Inflammatory Bowel Disease: NICE Updates Advice on Remission

Sarah Cripps Highlights Key Learning Points from the Updated NICE Recommendations on the Management of Crohn’s Disease and Ulcerative Colitis

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inflammatory bowel disease and differences between Crohn’s disease and ulcerative colitis updates on maintaining remission after surgery in Crohn’s disease new recommendations on the induction of remission in mild-to-moderate ulcerative colitis choice and dose of aminosalicylates and corticosteroids in ulcerative colitis. Find key points and implementation actions for STPs and ICSs at the end of this article

Inflammatory bowel disease (IBD) can be divided into two chronic inflammatory disorders of the gastrointestinal tract, namely Crohn’s disease (CD) and ulcerative colitis (UC). Crohn’s disease can affect any part of the gastrointestinal tract whereas ulcerative colitis affects only the large bowel.

Inflammatory bowel disease follows a relapsing and remitting course that is unpredictable, causes disruption to a patient’s lifestyle, and places a burden on the workplace and healthcare setting. Up to 50% of patients with IBD experience at least one extra-intestinal complication, more commonly when disease affects the colon.¹ Complications affect the joints, skin, bone, eyes, liver, and biliary tree and are mostly (but not exclusively) associated with active disease. Other complications of IBD include anaemia, colorectal cancer, and the impairment of growth and pubertal development in children and young people.^2–7

Introduction

Around 260,000 people in the UK have a diagnosis of IBD.^2,3 Table 1 highlights the main differences between the two types of inflammatory bowel conditions.

Table 1: Similarities and Differences Between Crohn’s Disease and Ulcerative Colitis

Feature		Crohn’s Disease	Ulcerative Colitis
Disease profile	Affected areas	Can affect any part of the gut. Most likely to develop in the ileum or the colon	Parts of the colon and/or rectum become inflamed and sore. Ulcers can develop on the colon lining and these can bleed or produce mucus
	UK prevalence	Approximately 115,000 patientsA Affects around 1 in 650 peopleA	Approximately 146,000 patientsB Affects around 1 in 420 peopleB
	Disease pattern	Relapsing-remitting patternC,D
Symptoms	Fever	Some people may feel generally unwell, feverish, with raised tempeartureA,B
		Suggests severe disease with systemic toxicityC	Temperature >37.8ºC indicative of severe UCD
	Diarrhoea	Sometimes mixed with mucus, pus, or bloodA	Often with blood and mucus, and an urgent need to rush to the toiletB
	Abdominal pain	CommonA	Cramping pain, often before passing a stoolB
	Abdominal mass	Common6	Absent6
	Tachycardia	Suggests severe disease with systemic toxicityC	Pulse rate >90 bpm suggests severe UCD
	Other	Fatigue, anaemia, weight loss, loss of appetite, and growth impairment in children and young peopleA,B
Complications	Fistulae	Often perianal,7 occurs in around one‑quarter of casesC	Rare, more likely in those who have had pouch surgeryB
	Strictures	As a result of scar tissue or inflammationA	Unusual in UC, sometimes a sign of bowel cancerB
	Fissures	Complication of perianal diseaseC	Absent6
	Extraintestinal manifestations	More common when disease affects the colon; can affect the joints, skin, bone, eyes, liver, and biliary tree and are mostly (but not exclusively) associated with active disease Thromboembolic complications occur in 1–2% of patients; this risk is higher in acute cases resulting in hospitalisation, but this is low due to routine use of VTE prophylaxis6
Risk Factors	Smoking	Smoking increases risk of Crohn’s diseaseC,7 and cessation reduces severityA	Smoking decreases risk of UC,7 but overall risks of smoking outweigh benefitsB
	Cancer	Increases risk of developing colon cancerA,B
A Crohn’s & Colitis UK. Crohn’s disease: your guide. Crohn’s & Colitis UK, 2019.  B Crohn’s & Colitis UK. Ulcerative colitis: your guide. Crohn’s & Colitis UK, 2018.  C NICE. Crohn’s disease: management (full guideline). NICE, 2019. Available at: www.nice.org.uk/guidance/ng129/evidence D NICE.Ulcerative colitis: management (full guideline). NICE, 2019. Available at: www.nice.org.uk/guidance/ng130/evidence
UC=ulcerative colitis; GI=gastrointestinal; VTE=venous thromboembolism

