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BMJ Clin Evid. 2007; 2007: 0416.
Published online 2007 November 7.
PMCID: PMC2943777

Crohn's disease

Alexander C von Roon,# George E. Reese,# Timothy R. Orchard, Honorary Senior Lecturer and Consultant Gastroenterologist,# and Paris P. Tekkis#

Abstract

Introduction

Crohn's disease is a long-term chronic condition of the gastrointestinal tract. It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae. The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of medical treatments in adults to induce remission in Crohn's disease? What are the effects of lifestyle interventions in adults with Crohn's disease to maintain remission? What are the effects of surgical interventions in adults with small-bowel Crohn's disease to induce remission? What are the effects of surgical interventions in adults with colonic Crohn's disease to induce remission? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 60 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: aminosalicylates, antibiotics, azathioprine/mercaptopurine, ciclosporin, corticosteroids (oral), enteral nutrition, fish oil, infliximab, methotrexate, probiotics, resection, segmental colectomy, smoking cessation, and strictureplasty.

Key Points

Crohn's disease is a long-term chronic condition of the gastrointestinal tract.

  • It is characterised by transmural, granulomatous inflammation that occurs in a discontinuous pattern, with a tendency to form fistulae.
  • The cause is unknown but may depend on interactions between genetic predisposition, environmental triggers, and mucosal immunity.

First-line treatment to induce remission of acute disease is corticosteroids.

  • Budesonide is generally recommended in mild to moderate ileocaecal disease because it is only slightly less effective in inducing remission than prednisolone, and has a superior adverse-effect profile.
  • Prednisolone or methylprednisolone are generally recommended for severe or more extensive disease because of their superior efficacy.

Azathioprine and mercaptopurine are effective in inducing remission and healing fistulae in Crohn's disease, provided that 17 weeks or more of treatment are given. Monitoring for myelosuppression is obligatory.

  • Aminosalicylates (mesalazine, sulfasalazine) may reduce disease activity, but we don't know which is the best regimen to induce remission.
  • Methotrexate 25 mg weekly increases remission rates, and has a corticosteroid-sparing effect. There is consensus that it is also effective for maintenance.
  • Cytokine inhibitors (e.g. infliximab) are effective in inducing and maintaining remission in Crohn's disease, but the long-term adverse-effect profile is unclear; they are therefore generally reserved for treatment of disease that is refractory to treatment with corticosteroids or other immunomodulators.
  • Antibiotics and ciclosporin are unlikely to be beneficial in inducing remission.

Bowel-sparing surgery to induce remission may be preferable to extensive resection, to avoid short bowel syndrome. Segmental and subtotal colectomy have similar remission rates.

Laparoscopic resection may reduce postoperative hospital stay, but we don't know whether strictureplasty is effective.

Azathioprine has been shown to be beneficial in maintaining remission in Crohn's disease, either alone or after surgery, and has a corticosteroid-sparing effect, but is associated with important adverse effects.

About this condition

Definition

Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract, characterised by transmural granulomatous inflammation, a discontinuous pattern of distribution, and fistulae. Although any part of the digestive tract from mouth to anus may be affected, Crohn's disease most frequently occurs in the terminal ileum, ileocaecal region, colon, and perianal region. The disease may be further classified into inflammatory, fistulating, and stricturing disease. The symptoms vary, but commonly include diarrhoea, abdominal pain, weight loss, blood or mucus in the stool, perineal pain, discharge, and irritation resulting from perianal fistulae. Extraintestinal manifestations of the disease include arthritis, uveitis, and skin rash. Diagnosis: There is no single gold standard for the diagnosis of Crohn's disease. Diagnosis is made by clinical evaluation and a combination of endoscopic, histological, radiological, and biochemical investigations. Internationally accepted criteria for the diagnosis of Crohn's disease have been defined by Lennard-Jones. After exclusion of infection, ischaemia, irradiation, and malignancy as causes for intestinal inflammation, a combination of three or more of the following findings on clinical examination, radiological investigation, endoscopy, and histological examination of endoscopic biopsies or excised specimens is considered diagnostic: chronic inflammatory lesions of the oral cavity, pylorus or duodenum, small bowel or anus; a discontinuous disease distribution (areas of abnormal mucosa separated by normal mucosa); transmural inflammation (fissuring ulcer, abscess, or fistula); fibrosis (stricture); lymphoid aggregates or aphthoid ulcers; retention of colonic mucin on biopsy in the presence of active inflammation; and granulomata (of the non-caseating type and not caused by foreign bodies). Further macroscopic findings not included in the Lennard-Jones classification that are considered diagnostic for Crohn's disease include fat wrapping, cobblestoning, and thickening of the intestinal wall. Laboratory findings consistent with Crohn's disease include anaemia, thrombocytosis, raised C-reactive protein levels, and a raised erythrocyte sedimentation rate. It may be difficult to distinguish Crohn's disease from ulcerative colitis, particularly when only the colon is affected. In 10-15% of patients originally diagnosed as having Crohn's disease, the diagnosis changes to ulcerative colitis during the first year.

Incidence/ Prevalence

Estimates of the incidence of Crohn's disease worldwide vary considerably. In Europe, incidence rates range from 0.7 (Croatia) to 9.8 (Scotland) new cases per 100,000 people per year, whereas in North America these range from 3.6 (California) to 15.6 (Manitoba, Canada). The incidence of Crohn's disease is increasing, with incidence rates in the UK, Italy, Iceland, Finland, and the USA having doubled between 1955 and 1995. Crohn's disease is most commonly diagnosed in late adolescence and early adulthood, but the mean age at diagnosis in North American studies ranges from 33.4 to 45 years. Crohn's disease appears to affect women more commonly than men. In a systematic review of North American cohort studies of Crohn's disease, the percentage of females affected by the disease varied from 48% to 66%, and was above 50% in nine out of 11 studies.

Aetiology/ Risk factors

The true aetiology of Crohn's disease remains unknown. Current aetiological theories suggest that the disease results from a genetic predisposition, regulatory defects in the gut mucosal immune system, and environmental triggers. Defects in the gut mucosal immune system are mainly related to disordered activity of T cells (a type of white blood cell). Environmental triggers that have been linked with Crohn's disease include smoking, diet (high sugar intake), and the balance of beneficial and harmful bacteria in the gut. Finally, debate has raged since Mycobacterium avium paratuberculosis was cultured from intestinal tissue of people with Crohn's disease, with little agreement on whether this bacterium is an infective cause of Crohn's disease.

Prognosis

Crohn's disease is a lifelong condition, with periods of active disease alternating with periods of remission. The disease causes significant disability, with only 75% of sufferers being fully capable of work in the year of diagnosis, and 15% of people unable to work after 5-10 years of disease. At least 50% of people with Crohn's disease require surgical treatment during the first 10 years of disease, and approximately 70-80% will require surgery during their lifetime. People with Crohn's disease are at higher risk than those without the disease of developing colorectal and small bowel cancer. Mortality: Mortality rates among people with Crohn's disease are slightly higher than in those without it. A systematic review of seven population-based cohort studies found that estimates of standardised mortality ratios were greater than 1 in six of the seven studies, with estimates ranging from 0.72 (95% CI 0.49 to 1.01) to 2.16 (95% CI 1.54 to 2.94). The review also found that mortality rates in Crohn's disease have not changed during the past 40 years.

Aims of intervention

To induce remission, prevent recurrence, allow return to normal activities, and improve quality of life, while minimising the adverse effects of treatment.

Outcomes

Benefits: Reduction in disease activity (as measured using the Crohn's Disease Activity Index, Disease Activity Score, and Harvey-Bradshaw Index), increase in crude remission rates, reduction in crude rates of clinical relapse, reduction in endoscopic recurrence rates (as measured using Rutgeerts' classification), reduction in radiological recurrence rates, reoperation rates, and improvement in quality of life (as measured by using the Inflammatory Bowel Disease Questionnaire). Harms: Corticosteroid-related adverse effects (e.g. moon face, buffalo hump, bruising, striae, central obesity, hirsutism, hypertension), other adverse effects (infection, drug hypersensitivity reactions, impaired renal function, drug-induced lupus syndrome, serum sickness, gastrointestinal bleeding, nausea, vomiting, heartburn, diarrhoea, leukopenia, headache, back pain, gingival hyperplasia, alopecia), duration of post-operative stay in hospital, death, and postoperative adverse effects (enterocutaneous fistula, gastrointestinal haemorrhage, wound infection, abdominal sepsis, bowel obstruction, anastomotic leak).

Methods

BMJ Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1986 to March 2007, Embase 1986 to March 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in the Review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 40 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We also searched for cohort studies on specific harms of interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required.

Glossary

Crohn's disease activity index (CDAI)
Validated composite score grading the severity of Crohn's disease based on the following clinical parameters measured over 7 days: number of soft or liquid stools, use of antidiarrhoeal medication (0 or 1), abdominal pain (0–3), general well being (0–4), number of extraintestinal manifestations, abdominal mass (0, 2, or 5), haematocrit (% decrease from expected), and body weight (% decrease from expected. The scores achieved for each parameter are multiplied by a predefined factor, and the products are added to give a final score. Scores range from 0 to approximately 600. A CDAI score below 150 is generally considered to mean quiescent disease, whereas a score above 450 generally signifies very severe disease.
Disease Activity Score
A non-validated composite score grading the severity of Crohn's disease based on the following paramenters: number of soft or liquid stools, use of antidiarrhoeal medication, abdominal pain, general well being, number of extraintestinal manifestations, abdominal mass, weight loss, fever, hypoalbumenaemia, anaemia, and increase in erythrocyte sedimentation rate. Scores range from 0 to 10. A CDAI score below 5 signifies quiescent disease, whereas a score of > 10 signifies severe disease.
Elemental diet
A liquid diet, made up of simple forms of protein, carbohydrates, and fats that can be absorbed without further digestion. They are given either as total nutritional support to induce remission, or to support an exclusion diet or to supplement a normal diet. They are taken diluted in water, either orally or via a nasogastric tube or a percutaneous enterostomy tube.
Fistula
An abnormal communication between two epithelial surfaces (for example, bowel lumen and skin).
Harvey-Bradshaw Index
A validated clinical index used for Crohn's disease. It includes general well being, abdominal pain, number of liquid stools, abdominal mass and complications, and ranges from 0 to 25, with remission defined as a score below 5.
Inflammatory Bowel Disease Questionnaire (IBDQ)
The IBDQ is a validated health related quality of life questionnaire. It contains 32 questions, which are divided into four health domains: bowel symptoms (10 questions), systemic symptoms (5 questions), emotional function (12 questions), and social function (5 questions).The total IBDQ score ranges from 32 to 224, with higher scores reflecting better well being.
Olsalazine
is broken down by the colonic flora into two molecules of mesalazine
Rutgeerts' classification
Score grading the severity of recurrence of Crohn's disease following surgical resection of the terminal ileum, which is based on the following endoscopic findings: number of isolated aphthous ulcers (< 5 = 1 and > 5 = 2), generalised inflammation (diffuse ileitis = 3), and mucosal irregularity with narrowing ( = 4) in the neo-terminal ileum. A score of 0 denotes no recurrence, and 4 denotes severe recurrence.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Alexander C von Roon, Department of Biosurgery and Surgical Technology, Imperial College, London, UK.

George E. Reese, Department of Biosurgery and Surgical Technology, Imperial College, London, UK.

Timothy R. Orchard, Imperial College, London, UK.

Paris P. Tekkis, Department of Surgical Oncology and Technology, Imperial College, London, UK.

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2007; 2007: 0416.
Published online 2007 November 7.

Corticosteroids (oral) to induce remission

Summary

One systematic review and two additional RCTs found that, compared with placebo, corticosteroids increased remission rates in active Crohn's disease, although remission rates for budesonide were slightly lower than for methylprednisolone and prednisolone. The optimal budesonide dose — and whether this should be given in a single or in two divided daily doses — remains unclear. One small RCT found similar remission rates between a 7-week and a 15-week tapering regimen of methylprednisolone. We found no evidence on the relative efficacy of methylprednisolone and prednisolone, or on different routes of administration. Two RCTs found that, compared with placebo, methylprednisolone and prednisolone increased adverse effects, including bleeding and infection. One systematic review found no significant difference in adverse effects between budesonide and placebo. The same review found that budesonide was associated with fewer adverse effects than methylprednisolone and prednisolone. One RCT found no significant difference in bone mineral density reduction between budesonide and prednisolone.

