Sarah Cripps presents an overview of NICE Evidence Update 65 for Crohn’s disease and discusses some key points for consideration alongside current guidance
  • A summary of selected new evidence relevant to NICE Clinical Guideline (CG) 152 on Crohn’s disease: management in adults, children and young people (2012)2 has recently been published:
    • this summary, NICE Evidence Update 651 is intended to increase awareness of some new and relevant evidence published in the literature that suggests a change in practice and potential impact on current guidance
  • The key points from NICE Evidence Update 651 are linked to the key priority areas of NICE CG1522 and should be used in conjunction with the recommendations made in NICE CG1522
  • Crohn’s disease affects people of all ages and is a lifelong condition. Appropriate patient information and support remain key:
    •  general practitioners should be aware of contact details for colleagues within secondary care, including IBD specialist nurses and patient support groups such as Crohn’s and Colitis UK19
  • Hospital admissions and biologics are among the biggest cost pressures for CCGs in the management of patients with IBD  
  • Prescribing of biologics should be under the care of a specialist gastroenterologist but it is important that GPs are aware of patients in their practice who are receiving these treatments. The use of biologics is likely to increase
  • The range of biologics licensed for IBD is increasing and some are the subject of future NICE reviews. Because specialist gastroenterologists may wish to use these agents outside current NICE guidance, GP commissioners are likely to see an increase in Individual Funding Requests for them
  • Clinical commissioning groups should participate in regular audit of patients on biologics and agree formularies and budgets with their colleagues in secondary care to ensure cost effective and appropriate use of these agents
  • Shared-care policies should be in place for the prescribing of immunomodulators between primary and secondary care
  • Patients on immunomodulators and/or biologics are a priority group for seasonal influenza vaccination (and pneumonococcal, human papillomavirus, hepatitis B, as per national guidelines):
    • these patients should avoid any live vaccines 
  • The care of pregnant patients with IBD should be done conjunctively between primary and secondary care.
CCG=clinical commissioning group; IBD=inflammatory bowel disease
NICE Evidence Update 65 on Crohn’s disease1 was recently published with the intention of increasing awareness of new evidence that may impact on the current clinical guideline for this condition. This brief review article highlights and discusses some of the key points of the update and reinforces some key messages and considerations for primary care in implementing NICE CG152.

Background

Crohn’s disease is a chronic, non-specific inflammatory condition of the gastrointestinal tract that affects at least 115,000 people in the UK.2 Classic symptoms of Crohn’s disease are abdominal pain, diarrhoea, fatigue, and unintended weight loss.2,3 Extra-intestinal complications (more commonly seen in colonic disease and/or active disease) can affect joints, skin, bone, and the liver.3 People with the condition have unpredictable periods of acute exacerbations, with periods of remission or less active disease in between.
  
Between 50% and 80% of people with Crohn’s disease will eventually need surgery for strictures causing symptoms of obstruction, other complications such as fistula formation, perforation, or failure of medical therapy.Crohn’s disease is also associated with an increased risk of developing other conditions, such as colorectal cancer, osteoporosis, and anaemia, and can impair growth and pubertal development in children and young people.4

Treatment

Glucocorticosteroids, (e.g. prednisolone), immunomodulators (e.g. azathioprine, mercaptopurine, methotrexate), aminosalicylates, antibiotics, and biologics (e.g. anti-tumour necrosis factor alpha [TNF]-α inhibitors) form the basis of drug treatment. Current available treatment is not curative but largely directed at:
  • 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
  • optimisation of nutrition and/or growth
  • smoking cessation
  • minimising psychological concerns
  • management of disease complications 
  • maintaining or improving quality of life. 

NICE Clinical Guideline 152

Patients with Crohn’s disease pose a challenge to the multidisciplinary team both clinically and economically. In October 2012, NICE published Clinical Guideline 152 (CG152) on Crohn’s disease: Management in adults, children and young people.2 It was the first evidence-based clinical and cost-effective guideline in the UK on this disease and covers adults, children, and young people collectively in one document. The challenges and responsibilities for primary care in implementing this guideline were reviewed by this author in a Guidelines in Practice article in April 2013.5 

NICE Evidence Update 65

About 2 years after NICE CG152, NICE published Evidence Update 65 on Crohn’s disease.1 This update was intended to increase awareness of some new and relevant evidence published in the literature since the guideline was produced that suggests a change in practice and potential impact on current guidance.

