Dr A. K. Akobeng, Department of Paediatric Gastroenterology, Booth Hall Children’s Hospital, Charlestown Road, Blackley, Manchester, M9 7AA, UK. E-mail: firstname.lastname@example.org
Background Crohn’s disease is characterised by recurrent flare-ups alternating with periods of remission. A number of interventions are currently used in clinical practice to try and maintain remission in Crohn’s disease but the evidence base for some of them may be questionable.
Aim To review the available evidence on interventions, which are currently used to maintain remission in Crohn’s disease.
Methods The Cochrane Library and Medline (Pubmed) were searched for level 1 evidence on specific interventions. Search terms included ‘Crohn’s disease or synonyms’, ‘remission or synonyms’ and the names of specific interventions.
Results Azathioprine, infliximab and adalimumab are effective at maintaining remission in Crohn’s disease. Natalizumab is also effective, but there are concerns about its potential association with progressive multifocal leukoencephalopathy. Long-term enteral nutritional supplementation, enteric-coated omega-3 fatty acids and intramuscular methotrexate may also be effective but the evidence for these is based on relatively small studies. The available evidence does not support the use of oral 5-aminosalicylates agents, corticosteroids, anti-mycobacterial agents, probiotics or ciclosporin as maintenance therapy in Crohn’s disease.
Conclusion A better understanding of the evidence base of existing interventions could result in the use of treatments, which are more likely to lead to improved patient outcomes.
Crohn’s disease (CD) is a chronic inflammatory disorder that can affect any part of the gastrointestinal tract. Symptoms of the disorder including abdominal pain, diarrhoea, rectal bleeding, weight loss and loss of energy can significantly affect patients’ physical and psychosocial functioning. The disease may also be associated with a number of intestinal and extra-intestinal complications. The natural history of CD is characterised by recurrent flare-ups alternating with periods of remission. Whilst some patients may remain in remission for prolonged periods, many continue to have frequent relapses, and others may have continuous periods of active disease.
There is no cure for CD and treatment regimens are geared mainly towards the induction of remission and the maintenance of remission. This means that many patients require long-term treatments either for inducing remission during periods of active disease or for maintaining remission. Maintenance of remission is important for patients with CD. Recent studies suggest that the health-related quality of life of patients in remission is significantly better than that of those not in remissions1 and may even be comparable to that of the general population.2
A number of treatments are currently used in clinical practice to try and maintain remission in CD but the evidence base for some of these may be questionable. The aim of this review was to summarise the available evidence on interventions that are currently used for the maintenance of remission in CD.
A search of the medical literature was performed using the following electronic databases: the Cochrane Database of Systematic Reviews (Issue 2, 2007), the Cochrane Database of Abstracts of Review of Effects (Issue 2, 2007), the Cochrane Central Register of Controlled Trials (Issue 2, 2007), and Medline (Pubmed) (1966 to May 2007). Search terms included ‘Crohn’s disease or synonyms’, ‘remission or synonyms’, and the names of specific interventions. The Cochrane Inflammatory Bowel Disease Group co-ordinating centre (Toronto, Canada) was also contacted to ensure that no Cochrane review was missed and to obtain information on completed but yet to be published reviews.
Studies were included in the review, if they were systematic reviews and/or meta-analyses of randomised controlled trials (RCTs) or randomised controlled trials. The rationale for this approach was that these study designs provide the most powerful form of evidence with regard to the effectiveness of interventions.3
Level 1 evidence3 was found on a total of 13 interventions, which are used to maintain remission in CD. The effectiveness of eight interventions [5-aminosalicylates (5-ASA), azathioprine, traditional corticosteroids, budesonide, anti-mycobacterial agents, probiotics, omega-3 fatty acids (fish oil), and enteral nutrition] has been evaluated with Cochrane systematic reviews. The other five interventions (methotrexate, infliximab, adalimumab, ciclosporin, and natalizumab) are yet to be the subject of systematic reviews, but their efficacy has been evaluated with RCTs. The evidence base of these interventions is summarised below. Where appropriate, the limitations of the available evidence are discussed.