Benefits

Methylprednisolone or prednisolone versus placebo:

We found no systematic reviews, but found two RCTs. The first RCT found that, compared with placebo, oral prednisolone 0.25–0.75 mg/kg daily (tapered over 17 weeks) significantly increased the proportion of people achieving clinical remission (defined as Crohn's Disease Activity Index [CDAI] score less than 150) at 17 weeks (1 RCT, 162 people, CDAI at least 150; Kaplan–Meier life table analysis: 24/40 [60%] with prednisolone v 17/57 [30%] with placebo; P less than 0.0001). The second RCT found that, compared with placebo, oral methylprednisolone 48 mg daily (tapered over 6 weeks) significantly increased the proportion of people achieving clinical remission (defined as CDAI less than 150) at 18 weeks (1 RCT, 105 people aged at least 18 years, CDAI at least 150; AR 39/47 [83%] with methylprednisolone v 22/58 [38%] with placebo; P less than 0.05).

Different methylprednisolone regimens:

We found no systematic reviews but found one RCT. It found similar remission rates when methylprednisolone 40 mg daily for 3 weeks was tapered over 7 weeks compared with the same initial methylprednisolone dose tapered over 15 weeks. However, participant numbers were small (1 RCT, 54 people, CDAI 280–380; AR 22/27 [81%] after a 7-week course v 23/27 [85%] after a 15-week course; P value not reported).

Budesonide versus placebo:

We found one systematic review (search date 2005). It found that, compared with placebo, budesonide 3–9 mg daily significantly increased the proportion of people who achieved remission at 8 weeks (2 RCTs, 324 people aged at least 18 years, with ileocolonic Crohn's disease not extending beyond the hepatic flexure; AR 109/218 [50%] with budesonide v 26/106 [25%] with placebo; OR 2.85, 95% CI 1.67 to 4.87).

Different budesonide regimens versus each other:

We found one systematic review (search date 2002, 2 RCTs ) and two additional RCTs. The first RCT identified by the review included four arms: 15 mg, 9 mg and 3 mg budesonide, and placebo, all given in two daily divided doses for 8 weeks. It found that, compared with 3 mg budesonide and placebo, 9 mg and 15 mg budesonide significantly increased the proportion of people who achieved remission (see table 1 ). The second RCT identified by the review found no significant difference in the proportion of people who achieved remission at 8 weeks between budesonide 9 mg daily in a single dose, budesonide 9 mg daily in two divided doses, and prednisolone 40 mg daily (reducing to 5 mg/day after 9 weeks) (see table 1 ). (Also see budesonide versus methylprednisolone or prednisolone below). The first additional RCT found no significant difference in the proportion of people who achieved remission at 8 weeks between budesonide 9 mg daily in a single dose, budesonide 9 mg daily in two divided doses, and placebo (see table 1 ). The second additional RCT compared 6 mg, 9 mg, and 18 mg budesonide (each in three daily divided doses). It found that, compared with 6 mg budesonide, the 9 mg and 18 mg dosages increased the proportion of people in remission at 6 weeks, although this reached significance only in the 18 mg group (see table 1 ).

Table 1
Randomised controlled trials comparing different dosing regimens of oral budesonide for inducing remission in active Crohn's disease (see text).

Budesonide versus methylprednisolone or prednisolone:

We identified one systematic review (search date 2005). It found that significantly fewer people achieved remission at 8 weeks with several budesonide regimens (3, 9, or 15 mg/day) than with prednisolone (40 mg daily tapering to 5 mg daily or 1 mg/kg tapering to 0.25 mg/kg daily) or with methylprednisolone (48 mg daily tapering to 8 mg daily; 5 RCTs, 667 people, CDAI greater than 150; AR 189/363 [52%] with budesonide v 186/304 [61%] with methylprednisolone and prednisolone; OR 0.69, 95% CI 0.51 to 0.95). (See also different budesonide regimens versus each other, above.)

Harms

Methylprednisolone or prednisolone versus placebo:

We found two RCTs that gave information on adverse effects. The first RCT (119 people randomised to azathioprine, prednisolone, sulfasalazine, or placebo) found that prednisolone significantly increased petechial bleeding (6% v 0%; P less than 0.05), ecchymosis (17% v 3%; P less than 0.01), striae (6% v 0%; P less than 0.05), moon face (47% v 3%; P less than 0.01), acne (30% v 7%; P less than 0.01), hypertension (13% v 0%; P less than 0.01), and infection (27% v 10%; P less than 0.01) at 17 weeks compared with placebo. It also found that prednisolone significantly reduced nausea and vomiting (38% v 19%; P less than 0.05) and anorexia (25% v 8%; P less than 0.01) at 17 weeks compared with placebo. The second RCT (452 people randomized to methylprednisolone, methylprednisolone plus sulfasalazine, sulfasalazine, or placebo for 6 weeks) found that methylprednisolone significantly increased the proportion of people with moon face at 2 years (2.51 per 100 participant months with methylprednisolone v 0.49 per 100 participant months with placebo; P less than 0.05) compared with placebo.

Budesonide versus placebo or different budesonide regimens:

We found one systematic review (search date 2005). It found no significant difference in adverse effects at 8 weeks between budesonide 3 mg, 9 mg, and 15 mg daily, and placebo (2 RCTs, 324 people; AR 115/220 [52%] with budesonide v 43/107 [40%] with placebo; OR 0.98, 95% CI 0.58 to1.67).

Budesonide versus methylprednisolone or prednisolone:

We found one systematic review (search date 2005). It found that budesonide significantly reduced the proportion of people with adverse effects compared with methylprednisolone or prednisolone (5 RCTs, 667 people; AR 136/364 [37%] with budesonide v 179/306 [58%] with conventional corticosteroids; OR 0.39, 95% CI 0.28 to 0.54). Budesonide also significantly reduced the proportion of people whose plasma cortisol levels were below the normal range (379 people; AR 81/229 [35%] with budesonide v 108/170 [64%] with conventional corticosteroids; OR 0.28, 95% CI 0.18 to 0.53). There was no significant difference between groups in the number of people who withdrew from the studies because of adverse effects (5 RCTs, 667 people; AR 37/362 [10%] with budesonide v 26/307 [8%] with methylprednisolone or prednisolone; OR 1.00, 95% CI 0.57 to 1.75). We found one RCT that examined the effects on bone mineral density of budesonide 9 mg daily and prednisolone 40 mg daily. It found no significant difference in bone mineral density between budesonide and prednisolone, although people who received budesonide had smaller reductions in bone mineral density at 2 years (1 RCT, 98 corticosteroid-naïve people aged 20–70 years, CDAI greater than 150; bone mineral density change from baseline: –1.04% with budesonide v –3.84% with prednisolone; P = 0.084).

Comment

Clinical guide:

In mild to moderate ileocaecal Crohn's disease, budesonide's favourable adverse-effect profile makes it preferable to methylprednisolone or prednisolone. Both RCTs in the systematic review that compared the efficacy of budesonide versus placebo excluded people with disease extending beyond the hepatic flexure. Of the five RCTs that compared the efficacy of budesonide versus that of methylprednisolone or prednisolone, only two included people with disease extending beyond the hepatic flexure. The efficacy of budesonide for colonic Crohn's disease is, therefore, less well established. Consequently, when ileocaecal disease is severe, or where there is extensive small bowel or colonic disease, methylprednisolone or prednisolone are often used because of their superior efficacy compared with budesonide. Although one systematic review found no difference in adverse effects between budesonide and placebo in the short term, all corticosteroids have significant adverse effects with long-term or repeated use, and these must be weighed against the benefits of treatment while taking into account the recipient's wishes.

Substantive changes

Corticosteroids (oral) to induce remission Evidence reassessed; recategorised from Likely to be benefical to Beneficial.

2007; 2007: 0416.
Published online 2007 November 7.

Aminosalicylates to induce remission

Summary

Four RCTs found that, compared with placebo, mesalazine reduced Crohn's Disease Activity Index scores at doses greater than 3 g daily. Meta-analysis has shown the improvement in Crohn's Disease Activity Index to be only marginally better than with placebo. Lower mesalazine doses (1 g/day or 2 g/day) were not different from placebo in terms of efficacy. We found insufficient evidence to assess different mesalazine formulations for different disease locations. One RCT found sulfasalazine to be better than placebo. Four RCTs described adverse effects, including headache, nausea, and diarrhoea, in people taking mesalazine, which were not analysed for significance.

Benefits

Aminosalicylates versus placebo:

We found one systematic review (search date 1998) of three RCTs comparing mesalazine 4 g daily versus placebo. It found that 4 g mesalazine significantly reduced Crohn's Disease Activity Index (CDAI) compared with placebo at 3 months (3 RCTs, 625 people aged 16–82 years, CDAI 77–300; change in CDAI: –63 ± 6 with mesalazine v –45 ± 6 with placebo; P = 0.04). We identified two further systematic reviews (search dates 1999 and 2000), which did not include a meta-analysis for the clinical outcomes of interest. They identified three further RCTs. The first RCT found no significant difference in remission rates at 16 weeks between mesalazine 1.5 g daily and placebo (1 RCT, 67 people aged 14–79 years with mild to moderate disease; improvement [subjective clinical and endoscopic]: AR 12/30 [40%] with mesalazine v 11/37 [30%] with placebo; P greater than 0.2). The second RCT found no significant difference at 6 weeks in remission rates (defined as decrease in Harvey-Bradshaw Index of at least 2 points) between mesalazine 1.5 g daily and placebo (1 RCT, 40 people aged 18–74; AR 9/20 [45%] with mesalazine v 7/20 [35%] with placebo; P greater than 0.10). The third RCT found no significant difference in the proportion of people in remission between olsalazine 2 g daily (in 2 divided doses) and placebo (1 RCT, 91 people; remission: 8/46 [17%] with olsalazine v 22/45 [49%] with placebo; P less than 0.03). We found one additional RCT, which found that sulfasalazine (1 g/day per 15 kg body weight) significantly increased remission rates (defined as CDAI lss than 150) compared with placebo at 17 weeks after the start of treatment (1 RCT, 159 people randomised to placebo [mean age 33.7 years] or sulfasalazine [mean age 29.6 years], matched for disease severity, body weight, prior abdominal surgery, sex, and race; AR 20/77 [26%] with placebo v 28/74 [38%] with sulfasalazine; P = 0.0175).

Harms

Aminosalicylates versus placebo:

We found five RCTs reporting on adverse effects. One RCT found that more people taking mesalazine than placebo had adverse effects (AR 11/30 [37%] with mesalazine v 12/37 [32%] with placebo; significance not reported). Another RCT found that three people stopped taking mesalazine because of abdominal distension and pain (1/20 [5%]) or malaise (2/20 [10%]) with mesalazine, compared with one person withdrawing from the placebo group because of nausea (1/20 [5%]; significance not reported). One RCT found that mesalazine (1 g, 2 g, or 4 g) significantly increased the proportion of people with adverse effects compared with placebo (17/80 [21%] with 1 g mesalazine v 23/75 [31%] with 2 g mesalazine v 20/75 [27%] with 4 g mesalazine v 15/80 [19%] with placebo; significance not reported). A further RCT found no significant difference in adverse effects between sulfasalazine and placebo when used for induction of remission (reported as non-significant, P value not reported). The most commonly reported adverse effects were headache, nausea, and diarrhoea. Another RCT reported a significantly higher rate of withdrawals caused by adverse effects with olsalazine (diarrhea, vomiting, pain, and anorexia) compared with placebo (91 people; withdrawal: AR 15/46 [33%] with olsalazine v 3/45 [7%] with placebo; P value not reported).. The final RCT did not report on adverse effects with mesalazine or sulfasalazine.