Current available drug treatment for IBD includes corticosteroids, aminosalicylates, immunosuppressants (immunomodulators), antibiotics, and biologics. These may be used alone or in combination to induce and maintain remission. However, none of these are curative and disease progression and loss of treatment efficacy over time can result in loss of remission for some patients without alternative treatment options. Choice and route of drug therapy will depend on site, extent, and severity of the disease, together with knowledge of current or previous treatment. Safety (including under-treating), patient preference, and adherence are important factors for consideration. Nutrition and smoking cessation also form part of the management and in severe or chronic active disease, surgery may be necessary.^2,3,7,8

Note: Not all of the treatment preparations and combinations, topical or oral, discussed in this article currently (June 2019) have UK marketing authorisation for the uses described, or for use in children and young people. The prescriber should follow relevant professional guidance, taking full responsibility for all clinical decisions. Informed consent should be obtained and documented. See the General Medical Council’s guidance on Good practice in prescribing and managing medicines and devices⁹ for further information.

Updated NICE Guidelines on Crohn’s Disease and Ulcerative Colitis

In May 2019, NICE published NICE Guideline (NG) 129 on Crohn’s disease: management² and NG130 on Ulcerative colitis: management,³ replacing and updating Clinical Guideline (CG) 152 and CG166, respectively.

The new recommendations made in both guidelines^2,3 supplement the existing recommendations for:

• providing patient information and support
• induction of remission
• maintenance of remission
• providing information about surgery (ulcerative colitis)
• surgery (Crohn’s disease)
• bone health, growth, and pubertal development (ulcerative colitis)
• monitoring for osteopenia and assessing fracture risk (Crohn’s disease)
• conception and pregnancy.

This article focuses on the key updated recommendations from NG129 and NG130 that GPs and primary care healthcare professionals should be aware of.

Crohn’s Disease Guideline: Key Updates

Maintaining Remission After Surgery

NICE Guideline 129 includes new recommendations on maintaining remission after surgery.² These recommendations apply only to those people with ileocolonic Crohn’s disease who have had complete macroscopic resection (defined as the surgical removal of the section of the bowel with visible [rather than microscopic] disease) within the last 3 months and who have no active residual disease (i.e. who are in remission). The previous recommendations were applicable to any person with adverse prognostic factors post-operatively, whereas now the recommendations relate to a specific postoperative group. Box 1 summarises the new recommendations.²

Up to 3 months of metronidazole should now be considered in conjunction with azathioprine following complete macroscopic resection of ileocolonic disease. While there is evidence to support its use in combination with azathioprine for maintaining endoscopic remission, metronidazole should not be used as monotherapy as the potential benefits are not considered to outweigh the risk of adverse effects.

Patients should be counselled on the side-effects associated with metronidazole, which include gastrointestinal upset, metallic taste, dizziness and drowsiness. They should contact a doctor if they experience more severe adverse effects such as a severe skin rash, pancreatitis, jaundice, and blood dyscrasias (e.g. bruising, sore throat), or difficulty in breathing. Peripheral neuropathy is generally associated with prolonged courses exceeding 3 months.⁸

Twenty percent of patients will not tolerate thiopurines due to adverse effects.⁷ The guideline committee reviewed mercaptopurine as an alternative thiopurine to azathioprine in this setting but did not find it cost effective for maintaining remission and therefore have removed it from the recommendations. The role of aminosalicylates in post-operative management was also reviewed and, based on evidence of endoscopic relapse rate, these were found not to be clinically or cost effective and their recommendation for use has also been removed from the updated guideline.²

Because of limited evidence and high costs compared with other options for maintaining remission, NG129 recommends: ‘Do not offer biologics to maintain remission after complete macroscopic resection of ileocolonic Crohn’s disease’.² This advice has the potential for cost savings and maintaining consistency in clinical practice. The review committee, however, agreed that for those people who had surgery and started taking biologics before this guideline was published (May 2019), current treatment can continue until both they and their NHS healthcare professional agree it is appropriate to change.