This Cochrane systematic review investigated the effectiveness of oral 5-ASA in the maintenance of medically-induced remission in CD.4 Seven placebo-controlled trials were included in the review. Doses of 5-ASA used in the primary studies ranged from 1 g/day to 3 g/day. The main meta-analysis was based on all 1500 participants who were randomised in the primary studies. As shown in Figure 1, the odds ratio for six of the studies in which participants were followed up for 12 months was 1.00 (95% CI 0.80 to 1.24). For the seventh study where follow-up was for 24 months, the odds ratio was 0.98 (95% CI, 0.51 to 1.90). The effect sizes were small even when withdrawals and drop-outs were ignored in a sensitivity analysis. These data show that 5-ASA is not effective for the maintenance of medically-induced remission over 12–24 months.
Published data are conflicting about whether 5-ASA has chemopreventive properties against inflammatory bowel disease-related carcinogenesis.5 The results of a recent case control study suggested that 5-ASA therapy over 2 years may be associated with a reduced risk of small bowel adenocarcinoma in patients with CD.6 However, in another case-control study, Treidman et al. found that treating IBD patients with 5-ASA over a 1-year period had no protective effect against colorectal cancer.5
Six randomized, placebo-controlled trials were included in the Cochrane review on oral azathioprine.7 The doses of azathioprine used in the primary studies were 2.5 mg/kg/day, 2.0 mg/kg/day, and 1.0 mg/kg/day. 319 participants were included in meta-analyses. As shown in Figure 2, the combined results of two studies which used a dose of 2.5 mg/kg/day of azathioprine and those of three studies which used a dose of 2 mg/kg/day showed a statistically significant benefit for azathioprine. However, the results of a single study that used a dose of 1 mg/kg/day did not demonstrate a statistically significant benefit. The combined results of all the studies showed a clear statistically significant benefit for azathioprine (OR 2.16 95% CI, 1.35 to 3.47). It can therefore be concluded that azathioprine (at least, 2 and 2.5 mg/kg/day) is effective for maintaining remission in CD. It must be pointed out that the individual trials were of relatively short duration (between 24 weeks and12 months), so the longer term effectiveness of azathioprine remains unclear.
Three placebo-controlled trials were included in this systematic review.8 In one study, the experimental treatment was 6-methylprednisolone (8 mg/day) and in the other two studies, the experimental treatments were prednisone 0.25 mg/kg/day (maximum daily dose 20 mg), and prednisolone 7.5 mg/day respectively. The total number of subjects included in meta-analyses at three time points (6 months, 12 months and 24 months) respectively were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios of relapse and the corresponding 95% confidence intervals were 0.71 (0.39 to 1.31), 0.82 (0.47 to 1.43) and 0.72 (0.38 to 1.35) at 6, 12 and 24 months. These results suggest that corticosteroids are not effective for maintaining remission over 6 months, 12 months or 24 months.
Three RCTs on 270 patients whose disease was restricted to the ileum and right colon were included in the review on budesonide.9 There was no statistically significant difference between budesonide 6 mg/day and placebo for prevention of relapse of CD over 12 months (Relative risk 0.89, 95% CI 0.71 to1.13). There was also no statistically significant difference between 3 mg/day budesonide and placebo over the same time period (RR 1.0, 95% CI 0.80 to1.24). This review therefore did not find any evidence to support the use of budesonide (6 mg/day or 3 mg/day) for maintaining remission over 12 months. In a recent combined analysis of four multicentre trials (which included the three studies included in the Cochrane review), Sandborn et al. suggested that budesonide 6 mg/day may be effective for maintaining remission through 3 and 6 months but not 12 months.10
Seven placebo-controlled studies involving 355 participants were included in the review.11 Meta-analyses of data of all the seven studies did not show any statistically significant difference between placebo and anti-mycobacterials (odds ratio 1.38, 95% CI 0.87 to 2.17). In a recent clinical trial, Selby et al. randomized patients to receive either a combination of the anti-mycobacterials, clarithromycin, rifabutin, and clofazimine or placebo.12 No evidence of a sustained benefit for anti-mycobacterials was seen after 2 years.
Seven small placebo-controlled trials were included in this review.13 The sample sizes of the studies were quite small and the main meta-analysis was based on three studies with only 66 participants. None of the three studies demonstrated a statistically significant difference between placebo and probiotics and the pooled data also showed no difference (RR 0.68, 95% CI 0.34 to 1.39). There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD but because of the small sample sizes of the primary studies, the risk of a type 2 error cannot be ruled out.