Comment

Clinical guide:

Aminosalicylates may be used for induction of remission in ambulatory people with mild to moderate disease who can tolerate oral intake. However, evidence suggests that benefit over placebo is marginal, and previous response to aminosalicylates should be taken into account when deciding whether to prescribe these drugs. Treatment decisions are often based on the site of disease and whether it is active, but there are not enough participant numbers in the RCTs to confirm this approach.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Antibiotics to induce remission

Summary

One small RCT found that metronidazole in active Crohn's disease achieved the same remission rates as sulfasalazine. Common adverse effects included nausea, fatigue, and anorexia. We found no RCTs that met our inclusion criteria assessing ciprofloxacin. One small RCT found that combination therapy with ciprofloxacin and metronidazole achieved similar remission rates compared with methylprednisolone. A further RCT found no significant difference in remission rates between ciprofloxacin plus metronidazole and placebo when given as an adjunct to oral budesonide. Participant withdrawal rates owing to adverse effects were high in both trials, at 20% and 27% respectively. One RCT found no significant difference in remission rates between rifaximin and placebo. One small RCT found similar remission rates between antimycobacterial therapy with clofazimine and placebo when given in conjunction with oral prednisolone. Adverse reactions were skin pigmentation and rash.

Benefits

We found no systematic reviews on antibiotics to induce remission.

Metronidazole versus placebo:

We found one RCT, which was too small to meet our quality criteria (see Methods) and has been excluded.

Metronidazole versus sulfasalazine:

One RCT (78 people, Crohn's Disease Activity Index [CDAI] greater than 150) compared metronidazole versus sulfasalazine. After 4 months of treatment it found no significant difference in response rates between the two drugs (reduction in CDAI [mean ± standard error]: from 262 ± 13 to 113 ± 16 with metronidazole v from 257 ± 10 to 120 ± 16 with sulfasalazine; reported as not significant). Participants did not receive any other concomitant treatment.

Ciprofloxacin versus placebo or other treatments:

We found no RCTs comparing ciprofloxacin versus placebo or other treatments.

Rifaximin versus placebo:

We found one RCT (83 people with ileal or colonic disease, CDAI 200–400), which was a three-arm trial comparing rifaximin 800 mg twice daily versus rifaximin 800 mg once daily plus placebo versus placebo alone.It found no significant difference in remission rates (defined as CDAI less than 150) after 12 weeks of treatment between rifaximin and placebo (AR 14/27 [52%] with rifaximin 800 mg twice daily v 8/25 [32%] with rifaximin 800 mg once daily plus placebo v 9/27 [33%] with placebo, P value not reported; reported as not significant).

Combination therapy with metronidazole plus ciprofloxacin:

We found no systematic review but found two RCTs. The first RCT (41 people aged 18–75 years, CDAI greater than 200, and with ileal and/or colonic disease) compared antibiotics versus corticosteroids. It found no difference after 12 weeks in remission rates (defined as CDAI less than 150) between people receiving ciprofloxacin 500 mg twice daily plus metronidazole 250 mg four times daily and those receiving a tapering regimen of methylprednisolone 0.7–1 mg/kg (AR 10/22 [46%] with antibiotics v 12/19 [63%] with methylprednisolone; reported as non-significant, P value not reported). The second RCT (130 people aged at least 14 years, CDAI 200–400, ileal or colonic disease to mid-transverse colon) compared antibiotics (ciprofloxacin plus metronidazole, both 500 mg twice daily) versus placebo, both in addition to oral budesonide 9 mg once daily. It found no significant difference in remission rates (defined as CDAI less than 150) at 8 weeks between antibiotics and placebo (AR 21/64 [33%] with antibiotics v 25/66 [38%] with placebo; P = 0.55). A trend towards increased remission rates with antibiotics compared with placebo was noted in a subgroup of people with colonic disease, but this was not significant (33 people with ileocolonic disease; AR 9/17 [53%] with antibiotics v 4/16 [25%] with placebo; P = 0.10).

Antimycobacterial therapy:

We found no systematic review but found one RCT that assessed antimycobacterial therapy in combination with corticosteroids. It found no significant difference in remission rates between people treated with clofazimine 100 mg daily and placebo, both in combination with a reducing regimen of 45 mg prednisolone after 3 months (1 RCT, 49 people [aged 14–46 years], with ileal and colonic disease; Disease Activity Score reduction: from 10 ± 4.4 to 3.1 ± 3.4 with clofazimine v from 10 ± 4 to 3.6 ± 3.7 with placebo; reported as non-significant, P value not reported).

Harms

Metronidazole:

We found no systematic review but found one RCT reporting on harms. The RCT found that, after treatment with metronidazole 400 mg twice daily for 4 months, 40 participants experienced the following adverse effects: nausea (38%), fatigue (30%), anorexia (25%), itching (20%), rash (13%), paraesthesia (5%). The incidence of the same adverse effects was similar when people crossed over to sulfasalazine. No participants withdrew from the trial because of adverse effects.

Rifaximin:

The most common adverse events reported by the RCT (see comment below) included gastrointestinal disorders, infections and infestations, and skin and subcutaneous tissue disorders (number of people experiencing adverse events: 12/27 [44%] with rifaximin 800 mg twice daily v 10/25 [40%] with rifaximin 800 mg once daily plus placebo v 16/27 [50%] with placebo alone; gastrointestinal disorders: 5/27 [19%] with rifaximin 800 mg twice daily v 17/27 [63%] with rifaximin 800 mg once daily plus placebo v 16/27 [59%] with placebo alone; infections and infestations: 2/27 [7%] rifaximin 800 mg twice daily v 2/25 [8%] with rifaximin 800 mg once daily plus placebo v 6/27 [22%] with placebo alone; skin and subcutaneous tissue disorders: 4/27 [15%] rifaximin 800 mg twice daily v 1/25 [4%] with rifaximin 800 mg once daily plus placebo v 2/27 [7%] with placebo alone; P values and significance not reported). Five people withdrew because of adverse events (3/27 [11%] with rifaximin 800 mg twice daily v 0/25 [0%] with rifaximin 800 mg once daily plus placebo v 2/27 [7%] with placebo alone; P value and significance not reported).

Combination therapy with metronidazole plus ciprofloxacin:

We found no systematic reviews but found two RCTs reporting on harms. The first RCT reported the following adverse effects with ciprofloxacin plus metronidazole (both 500 mg/day) in 22 people after 8 weeks: nausea (32%), metallic taste (32%), and heartburn (23%). Six people (27%) withdrew from the trial because of adverse effects. By comparison, 79% of people in the corticosteroid group had adverse effects, and one person withdrew from the trial. The second RCT, which administered the same antibiotic combination to 66 people, plus budesonide 9 mg daily for 12 weeks, reported a significantly higher proportion of the following non-corticosteroid-related adverse effects in people in the antibiotic group compared with the placebo group: taste disturbance (27% v 0%), dizziness (21% v 6%), diarrhoea (20% v 6%), vaginitis (17% v 0%), and oral candidiasis (14% v 0%; P less than 0.05 in all cases). Thirteen people (20%) stopped antiobiotic treatment because of adverse effects compared with none in the placebo group (P less than 0.001).

Antimycobacterial therapy:

We found no systematic review but found one RCT reporting on harms. It reported that, of 25 people treated with clofazimine 100 mg plus prednisolone for 12 weeks, 12 (48%) developed skin pigmentation and three (12%) developed rash; in comparison, five people in the placebo group (21%) developed skin pigmentation and none developed rash (P value not reported).

Comment

Clinical guide:

At present there is little evidence of benefit from antibiotics (including antimycobacterial therapy), either as a substitute for or as an adjunct to corticosteroids or mesalazine, for inducing remission in ileal or colonic Crohn's disease. However, ciprofloxacin and metronidazole are indicated by general consensus in the treatment of septic complications of Crohn's disease, symptoms attributable to bacterial overgrowth, and perineal disease.

Rifaximin versus placebo:

Two people in the placebo group experienced adverse events (severe nausea and eye oedema), which the investigators ascribed to the study medication. The substance used as placebo was not described accurately, thus it is possible that genuine differences between the adverse-effect profiles of rifaximin and placebo were masked by the use of a non-inert substance as placebo.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Azathioprine or mercaptopurine to induce remission

Summary

One systematic review found that azathioprine and mercaptopurine increased remission rates compared with placebo and had greater corticosteroid-sparing effects. However, a minimum treatment period of 17 weeks was necessary for maximal benefit. Adverse effects are dose-related and may be severe.

Benefits

Azathioprine/mercaptopurine versus placebo:

We found one systematic review (search date 1997, 8 RCTs, 425 people, age range not given, with active disease [Crohn's Disease Activity Index greater than 150 or Harvey Bradshaw Index 7 or greater]). It found that, compared with placebo, azathioprine or mercaptopurine significantly increased remission rates (remission was defined as either Crohn's Disease Activity Index less than 150 or Harvey Bradshaw Index 3 or less; AR 113/209 [54%] with azathioprine or mercaptopurine v 72/216 [33%] with placebo; OR 2.36, 95% CI 1.57 to 3.53; P less than 0.001). The review found that azathioprine or mercaptopurine were more effective at inducing remission when the duration of treatment was 17 weeks or longer (treatment at least 17 weeks: OR 2.51, 95% CI 1.63 to 3.88; treatment less than 17 weeks: OR 1.56, 95% CI 0.52 to 4.69). Azathioprine and mercaptopurine had significantly greater corticosteroid-sparing effects than placebo (5 RCTs, 226 people; AR for reduction in corticosteroid consumption: 76/117 [65%] with azathioprine or mercaptopurine v 39/109 [36%] with placebo; OR 3.86, 95% CI 2.14 to 6.96).

Harms

Azathioprine or mercaptopurine versus placebo:

The systematic review reported adverse effects severe enough to cause withdrawal in more people with azathioprine or mercaptopurine than with placebo (AR 20/214 [9%] with azathioprine or mercaptopurine v 5/215 [2%] with placebo; OR 3.01, 95% CI 1.30 to 6.96). Common adverse effects included pancreatitis, leukopenia, nausea, allergy, and infection (numbers not reported). We found one additional study reporting adverse effects from azathioprine or mercaptopurine (1 cohort study, 50 people, aged 19–71 years). Adverse effects occurred in 15/50 (30%) people; three people required hospitalisation (pancreatitis, high fever, pneumonia), two people developed leukopenia that resolved on discontinuation of treatment, and four people had nausea. Most adverse effects occurred at doses of at least 100 mg/kg.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Methotrexate to induce remission

Summary

One RCT found that intramuscular methotrexate induced remission compared with placebo in chronic active Crohn's disease. Adverse effects were more frequent than with placebo.

Benefits

Methotrexate versus placebo:

We found one systematic review (search date 2004), which did not include a meta-analysis for the clinical outcomes of interest. It identified one RCT that met our inclusion criteria. The RCT found that, compared with placebo, intramuscular methotrexate 25 mg weekly achieved higher rates of remission at 16 weeks (1 RCT, 141 people, mean age 35 years, corticosteroid dependent [greater than 12.5 mg/day prednisolone]; AR 37/94 [39%] for methotrexate v 9/47 [19%] with placebo; P = 0.025, RR 1.95, 95% CI 1.09 to 3.48; NNT 5). Quality of life at 16 weeks was found to be greater (as measured using the Inflammatory Bowel Disease Questionnaire) in the methotrexate group compared with placebo (169 ± 4 for methotrexate v 151 ± 6 for placebo; P less than 0.002). Methotrexate was found to have a significant corticosteroid-sparing effect compared with placebo (numbers not reported; P = 0.003).

Harms

Methotrexate versus placebo:

The RCT found that more people withdrew from treatment because of adverse effects with methotrexate than with placebo (AR 16/94 [17%] with methotrexate v 1/47 [2%] with placebo; P = 0.012). Adverse effects with methotrexate resulting in withdrawal, were abnormal liver function tests (7/94 [7%]), nausea (6/94 [6%]), skin rash (1/94 [1%]), pneumonia (1/94 [1%]), and optic neuritis (1/94 [1%]).