Over 3000 pieces of evidence published between March 2012 and April 2014 were identified. Following a robust selection process, an Evidence Advisory Group comprising some of the original NICE CG152 Guideline Development Group members reviewed and advised on a final list of 14 articles they considered had a potential impact on current guidance, were a ‘key read,’ or substantially strengthened the evidence base underpinning current recommendations. 

The key points from Evidence Update 65 are linked to the key priority areas of NICE CG152 and are summarised in Table 1, below. These points should be used in conjunction with the recommendations made in NICE CG152.2 The evidence update publication provides a summary of the evidence for each key point made and the key reference(s) to support these.
 
Important note: It must be noted that this Evidence Update does not replace the original NICE CG152 and does not at this stage provide formal practice recommendations. As part of the process of updating published guidelines, NICE will determine the impact of the new key references described in the update and the timeframe for formal review of the current guidelines.

NICE Quality Standard for inflammatory bowel disease

A NICE quality standard for IBD is due for publication soon and is expected to contribute to improvements in the following outcomes in patients with this condition:4
  • attendance at school
  • work absenteeism
  • unplanned hospital admissions for IBD
  • length of hospital stay after surgery for IBD
  • readmissions after surgery for IBD
  • people with long-term conditions feeling supported to manage their condition
  • patient experience of services.
At the time of writing (November 2014), publication of this quality standard has been delayed to allow consideration of points raised during internal validation. A new publication date will be confirmed shortly.

Patient information and support

A key recommendation of CG152 was the provision of appropriate patient information.2 Evidence Update 65 highlights a specific need for discussion of the use of anti-TNF agents in children with their parents or carers.1 Infliximab and adalimumab are licensed for the treatment of people aged 6 years or over with severe active Crohn’s disease, whose disease has not responded to conventional therapy (including immunomodulators, corticosteroids, and nutrition therapy), or who are intolerant or have contraindications to such therapies.6  These agents have also been recommended by NICE Technology Appraisal 187.7 The prescribing of biologics should be under the care of a specialist gastroenterologist but it is important that GPs are aware of patients in their practice who are receiving these treatments.

Induction and maintenance of remission

Biologics and biosimilars

Several references that were considered important to be included in NICE Evidence Update 65 related to the use of biological therapy in the management of Crohn’s disease.
 

Biologics

Biologics remain one of the biggest cost pressures for clinical commissioning groups in the management of people with IBD. It is estimated around 10%–15% of all IBD patients receive an anti-TNF agent as maintenance treatment. This includes people who have had surgery.8
 
The anti-TNF inhibitors (infliximab and adalimumab) have been reviewed in NICE Technology Appraisal (TA) 187 (see nice.org.uk/TA187), published in 2010.7 The range of biologic drugs (licensed and unlicensed) used in practice for IBD is increasing (e.g. golimumab, certolizumab,  vedolizumab, ustekinumab)6 and some are the subject of future NICE reviews.9 (NB At the time of writing, certolizumab and ustekinumab do not have marketing authorisation for this indication. 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 and managing medicines and devices for further information) GP commissioners are beginning to see Individual Funding Requests from specialist gastroenterologists to use agents that target TNF-α or other molecules in the inflammatory pathway before these agents have received NICE approval, or because practitioners wish to use certain biologics in situations not currently recommended in NICE guidance. 
 
