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn’s disease

What is the aim of this review?

The aim of this review was to understand the effectiveness and safety of 5-ASA drugs for maintaining remission following surgery in people with Crohn disease. This review is an update of a previously published Cochrane review.

What is Crohn's disease?

Crohn's is a chronic disease of the gut. Crohn's changes from periods when sufferers have symptoms (relapse) to periods when the symptoms disappear (remission). Symptoms include abdominal pain, diarrhoea and weight loss. People with Crohn's disease may undergo surgery to remove diseased parts of their gut. However, their symptoms may return after a short time. Different drugs can be given to maintain remission, however, there are concerns about possible side effects. 5-ASA drugs reduce inflammation (pain and swelling) in the gut. We researched whether 5-ASA can maintain remission in people with Crohn's after the diseased part of their gut has been removed.

How up-to-date is this review?

The review authors searched for studies that had been published up to 16 July 2018.

What are the main results of the review?

We found 14 studies (1867 participants). One study was judged to be of high quality, six studies were of low quality and seven were judged to be unclear as authors reported insufficient information to allow a judgement. People who took 5-ASA had fewer relapses than people who had no maintenance treatment. At 12 months, 36% (20/55) of participants in the 5-ASA group relapsed compared to 51% (28/55) in the no treatment control group (1 study, low certainty evidence). Moderate quality evidence from five studies showed that 5-ASA drugs are superior to placebo (e.g. a sugar pill) for maintaining surgically-induced remission of Crohn's disease. During a follow-up period of 12 to 72 months, 36% (131/361) of 5-ASA participants relapsed compared to 43% (160/369) of placebo participants. The analysis of four studies that compared 5-ASA medications to purine antimetabolites (i.e. azathioprine or 6-mercaptopurine - both immunosuppressive drugs) found no difference in the proportion of participants that remained in remission, although the overall quality of evidence was low. At 24 months, 61% (103/170) of 5-ASA participants relapsed compared to 67% (119/177) of purine antimetabolite participants. People who took high dose 5-ASA had fewer relapses than those who took lower dose 5-ASA. At 12 months, 17% (17/101) of the 4 g/day 5-ASA group relapsed compared to 26% (27/105) of the 2.4 g/day group (1 study, moderate certainty evidence). The analysis of the single small study that compared 5-ASA and adalimumab (a biologic drug) showed that 5-ASA was inferior to adalimumab for maintaining surgically-induced remission of Crohn's disease. At 24 months, 50% (9/18) of 5-ASA participants relapsed compared to 13% (2/16) in the adalimumab group (very low certainty evidence). The analysis of two studies that compared sulphasalazine to placebo found no difference in relapse rates. After 18 to 36 months, 66% (95/143) of sulphasalazine participants relapsed compared to 71% (110/155) of placebo participants (low certainty evidence). There was no difference in rates of side effects, serious side effects and withdrawal due to side effects when 5-ASA was compared to placebo. 5-ASA was safer than purine analogues resulting in less serious side effects and discontinuation of treatment due to side effects. Commonly reported side effects included diarrhoea, nausea, increased liver function tests, pancreatitis and abdominal pain.

Conclusions

5-ASA drugs are superior to placebo for maintaining surgically-induced remission of Crohn's disease (moderate certainty evidence). Sulphasalazine failed to demonstrate superiority against placebo (very low certainty evidence), and similarly 5-ASAs failed to demonstrate superiority to no treatment (low certainty evidence). The effectiveness of two different doses of the same 5-ASA and the effectiveness of 5-ASA compared to purine antimetabolites (azathioprine or 6-mercaptopurine) for maintaining surgically-induced remission of Crohn's disease remains unclear. However, purine analogues lead to more serious side effects and discontinuation due to side effects than 5-ASA. There is a low certainty that 5-ASA is inferior to adalimumab for maintaining surgically-induced remission of CD. There was no evidence of a difference in the occurrence of side effects or withdrawal due to side effects with 5-ASA formulations when compared with placebo, no treatment or biologics.

Authors' conclusions: 

5-ASA preparations are superior to placebo for the maintenance of surgically-induced clinical remission in patients with CD (moderate certainty). The number needed to treat to prevent one relapse was 13 patients. The evidence for endoscopic remission is uncertain. The sulphasalazine class of 5-ASA agents failed to demonstrate superiority against placebo, 5-ASAs failed to demonstrate superiority compared to no treatment (very low and low certainty). The efficacy of two different doses of the same 5-ASA and the efficacy of 5-ASA compared to purine antimetabolites (azathioprine or 6-mercaptopurine) in maintaining surgically-induced remission of CD remains unclear. However, purine analogues lead to more serious adverse events and discontinuation due to adverse events. There is a low certainty that 5-ASA is inferior for maintaining surgically-induced remission of CD compared to biologics (anti TNF-ɑ). 5-ASA formulations appear to be safe with no difference in the occurrence of adverse events or withdrawal when compared with placebo, no treatment or biologics.