Comment

Clinical guide:

Intramuscular methotrexate 25 mg weekly may be used for induction of remission in refractory Crohn's disease. Subcutaneous injection may be used as an alternative, with fewer injection site reactions and greater comfort. Caution must be exercised in people with known hepatic impairment. Regular liver-function testing and monitoring of haematological parameters is obligatory. Methotrexate is contraindicated in women who may become pregnant and in men who may father a child during and for 3 months after administration.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Infliximab to induce remission

Summary

One RCT found that a single dose of infliximab increased remission rates in moderate to severe Crohn's disease after 4 weeks compared with placebo. A dose of 5 mg/kg had similar effects to 10 mg/kg or 20 mg/kg. There was no significant difference in adverse effects between infliximab and placebo. Infliximab is indicated in the treatment of moderate or severe Crohn's disease that is refractory to treatment with corticosteroids and other immunomodulators because its long term safety remains unclear.

Benefits

Infliximab versus placebo:

We found two systematic reviews (search dates 2003 and 2001; neither performed a meta-analysis), which included one RCT that met our inclusion criteria. The RCT found that single dose infliximab significantly increased remission rates compared with placebo at 4 weeks, in people with moderate to severe Crohn's disease refractory to aminosalicylates, corticosteroids, and immunomodulators (1 RCT, 181 adults with Crohn's Disease Activity Index 220–400, matched for age, sex, disease duration, ileal and colonic disease distribution, and concomitant medical therapy; AR 27/83 [33%] with infliximab v 1/25 [4%] with placebo; RR 8.1, 95% CI 1.2 to 56.9; NNT 4, 95% CI 1.6 to 10.1). Participants received infliximab doses of 5 mg/kg (27 people), 10 mg/kg (28 people), or 20 mg/kg (28 people). No dose response was seen at 4 weeks, and the authors of the RCT concluded that 5 mg/kg was therefore the most appropriate dose.

Harms

Infliximab versus placebo:

The RCT found no significant difference in the incidence of adverse effects over a period of 12 weeks after placebo or a single infusion of infliximab (5 mg/kg, 10 mg/kg, or 20 mg/kg) for the induction of remission in Crohn's disease.For long-term adverse effects see harms of infliximab under question on medical interventions to maintain remission in adults with Crohn's disease.

Drug safety alert

FDA issues a drug safety alert on the risk of opportunistic fungal infections associated with TNF-alpha blockers (tumour necrosis factor alpha-blockers). Some of these invasive fungal infections could be fatal (4 September 2008). FDA issues drug safety alert on the increased risk of lymphoma and other malignancies in children and adolescents, and the risks of leukaemia and new onset psoriasis, associated with TNF blockers (04 August 2009).

The FDA has issued a drug safety alert on the risk of opportunistic fungal infections associated with TNF-alpha blockers (tumour necrosis factor alpha-blockers). Some of these invasive fungal infections could be fatal (http://www.fda.gov). A drug safety alert has been issued on the increased risk of lymphoma and other malignancies in children and adolescents, and the risks of leukaemia and new onset psoriasis, associated with TNF blockers (http://www.fda.gov).

Comment

Clinical guide:

Infliximab is indicated in the treatment of moderate or severe Crohn's disease that is refractory to treatment with corticosteroids and other immunomodulators. The drug's high cost means that the decision to prescribe infliximab may be influenced by national guidelines. Long-term studies have shown that the presence of sepsis is an absolute contraindication to infliximab therapy, because it may lead to overwhelming septicaemia. Infliximab also increases fourfold or fivefold the risk of contracting tuberculosis, and people should be appropriately screened. Infliximab should be used with caution in people with congestive heart failure, because it may exacerbate the condition. The long-term safety profile of the drug remains to be determined; it is unclear whether infliximab is associated with an increased risk of malignancy, and whether people should be monitored for this.

Substantive changes

Infliximab to induce remission Evidence reassessed; categorisation changed from Likely to be benefical to Beneficial.

2007; 2007: 0416.
Published online 2007 November 7.

Ciclosporin to induce remission

Summary

Four RCTs found no evidence that ciclosporin increased remission rates compared with placebo. Adverse effects were more common with ciclosporin.

Benefits

Ciclosporin versus placebo:

We found one systematic review (search date 2004, 4 RCTs).

The review found that ciclosporin (5 mg/kg daily) did not significantly increase rates of remission after 16 weeks compared with placebo (2 RCTs, 176 people aged 18 to 70 years, remission defined as CDAI greater than 150 or requiring continuous corticosteroid therapy: 25/85 [29%] with ciclosporin v 16/91 [18%] with placebo; OR 1.96, 95% CI: 0.97 to 3.93; P = 0.06).]

The third included RCT compared ciclosporin 5 mg/kg daily versus placebo in people taking prednisolone. It found no significant difference between groups in rates of clinical improvement (defined as freedom from symptoms or clinically significant improvement plus successful withdrawal or reduction below initial dose of prednisolone) after 12 weeks (1 RCT, 146 people: 26/72 [36%] with ciclosporin v 32/74 [43%] with placebo; OR 0.74, 95% CI 0.38 to 1.44; P = 0.4).

The fourth included RCT compared ciclosporin (5−7.5 mg/kg daily) versus placebo. Although it found that a significantly higher proportion of people had clinical improvement after 12 weeks, assessed using a non-validated modified clinical grading scale (71 people: 22/37 [60%] with ciclosporin v 11/34 [32%] with placebo; OR 3.07, 95% CI 1.16 to 8.11; P less than 0.02), it found no significant difference in median CDAI values between groups after 12 weeks (71 people, median CDAI value: 227 with ciclosporine v 245 with placebo; weighted mean difference –18.0, 95% CI: –82.3 to +46.3).

Harms

Ciclosporin versus placebo:

The systematic review reported that a higher proportion of people had adverse effects severe enough to cause withdrawal with ciclosporin compared with placebo (124/198 [63%] with ciclosporin v 16/201 [8%] with placebo; OR 16.63, 95% CI 10.65 to 25.95, P less than 0.00001)Adverse effects included paraesthesia, hypertrichosis, dyspepsia, hypertension, rash, vertigo, diarrhoea, headaches, mouth ulcers, ocular photosensitivity, nausea, vomiting, epigastric pain, tremor, back pain, weight increase, gingival hyperplasia, impaired renal function (3 with ciclosporin v 0 with placebo) and increases in serum creatinine level (numbers not given).

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Omega 3 oil

Summary

One RCT found that treatment with enteric-coated fish oil capsules reduced relapse rates and increased the proportion of people with Crohn's disease in remission after 1 year compared with placebo. Another RCT found no evidence that non-enteric-coated fish oil capsules were effective compared with placebo. Adverse effects were diarrhoea with enteric-coated capsules, and belching or heartburn with non-enteric-coated capsules.

Benefits

Fish oil versus placebo:

We found one systematic review (search date 2001), which included two RCTs examining the effect of fish oil on maintenance of remission. The first RCT found that, in people with Crohn's disease in remission, treatment with three enteric-coated capsules of fish oil three times daily resulted in significantly higher remission rates at 1 year compared with placebo (1 RCT, 78 people aged 18–75 years, with Crohn's Disease Activity Index less than 150 for 3 months, and with ileal and colonic disease, not on medical maintenance therapy; AR 23/39 [59%] with fish oil v 10/39 [26%] with placebo; P = 0.003; OR for relapse with placebo v fish oil 4.2, 95% CI 1.6 to 10.7). The second RCT found that a similar proportion of people with quiescent Crohn's disease remained in remission after 1 year of treatment with two capsules of fish oil (not enteric coated) three times a day or placebo (1 RCT, 135 people aged 17–65 years, with Crohn's Disease Activity Index less than 150 for 3 months, and with ileal and colonic disease, not on medical maintenance therapy; remission: AR 30% with fish oil v 30% with placebo; P value not reported). Notably, both groups received a 2-month course of low-dose methylprednisolone at the start of the trial.

Harms

Fish oil versus placebo:

The first RCT reported diarrhoea and subsequent withdrawal from the trial (4/39 [10%] with fish oil v 1/39 [3%] with placebo; significance not reported), but no other adverse effects. The second RCT, which used non-enteric-coated capsules, reported belching with fishy odour or heartburn (14%), acne (3%), diarrhoea (1%), and feeling of over-indulgence (1%; significance not reported).

Comment

Currently there is insufficient evidence to recommend the routine use of fish oil for maintenance therapy in Crohn's disease. Further evidence will be provided by two currently running phase III trials utilising an enteric-coated formulation, which are expected to report shortly.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Enteral nutrition

Summary

One RCT found that people in remission who were treated with half-elemental diet had lower relapse rates than those on a free diet, with no adverse effects occurring in either group.

Benefits

Half elemental diet versus unrestricted diet:

We found one RCT, comparing "half-elemental diet" (where half the person’s daily calorie intake was given by elemental diet [900−1200 kcal a day; 240−320 g as powder, 900−1200 mL as solution in water, through self-inserted tube or by oral intake] and half by an unrestricted diet) versus an unrestricted diet. It found that the half-elemental diet reduced rates of relapse (defined as CDAI greaater than 200 or need for medical therapy to induce remission) compared with an unrestricted diet at 2 years (51 people with ileal and colonic disease and CDAI less than 150; relapse rates at 2 years: 9/26 [35%] with half-elemental diet v 16/25 [64%] with unrestricted diet; hazard ratio: 0.40, 95% CI: 0.16 to 0.98).

Harms

The RCT reported that no adverse effects occurred in either group.

Comment

Enteral nutrition has an established role in the treatment of children with Crohn's disease, and evidence suggests that it may also be beneficial in maintaining remission in adults. Although elemental diet has been shown to be less effective than corticosteroids for inducing remission in adults with Crohn's disease, it is used in some centres because of its favourable adverse-effects profile when compared with corticosteroids.

Substantive changes

Enteral nutrition One RCT added,which found lower rates of relapse with enteral diet compared with placebo; categorisation changed from Unknown effectiveness to Likely to be beneficial.

2007; 2007: 0416.
Published online 2007 November 7.

Probiotics

Summary

One RCT found no significant difference in rates of recurrence between Lactobacillus johnsonii compared with placebo after 6 months in people in remission from Crohn's disease. No adverse effects were reported with L johnsonii: administration. We found no systematic review or RCTs comparing other probiotics versus placebo to maintain remission in Crohn's disease.

Benefits

LA1 versus placebo:

We found one systematic review (search date 2005) which identified no RCTs that met our inclusion criteria, and one subsequent RCT. The subsequent RCT found no significant difference 6 months after curative surgical bowel resection in endoscopic recurrence rates (defined as Rutgeerts' classification score greater than 1) between people treated with L johnsonii LA1 (2 × 109 lyophilised bacteria) twice daily compared with placebo (1 RCT, 98 people aged 27–42 years, with small bowel, ileocaecal and colonic disease; recurrence: AR 21/43 [49%] with L johnsonii v 30/47 [64%] with placebo; OR 1.85, 95% CI 0.80 to 4.30; P = 0.15).

Other probiotics:

We found no systematic review or RCTs comparing other probiotics versus placebo in Crohn's disease.

Harms

LA1 versus placebo:

The subsequent RCT found no adverse effects that were considered by the investigators to be linked to the administration of L johnsonii.

Comment

Clinical guide:

Based on current evidence, treatment with probiotics cannot be recommended for maintenance of remission in Crohn's disease. It should be noted that a number of trials too small to meet our inclusion criteria have shown beneficial effects of probiotic strains other than Lactobacillus johnsonii LA1, and that negative results for one strain can not be extrapolated to another.

Substantive changes

Probiotics One systematic review added;categorisation unchanged (Unknown effectiveness).

2007; 2007: 0416.
Published online 2007 November 7.

