Sarah Cripps explores the challenges and responsibilities for primary care in the treatment and care of children, young people, and adults with Crohn’s disease


NICE Accreditation Mark

NICE Clinical Guideline 152 on The management of Crohn’s disease in adults, children and young people has been awarded the NICE Accreditation Mark.

This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.

C rohn’s disease is a chronic, non-specific inflammatory condition of the gastrointestinal tract affecting at least 115,000 people in the UK.1,2 It can occur at any age but tends to peak between 20–40 years of age.3 It is characterised by unpredictable periods of acute exacerbations interspersed with periods of remission or less active disease. Crohn’s disease can affect the entire gastrointestinal tract, including the mouth and perianal region, although the terminal ileum and colon are the most commonly affected sites. Abdominal pain, diarrhoea, and unintended weight loss are classic symptoms of Crohn’s disease.1 Extraintestinal complications (more commonly seen in colonic disease and/or active disease) can occur in the joints, skin, bone, and liver.1-4 The cause of Crohn’s disease is widely debated, although smoking and genetic predisposition are important factors.1

The impact of a diagnosis of Crohn’s disease should not be underestimated. In general, most patients are diagnosed when they are relatively young, with one-third of patients diagnosed before the age of 21 years.1,2 Diagnosis at such a young age has a significant impact on the rest of the individual’s life. As well as the difficulty in managing symptoms, individuals can experience impaired education and employment prospects, and problems obtaining insurance. Crohn’s disease can cause psychological problems and growth failure, or retarded sexual development in young patients.1,2 Anxiety and loss of self-esteem are common. Psychological support in addition to pharmacological interventions, is therefore important. Medical treatment with corticosteroids and immunomodulators causes secondary health problems, such as infection, and surgery may result in complications such as short bowel syndrome.1-3 The care of patients with Crohn’s disease poses a challenge to the multidisciplinary team both clinically and economically.

Need for the guideline

In October 2012, NICE published Clinical Guideline 152 (CG152) on the management of Crohn’s disease. It is the first evidence-based clinical and cost-effective guideline on this disease in the UK, and covers adults, children, and young people collectively, in one document.1,2 Paediatric practice is often based on extrapolation from adult studies because of a lack of studies in this population. The guideline recommendations are relevant to both primary and secondary care.

The guideline is presented in a variety of formats and includes links to other relevant NICE guidance; it can be accessed via www.nice.org.uk/CG152

The NICE guideline aims to put new and established treatments in the context of the wider care pathway for Crohn’s disease.1 This is particularly useful as many new drugs have been licensed for this disease within the last decade. The recommendations will also help to improve the care offered to people with severe Crohn’s disease, and provide information about the clinical and cost effectiveness of potential care pathways. This article aims to raise awareness of the guideline and to highlight:

  • the main principles of care
  • key areas for implementation
  • key responsibilities for primary care.

Scope of the guideline

The NICE guideline does not cover every aspect of Crohn’s disease—diagnosis, treatment of intestinal manifestations, anaemia, surgical techniques, and vaccination recommendations for people on immunomodulators are not discussed. The extensive processes and methodology required to produce an up-to-date evidence-based guideline within the given timeframe, limited its scope to priority aspects; the recommendations cover:1,2

  • patient information and support
  • induction of remission
  • maintenance of remission
  • maintenance of remission after surgery
  • drug therapy (i.e. corticosteroids, azathioprine, mercaptopurine, methotrexate, aminosalicylates) and enteral nutrition
  • surgery (terminal ileum and strictures)
  • monitoring for osteopenia and assessment of fracture risk
  • conception and pregnancy.

For each of the priority aspects, recommendations were made following a systematic review of the evidence, including critical appraisal, meta-analysis and cost-effective modelling. Where evidence was lacking, the recommendations were based on a consensus experience of good practice within the Guideline Development Group (GDG).2

Patient information and support

Appropriate patient information and support were considered key priorities for implementation (i.e. as having the biggest impact on care and patient outcomes). The evidence on information and support is lacking for patients with Crohn’s disease and recommendations were based on the available data and the GDG consensus—one of the guideline research recommendations was to explore the information and support needs of people with Crohn’s disease.

