Interventions for maintaining surgically included remission in Crohn's disease

What is the aim of this review?

The aim of this Cochrane Review was to find out which drugs are most effective for maintaining remission in people with Crohn's disease who have undergone surgery to achieve remission. We collected and analysed all relevant studies to answer this question. We examined these studies using a method known as network meta-analysis (NMA) in order to compare and rank all the treatments in terms of clinical relapse, endoscopic relapse and safety.

What was studied in the review?

Crohn's disease is a chronic disease of the gut. It is known to change from periods when people experience a flare-up of the disease (relapse) to periods of good health (remission). Symptoms include abdominal pain, diarrhoea and weight loss. People with Crohn's disease may undergo surgery to remove diseased parts of their gut and achieve remission. However, their symptoms return after a while. Different drugs can be given to ensure that people with Crohn's disease remain in remission for as long as possible. These drugs include mesalazine, antibiotics, corticosteroids, and adalimumab, amongst others. Whilst these drugs have been known to reduce inflammation (pain and swelling) in the gut, side effects can occur with their use. We attempted to find out which treatments are the safest and most effective for maintaining remission in people with Crohn's disease after surgery.

How up-to-date is the review?

We searched for studies published up to 15 January 2019.

What are the main results of the review?

We included 35 relevant trials, which were published between 1976 and 2018. The studies included a total of 3249 participants who were mostly adults. Our NMA included 26 studies (2581 participants) and compared nine groups of treatments such as 5-aminosalicylic acid, adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogues, sulfasalazine, and a combination of sulfasalazine and prednisolone, which are used in preventing relapse after surgery in people with Crohn's disease. Adalimumab may reduce the chance of clinical relapse compared with placebo (dummy treatment). 5-aminosalicylic acid probably reduces the chance of clinical relapse compared with placebo. Budesonide may not be effective in preventing clinical relapse. The entire network evidence is of low certainty due to the small number of participants included in the studies and high risk of bias. This means that are confidence in these results is limited. Research to understand the effect of the treatments on endoscopic relapse and safety was limited, however cases of pancreatitis and leukopenia were reported in participants who received purine analogues.

Key messages

We uncertain about which treatments are most effective in preventing postoperative relapse in Crohn's disease. Alhough there is limited research on the harms (side effects) of these treatments, there were reported instances of pancreatitis and leukopenia in participants who received purine analogues.

Authors' conclusions: 

Due to low-certainty evidence in the networks, we are unable to draw conclusions on which treatment is most effective for preventing clinical relapse and endoscopic relapse. Evidence on the safety of the interventions was inconclusive, however cases of pancreatitis and leukopenia from purine analogues were evident in the studies. Larger trials are needed to further understand the effect of the interventions on endoscopic relapse.

Read the full abstract...
Background: 

Crohn's disease (CD) is a chronic disease of the gut. About 75% of people with CD undergo surgery at least once in their lifetime to induce remission. However, as there is no known cure for the disease, patients usually experience a recurrence even after surgery. Different interventions are routinely used in maintaining postsurgical remission. There is currently no consensus on which treatment is the most effective.

Objectives: 

To assess the effects and harms of interventions for the maintenance of surgically induced remission in Crohn's disease and rank the treatments in order of effectiveness.

Search strategy: 

We searched the Cochrane IBD Group Specialized Register, CENTRAL, MEDLINE, and Embase from inception to 15 January 2019. We also searched reference lists of relevant articles, abstracts from major gastroenterology meetings, ClinicalTrials.gov, and the WHO ICTRP. There was no restriction on language, date, or publication status.

Selection criteria: 

We considered for inclusion randomised controlled trials (RCTs) that compared different interventions used for maintaining surgically induced remission in people with CD who were in postsurgical remission. Participants had to have received maintenance treatment for at least three months. We excluded studies assessing enteral diet, diet manipulation, herbal medicine, and nutritional supplementation.