Smoking cessation

Summary

Nine cohort studies provided good evidence that people with Crohn's disease who smoke experience more episodes of clinical relapse and surgery rates compared with non-smokers. One intervention study found strong evidence that people with Crohn's disease who stop smoking experience fewer relapses and require less immunosuppressive therapy than those who continue to smoke.

Benefits

We found two systematic reviews (search dates 1999 and 2004; neither contained a meta-analysis) that largely included the same studies. Between them the two reviews reported on 10 cohort studies matching our inclusion criteria, nine of which compared clinical relapse or reoperation rates in people with Crohn's disease in remission in relation to smoking status. All but one study found that non-smokers had 16–33% fewer episodes of clinical relapse and 7–34% fewer reoperations compared with non-smokers (table 2 ). Ex-smokers were universally found to have lower rates of clinical relapse and reoperation than smokers, but tended to have higher relapse and reoperation rates than non-smokers (table 2 ). One cohort study found that people who stopped smoking for more than 1 year had significantly fewer flare-ups and required significantly less immunosuppressive therapy than those who continued smoking, and had the same risk of flare-ups as non-smokers after 4 years of observation (1 cohort study, 177 people matched for age, sex, disease location and activity, concurrent medical therapy, and previous smoking habit; Kaplan–Meier life table analysis: P less than 0.001).

Table 2
Cohort studies comparing the relationship of disease recurrence and smoking in people with Crohn's disease in remission (see text).

Harms

None of the studies reported harms associated with smoking cessation.

Comment

Clinical guide:

There is good evidence that smoking cessation in people with Crohn's disease reduces the frequency of clinical relapse and the need for immunosuppressive medication as well as surgery. All people with Crohn's disease who smoke should be urged to give up smoking, and should be offered support through evidence-based, structured smoking cessation programmes.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Strictureplasty

Summary

One systematic review found that Finney strictureplasty may be superior to the Heineke–Mikulicz procedure in inducing remission and reducing reoperation rate in Crohn's disease. However, the review was of low quality and it is therefore difficult to draw reliable conclusions.

Benefits

Finney versus Heineke-Mikulicz procedure:

We found one low-quality systematic review (search date 1999, 15 non-randomised retrospective studies, 506 people [aged 24–43 years] undergoing 1825 strictureplasties).It found that, at 30 months, Finney strictureplasty significantly reduced recurrence (0% recurrence with Finney v 32% with Heineke–Mikulicz; P = 0.008, absolute numbers not reported) and reoperation rates (0% reoperations with Finney v 23% with Heineke–Mikulicz; P = 0.005, absolute numbers not reported) compared with Heineke–Mikulicz. No data on sample size for the outcome of interest were given.

Harms

The review reported postoperative complications in 66/506 (13%) people.Adverse effects were enterocutaneous fistula (23%), gastrointestinal haemorrhage (11%), wound infection (8%), abdominal sepsis (5%), bowel obstruction (4%), and anastomotic leak (3%). Overall recurrence was 26%. The review did not compare Finney versus Heineke–Mikulicz strictureplasty when assessing complications.

Comment

Clinical guide:

Strictureplasty is generally considered a safe and effective procedure for small bowel stenosis in Crohn's disease.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Limited versus extended resection

Summary

One RCT found similar incidence of Crohn's disease recurrence with limited resection margins compared with extended resection margins.

Benefits

Limited versus extended resection:

We identified one RCT (131 people, median age 33.2 years, median follow up 55.7 months, indications for surgery: bowel obstruction 42/131 [32%], perforating disease 29/131 [22%], non-perforating and perforating disease 34/131 [26%], other disease 26/131 [20%]).It found no evidence that extended resection margins reduced surgical recurrence rates (AR 10/56 [18%] for extended resection v 19/75 [25%] for limited resection; P = 0.38).

Harms

Limited versus extended resection:

The RCT did not compare limited versus extended resection when assessing harms.A total of 20/131 (15%) people experienced an adverse event, of whom 9/131 (7%) experienced post operative ileus, 6/131 (5%) developed a wound infection, 2/131 (2%) required blood transfusion, intra-abdominal sepsis occurred in 1/131 (1%), 1/131 (1%) developed pneumonia, and 1/131 (1%) developed pyrexia with no focal sepsis.

Comment

Clinical guide:

Bowel-sparing surgery with mini-resections is preferable to extensive resection in Crohn's disease in an attempt to avoid the short bowel syndrome.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Laparoscopic versus open ileocaecal resection

Summary

We found no systematic reviews comparing the effects of of laparoscopic versus open ileocaecal resection on inducing remission. One systematic review of two RCTs and 14 non-randomised studies found that people who had laparoscopic ileocaecal resection had a reduced post-operative stay compared with those who had open resection, with no significant difference in adverse effects.

Benefits

Laparoscopic versus open ileocaecal resection:

We found two systematic reviews (search dates 2004 and 2005 ) and one additional RCT, which did not report on the effects of surgery on remission rates in Crohn's disease.

Harms

We found two systematic reviews (search dates 2004 and 2005 ) and one additional RCT. We have reported results from the second, most recent review. The review found that laparoscopic surgery significantly reduced length of post-operative hospital stay compared with open ileocaecal resection (1 RCT, 6 prospective non-randomised, and 8 retrospective studies; 783 people, follow-up 1−63 years: WMD –2.97 days, 95% CI –3.89 to –2.04 days, P less than 0.001). It also found that time to recovery of enteric function was significantly shorter after laparoscopic surgery compared with open surgery (time to first flatus, 4 studies, 191 people: WMD –0.68 days, 95% CI –1.2 to –0.17, P = 0.009; time to first bowel movement, 5 studies, 253 people: WMD –0.58 days, 95% CI –1.12 to –0.03; P = 0.04).The review found no significant difference between groups in postoperative adverse effects (anastomotic leak, 7 studies, 406 people: OR 1.33, 95% CI 0.4 to 4.43; P = 0.64; wound infection, 10 studies, 525 people: OR 1.25, 95% CI 0.57 to 2.77; P = 0.57; chest infection, 5 studies, 329 people, OR 0.60, 95% CI 0.15 to 2.43; P = 0.48; intra-abdominal abscess, 6 studies, 254 people: OR 0.83, 95% CI 0.22 to 3.17; P = 0.79).The additional RCT (60 people aged 18–63 years, having elective ileocaecal resection for Crohn’s disease, excluding people with previous midline laparotomy or a fixed inflammatory mass) found that laparoscopic surgery significantly reduced the overall proportion of people with post-operative complications compared with open surgery at up to 30 days (total number of people with complications: 3/30 [10%] with laparoscopic v 10/30 [33%] with open; P = 0.028). Complications included wound infection (0/30 [0%] with laparoscopic v 6/30 [20%] with open; P value and significance not reported), urinary tract infection (2/30 [7%] with laparoscopic v 2/30 [7%] with open; P value and significance not reported), pneumonia (1/30 [3%] with laparoscopic v 0/30 [0%] with open; P value and significance not reported), ileus (1/30 [3%] with laparoscopic v 2/30 [7%] with open; P value and significance not reported), and intra-abdominal abscess (0/30 [0%] with laparoscopic v 2/30 [7%] with open; P value and significance not reported). It also found a significantly shorter length of hospital stay after laparoscopic surgery compared with open surgery (median stay: 5 days with laparoscopic surgery v 7 days with open surgery; P = 0.008). It found no significant difference in post-operative SF-36 quality-of-life scores between groups (data presented graphically; P value not reported; reported as not significant).

Comment

Clinical guide:

There is evidence to suggest that laparoscopic ileocaecal resection for Crohn’s disease is equivalent to open surgery in terms of clinical outcomes. The main benefit of laparoscopic surgery is an earlier post-operative recovery. The indications for laparoscopic versus open surgery remain undefined.

Substantive changes

Laparoscopic versus open ileocaecal resection New option with two systematic reviews ) and one additional RCT. Categorised as Likely to be beneficial.

2007; 2007: 0416.
Published online 2007 November 7.

Segmental versus subtotal colectomy

Summary

One systematic review found that segmental and subtotal colectomy had similar remission rates. There is some evidence that recurrence occurs earlier after segmental colectomy than after subtotal colectomy.

Benefits

Segmental versus subtotal colectomy:

We found one systematic review (search date 2005).It found no significant difference in recurrence rates between people who had a segmental colectomy and those who had a subtotal colectomy (5 non-randomised studies, 248 people, aged 11–78 years, mean follow up range 4.6–15.3 years; AR 55/111 [50%] for sub-total v 63/137 [46%] for segmental; OR 1.08, 95% CI 0.39 to 2.95; P = 0.88). The timing of recurrence was found to be earlier in the segmental colectomy group (WMD 4.43 years, 95% CI 3.08 to 5.78 years).

Harms

There was no evidence that overall adverse effects differed postoperatively between segmental colectomy and subtotal colectomy (OR 1.24, 95% CI 0.17 to 8.89; specific adverse effects not given).

Comment

There is some evidence to suggest quality of life is better after segmental than after subtotal colectomy. The difference is mainly accounted for by improved continence after segmental colectomy. Subtotal colectomy is normally performed for more diffuse disease.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Aminosalicylates to maintain remission

Summary

One systematic review found similar recurrence and remission rates between aminosalicylates and placebo for maintenance of remission in Crohn's disease.

Benefits

Aminosalicylates versus placebo:

We found one systematic review (search date 2003). The review found that, compared with placebo, there was no evidence that aminosalicylates reduced recurrence rates in medically-induced remission at 12 months (6 RCTs, 1339 people, with Crohn's Disease Activity Index less than 150; AR 362/663 [55%] with mesalazine v 370/676 [55%] with placebo; OR 1.0, 95% CI 0.80 to1.24). At 24 months there was no change in remission rates (1 RCT, 161 people, with Crohn's Disease Activity Index less than 150; AR 54/80 [67.5%] with mesalazine v 55/81 [68%] with placebo; OR 0.98, 95% CI 0.51 to 1.90).

Harms

Aminosalicylates versus placebo:

The systematic review reported on harms. There was no meta-analysis of adverse effects. Only one of the included studies found that people treated with mesalazine suffered significantly more adverse effects than with placebo. Adverse effects were predominantly diarrhoea and nausea (1 RCT, 327 people; AR for gastrointestinal adverse effects 54/167 [32%] with olsalazine v 27/160 [17%] with placebo; P = 0.001).

Comment

Clinical guide:

The available data do not support use of mesalazine to maintain medically-induced remission. However, the possibility of a minor beneficial effect in maintaining remission, combined with the relative safety of this drug and the suggestion that mesalazine may have a role in reducing cancer risk in inflammatory bowel disease, means that in practice many people remain on aminosalicylates in the long term.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Azathioprine to maintain remission

Summary

One systematic review and one RCT found that azathioprine was effective in maintaining remission in Crohn's disease. Adverse effects included pancreatitis, leukopenia and myelodysplastic syndrome, and benefits and risks must be discussed on an individual basis. A dose of 2.0–2.5 mg/kg daily is required to achieve adequate response. We found no evidence on mercaptopurine for maintaining remission in Crohn's disease.

Benefits

Azathioprine versus placebo:

We found one systematic review (search date 1998)and one additional RCT.The review found evidence that azathioprine increased the proportion of people in remission (remission not defined; 5 RCTs, 319 people, age range not reported; AR 91/136 [67%] with azathioprine v 96/183 [52%] with placebo; OR 2.16, 95% CI 1.35 to 3.47). A dose-related response was found from 1.0 to 2.5 mg/kg daily. The likelihood of maintaining remission increased with increasing daily dose of azathioprine (at 1.0 mg: OR for maintaining remission 1.20, 95% CI 0.60 to 2.41; at 2.0 mg: OR 3.17, 95% CI 1.33 to 7.59; at 2.5 mg: OR 4.13, 95% CI 1.59 to 10.71). The additional RCT (an equivalence study), which found that azathioprine therapy was not equivalent to placebo for maintaining remission at 18 months (remission defined as Crohn's Disease Activity Index 150 or greater; 1 RCT, 83 people, mean age 38 years; relapse: AR 3/40 [8%] for azathioprine v 9/43 [21%] for placebo; difference: 13% ± 8%; this was too great a difference to prove equivalence; P = 0.195).