Two small RCT’s were included in this review.14 Because of the fact that the primary studies used different control interventions, the results were not combined statistically. The first study which involved 51 participants compared patients receiving half of their daily calorie requirement as elemental diet with those receiving unrestricted normal diet with no supplements. Nine of 26 patients (34%) in the elemental diet group suffered a relapse during the 12-month follow-up period, compared to 16 of 24 patients (64%) in the ‘no supplements group.’ (OR 0.30, 95% CI 0.09, 0.94).
The other study had 33 participants and compared an elemental diet with a polymeric diet (patients received 33–50% of pre-trial caloric intake as supplements in each group). About 42% of patients in each group achieved ‘treatment success’ during the study period. The results of these studies appear promising and may suggest some beneficial effects of enteral nutrition but the small sample sizes do not allow firm conclusions to be made. Larger trials are needed.
Omega 3 fatty acids
Four small placebo-controlled trials were included in this review.15 As shown in Figure 3 (top graph), meta-analysis of data from all the four studies did not show a statistically significant beneficial effect for omega-3 (RR 0.64, 95% CI 0.40 to 1.04). However, as shown in the bottom graph of Figure 3, when the authors performed a sensitivity analysis using only data from three of the four studies that had used enteric-coated omega-3 fatty acid preparations, a statistically significant beneficial effect of omega-3 fatty acids was demonstrated (RR 0.49, 95% CI 0.35 to 0.69). It appears from these results that daily oral therapy with enteric coated omega-3 may be effective for the maintenance of remission in CD, but again, the small sample sizes of the primary studies do not allow any firm conclusions to be made. I understand that two large studies on omega-3 fatty acids involving about 760 participants have recently been completed, but the results of these are not yet available (John McDonald, personal communication).
Two RCTs were identified on methotrexate. The first study in 1999 was a small study that compared oral methotrexate with placebo.16 After 1 year, six of 13 patients receiving 15 mg/week oral methotrexate had relapsed as compared to 12 of 15 placebo-treated patients (RR 0.57; 95% CI, 0.28 to 1.03). This study did not demonstrate any statistically significant benefit for oral methotrexate, but the small sample size means that a type 2 error is a possibility.
The second study published in 2000 compared intramuscular (IM) methotrexate with placebo.17 At week 40, 26 of 40 patients were in remission in the IM methotrexate weekly group, as compared with 14 of 36 patients in the placebo group (RR 1.67, 95% CI 1.07 to 2.73). Thus a statistically significant benefit for IM methotrexate was shown and the number needed to treat (NNT) for that population was 4, with a wide 95% CI of 3 to 29 reflecting the relatively small sample size of the study. IM methotrexate (15 mg/week) therefore appears effective for maintaining remission in CD. However, this evidence is based on a relatively small study. There is lack of evidence on the effectiveness of oral methotrexate. It is important to note that because of its teratogenic effects, methotrexate is contraindicated during pregnancy and conception must be deferred for several months after withdrawal of therapy.18
At least, two RCTs are available on infliximab.19, 20 In both studies, patients had had initial clinical response to infliximab. The results of both studies suggested a statistically significant beneficial effect in favour of infliximab. In the larger study published in 2002, 94 of 225 patients receiving 8-weekly infusions of infliximab compared with 23 of 110 patients receiving placebo were in remission at Week 30 (RR 2.0, 95% CI 1.4 to 3.0; NNT 5, 95% CI 4 to 10).20 The available evidence suggests that 8 weekly infusions of infliximab (5 or 10 mg/kg) are effective in maintaining an infliximab-induced remission. In a recent paediatric study, Hyams et al. showed that patients who received 8-weekly infliximab infusions (5 mg/kg/dose) were more likely to be in remission after 54 weeks compared to children who received the same dose of infliximab every 12 weeks.21 The results of some studies suggest that combining infliximab with immunosuppressant agents such as azathioprine22 or methotrexate23 may be a more effective strategy than monotherapy.