The presence of antibodies against TNF inhibitors is associated with loss of response to treatment and lower trough levels (i.e. lowest point, immediately before receiving next dose) of the drug in the blood. This was highlighted as a key point in the Evidence Update1 and testing for the presence of antibodies and trough levels of drug is increasingly being used to determine loss of response and the possible need to increase dose, stop treatment, or switch to another agent. The routine use of monitoring response of anti-TNF agents in this way is currently being looked at in a separate review by NICE.9

Biosimilars

Biosimilars of anti-TNF agents for IBD are likely to be coming to the market in 2015 and will offer a potential significant cost-saving for commissioners. Infliximab is the first biosimilar to be licensed for IBD, based on two trials in rheumatological disorders.6 Discussions will be needed between specialist clinicians and commissioners regarding the evidence for interchangeability and switching. The call for post-marketing surveillance is essential in view of the uncertainty of the impact of the potential differences between biosimilars and biologics on efficacy and safety.10 Clinical commissioning groups should participate in regular audit of patients receiving biologics and agree formularies and budgets with their colleagues in secondary care to ensure their cost-effective and appropriate use.

Immunomodulators

Patients taking immunomodulators (e.g. azathioprone, mercaptopurine, methotrexate, tacrolimus, mycophenolate, ciclosporin) and/or biologics (e.g. infliximab, adalimumab) are at increased risk of opportunistic infections, a risk reiterated in NICE Evidence Update 65.1 Primary care doctors should work closely with secondary care colleagues to ensure that patients have regular blood monitoring to avoid toxicity (including pancreatitis, bone marrow suppression, liver dysfunction) with these medications and so that appropriate action is taken if blood results are abnormal. The implementation of shared-care protocols was a key recommendation of NICE CG152.2 These patients are also a priority group for seasonal influenza vaccination (as well as pneumonococcal, human papillomavirus, hepatitis B, as per national guidelines). Patients should avoid any live vaccines.6,11
 

Aminosalicylates

Although mainly used in ulcerative colitis, mesalazine may be taken by some Crohn’s patients, particularly for maintenance post surgery if they are unable to tolerate azathioprine and an anti-TNF agent is inappropriate. It should be noted that not all mesalazine preparations are licensed for Crohn’s disease.
 
The British National Formulary recently changed its wording to state that although there is no evidence to show that any one oral preparation of mesalazine is more effective than the other, delivery characteristics may vary so patients who have to be switched to a different brand should be advised to report any changes in their symptoms. General practitioners are encouraged to prescribe by brand and patients should remain on the same preparation wherever possible.6

Monitoring for osteopenia and assessing fracture risk

NICE Evidence Update 65 highlights that a low body mass index may be the most important risk factor for osteoporosis in people with Crohn’s disease.1 Long-term steroid use and underlying IBD contribute to the risk. Nutritional therapy can be considered as an adjunctive or primary treatment in IBD patients. Although all people with IBD are at risk of nutritional problems, those with Crohn’s disease are at particular risk of being malnourished and developing a variety of conditions from nutritional deficiencies, including anaemia and osteoporosis. Patients may require advice from specialist dietitians on nutritional intake; preventative treatment such as calcium and vitamin D supplements and/or bisphosphonates may be necessary.12 General practitioners should also refer to NICE Clinical Guideline 146 (2012) on Osteoporosis: assessing the risk of fragility fracture.13

Conception and pregnancy

As an increasing number of female patients receive anti-TNF therapy, it is reassuring to see a growing body of evidence suggesting that these agents are not likely to be associated with adverse effects on the fetus.14 Infants exposed to these drugs in utero may, however, be at increased risk of adverse reactions to live vaccines. Guidelines should be in place regarding administration of vaccines to babies whose mothers have received anti-TNF agents during pregnancy. It is usually advisable to avoid administering live attenuated vaccines to the baby in the first 6 months of life (pers. comm).1,15
 
Most drugs routinely used in the induction or maintenance of remission in patients with IBD are safe in pregnancy, with the exception of methotrexate, which is contraindicated.
 
Women with a diagnosis of IBD who are considering pregnancy or are known to be pregnant should be cared for jointly by a specialist gastroenterologist, GP, and obstetrician.

Other national guidelines

See Box 1, below, for some other relevant national guidelines on Crohn’s disease.