Harms

The systematic review found that a greater proportion of people withdrew from the studies because of adverse effects with azathioprine than with placebo (AR 13/191 [7%] with azathioprine v 4/256 [2%] with placebo; OR 4.36, 95% CI 1.63 to 11.67; P = 0.003; NNH 19). Adverse effects were pancreatitis, leukopenia, nausea, allergy, and infection. The equivalence study reported one death due to myelodysplastic syndrome in the azathioprine group.

Comment

Azathioprine is beneficial in maintaining remission in Crohn's disease, and there is some evidence that azathioprine has a corticosteroid-sparing effect, although the sample size is very small. The drug should be used in people who are corticosteroid dependent or resistant, and regular monitoring for myelosuppression is obligatory.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Methotrexate to maintain remission

Summary

One RCT found evidence that intramuscular methotrexate 15 mg weekly was beneficial in maintaining remission in Crohn's disease compared with placebo. Adverse effects were frequent, but no severe adverse effects were reported.

Benefits

Methotrexate versus placebo:

We found one systematic review (search date 2001), that did not include a meta-analysis for the clinical outcomes of interest. It identified one RCT that met our inclusion criteria. The review found that intramuscular methotrexate 15 mg weekly significantly increased remission rates at 40 weeks compared with placebo (1 RCT, 76 people, 23/76 double blinded, 53/76 open label, mean age 33 years, 38/76 [50%] male, 35/76 [46%] smokers, Crohn's Disease Activity Index 94 ± 7 in methotrexate group and 84 ± 7 in placebo group; AR 26/40 [65%] with methotrexate v 14/36 [39%] for placebo; P = 0.04; absolute risk reduction for relapse: 26.1%, 95% CI 4.4% to 47.8%).

Harms

Methotrexate versus placebo:

The RCT reported no severe adverse effects (leukopenia, myelotoxicity, liver impairment, or serious infections) with methotrexate. Mild adverse effects were nausea and vomiting (16/40 [40%] with methotrexate v 9/36 [25%] with placebo), coryzal symptoms (10/40 [25%] v 10/36 [28%]), flu-like illness (2/40 [5%] v 2/36 [6%]), abdominal pain (7/40[18%] v 9/36 [25%]), headache (7/40[18%] v 6/36[17%]), arthralgia (5/40 [12%] v 10/36 [28%]), fatigue (5/40 [12%] v 5/36 [14%]), diarrhoea (1/40 [2%] v 7/36 [19%]), abdominal bloating or distention (1/40 [2%] v 1/36 [3%]), rash (2/40 [5%] v 4/36 [11%]), insomnia (1/40 [2%] v 0/36 [0%]; significance not reported). The systematic review found that adverse effects occurred in 46–49% of 264 people receiving methotrexate. Nausea and vomiting were reported in 12–40%, headache in 10–18%, liver abnormalities in 15–53%, pain in 13%, pneumonitis in 7%, and coryzal symptoms in 25%. No severe adverse effects (leukopenia, myelotoxicity, liver impairment, or serious infections) were reported with methotrexate.

Comment

In people unresponsive to azathioprine, methotrexate may be very effective. See also comment on methotrexate to induce remission in Crohn's disease.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Infliximab to maintain remission

Summary

Two RCTs found that, in people with refractory Crohn's disease who went into remission after an initial dose of infliximab, further doses of infliximab resulted in higher rates of maintained remission compared with placebo. One of the RCTs found that continued infliximab reduced the need for conventional corticosteroid treatment and improved quality of life compared with placebo. A dosage regimen of 5 mg/kg every 8 weeks was as effective at maintaining remission as 10 mg/kg. Scheduled treatment every 8 weeks as opposed to episodic (on-demand) treatment did not increase long-term remission rates. However, scheduled treatment improved rates of endoscopic mucosal healing, fewer hospitalisations, and fewer abdominal operations after 1 year than episodic therapy. The was no significant difference in adverse effects was reported between people receiving a single dose of infliximab followed by regular placebo over 1 year, compared with people who continued to receive infliximab every 8 weeks, regardless of the dose used. However, infliximab is associated with serious adverse effects, including infusion reactions, serum sickness, drug-induced lupus syndrome, fatal sepsis, and tuberculosis.

Benefits

Infliximab versus placebo:

We found one systematic review (search date 2001). It contained two RCTs that met our inclusion criteria. The first RCT found that, in people who had responded to an initial dose of 5 mg/kg, 10 mg/kg, or 20 mg/kg infliximab, further doses of 10 mg/kg infliximab every 8 weeks significantly increased remission rates (defined as Crohn's Disease Activity Index [CDAI] less than 150) at 44 weeks compared with placebo (73 people aged 18–65 years, CDAI 220–400, ileal and colonic disease refractory to corticosteroids, aminosalicylates, or other immunomodulators; AR 53% with infliximab v 20% with placebo; P = 0.013, absolute numbers not recorded). The second RCT found that, in people with Crohn's disease who had responded to an initial dose of 5 mg/kg, further doses of 5 mg/kg or 10 mg/kg infiximab every 8 weeks significantly increased remission rates (defined as CDAI less than 150) compared with placebo at 30 weeks (335 people, median age 35 years, CDAI 220–400, gastroduodenal, ileal, and colonic disease refractory to corticosteroids, aminosalicylates, or other immunomodulators; remission: AR 44/113 [39%] with 5 mg/kg infiximab, 50/112 [45%] with 10 mg/kg infliximab, and 23/110 [21%] with placebo; 5 mg/kg infiximab v placebo: P = 0.003; 10 mg/kg infliximab v placebo: P = 0.002; 5 mg/kg infliximab v 10 mg/kg infliximab: P = 0.386). At 54 weeks, three times as many people receiving infliximab had discontinued corticosteroids while in remission compared with placebo (AR 32/110 [29%] with infliximab v 5/56 [9%] with placebo; OR 4.2, 95% CI 1.5 to 11.5; P = 0.004). The same study cohort was assessed for quality of life in a separate study, which found that infliximab therapy achieved a greater improvement in quality-of-life scores, as assessed using the Inflammatory Bowel Disease Questionnaire and SF-36 instruments, at 54 weeks compared with placebo (change from baseline in Inflammatory Bowel Disease Questionnaire score: 22.1 with 5 mg/kg [P less than 0.05] v 30.2 with 10 mg/kg [P less than 0.001] v 8.9 with placebo; change from baseline in SF-36 score: 6.1 with 5 mg/kg [P less than 0.05] v 7.2 with 10 mg/kg [P less than 0.01] v 2.5 with placebo).

Different dosing regimens:

We found one RCT. It found no significant difference in remission rates (defined as CDAI less than 150) at weeks 30 or 54, between people treated with 5 mg/kg and 10 mg/kg infliximab, given every 8 weeks, (335 people, median age 35 years, CDAI 220–400, gastroduodenal, ileal and colonic disease refractory to corticosteroids, aminosalicylates, or other immunomodulators; week 30: OR 1.3, 95% CI 0.74 to 2.20; week 54: OR 1.58, 95% CI 0.90 to 2.80). The same cohort was analysed in a separate study, which found that, at 14 weeks, scheduled treatment with infliximab 5 mg/kg or 10 mg/kg every 8 weeks resulted in a higher proportion of people in remission than did episodic treatment when clinical need arose with infliximab 5, 10, or 15 mg/kg (573 people, CDAI 220–400, gastroduodenal, ileal, and colonic disease refractory to corticosteroids, aminosalicylates, or immunomodulators; remission; remission defined as an increase in CDAI of 70 points or 35% from baseline, or introduction of new treatment for Crohn's disease: P = 0.006, absolute numbers or percentages not stated).However, this benefit was not maintained at week 30 (155/385 [40%] with scheduled infliximab v 61/188 [32%] with episodic infliximab; P = 0.07) or at week 54 (158/385 [41%] with scheduled infliximab v 65/188 [35%] with episodic infliximab; P value not stated). People in the scheduled group had significantly higher rates of endoscopic mucosal healing than those in the episodic group (44% scheduled v 18% episodic; P = 0.041), fewer hospitalisations (24 per 100 people scheduled v 38 per 100 episodic; P = 0.014) and lower rates of Crohn's disease-related abdominal surgery (11/385 [3%] scheduled v 14/188 [7%] episodic; P = 0.01) after 54 weeks.

Harms

We found two systematic reviews and one large cohort study, published in two papers, that reported on harms.

Infliximab versus placebo:

The first systematic review (search date 2001) contained two RCTs that met our inclusion criteria. The first RCT found a similar overall incidence of adverse effects between placebo or infliximab 10 mg/kg every 8 weeks for 36 weeks, after an initial dose of 5, 10, or 20 mg/kg (73 people; 35/36 [97%] with placebo v 35/37 [95%] with infliximab). Common adverse effects were upper respiratory tract infection (24%), headache (16%), abdominal pain (14%), nausea (19%), fever (11%), bronchitis (16%), and pharyngitis (19%). Of 47 evaluable people, seven developed antibodies to infliximab. The second RCT compared doses of 5 and 10 mg/kg of infliximab, given every 8 weeks, with placebo, after an initial dose of infliximab 5 mg/kg in all three groups. Headache, abdominal pain, and upper respiratory tract infection were the most frequently occurring adverse effects (incidences not reported). After 54 weeks, the most common adverse effects leading to discontinuation of infliximab were infusion reactions (1%), allergic reaction (1%), arthralgia (1%), serum sickness (1%), and rash (1%). Infections requiring treatment occurred in 32% of people, and were considered serious in 4% of the study population; one person died from sepsis secondary to bowel obstruction. One person developed tuberculosis following infliximab treatment. Malignancy occurred in 1% of study participants. Two people developed a lupus-like syndrome, anti-double stranded DNA antibodies developed in 11–34% of people, and anti-nuclear antibodies developed in 35–56% of people. Because the study design allowed approximately half the people in the placebo group to cross over to episodic treatment with infliximab on clinical worsening, a direct comparison between adverse effects in the infliximab and placebo groups was not possible. However, the study did report that there was no significant difference in serious adverse effects between people receiving a single infusion of infliximab and those receiving multiple infusions (AR 22/88 [12%] with single infusion v 38/385 [10%] with multiple infusions; P = 0.561) up to week 14 of the study. The second systematic review (search date 2002) reported the following additional adverse effects, which were summarised from RCTs and post-marketing case reports of infliximab therapy for Crohn's disease and rheumatoid arthritis.Mild infusion reactions occurred in 22% of all those treated with infliximab and in 9% of those treated with placebo. Of approximately 170,000 people treated with infliximab worldwide, 84 developed tuberculosis, which was fatal in 14 cases. Histoplasmosis infection was reported in 9 out of 170,000 people and was fatal in one case. Exacerbation of demyelinating disease (e.g. multiple sclerosis) was reported in three cases.

Infliximab versus no treatment:

We found one large prospective cohort study (reported in two papers) comparing adverse effects in people receiving infliximab versus people not receiving infliximab. Although univariate analysis found that infliximab significantly increased rates of intestinal stenosis, stricture, or obstruction (SSO) at a median follow up of 1.8 years (5336 people: 1.95 events per 100 patient years with infliximab v 0.99 events per 100 patient years without infliximab, P less than 0.001), multivariate analysis found no significant difference in SSO rates between groups (SSO hazard ratio: 1.11, 95% CI 0.72 to 1.73; P = 0.63). It also found no significant difference in mortality between infliximab and no infliximab (6290 people, mortality: 0.53 per 100 patient years with infliximab v 0.43 per 100 patient years without infliximab; RR 1.24, 95% CI: 0.73 to 2.10). Univariate analysis found a significantly higher rate of serious infections with infliximab compared with no infliximab (6253 people, AR 1.37 per 100 patient years with infliximab v 0.65 per 100 patient years without infliximab, RR 2.15, 95% CI 1.44 to 3.21, P less than 0.001). However, multivariate analysis adjusted for previous corticosteroid use found that infliximab was not a significant independent predictor of serious infection (6253 people, OR 0.99, 95% CI: 0.64 to 1.54, P = 0.97).