Recent reports suggest that infliximab may be associated with an increased risk of hepatosplenic T cell lymphoma (HSTCL). Eight cases of HSTCL in young patients using infliximab to treat inflammatory bowel disease were reported to the US Food and Drug Administration (FDA) between 1998 and October 2006.24 Interestingly, all the eight patients were receiving concomitant treatment with azathioprine or mercaptopurine. Whilst a definite evidence on the association between the development of lymphoma and the use of infliximab in CD is lacking,25 there may be a very small risk (about 8/10 000), especially in patients treated with a combination of infliximab and purine analogues.26
At least two RCTs have recently been published on adalimumab.27, 28 The main results of the larger of the two studies were on patients who had earlier achieved clinical response through the use of adalimumab.27 The maintenance results showed that after 56 weeks, 65 of 157 patients who received weekly subcutaneous adalimumab (40 mg/dose) were in remission compared with 20/170 receiving placebo (RR 3.5, 95% CI 2.2 to 5.5; NNT 4, 95% CI 3 to 5).27 In the same study, no statistically significant difference was found between patients receiving weekly injections and those receiving every other week injections. The results of the other study by Sandborn et al. showed that at Week 56, there was a significant difference in the remission rates among patients receiving adalimumab 40-mg every other week (15/19, 79%), adalimumab 40-mg weekly (15/18, 83%),and placebo (8/18, 44%) (P < 0.05 for each adalimumab group vs. placebo).28 Data from these RCT’s show that weekly or every other week subcutaneous injections of adalimumab (40 mg) are effective in maintaining an adalimumab-induced remission.
One RCT was identified on Natalizumab.29 57 of 130 patients receiving 4-weekly natalizumab (300 mg/dose) remained in remission at week 36, as compared to 31 of 120 of those receiving placebo (RR 1.69; 95% CI 1.19 to 2.44; NNT 6, 95% CI 4 to 17). In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus. There have been at least two other reports of patients with multiple sclerosis developing progressive multifocal leukoencephalopathy after receiving natalizumab.30 Therefore, although 4-weekly infusions (300 mg/dose) of natalizumab appears effective for maintaining remission in CD, reports of severe adverse effects (multifocal leukoencephalopathy) are a source of concern.
One RCT on the use of certolizumab for maintaining remission in CD has recently been published.31 Patients with moderate-to-severe CD who had earlier achieved a clinical response with certolizumab pegol were more likely to remain in remission at 26 weeks with 4-weekly subcutaneous injections of 400 mg certolizumab pegol compared with patients receiving placebo. Remission rates at week 26 were 48% (103 of 215) in the certolizumab group and 29% (60 of 210) in the placebo group (RR, 1.6; 95% CI 1.3 to 2.2).
One small RCT is available on ciclosporin.32 There was no statistically significant difference between patients receiving low-dose steroids and ciclosporin (5 mg/kg/day) or those receiving low-dose steroids and placebo. 20% in each group were in remission after 1 year. There is no evidence to support the use of ciclosporin as maintenance therapy in CD.
Other interventions not yet subjected to randomised controlled trials
There are a number of other interventions that are used but which have not yet been subjected to RCTs with regard to the maintenance of remission in CD. These include tacrolimus, mycophenolate mofetil, thalidomide, and other biological agents such as etanercep, onercept, and CDP571.
Smoking cessation is widely regarded as being useful for maintaining remission in CD. Data from observational studies show that smoking increases the risk of developing CD and worsens its course, and therefore increases the need for steroids, immunosuppressants and reoperations.33 Smoking cessation appears to be an effective intervention for improving CD34 and could be considered a form of maintenance therapy.
Whilst the indications for surgery in CD are mainly to induce remission in cases refractory to medical treatment and to treat complications, uncontrolled studies suggest that many patients will remain symptom- and medication-free for a number of years following ileo-caecal resection.35 Thus, this type of surgery may also be seen as a form of maintenance intervention for some patients.
The available evidence shows that the stated regimens of the following interventions are effective for maintaining remission in CD: azathioprine, infliximab and adalimumab. Natalizumab is also effective but there are concerns about its potential association with progressive multifocal leukoencephalopathy. Enteral nutritional supplementation, enteric-coated omega-3 fatty acids and IM methotrexate may also be effective but the evidence for these is based on relatively small studies, and these interventions should be subjected to larger trials. The available evidence does not support the use of oral 5-ASA agents, conventional corticosteroids, budesonide, anti-mycobacterial agents, probiotics and ciclosporin as maintenance therapy in CD. Whilst factors such as patient’s values and preferences should be taken into consideration when deciding on maintenance therapy for an individual patient, a better understanding of the evidence base of existing interventions could result in the use of treatments, which are more likely to lead to improved patient outcomes.
I thank John McDonald and the Cochrane Inflammatory Bowel Disease and Functional Gastrointestinal Disorders Group for their help in the reproduction of the meta-analyses forest plots shown in this article. Declaration of personal and funding interests: None.