Data collection and analysis: 

Two review authors independently selected relevant studies, extracted data, and assessed the risk of bias. Any disagreements were resolved by discussion or by arbitration of a third review author when necessary. We conducted a network meta-analysis (NMA) using a Bayesian approach through Markov Chain Monte Carlo (MCMC) simulation. For the pairwise comparisons carried out in Review Manager 5, we calculated risk ratios (RR) with their corresponding 95% confidence intervals (95% CI). For the NMA, we presented hazard ratios (HR) with corresponding 95% credible intervals (95% CrI) and reported ranking probabilities for each intervention. For the NMA, we focused on three main outcomes: clinical relapse, endoscopic relapse, and withdrawals due to adverse events. Data were insufficient to assess time to relapse and histologic relapse. Adverse events and serious adverse events were not sufficiently or objectively reported to permit an NMA. We used CINeMA (Confidence in Network Meta-Analysis) methods to evaluate our confidence in the findings within networks, and GRADE for entire networks.

Main results: 

We included 35 RCTs (3249 participants) in the review. The average age of study participants ranged between 33.6 and 38.8 years. Risk of bias was high in 18 studies, low in four studies, and unclear in 13 studies. Of the 35 included RCTs, 26 studies (2581 participants; 9 interventions) were considered eligible for inclusion in the NMA. The interventions studied included 5-aminosalicylic acid (5-ASA), adalimumab, antibiotics, budesonide, infliximab, probiotics, purine analogues, sulfasalazine, and a combination of sulfasalazine and prednisolone. This resulted in 30 direct contrasts, which informed 102 mixed-treatment contrasts.

The evidence for the clinical relapse network (21 studies; 2245 participants) and endoscopic relapse (12 studies; 1128 participants) were of low certainty while the evidence for withdrawal due to adverse events (15 studies; 1498 participants) was of very low certainty. This assessment was due to high risk of bias in most of the studies, inconsistency, and imprecision across networks. We mainly judged individual contrasts as of low or very low certainty, except 5-ASA versus placebo, the evidence for which was judged as of moderate certainty.

We ranked the treatments based on effectiveness and the certainty of the evidence. For clinical relapse, the five most highly ranked treatments were adalimumab, infliximab, budesonide, 5-ASA, and purine analogues. We found some evidence that adalimumab (HR 0.11, 95% Crl 0.02 to 0.33; low-certainty evidence) and 5-ASA may reduce the probability of clinical relapse compared to placebo (HR 0.69, 95% Crl 0.53 to 0.87; moderate-certainty evidence). However, budesonide may not be effective in preventing clinical relapse (HR 0.66, 95% CrI 0.27 to 1.34; low-certainty evidence). We are less confident about the effectiveness of infliximab (HR 0.36, 95% CrI 0.02 to 1.74; very low-certainty evidence) and purine analogues (HR 0.75, 95% CrI 0.55 to 1.00; low-certainty evidence). It was unclear whether the other interventions reduced the probability of a clinical relapse, as the certainty of the evidence was very low.

Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing endoscopic relapse. Whilst there might be some evidence of prevention of endoscopic relapse with adalimumab (HR 0.10, 95% CrI 0.01 to 0.32; low-certainty evidence), no other intervention studied appeared to be effective.

Due to high risk of bias and limited data across the network, we are uncertain about the effectiveness of interventions for preventing withdrawal due to adverse events. Withdrawal due to adverse events appeared to be least likely with sulfasalazine (HR 1.96, 95% Crl 0.00 to 8.90; very low-certainty evidence) and most likely with antibiotics (HR 53.92, 95% Crl 0.43 to 259.80; very low-certainty evidence). When considering the network as a whole, two adverse events leading to study withdrawal (i.e. pancreatitis and leukopenia) occurred in more than 1% of participants treated with an intervention. Pancreatitis occurred in 2.8% (11/399) of purine analogue participants compared to 0.17% (2/1210) of all other groups studied. Leukopenia occurred in 2.5% (10/399) of purine analogue participants compared to 0.08% (1/1210) of all other groups studied.

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