The NICE guideline makes the following recommendations on patient information and support for people with Crohn’s disease:1,2

  • ensure that information and advice on Crohn’s disease is appropriate for the patient’s age, cognitive/literacy levels, and cultural/linguistic needs
  • discuss treatment options and monitoring with the patient, and/or their parent or carer as appropriate, and within the multidisciplinary team. The principles outlined in the NICE guideline on patient experience in adult NHS services (see www.nice.org.uk/guidance/CG138) should be applied
  • discuss the possible nature, frequency, and severity of side-effects of drug treatment with people, and/or their parents or carers if appropriate
  • give patients, and/or their parents or carers, additional information on the following topics when appropriate:
    • possible delay of growth and puberty in children
    • diet and nutrition
    • fertility and sexual relationships
    • prognosis
    • side-effects of treatment
    • cancer risk
    • surgery
    • care of young people in transition services
    • contact details for support groups
  • offer adults, children, and young people, and/or their parents or carers, age-appropriate multidisciplinary support addressing concerns about the disease and its treatment, such as body image, living with a chronic illness, attending school, and higher education.

Where appropriate, people with Crohn’s disease, and/or their parents or carers, should be given information, advice, and support in line with NICE guidance on smoking cessation, patient experience, medicines adherence, and fertility.1 A summary of the guideline, Information for the public, can be accessed via www.nice.org.uk/CG152. All NHS and voluntary sector organisations are encouraged to use this text in their own information about Crohn’s disease.

Certain patient groups (e.g. women or those newly diagnosed) may require specific tailored information and support about Crohn’s disease and its treatment. Leaflets on issues such as the disease itself, treatments, insurance, employment, and pregnancy have been prepared by the national group, Crohn’s and Colitis UK.4 General practitioners should be aware of contact details for their local inflammatory bowel disease (IBD) nurse specialist if available. As with any condition, patients should be warned about unreliable information sources.

Treatment of Crohn’s disease

The available treatments for Crohn’s disease are not curative, but largely aimed at:1,2,5-7

  • treating acute attacks promptly and effectively to induce remission
  • maintenance of remission
  • minimising toxicity related to drug treatment
  • selecting patients who will benefit from surgery and/or endoscopic treatment (50%–80% of patients with Crohn’s disease will eventually need surgery due to failure of medical therapy and/or strictures causing symptoms of obstruction, fistulae, or perforation)
  • optimising nutrition and/or growth
  • encouraging smoking cessation
  • minimising psychological concerns
  • managing disease complications
  • maintaining or improving quality of life.

Pharmacological treatment

The main drugs used for treatment of Crohn’s disease are glucocorticosteroids (prednisolone, hydrocortisone, methylprednisolone), immunomodulators (azathioprine, mercaptopurine, methotrexate), aminosalicylates, and antibiotics (see notes for prescribers, below).1,2 People are likely to receive several different treatments during the course of their illness owing to intolerance or lack of response. As medical treatment is often required for many years, patient preference, the acceptability of treatment and possible side-effects not only influence treatment choices, but also affect the degree to which the patient adheres to therapy. Therapeutic strategy and consistency is therefore needed in the management of patients with Crohn’s disease, and the NICE guideline is intended to help achieve this goal.1,2

Tumour necrosis factor alpha (TNF-?) inhibitors (infliximab and adalimumab) are increasingly used in more severe cases of Crohn’s disease to both induce and maintain remission. They should be prescribed and reviewed only by clinicians with experience of TNF-? inhibitors and of managing Crohn’s disease. Both agents are the subject of a separate NICE technology appraisal (TA187) published in 2010 (see www.nice.org.uk/TA187). 8 In practice, complex cases and patients prescribed biologics are generally managed by secondary care, whereas those in remission or off medication are managed in primary care. Referral to secondary care is required for patients who fail to respond to oral treatment for acute exacerbation, and in cases where there is toxicity to immunomodulators.3,6,9,10

Surgical treatment

The NICE guideline only covers surgical interventions where Crohn’s disease is limited to the distal ileum and strictures (balloon dilation), and not other surgical techniques.1,2

Induction of remission

The pathway for inducing remission in Crohn’s disease is shown in Figure 1.2 It covers the use of monotherapy, add-on treatment, and infliximab and adalimumab.2

Clinicians should assess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine. These drugs should not be offered if TPMT activity is deficient (very low or absent).1,2 Lower doses of azathioprine or mercaptopurine can be considered if TPMT activity is below normal but not deficient.1,2 The effects of azathioprine, mercaptopurine, and methotrexate should be monitored as advised in the current online version of the British National Formulary (BNF) or British National Formulary for Children (BNFC) (see bnf.org).