Table 1: NICE Evidence Update 65 on Crohn’s disease:1 summary of key points indicating whether the new evidence may have a potential impact on NICE CG1522
Potential impact on guidance
Key point Yes No
Patient information and support
Parents of children with Crohn’s disease need information to help decide whether to start TNF inhibitor treatments. Parents have particular worries about the risk of cancer and lack of long-term safety data
Inducing remission in Crohn’s disease
Azathioprinea and mercaptopurineb may not be better than placebo for inducing remission of Crohn’s disease; however infliximab plus azathioprine may be more effective than infliximab alone √*
Methotrexatec may not be effective for inducing remission in Crohn’s disease, and infliximab plus methotrexate may not be more effective than infliximab alone
There is no evidence to suggest that naltrexoned is effective for inducing remission of Crohn’s disease
Adalimumab may be an effective treatment for inducing remission of Crohn’s disease in people who previously had infliximab treatment failure. √*
People taking TNF inhibitors may be at increased risk of opportunistic infections √*
The presence of antibodies against TNF inhibitors is associated with loss of response to treatment and lower trough levels of the drug in blood serum
Maintaining remission in Crohn’s disease
Thiopurine treatment may be feasible in people who previously stopped treatment with these drugs because of adverse events. However, rare but serious adverse events, such as pancreatitis or bone marrow failure, may reoccur.
On continuing adalimumab treatment for 4 years, less than a third of people maintain remission; the same proportion of people may stop treatment because of adverse events.
Maintaining remission in Crohn’s disease after surgery
Adalimumab may be more effective than azathioprine or mesalazinee in maintaining remission of Crohn’s disease after surgery √*
Monitoring for osteopenia and assessing fracture risk
Low BMI may be the most important risk factor for osteoporosis in people with Crohn’s disease
Conception and pregnancy
TNF inhibitors do not seem to be associated with major adverse effects when used during pregnancy, but infants exposed to these drugs in utero may be at increased risk of adverse reactions to live vaccines
Thiopurine use in pregnancy may be associated with pre-term birth, but may not be associated with low birth weight or congenital malformations

Please see the full commentaries for details of the evidence informing these key points.

The section headings used in the table above are taken from NICE CG152.1

NB: Evidence Updates do not replace current NICE guidance and do not provide formal practice recommendations.

a At the time of publication of this Evidence Update, not all azathioprine products had UK marketing authorisation for this indication, please see the summary of product characteristics for each drug formulation.

b At the time of publication of this Evidence Update, mercaptopurine did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented.

c At the time of publication of this Evidence Update, methotrexate did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented.

d At the time of publication of this Evidence Update, naltrexone did not have UK marketing authorisation for this indication and was not considered for NICE CG152.

e At the time of publication of this Evidence Update, mesalazine did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented.

* Evidence Updates are intended to increase awareness of new evidence and do not change the recommended practice as set out in current guidance. Decisions on how the new evidence may impact guidance will be made when the need to update guidance is reviewed by NICE. For further details of this evidence in the context of current guidance, please see the full commentary.

NICE. Crohn’s disease: Evidence update. Evidence Update 65. NICE, 2014. Available at: www.evidence.nhs.uk/about-evidence-services/bulletins-and-alerts/evidence-updates/evidence-updates-by-date Reproduced by kind permission.

Box 1: Other relevant national guidelines on Crohn’s disease

Summary

General practitioners are integral to the multidisciplinary team providing care to patients diagnosed with Crohn’s disease.  NICE CG152 provides recommendations for the management of this patient group. A summary of selected new evidence relevant to NICE CG152 has recently been published and GPs are encouraged to familiarise themselves with the key points to improve implementation of the clinical guideline and consistency and quality of care in this patient group.

