Crohn's disease

Abstract

Introduction

Crohn's disease is a 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 to induce remission in adults with Crohn's disease? What are the effects of surgical interventions to induce and maintain remission in adults with small-bowel Crohn's disease? What are the effects of surgical interventions to induce remission in adults with colonic Crohn's disease? What are the effects of medical interventions to maintain remission in adults with Crohn's disease; and to maintain remission following surgery? What are the effects of lifestyle interventions to maintain remission in adults with Crohn's disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (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 93 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 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 at least 17 weeks of treatment are given. Monitoring for myelosuppression is obligatory.

• Aminosalicylates (mesalazine, sulfasalazine) may reduce disease activity, but we don't know which regimen is best 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.

• Infliximab (a cytokine inhibitor) is effective in inducing and maintaining remission in Crohn's disease, but the long-term adverse-effect profile is unclear; infliximab is 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 sub-total 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 it is associated with important adverse effects.

• Ciclosporin, or oral corticosteroids, alone are unlikely to be beneficial in maintaining remission after medical treatment.

• Methotrexate and infliximab may also maintain remission compared with placebo.

• Smoking cessation reduces the risk of relapse, and enteral nutrition may be effective.

• Fish oil and probiotics have not been shown to be effective.

Mesalazine seems effective in maintaining medically induced remission, but we don't know how effective other aminosalicylates are in maintaining remission.

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.[1] 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.[2] 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.[3] 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.[4] After exclusion of infection, ischaemia, irradiation, and malignancy as causes for intestinal inflammation, a combination of 3 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.[3] It may be difficult to distinguish Crohn's disease from ulcerative colitis, particularly when only the colon is affected. In 10% to 15% of patients originally diagnosed as having Crohn's disease, the diagnosis changes to ulcerative colitis during the first year.[3]

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.[5] 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.[6] 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 9 out of 11 studies.[6]

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.[7] 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.[5] 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.[8]

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 to 10 years of disease.[2] At least 50% of people with Crohn's disease require surgical treatment during the first 10 years of disease, and approximately 70% to 80% will require surgery during their lifetime.[9] People with Crohn's disease are at higher risk than those without the disease of developing colorectal and small bowel cancer.[10] Mortality: Mortality rates among people with Crohn's disease are slightly higher than in those without it. A systematic review of 7 population-based cohort studies found that estimates of standardised mortality ratios were >1 in 6 of the 7 studies, with estimates ranging from 0.72 (95% CI 0.49 to 1.01) to 2.16 (95% CI 1.54 to 2.94).[11] 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

Remission rate (includes reporting on results for inducing complete remission and also improvement in symptoms that are part of the same spectrum of improvement, as measured using the Crohn's Disease Activity Index, Disease Activity Score, and Harvey–Bradshaw Index, increase in crude remission rates) Relapse rate (includes crude rates of clinical relapse, reduction in endoscopic recurrence rates [as measured using Rutgeerts' classification], reduction in radiological recurrence rates) Re-operation rate, Quality of life (as measured by using the Inflammatory Bowel Disease Questionnaire), Adverse effects (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 postoperative stay in hospital, death, and postoperative adverse effects [enterocutaneous fistula, gastrointestinal haemorrhage, wound infection, abdominal sepsis, bowel obstruction, anastomotic leak]).

Methods

Clinical Evidence search and appraisal December 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2009, Embase 1980 to December 2009, and The Cochrane Database of Systematic Reviews 2009, Issue 4 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). 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 contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing more than 20 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 included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition, we did an observational harms search for specific harms as highlighted by the contributor, peer reviewer and editor. We searched for prospective and retrospective cohort studies on specific harms for azathioprine and infliximab. 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. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ). The categorisation of the quality of the evidence (into high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table 1.