NICE CG152 recommends ensuring that documented local safety monitoring policies and procedures are in place (including audit) for all patients receiving treatment that requires monitoring.1,2 A member of staff should be nominated to act on abnormal results and communicate with GPs and people with Crohn’s disease and/or their parent or carer, as appropriate.

Figure 1: Inducing remission in Crohn’s disease2
Click here to download a PDF of Figure 1: Inducing remission in Crohn’s disease.
  • * Refer to Clinical Guideline 152 on when to consider surgery early in the course of the disease for people whose disease is limited to the distal ileum.
  • Although use is common in UK clinical practice, at the time of publication (October 2012) azathioprine, mercaptopurine, methotrexate, mesalazine, olsalazine, and balsalazide did not have UK marketing authorisation for inducing remission in Crohn’s disease and budesonide did not have a UK marketing authorisation specifically for children and young people. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
  • Follow BNF/BNFC cautions on prescribing methotrexate.
  • § Advice on monitoring of immunosuppressives can be found in the BNF/BNFC. The gastroenterology chapter and other relevant sections should be consulted.
  • 5-ASA=5-aminosalicylate; BNF=British National Formulary; BNFC=British National Formulary for Children; TPMT=thiopurine methyltransferase
  • Adapted from Crohn’s disease: management in adults, children and young people. Clinical Guideline 152. Published by the National Clinical Guidelines Centre at The Royal College of Physicians, 11 St Andrews Place, Regent’s Park, London, NW11 4LE. First published October 2012. Copyright © NCGC. Reproduced by permission. Available at: www.nice.org.uk/nicemedia/live/13936/61002/61002.pdf

Maintenance of remission

The pathway for maintaining remission in Crohn’s disease is shown in Figure 2.2 Healthcare professionals should discuss options for managing Crohn’s disease when in remission, including both treatment and no treatment, with patients (and/or their parent or carer, as appropriate). This should include discussion of the risk of inflammatory exacerbations (with and without drug treatment) and potential side-effects of treatment. The patient’s views should be recorded in their notes.1,2

Neither a conventional glucocorticosteroid nor budesonide should be offered to maintain remission.1,2

Figure 2: Maintaining remission in Crohn’s disease2
Maintaining remission in Crohn’s disease
  • * Although use is common in UK clinical practice, at the time of publication (October 2012), azathioprine, mercaptopurine and methotrexate did not have UK marketing authorisation for maintaining remission in Crohn’s disease. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council’s Good practice in prescribing medicines – guidance for doctors for further information.
  • Advice on monitoring of immunosuppressives can be found in the BNF/BNFC. The gastroenterology chapter and other relevant sections should be consulted.
  • Follow BNF/BNFC cautions on prescribing methotrexate.
  • TPMT=thiopurine methyltransferase; BNF=British National Formulary; British National Formulary for Children
  • Adapted from Crohn’s disease: management in adults, children and young people. Clinical Guideline 152. Published by the National Clinical Guidelines Centre at The Royal College of Physicians, 11 St Andrews Place, Regent’s Park, London, NW11 4LE. First published October 2012. Copyright © NCGC. Reproduced by permission. Available at: www.nice.org.uk/nicemedia/live/13936/61002/61002.pdf

Maintenance of remission post surgery

The following interventions may be considered to maintain remission after surgery:1,2

  • azathioprine or mercaptopurine in people with adverse prognostic factors (e.g. more than one resection, previously complicated or debilitating disease, such as abscess, fistulae, or penetrating disease)
  • 5-aminosalicylate (if azathioprine or mercaptopurine not tolerated or contraindicated).