Read the full abstract...
Background: 

Crohn’s disease (CD) is a chronic inflammatory disorder that can involve any part of the gastrointestinal tract. 5-Aminosalicylates (5-ASAs) are locally acting, anti-inflammatory compounds that reduce inflammation of the colonic mucosa with release profiles that vary among various commercially available formulations. This updated Cochrane review summarizes current evidence on the use of 5-ASA formulations for maintenance of surgically-induced remission in CD.

Objectives: 

To assess the efficacy and safety of 5-ASA agents for the maintenance of surgically-induced remission in CD.

Search strategy: 

We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register from inception to 16 July 2018. We also searched references, conference abstracts, and trials registers.

Selection criteria: 

Randomised controlled trials (RCTs) that included participants with CD in remission following surgery and compared 5-ASAs to no treatment, placebo or any other active intervention with duration of at least three months were considered for inclusion.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane. The primary outcome was clinical relapse. Secondary outcomes included endoscopic recurrence, radiologic and surgical relapse, adverse events, serious adverse events and withdrawal due to adverse events.

Main results: 

Fourteen RCTs (1867 participants) were included in the review. Participants (15 to 70 years) were recruited from gastroenterology hospitals and medical clinics in Europe and North America and followed up between 3 and 72 months. The risk of bias was assessed as 'low' in one study, 'unclear' in seven and as 'high' in six.

At 12 months, 36% (20/55) of participants in the 5-ASA group experienced clinical relapse compared to 51% (28/55) in the no treatment control group (RR 0.71, 95% CI 0.46 to 1.10; low certainty evidence). Moderate certainty evidence suggests that 5-ASAs are more effective for preventing clinical relapse than placebo. During a follow-up period of 12 to 72 months, 36% (131/361) of 5-ASA participants relapsed compared to 43% (160/369) of placebo participants (RR 0.83, 95% CI 0.72 to 0.96; I² = 0%; moderate certainty evidence). At 12 months, 17% (17/101) of the 4 g/day mesalamine group relapsed compared to 26% (27/105) of the 2.4 g/day group (RR 0.65, 95% CI 0.38 to 1.13; moderate certainty evidence). There was no evidence of a difference in clinical relapse rates when 5-ASA compounds were compared to purine antimetabolites. At 24 months, 61% (103/170) of mesalamine participants relapsed compared to 67% (119/177) of azathioprine participants (RR 0.90, 95% CI 0.76 to 1.07; I² = 28%; low certainty evidence). During 24 months, 50% (9/18) of 5-ASA participants had clinical relapse compared to 13% (2/16) of adalimumab participants (RR 4.0, 95% CI 1.01 to 15.84; low certainty evidence). The effects of sulphasalazine compared to placebo on clinical relapse rate is uncertain. After 18 to 36 months, 66% (95/143) of participants treated with sulphasalazine relapsed compared to 71% (110/155) in the placebo group (RR 0.88, 95% CI 0.56 to 1.38; I² = 38%; low certainty evidence).

The effect of 5-ASA drugs on safety was uncertain. During 24 months follow-up, 4% (2/55) of 5-ASA participants experienced adverse events compared to none (0/55) in the no treatment control group (RR 5.00, 95% CI 0.25 to 101.81; very low certainty evidence). An equal proportion of 5-ASA participants (10%; 23/241) and placebo (9%; 20/225) groups experienced an adverse event during a follow-up of 3 to 72 months (RR 1.07, 95% CI 0.60 to 1.91; I² = 0%; low certainty evidence). Adverse event rates were similar in the 5-ASA and purine analogues groups. However, serious adverse events and withdrawals due to adverse events were more common in participants who received purine analogues than 5-ASA. At 52 weeks to 24 months, 52% (107/207) of 5-ASA participants had an adverse event compared to 47% (102/218) of purine analogue participants (RR 1.11, 95% CI 0.97 to 1.27, I² = 0%; low certainty evidence). Four per cent (6/152) of 5-ASA participants had a serious adverse event compared to 17% (27/159) of purine analogue participants (RR 0.30, 95% CI 0.11 to 0.80; very low certainty evidence). Eight per cent (17/207) of 5-ASA participants withdrew due to an adverse event compared to 19% (42/218) of purine analogue participants (RR 0.48, 95% CI 0.28 to 0.83; low certainty evidence). Adverse event rates were similar in high and low dose mesalamine participants. After 12 months, 2% (2/101) of 4 g/day mesalamine participants had an adverse event compared to 2% (2/105) of 2.4 g/day participants (RR 1.04, 95% CI 0.15 to 7.24; low certainty evidence). The proportion of participants who experienced adverse events over a 24 month follow-up in the mesalamine group was 78% (14/18) compared to 69% (11/16) of adalimumab participants (RR 1.13, 95% CI 0.75 to 1.71; very low certainty evidence). None (0/32) of the sulphasalazine participants had an adverse event at 18 months follow-up compared to 3% (1/34) of the placebo group (RR 0.35, 95% CI 0.01 to 8.38; very low certainty evidence). Commonly reported adverse events in the included studies were diarrhoea, nausea, increased liver function tests, pancreatitis, and abdominal pain.

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