Different dosing regimens:

We found one RCT, reported in three publications. The RCT compared groups of people receiving 5 mg/kg and 10 mg/kg infliximab every 8 weeks, and found no significant difference in serious adverse effects after 54 weeks (15/193 [8%] with 5 mg/kg v 11/192 [6%] with 10 mg/kg; P value not reported): serious infections (8/193 [4%] with 5 mg/kg v 6/192 [3%] with 10 mg/kg; P value not reported), infusion reactions (44/193 [23%] with 5 mg/kg v 36/192 [19%] with 10 mg/kg; P value not reported), and serum sickness-like reactions (5/193 [3%] with 5 mg/kg v 6/192 [3%] with 10 mg/kg; P value not reported). The same cohort was analysed and compared episodic infliximab treatment (5, 10, or 15 mg/kg on-demand) versus regular infliximab treatment (5 or 10 mg/kg every 8 weeks).At 54 weeks, the investigators found similar rates between groups of serious infections (8/188 [4%] with episodic infliximab v 8/192 [4%] with regular 5 mg/kg v 6/193 [3%] with regular 10 mg/kg; P value not reported), malignancy (2/188 [1%] with episodic infliximab v 3/192 [2%] with regular 5 mg/kg v 1/193 [0.5%] with regular 10 mg/kg; P value not reported), serious infusion reactions (1/188 [0.5%] with episodic infliximab v 4/192 [2%] with regular 5 mg/kg v 1/193 [0.5%] with regular 10 mg/kg; P value not reported), and serum sickness-like reactions (3/188 [2%] with episodic infliximab v 5/192 [3%] with regular 5 mg/kg v 6/193 [3%] with regular 10 mg/kg; P value not reported). Compared with the episodic treatment group, a higher proportion of people in the regular treatment group developed anti-double-stranded DNA antibodies (34% with regular infliximab v 11% with episodic infliximab; P value not reported) and anti-nuclear antibodies (56% v 35%; P value not reported). However, only one person in the regular treatment group developed a clinical lupus-like syndrome. People who received episodic treatment with infliximab had significantly higher levels of antibodies to infliximab than those who received regular treatment (51/170 [30%] with episodic v 29/344 [8%] with regular treatment; OR 0.21; 95% CI 0.13 to 0.36; P less than 0.0001).People in all three treatment groups experienced similar rates of intestinal stenosis, stricture, or obstruction (573 people, AR 12/188 [6%] with episodic infliximab treatment v 10/192 [5%] with infliximab 5 mg/kg v 13/193 [7%] with infliximab 10 mg/kg; significance and P values not reported).

Drug safety alert

FDA issues a drug safety alert on the risk of opportunistic fungal infections associated with TNF-alpha blockers (tumour necrosis factor alpha-blockers). Some of these invasive fungal infections could be fatal (4 September 2008). FDA issues drug safety alert on the increased risk of lymphoma and other malignancies in children and adolescents, and the risks of leukaemia and new onset psoriasis, associated with TNF blockers (04 August 2009).

The FDA has issued a drug safety alert on the risk of opportunistic fungal infections associated with TNF-alpha blockers (tumour necrosis factor alpha-blockers). Some of these invasive fungal infections could be fatal (http://www.fda.gov). A drug safety alert has been issued on the increased risk of lymphoma and other malignancies in children and adolescents, and the risks of leukaemia and new onset psoriasis, associated with TNF blockers (http://www.fda.gov).

Comment

Clinical guide:

There is good evidence to support the use of infliximab to maintain remission in people with Crohn's disease that is refractory to corticosteroids or conventional immunosuppressants (azathioprine, mercaptopurine, and methotrexate), after successful three-dose induction therapy. Scheduled treatment with infliximab every 8 weeks appears superior to episodic treatment with respect to some but not all clinical end points. This superiority may be due to the lower incidence of antibody development to the drug in a scheduled regimen. Small trials have suggested that concomitant use of azathioprine during the first 6 months also decreases antibody levels. However, many centres still use an episodic policy, converting to scheduled treatment regimens in those who relapse quickly. For clinical guidance on infliximab, see comment on infliximab to induce remission in Crohn's disease.

Substantive changes

Infliximab to maintain remission One cohort study on harms added (reported in two papers); categorisation unchanged (Likely to be beneficial).

2007; 2007: 0416.
Published online 2007 November 7.

Ciclosporin to maintain remission

Summary

Two RCTs found no evidence that oral ciclosporin maintained remission in people with quiescent or mildly active Crohn's disease after 1 year compared with placebo. People treated with ciclosporin had more adverse effects compared with placebo, and both trials reported a higher withdrawal rate because of adverse effects with ciclosporin than with placebo.

Benefits

Ciclosporin versus placebo:

We found no systematic review but found two RCTs. The first RCT found that ciclosporin (5 mg/kg daily in two divided doses) worsened (defined as an increase in Crohn's Disease Activity Index [CDAI] of 100 points) quiescent Crohn's disease in more people compared with placebo, although this difference did not reach significance (305 people, age 18–65 years, CDAI less than 150, ileal and colonic disease, concomitant prednisolone or mesalazine therapy; AR 91/151 [60%] with ciclosporin v 80/154 [52%] with placebo; P = 0.11).People in the ciclosporin group also had significantly higher CDAI scores than those in the placebo group (repeated measures analysis, absolute difference not given; P = 0.02), and there was no significant difference in Inflammatory Bowel Disease Questionnaire scores between the groups (repeated measures analysis; P = 0.24) over the study period of 18 months. The second RCT found no difference after 12 months in remission rates (defined as CDAI less than 150) in people with quiescent or mildy active Crohn's disease treated with oral ciclosporin (5 mg/kg daily in two divided doses) and placebo (118 people, age 18–60 years, CDAI less than 200, ileal and colonic disease; AR 16/56 [29%] with ciclosporine v 16/62 [26%] with placebo; P value not given).

Different dosing regimens:

We found no systematic reviews or RCTs comparing different dosing regimens of oral ciclosporine for maintaining remission in Crohn's disease.

Harms

Ciclosporin versus placebo:

We found no systematic review but found two RCTs reporting on harms. The first RCT reported a significantly higher withdrawal rate because of adverse effects (increases in serum creatinine levels, hypertension, tingling, headaches, and hair overgrowth) with oral ciclosporin (5 mg/kg daily in two divided doses) for 18 months compared with placebo (305 people, age 18–65 years; AR 22/151 [15%] with ciclosporin v 5/154 [3%] with placebo; P = 0.003). The second RCT (182 people treated with oral ciclosporin 5 mg/kg daily in two divided doses or placebo) reported that the following adverse effects occurred notably (but not significantly) more often in the ciclosporin group: tingling (31%), increased hair growth (24%), back pain (11%), weight gain (8%), tremor (7%), gingival hyperplasia (7%), and impaired renal function (7%)..Seven people taking ciclosporin and four people taking placebo stopped treatment because of adverse effects. Ciclosporin was associated with a 10% increase in serum creatinine levels, and a blood pressure rise of 3–8 mm Hg.

Comment

Clinical guide:

Although there is debate about the effectiveness of short courses of oral or intravenous ciclosporin to induce remission in active Crohn's disease, current evidence does not support the use of oral ciclosporin for maintenance of remission.

Substantive changes

No new evidence

2007; 2007: 0416.
Published online 2007 November 7.

Corticosteroids (oral) to maintain remission

Summary

One systematic review found no significant difference in relapse rates over 24 months between prednisolone or methylprednisolone compared with placebo, although corticosteroids increased adverse effects. One systematic review and two RCTs found no significant difference in relapse rates or incidence of adverse effects between budesonide 3 mg or 6 mg compared with placebo at 12 months. Budesonide increased median time to relapse compared with placebo in two out of five RCTs, but was associated with suppression of adrenocortical function in three out of five RCTs.

Benefits

Methylprednisolone or prednisolone versus placebo

:

We found one systematic review (search date 2003, 3 RCTs)comparing maintenance therapy using conventional corticosteroids (prednisolone 0.25 mg/kg/day, prednisolone 7.5 mg/day, or 6-methylprednisolone 8 mg/day) versus placebo in people with quiescent Crohn’s disease (defined as CDAI less than 150 or absence of symptoms). Meta-analysis of the three RCTs found no significant difference in rates of relapse (defined as CDAI greater than 150 or recurrence of symptoms) at 6, 12 , or 24 months between treatment and placebo groups (relapse at 6 months; 303 people: 23/142 [16%] with corticosteroids v 33/161 [20%] with placebo; OR 0.71, 95% CI 0.38 to 1.31; P = 0.3; relapse at 12 months; 269 people: 37/131 [28%] with corticosteroids v 43/138 [31%] with placebo; OR 0.82, 95% CI 0.47 to 1.43; P = 0.5; relapse at 24 months; 182 people: 36/95 [38%] with corticosteroids v 39/87 [45%] with placebo, OR 0.72, 95% CI 0.38 to 1.35; P = 0.3).

Budesonide versus placebo:

We found one systematic review (see comment below), one additional RCT, and one subsequent RCT.The systematic review (search date 2000, 3 RCTs, 180 people with ileocaecal disease and CDAI less than 150, ) found no significant difference in rates of relapse between budesonide 3 mg or 6 mg daily at 12 months compared with placebo (relapse [defined as CDAI greater than 150]: 58/90 [64%] with budesonide 3 mg v 58/90 [64%] with placebo; RR 1.00, 95% CI 0.80 to 1.24; P = 1.0; 52/90 [58%] with budesonide 6 mg v 58/90 [64%] with placebo; RR 0.89, 95% CI 0.71 to 1.13; P = 0.3). The additional RCT, comparing budesonide pH modified 3 mg daily versus placebo, found no significant difference in relapse rates between groups at 12 months (179 people with ileal and colonic disease and CDAI less than 150, relapse defined as CDAI more than 150: 56/84 [67%] with budesonide 3 mg v 62/95 [65%] with placebo; P value not reported; reported as not significant).The subsequent RCT found no significant difference in remission rates after 12 months between budesonide 6 mg daily and placebo (110 people with ileocaecal disease and CDAI less than 150; remission defined as CDAI greater than 150: 16/55 [29%] with budesonide v 13/55 [24%] with placebo; P = 0.132). Two out of four RCTs found that budesonide 3 mg or 6 mg significantly increased median time to relapse compared with placebo (see table 3 for results ).

Table 3
Median time to relapse in RCTs comparing budesonide versus placebo

Different budesonide regimens versus each other:

We found two systematic reviews (search dates 2000 and 2002). The more recent reviewdid not perform a meta-analysis but included an additional RCT to those included in the earlier review.The first systematic review found no significant difference in relapse rates between budesonide 6 and 3 mg daily (3 RCTs, 180 people with ileocaecal disease and CDAI less than 150; relapse defined as CDAI greater than 150: 52/90 [58%] with budesonide 6 mg v 58/90 [64%] with budesonide 3 mg, RR 0.89, 95% CI 0.70 to 1.11; P = 0.3). The additional RCT (see comment below) identified by the second review compared the effects of a fixed regimen (budesonide 6 mg daily) versus a flexible regimen (3, 6, or 9 mg daily, adjusted for symptom severity) on treatment failure (defined as moderate or severe symptoms after treatment at dose level 3 [9 mg flexible or 6 mg fixed] over any 8-week period, or withdrawal from, or completion of the trial with CDAI greater than 200 plus moderate to severe symptoms). It found limited evidence of no significant difference at 12 months in rates of treatment failure between groups (143 people with ileocaecal disease and mild or no symptoms; treatment failure: 11/75 [15%] with fixed v 8/66 [12%] with flexible; P greater than 0.8; discontinuation because of uncontrolled Crohn's [CDAI greater than 200] : 25/75 [33%] with fixed regimen v 24/66 [36%] with flexible regimen, P greater than 0.7). The average daily budesonide dose was similar in both treatment groups (6 mg with fixed v 5.8 mg with flexible; P value and significance not reported).