Budesonide and enteral nutrition should not be offered to maintain remission following surgery.1,2

Notes for prescribers

Healthcare professionals should be aware that although commonly used in UK clinical practice, certain drugs did not have UK marketing authorisation (at the time of the guideline publication) for indications recommended by NICE CG152 on Crohn’s disease. For example, 5-aminosalicylate drugs (balsalazide, mesalazine, olsalazine, and sulfasalazine) and the immunomodulators (azathioprine, mercaptopurine, and methotrexate) are currently unlicensed for the induction of remission in Crohn’s disease; and budesonide did not have a UK marketing authorisation specifically for children and young people.1,2 Informed consent should be obtained and documented for these drugs and the prescriber must take full responsibility for their use.1,2

Drug dosages are not specified in the NICE guideline but the following is a guide to typical dose ranges:3

  • azathioprine 2.0–2.5 mg/kg daily
  • mercaptopurine 1.0–1.5 mg/kg daily
  • methotrexate 15–25 mg once weekly
  • budesonide 9 mg daily for 8 weeks (reducing dose for last 2–4 weeks of treatment)
  • prednisolone 40 mg each morning for 7 days; 30 mg each morning for 7 days; 20 mg each morning for 28 days; then reduce by 5 mg each week.10

Some brands of mesalazine are licensed for the maintenance of remission of Crohn’s ileo-colitis and are not interchangeable because of variations in delivery characteristics; prescribers should refer to the BNF and relevant summary of product characteristics for details.

Shared-care protocols

Patients and primary care doctors may require additional reassurance as several of the treatments used (i.e. immunomodulators such as azathioprine, mercaptopurine, and methotrexate) are routinely used in the management of Crohn’s disease, but are unlicensed for this indication in the UK. Immunomodulators should only be initiated by or on the advice of a specialist gastroenterologist.

It is essential that patients who are receiving aminosalicylates and immunosuppressants have regular blood monitoring to ensure they avoid toxicity associated with these drugs. All patients taking corticosteroids must be issued with a steroid card. Shared care policies between primary care doctors, gastroenterologists, and patients are a key recommendation of CG152.1,2 These should clearly highlight responsibilities, in particular the prescribing of medication, monitoring of blood results and action to be taken if these blood results are abnormal. An example of guidance for handling abnormal blood results in people taking immunomodulators is shown in Box 1.11

General practitioner responsibilities within a shared care guideline for immunomodulators could include:

  • prescribing an immunomodulator once the dose is stable
  • advising the hospital consultant of any clinical deterioration, and monitoring for adverse effects as appropriate
  • checking bloods weekly for the first month then every 2–3 months
  • providing vaccinations (seasonal influenza, pneumococcal polysaccharide vaccine, human papillomavirus according to national guidance, hepatitis B for selected patients); live vaccines should be avoided.

Box 1: Example of monitoring guidance for azathioprine prescribed in patients with Crohn’s disease11

  • Baseline U&Es, LFTs, FBC, and TPMT activity should be carried out prior to initiation of azathioprine therapy by a hospital gastroenterologist. These should be repeated weekly for the first 4 weeks then every 2–3 months. Monitoring for toxicity should be performed throughout treatment
  • Azathioprine should be stopped and the relevant hospital gastroenterologist contacted if any of the following occurs:
    • white blood cell <3.5 x 109/L
    • neutrophils <2 x 109/L
    • platelets <150 x 109/L
    • AST/ALT >2 x from upper limit of reference range
    • significant reduction in renal function
    • mouth or throat ulceration, rash, unexplained bleeding, fever, upper abdominal or back pain, alopecia, recurrent sore throat, infections, fever or chills, nausea, vomiting, diarrhoea
  • Nausea may be relieved by taking the dose with/after food or in divided doses
  • The effect and toxicity of azathioprine are increased with allopurinol—avoid concurrent prescription of these two agents.
  • U&E=urea and electrolytes; LFT=liver function test; FBC=full blood count; TPMT=thiopurine methyltransferase; AST=aspartate transaminase; ALT=alanine transaminase

Monitoring for osteopenia and assessment of fracture risk

Long-term steroid use and underlying Crohn’s disease both contribute to a higher risk of developing osteoporosis.1,2 The recommendations on monitoring of osteopenia and assessment of fracture risk are based on NICE Clinical Guideline 146, Osteoporosis: assessing the risk of fragility fracture (see www.nice.org.uk/cg146). 12 Guidance on the treatment of osteoporosis in inflammatory bowel disease has also been published by the British Society of Gastroenterology (see www.bsg.org.uk/pdf_word_docs/ost_coe_ibd.pdf) 13

Conception and pregnancy

Crohn’s disease affects young adults so it is important to note its influence on pregnancy. Poorly controlled disease can affect fertility and pregnancy. Good nutrition, stopping smoking, and adherence to medication are important to a safe pregnancy. Active disease is a risk factor for pre-term delivery and low birth weight.14 With the exception of methotrexate, which is contraindicated in pregnancy,15 most drugs for the treatment of Crohn’s disease can be used in pregnant women; the greatest risk to the mother and foetus during pregnancy is active disease. The potential risks and benefits of any drug treatment administered during pregnancy should be understood by clinicians and patients. Any woman who is considering pregnancy or is known to be pregnant should consult a specialist gastroenterologist as there are other issues that need to be considered, not just medication.