 
written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead
  • The treatment of Crohn’s disease often requires specialist medications: 
    • CCGs need to commission services to support the use and monitoring of these agents
  • Non-biologic agents can be prescribed in primary care under specialist supervision but require CCGs to commission enhanced services and shared- care protocols to ensure regular blood-testing and monitoring, which are needed for the safe use of these agents:
    • these protocols should also include guidance for vaccination in patients with Crohn’s disease and who are on disease-modifying medication
  • Biologic agents are usually prescribed in secondary care but are expensive: 
    • the costs for these drugs are excluded from the Payment by Results tariff so the cost of them falls to CCGs
  • Clinical commissioning groups should therefore work with secondary care to agree formularies and ensure that these drugs are prescribed cost efficiently and in line with NICE technology appraisals (which CCGs have a legal duty to fund)
  • Clinical commissioning groups may also need to identify funding panels to consider exceptional requests from specialists to fund treatments outside NICE recommendations or awaiting NICE appraisal.
CCG=clinical commissioning group
  1. NICE. Crohn’s disease: Evidence update. Evidence Update 65. NICE, 2014. Available at: www.evidence.nhs.uk/about-evidence-services/bulletins-and-alerts/evidence-updates/evidence-updates-by-date (accessed 20 October 2014).
  2. NICE. Crohn’s disease: Management in adults, children and young people. Clinical Guideline 152. NICE, 2012. Available at: www.nice.org.uk/guidance/cg152 (accessed 20 October 2014).
  3. 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.pdf nhs_accreditation 
  4. NICE. Inflammatory bowel disease. Quality Standard, in development. NICE, 2014. Available at: www.nice.org.uk/guidance/indevelopment/gid-qsd70/documents (accessed 20 October 2014).
  5. Cripps S. Support and advice in treating patients with Crohn’s disease. Guidelines in Practice; 16 (4): 10–27.  Available at: bit.ly/10yoC7T (accessed 4 November 2014).
  6. British Medical Association and the Royal Pharmaceutical Society. British National Formulary. London, Pharmaceutical Press. Available at: www.medicinescomplete.com/about/publications.htm (accessed 20 October 2014).
  7. NICE. Infliximab (review) and adalimumab for the treatment of Crohn’s disease. Technology Appraisal 187. Available at: www.nice.org.uk/guidance/TA187 (accessed 21 October 2014).
  8. Van der Valk M, Mangen M-J, Leenders M et al. Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study. Gut 2014; 63 (1): 72–79.
  9. NICE website. Inflammatory bowel disease. In development. www.nice.org.uk/guidance/conditions-and-diseases/digestive-tract-conditions/inflammatory-bowel-disease (accessed 4 November 2014).
  10. Rinaudo-Gaujous M, Paul S, Tedesco E et al. Review article: biosimilars are the next generation of drugs for liver and gastrointestinal diseases. Aliment Pharmacol Ther 2013; 38 (8): 914–924.
  11. Rahier J, Ben-Horin S, Chowers Y et al. European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis 2009; 3 (2): 47–91.
  12. Mowat C, Cole A, Windsor A et al. Guidelines for the management of inflammatory bowel disease in adults. BSG 2011. Available at: www.bsg.org.uk/clinical-guidelines/ibd/guidelines-for-the-management-of-inflammatory-bowel-disease.html
  13. NICE. Osteoporosis: assessing the risk of fragility fracture. Clinical Guideline 146. Available at: www.nice.org.uk/guidance/CG146 (accessed 20 October 2014).
  14. Nielsen O, Loftus E Jr, Jess T. Safety of TNF-α inhibitors during IBD pregnancy: a systematic review. BMC Medicine 2013; 11: 174.
  15. Personal communication. Anja St Clair Jones, 2013.
  16. Sandhu B, Fell J, Beattie R, Mitton S. Guidelines for the management of IBD in children in the United Kingdom. British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), 2008. Available at: www.bspghan.org.uk/guidelines
  17. IBD Standards Group. Standards for the healthcare of people who have inflammatory bowel disease (IBD). IBD Standards 2013 update. Available at: www.ibdstandards.org.uk
  18. NICE. Ulcerative colitis: Management in adults, children and young people. Clinical Guideline 166. NICE, 2013. Available at: www.www.nice.org.uk/guidance/cg166
  19. Crohn’s and Colitis UK. www.crohnsandcolitis.org.uk (accessed 4 November 2014).