Harms

Methylprednisolone or prednisolone versus placebo:

See harms of Corticosteroids to induce remission.

Budesonide versus placebo:

The systematic review did not meta-analyse results for corticosteroid-related adverse effects. The five RCTs comparing budesonide versus placebo found no significant difference between groups in the incidence of corticosteroid-related adverse effects. Two of the RCTs noted a trend toward an increased incidence of adrenocortical suppression (as measured by an abnormal synacthen test or low baseline cortisol) with increasing budesonide doses, and the difference between groups was significant in one RCT (see table 4 for all results) .

Table 4
Adverse effects in RCTs of budesonide to maintain remission

Different budesonide regimens versus each other:

The systematic review did not meta-analyse results for corticosteroid-related adverse effects. The additional RCT identified by the second review, comparing fixed versus flexible regimens of budesonide, reported that adverse effects associated with the flexible dose included emotional lability, hypertrichosis, menstrual disorder, cramps, oedema, headache, dizziness, abdominal pain, and acne, and in the fixed-dose group included nausea, raised alkaline phosphatase, hot flushes, headache, flushing, and palpitation. Serious adverse events possibly caused by treatment included tooth disorder (further details not reported) and intestinal perforation in the flexible-dose group. (See table 4 for results ).

Comment

Budesonide versus placebo:

We found four systematic reviews (search dates 1999, 2000, and 2002). The earlier two reviews included the same four RCTs. The most recent review did not perform a meta-analysis and included one RCT that used a different formulation of budesonide (pH modified) to the other RCTs, and which was excluded by the third review. We have reported the meta-analysis from the third review and have reported the RCT it excluded as an additional RCT.

Different budesonide regimens versus each other:

In the additional RCT identified by the second review, people were allocated to either the fixed or flexible regimen from a randomisation list provided to each centre, rather than a centralised list, resulting in an imbalance between groups (75 people in the fixed group v 68 people in the flexible group), and a higher mean CDAI at entry in the fixed group (103.4 with fixed v 89.3 with flexible; significance not assessed), which may have affected the results.

Clinical guide:

Conventional corticosteroids have no place in maintenance therapy for Crohn’s disease. Although budesonide may delay the time to relapse, it has not been shown to maintain remission over 12 months.

Substantive changes

Corticosteroids (oral) to maintain remission New option with three systematic reviews and two RCTs; categorised as Likely to be ineffective or harmful.

2007; 2007: 0416.
Published online 2007 November 7.

Aminosalicylates to maintain remission after surgery

Summary

One systematic review found that, compared with placebo, mesalazine was more effective in maintaining remission after surgery. Three further large RCTs found a trend to reduced remission with mesalazine, but found no significant benefit compared with placebo. We found no evidence that 4 g/day mesalazine differed from 2.4 g/day mesalazine in maintaining clinical remission after 12 months' treatment. We found no reports of severe adverse effects. One RCT found that sulfasalazine reduced remission compared with placebo at 1 and 2 years, but not at 3 years, whereas a second RCT found that sulfasalazine did not significantly reduce relapse rates compared with placebo at 18 months.

Benefits

Mesalazine versus placebo:

We found two systematic reviews and one subsequent RCT. The first review (search date 1997) found that, compared with placebo, mesalazine doses of 2.4–3 g/day significantly reduced recurrence (at 12–36 months; 4 RCTs, 411 people, curative resections within previous 6 months, mean age 29–39 years; AR 51/209 [24%] with mesalazine v 78/202 [39%] with placebo; risk difference –13.1%, 95% CI –21.8 to –4.5; P = 0.0028). The second review (search date 2000) did not include a meta-analysis for the clinical outcomes of interest.It identified two further RCTs. The first RCT found that, compared with placebo, mesalazine 3 g/day did not significantly reduce endoscopic recurrence rates at 3 months, as measured using the Rutgeerts' classification score (126 people, mean age 32 years in the placebo group and 35 years in the mesalazine group; AR 27/65 [42%] with mesalazine v 21/61 [34%] with placebo; P = 0.411).The second RCT found that mesalazine did not significantly reduce postoperative recurrence (defined as Crohn's disease activity index [CDAI] greater than 200 for 2 weeks or above 250 for any period) at 18 months (318 people, aged 18–70 years, CDAI less than 150; AR 36/152 [24%] with mesalazine v 50/166 [30%] with placebo; P = 0.10). The subsequent RCT reported no significant difference in clinical recurrence rates (defined by moderate or severe clinical symptoms) or endoscopic recurrence rates (defined as Rutgeerts' classification score 1 or above) or radiographic recurrence (defined as abnormal small bowel barium study) between mesalazine and placebo at 24 months following ileocaecal resection for Crohn's disease (84 people, mean age 34 ± 10.9 years, disease confined to ileoceacal region, no concomitant medical therapy; clinical recurrence: AR 58%, 95% CI 41% to 75% with mesalazine v 77%, 95% CI 61% to 91% with placebo; HR 0.62; P = 0.123; endoscopic recurrence: AR 63%, 95% CI 47% to 79% with mesalazine v 64%, 95% CI 46% to 81% with placebo; HR 0.80; P = 0.458; radiographic recurrence: AR 46%, 95% CI 29% to 66% with mesalazine v 49%, 95% CI 30% to 72% with placebo; HR 0.61; P = 0.19).

Mesalazine 2.4 g/day versus 4 g/day:

We found one RCT. It found no significant difference between mesalazine 4 g/day compared with 2.4 g/day in maintaining endoscopic or clinical remission at 12 months (165 people, age 18–65 years, terminal ileal disease, CDAI less than 150; mild endoscopic recurrence: AR 39/84 [46%] with 4 g/day v 50/81 [62%] with 2.4 g/day; risk difference –0.153, 95% CI –0.303 to –0.003; P = 0.04; severe endoscopic recurrence: AR 23/84 [27%] with 4 g/day v 30/81 [37%] with 2.4 g/day; risk difference –0.097, 95% CI –0.238 to +0.045; P = 0.18; clinical recurrence [CDAI greater than 150 or increase by 100 points]: AR 11/84 [12%] with 4 g/day v 13/81 [14%] with 2.4 g/day; risk difference –0.027, 95% CI –0.124 to +0.069; P = 0.58).

Sulfasalazine versus placebo:

We found no systematic review but found two RCTs. The first RCT found that, compared with placebo, sulfasalazine significantly reduced remission at 1 and 2 years, but not at 3 years (232 people, age 15–66 years, 113 males and 119 females, who had had resections considered curative at the time of surgery: at 1 year: AR 18/111 [16%] with sulfasalazine v 34/121 [28%] with placebo; P less than 0.01; at year 2: AR 9/111 [8%] with sulfasalazine v 12/121 [10%] with placebo; P less than 0.01; at year 3: AR 42/111 [38%] with sulphasalazine v 58/121 [48%] with placebo; P = 0.09). The second RCT found that, compared with placebo, 3 g/day sulfasalazine did not significantly reduce relapse rates at 18 months (66 people, age 15–59 years with normal erythrocyte sedimentation rate; AR 4/32 [13%] for sulfasalazine v 9/34 [26%] for placebo; 0.1 < P < 0.15[sic]).Relapse was defined clinically based on the presence or absence of fever, diarrhoea, rectal haemorrhage, abdominal pain, extra-intestinal manifestations, palpable abdominal masses, fistulae, abscesses, and possible loss of working days (see comment below).

Harms

Mesalazine versus placebo:

We found two systematic reviews. The first systematic review (search date 1999) did not comment on harms. The second systematic review (search date 1997) did not analyse harms. It reported that adverse effects requiring withdrawal from trials was not increased by therapy. The subsequent RCT reported similar adverse-effect rates with mesalazine and placebo (6/44 [14%] with mesalazine v 4/40 [10%] with placebo; P = 0.498). Adverse effects with mesalazine were diarrhoea (2/44 [4.5%]), allergic reaction, elevated liver function tests, and arthralgia (1/44 [2.3%]). People randomised to placebo experienced abdominal pain (2/40 [5.0%]), headache (1/40 [2.5%]), and diarrhoea (1/40 [2.5%]; significance not reported).

Mesalazine 2.4 g/day versus 4 g/day:

We found one RCT, which reported similar adverse effect rates with mesalazine 4 g/day and 2.4 g/day (2/101 [2%] with 4.0 g/day v 2/105 [2%] with 2.4 g/day; significance not reported). In the 4 g/day group both people experienced severe dyspepsia; in the 2.4 g/day group 1 person had lower-limb cramps and the other had elevated liver function tests).

Sulfasalazine versus placebo:

We found two RCTs. Neither study gave any information on adverse effects.

Comment

Sulfasalazine versus placebo:

The second RCT was planned in 1969 and did not base relapse rates on an index calculation such as CDAI.

Clinical guide:

Aminosalicylates may have a role in preventing postoperative recurrence in Crohn's disease. Although the RCT comparing mesalazine 4 g/day and 2.4 g/day found no significant difference in clinical recurrence at 12 months between doses, the improvements in endoscopic recurrence rates in the 4 g/day group suggest that a total daily mesalazine dose of 4 g may be more effective than a total daily dose of 2.4 g. However, for people at high risk of recurrence after surgery, such as those who have had a second operation, expert opinion would generally suggest commencing an immunomodulator such as azathioprine.

Substantive changes

Aminosalicylates to maintain remission after surgery Evidence reassessed; categorisation changed form Unlikely to be beneficial to Likely to be beneficial.

2007; 2007: 0416.
Published online 2007 November 7.

Azathioprine/mercaptopurine to maintain remission after surgery

Summary

One RCT found evidence that mercaptopurine reduced clinical and endoscopic recurrence rates in people with Crohn's disease of the ileocaecal segment 2 years after surgical resection, with a low incidence of adverse events. We found no RCTs assessing the relative efficacy of different dosing regimens or on azathioprine.

Benefits

Azathioprine versus placebo:

We found no systematic review or RCT comparing azathioprine versus placebo or other treatments in adults with Crohn's disease to maintain remission following surgery.

Mercaptopurine versus placebo:

We found no systematic review but found one RCT. It found that, compared with placebo, mercaptopurine (50 mg once daily) resulted in lower clinical recurrence rates (defined as moderate or severe clinical symptoms) and lower endoscopic recurrence rates (defined as Rutgeerts' classification score 1 or greater) at 24 months following ileocaecal resection for Crohn's disease (87 people, aged [mean ± standard deviation] 35 ± 11 years, ileocaecal disease only, no concomitant medical therapy; clinical recurrence: AR 50%, 95% CI 34% to 68% with mercaptopurine v 77%, 95% CI 61% to 91%; HR 0.52; P = 0.045; endoscopic recurrence: AR 43%, 95% CI 28% to 63% with mercaptopurine v 64%, 95% CI 46% to 81% with placebo; HR 0.48; P = 0.030). There was no significant difference in radiographic recurrence (defined as abnormal small bowel barium study) between mercaptopurine and placebo groups at 24 months (AR 33%, 95% CI 19% to 54% with mercaptopurine v 49%, 95% CI 30% to 72% with placebo; HR 0.57; P = 0.15).

Different regimens:

We found no systematic reviews or RCTs that compared different doses of azathioprine or mercaptopurine in the prevention of postoperative recurrence in Crohn's disease.

Harms

The RCT reported no significant difference in adverse events across the treatment groups (P = 0.498). Of 47 people in the mercaptopurine group, two developed leukopaenia, two alopecia, two diarrhoea, one flatulence, one gastrointestinal bleeding, and one developed phlebitis.

Comment

There is some evidence that mercaptopurine reduces clinical and endoscopic recurrences in ileocaecal Crohn's disease following surgical resection. It should be noted that the trial specifically excluded people with proximal ileal or colonic Crohn's disease; therefore, the results do not apply to these people. Furthermore, the long-term benefit of treatment beyond 2 years has not been established. This drug is probably the drug of choice for people at high risk of relapse, particularly after second episodes of surgery.

Substantive changes

No new evidence


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