NICE CG152 recommends that information should be provided on the possible effects of Crohn’s disease on fertility and pregnancy, including the potential risks and benefits of medical treatment.1,2 In addition, in the care of pregnant women with Crohn’s disease there needs to be effective communication and sharing of information across specialities including primary care, obstetrics, and gastroenterology.1,2

Future research recommendations

Areas where evidence was lacking, and where continued uncertainty remains, were identified in the recommendations for further research. These topics cover: azathioprine, enteral nutrition, 5-ASA treatment, surgery versus medical treatment for the distal ileum, and patient information and support.

Audit

Audit support has been developed to support the implementation of the NICE guideline on Crohn’s disease, with the aim of helping NHS organisations with a baseline assessment and to assist with the audit process. These strategies should help to ensure that practice is in line with the NICE recommendations.1 The audit support is based on the clinical issues covered in the guideline and includes criteria and data collection tools. There is the potential for auditing primary and secondary care collaboration in terms of communication between these two settings, monitoring shared care, and the appropriate use of biologics.

Economic impact

There are unlikely to be any significant changes in medical or surgical treatment of Crohn’s disease in the immediate future. Additionally, the numbers of newly diagnosed patients per year is likely to remain small. Therefore implementing the guideline is unlikely to have a significant resource impact nationally, although there may be some local implications (e.g. TPMT monitoring, specialist nurse recruitment).

The main barriers to implementation of the NICE guideline are the financial implications (e.g. funding for specialist nurses and biologic drugs) and changes in certain hospital practices, which may be met with some resistance by clinicians.

Sources of guidance

An overview of the guideline recommendations on Crohn’s disease is available on NICE Pathways (pathways.nice.org.uk/pathways/crohns-disease). Other published guidance in this clinical area includes:

  • British Society of Gastroenterology (2011) guideline for the management of inflammatory bowel disease (IBD)6
  • European Crohn’s and Colitis Organisation guideline (2010)9
  • British Society of Paediatric Gastroenterology, Hepatology and Nutrition (2008) guidelines for the management of inflammatory bowel disease (IBD) in children in the UK16
  • Service standards for the healthcare of people who have inflammatory bowel disease (IBD).17

NICE is currently developing:

  • a quality standard on inflammatory bowel disease, which covers ulcerative colitis and Crohn’s disease, and is scheduled for publication on 30 September 2014
  • a clinical guideline on the management of ulcerative colitis, which is expected in June 2013.18

NICE implementation tools

NICE has developed the following tools to support implementation of Clinical Guideline 152 (CG152) on Crohn’s disease: management in adults, children and young people. The tools are now available to download from the NICE website: www.nice.org.uk/CG152

NICE support for commissioners

Costing statementCommissioning.eps

The costing statement estimates the financial impact to the NHS of implementing this clinical guideline. This statement focuses on the financial impact of the recommendations that require most change in resources to implement in England.

NICE support for service improvement systems and audit

Clinical audit toolAudit.eps

Audit tools aim to assist organisations with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. They consist of audit criteria and data collection tool(s) and can be edited or adapted for local use

Baseline assessment toolCommissioning.eps

The baseline assessment tool is an Excel spreadsheet that can be used by organisations to identify if they are in line with practice recommended in NICE guidance and to help them plan activity that will help them meet the recommendations.

NICE support for education and learning

Slide setEducation.eps

The slides provide a framework for discussing the NICE guideline with a variety of audiences and can assist in local dissemination. This information does not supersede or replace the guidance itself.

Clinical case scenariosEducation.eps

Clinical case scenarios are an educational resource designed to improve and assess users’ knowledge of the guideline on the management of Crohn’s disease.

PodcastEducation.eps

A podcast is available in which a member of the Guideline Development Group discusses the guidance.