GRADE evaluation of interventions for Crohn's disease

Important outcomes	Remission rate, Relapse rate, Re-operation rate, Quality of life, Adverse effects.
Number of studies (participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of medical treatments to induce remission in adults with Crohn's disease?
1 (267) [12]	Remission rate	Methylprednisolone or prednisolone v placebo	4	0	0	0	0	High
1 (54) [15]	Remission rate	Different regiments of methylprednisolone v each other	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
2 (327) [16]	Remission rate	Budesonide v placebo	4	0	0	0	0	High
4 (660 )[18] [20] [21] [17]	Remission rate	Different regimens of budesonide v each other	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting of data. Directness point for the inclusion of prednisolone
at least 8 (at least 750) [16]	Remission rate	Budesonide v methylprednisolone or prednisolone	4	0	0	0	0	High
5 (732) [27] [33] [34]	Remission rate	Mesalazine v placebo	4	0	–1	0	0	Moderate	Consistency point deducted for conflicting results
1 (91) [35]	Remission rate	Olsalazine v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (159) [13]	Remission rate	Sulfasalazine v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
6 (804) [37]	Remission rate	Antibiotics v placebo	4	0	–1	–2	0	Very low	Consistency point deducted for the use of different types of antibiotics. Directness points deducted for use of concomitant treatment and uncertainty of measure used to assess outcome
1 (78) [39]	Remission rate	Metronidazole v sulfasalazine	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (83) [40]	Remission rate	Rifaximin v placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (41)[41]	Remission rate	Ciprofloxacin plus metronidazole v methylprednisolone	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (130)[42]	Remission rate	Ciprofloxacin plus metronidazole plus budesonide v budesonide alone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (49)[43]	Remission rate	Clofazimine plus prednisolone v placebo plus prednisolone	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (213) [44]	Remission rate	Clarithromycin plus rifabutin plus clofazimine plus prednisolone v placebo plus prednisolone	4	0	0	0	0	High
8 (425) [46]	Remission rate	Azathioprine or mercaptopurine v placebo	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (141)[48]	Remission rate	Methotrexate v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (141)[48]	Quality of life	Methotrexate v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (181)[51] [50]	Remission rate	Infliximab v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
4 (176)[55]	Remission rate	Ciclosporin v placebo	4	–1	–1	0	0	Low	Quality point deducted for sparse data. Consistency point deducted for conflicting results
What are the effects of surgical interventions to induce and maintain remission in adults with small bowel Crohn's disease?
7 non-randomised trials (688)[60]	Relapse rate	Strictureplasty v resection	2	–1	0	0	0	Very low	Quality point deducted for incomplete reporting of results
15 non-randomised trials (506)[61]	Relapse rate	Finney v Heineke–Mikulicz procedure	2	–1	0	0	0	Very low	Quality point deducted for incomplete reporting of results
15 non-randomised trials (560) [61]	Reoperation rate	Finney v Heineke–Mikulicz procedure	2	–1	0	0	0	Very low	Quality point deducted for incomplete reporting of results
1 (131) [63]	Relapse rate	Limited v extended resection	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of surgical interventions to induce remission in adults with colonic Crohn's disease?
5 non-randomised trials (248) [69]	Relapse rate	Segmental colectomy v sub-total colectomy	2	–1	0	0	0	Very low	Quality point deducted for incomplete reporting of results
What are the effects of medical interventions to maintain remission in adults with Crohn's disease?
6 (1339) [70]	Relapse rate	Aminosalicylates (mesalazine or olsalazine) v placebo	4	0	0	–1	0	Moderate	Directness point deducted for including mesalazine and olsalazine
at least 9 (at least 1305) [71]	Relapse rate	Mesalazine v placebo	4	0	0	0	0	High
7 (463) [74]	Relapse rate	Azathioprine v placebo	4	0	0	0	0	High
1 (77) [75]	Relapse rate	Azathioprine v budesonide	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (98) [79]	Relapse rate	Methotrexate v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
3 (602)[82]	Relapse rate	Infliximab v placebo	4	0	0	0	0	High
1 (225)[84]	Relapse rate	Different doses of infliximab v each other	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (unclear) [82]	Quality of life	Infliximab v placebo	4	–2	0	0	0	Low	Quality points deducted for unclear population size and incomplete reporting of results
2 (423) [56] [57]	Relapse rate	Ciclosporin v placebo	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting or results. Consistency point deducted for conflicting results
3 (303) [95]	Relapse rate	Methylprednisolone or prednisolone v placebo	4	0	0	0	0	High
6 (maximum 540)[96]	Relapse rate	Budesonide v placebo	4	0	0	0	0	High
3 (180)[96]	Relapse rate	Different regimens of budesonide v each other	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of medical interventions to maintain remission after surgery in adults with Crohn's disease?
5 (maximum 788) [99] [71]	Relapse rate	Mesalazine v placebo	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (165) [100]	Relapse rate	Different regimens of mesalazine versus each other	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
2 (298) [101] [102]	Relapse rate	Sulfasalazine v placebo	4	0	–1	0	0	Moderate	Consistency point deducted for different results at different time frames
3 (349)[71]	Relapse rate	Mesalazine v azathioprine or 6-MP	4	0	0	0	0	High
2 (168) [99]	Relapse rate	Azathioprine/6-MP v placebo	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of lifestyle interventions to maintain remission in adults with Crohn's disease?
6 (1039) [105]	Relapse rate	Fish oil v placebo	4	0	–2	0	0	Low	Consistency points deducted for conflicting results, publication bias and heterogeneity among studies (clinical and statistical)
1 (51)[106]	Relapse rate	Half-elemental diet v unrestricted diet	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
1 (51) [108]	Quality of life	Half-elemental diet v unrestricted diet	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
6 (209) [112]	Relapse rate	Probiotics v placebo	4	0	–1	–1	0	Low	Consistency point deducted for conflicting results with different strains. Directness point deducted for inclusion a co intervention.
3 cohort studies (956)[113] [114]	Relapse rate	Smoking cessation v no smoking cessation	2	–1	0	0	0	Very low	Quality point deducted for incomplete results
7 cohort studies (1192) [113] [114]	Reoperation rate	Smoking cessation v no smoking cessation	2	–1	0	0	0	Very low	Quality point deducted for incomplete results

Type of evidence: 4 = RCT; 2 = Observational Consistency: similarity of results across studies; Directness: generalisability of population or outcomes; Effect size: based on relative risk or odds ratio; 6-MP, 6-mercaptopurine.

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 parameters: number of soft or liquid stools, use of antidiarrhoeal medication, abdominal pain, general well being, number of extra-intestinal manifestations, abdominal mass, weight loss, fever, hypoalbumenaemia, anaemia, and increase in erythrocyte sedimentation rate. Scores range from 0 to 10. A CDAI score <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 (e.g., 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.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

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.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

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.

Very low-quality evidence

Any estimate of effect is very uncertain.

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