Key to NICE implementation icons

Commissioning.epsNICE support for commissioners

  • Support package for commissioners and others for quality standards
  • NICE guide for commissioners
  • NICE cost impact support for guidance (selection from national report/local template/costing statement, dependent on topic)

Audit.epsNICE support for service improvement systems and audit

  • Forward planner
  • 'How to' guides (generic advice on processes)
  • Local government briefings (with Centre for Public Health Excellence)
  • Baseline assessment tool for guidance
  • Audit support including electronic data collection tools
  • E-learning modules (commissioned)

Education.epsNICE support for education and learning

  • Clinical case scenarios
  • Learning packages including slide sets
  • Podcasts
  • Shared learning and other local best practice examples

Conclusion

The care of patients with Crohn’s disease requires a multidisciplinary team approach. NICE CG152 on the management of Crohn’s disease in adults, children, and young people aims to improve the consistency and quality of care in this patient group. It is important that GPs are familiar with the recommendations when reviewing patients who have Crohn’s disease, particularly as many of these individuals are not routinely followed up by secondary care.

  1. NICE. The management of Crohn’s disease in adults, children and young people. Clinical Guideline 152. London: NICE, 2012. Available at: www.nice.org.uk/CG152nhs_accreditation
  2. National Clinical Guideline Centre. Crohn’s disease. Management in adults, children and young people. Clinical Guideline 152. Methods, evidence and recommendations. London: NCGC, 2012. Available at:
    www.nice.org.uk/nicemedia/live/13936/61002/61002.pdfnhs_accreditation
  3. British National Formulary website. www.bnf.org/bnf/index.htm (accessed 18 March 2013).
  4. Crohn’s and Colitis UK website. www.nacc.org.uk (accessed 18 March 2013).
  5. Gross V. The informed patient: Crohn’s disease and its associated disorders. Freiburg: Falk Foundation, 2008.
  6. Mowat C, Cole A, Windsor A et al. Guidelines on the management of inflammatory bowel disease in adults. Gut 2011; 60 (5): 571–607.
  7. Mayberry J, Lobo A, Ford A, Thomas A. NICE clinical guideline (CG152): the management of Crohn’s disease in adults, children and young people. Aliment Pharmacol Ther 2013; 37 (2): 195–203.
  8. NICE. Infliximab (review) and adalimumab for the treatment of Crohn’s disease. Technology Appraisal 187. London: NICE, 2010. Available at: www.nice.org.uk/TA187nhs_accreditation
  9. Dignass A, Van Assche G, Lindsay J et al. The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohn’s Colitis 2010; 4 (1): 63–101.
  10. Personal communication: Protocol for prednisolone dose reduction in the treatment of acute exacerbation of inflammatory bowel disease. Gastroenterology Unit, Oxford University Hospitals NHS Trust, 2012.
  11. Cripps S, Travis S. Azathioprine—shared care protocol for Oxfordshire. May 2012.
  12. NICE. Osteoporosis: assessing the risk of fragility fracture. Clinical Guideline 146. London: NICE, 2012. Available at: www.nice.org.uk/cg146nhs_accreditation
  13. British Society of Gastroenterology. Guidelines for osteoporosis in inflammatory bowel disease and coeliac disease. London: BSG, 2007. Available at: www.bsg.org.uk/pdf_word_docs/ost_coe_ibd.pdf
  14. Stephansson O, Larsson H, Pedersen L et al. Crohn’s disease is a risk factor for preterm
    birth. Clin Gastroenterol Hepatol 2010; 8 (6): 509–515.
  15. Hospira Inc. Methotrexate 10 mg tablets—summary of product characteristics. April 2012. Available at: www.medicines.org.uk/EMC/medicine/6005/SPC/Maxtrex+Tablets+10+mg/#contraindications
  16. British Society of Paediatric Gastroenterology Hepatology and Nutrition. Guidelines for the management of inflammatory bowel disease in children in the United Kingdom. BSPGHAN: 2008. Available at: www.bspghan.org.uk/working_groups/documents/IBDGuidelines_000.pdf
  17. IBD standards website. www.ibdstandards.org.uk (accessed 19 March 2013).
  18. NICE website. Ulcerative colitis. Available at: www.nice.org.uk/guidance/CG/Wave25/9G