Ulcerative Colitis Guideline: Key Updates

Induction of Remission in Mild-to-moderate Disease (First Presentation or Inflammatory Exacerbation)

NICE Guideline 130 includes new recommendations on the induction of remission in mild-to-moderate ulcerative colitis (first presentation or inflammatory exacerbation), which are summarised in Box 2.³

There is a subtle change in classification of the extents of ulcerative colitis compared with the original guideline, with proctitis defined as <15 cm; proctosigmoiditis or left-sided ulcerative colitis defined as up to 50 cm; and extensive disease defined as >50 cm.¹⁰

Topical Treatments Should be First Line in Mild-to-moderate Ulcerative Colitis

Disease confined to the anus, rectum, or left side of the colon is more clinically and cost effectively treated with rectally administered topical preparations where the drug is applied directly to the site of inflammation.^3,6 Drugs administered rectally have reduced systemic absorption and fewer side-effects than those administered orally or intravenously. The choice of topical formulation (suppository, foam, or liquid enema) depends on the site of inflammation, product presentation, acceptability, patient preference, and cost. Adherence to topical therapy is generally poor and good patient education is required for effective benefit. Patients with poor dexterity may find the use of rectal products difficult and these preparations may therefore be poorly tolerated and consequently of limited advantage. Enemas or suppositories should be administered just before bedtime in a supine position as this allows a much longer retention time. Liquid enemas can be warmed to body temperature and should be inserted while lying in the left lateral position.¹¹

Monotherapy with topical treatment was shown to be the cost-effective treatment within the initial 4 weeks of mild-to-moderate disease. Topical aminosalicylates are considered more effective than topical corticosteroids.³ In the guideline update, evidence for topical aminosalicylates for the treatment of proctitis did not show any difference in effectiveness between enemas and suppositories. Despite the lack of direct evidence for the effectiveness of topical (or oral) corticosteroids in proctitis, the consensus of the committee was that these should be an option if aminosalicylates are not tolerated.³

As clinical evidence on topical immunomodulators (e.g. tacrolimus) is limited, their use should be restricted to and managed by a specialist gastroenterologist.

Choice and Dose of Aminosalicylates and Corticosteroids in Ulcerative Colitis

Aminosalicylates and corticosteroids are now referred to as a class rather than individual treatments in the guideline. Choice of treatment should reflect current guidance in the British National Formulary (BNF), patient preference, and local formularies.

Clinicians should refer to the latest BNF for dose ranges for specific products and make a clinical judgment depending on the specific situation. For oral aminosalicylates, a low dose could be prescribed if the person has not taken an aminosalicylate before, or a high dose if the person was already taking a low dose.

Table 2 highlights the corticosteroids licensed for use in IBD.

Table 2: Corticosteroids Licensed for Use in IBD

The new recommendations specify that a course of oral corticosteroids to treat active disease should be time-limited, i.e. 4 to 8 weeks (depending on the steroid) to ensure adverse effects are minimised, and treatment is reassessed if induction of remission is not achieved. This may include referral to secondary care. Corticosteroids are not suitable for maintenance of remission.³

Oral prednisolone will control mild and moderate IBD and 70% of patients improve after 2–4 weeks of 40 mg/day dosing.⁷ This should gradually be reduced over the next 4–6 weeks to prevent acute adrenal insufficiency and early relapse. Prednisolone at doses higher than 40 mg/day increases the incidence of adverse effects and has little therapeutic advantage. Initial doses below 20 mg, faster reduction regimens, or short pulses of corticosteroids are generally ineffective in active disease.¹² An example of a reducing oral prednisolone regimen is detailed in Box 3.

Budesonide is less effective than conventional corticosteroids in inducing remission in active disease, but has fewer side-effects than prednisolone because of its rapid and extensive first-pass metabolism.^2,3

Oral corticosteroids should be taken in the morning to mimic the diurnal rhythm of the body’s cortisol secretion and prevent sleep disturbance. Uncoated steroid tablets are suitable for most patients while enteric-coated preparations do not offer any proven advantage and should be avoided in patients with short bowel or strictures because of poor absorption and bolus release at stricture sites.⁶

All patients taking corticosteroids must be issued with a steroid card and counselled on potential side-effects.⁸

Immunomodulators are Not Recommended in Induction of Mild-to-moderate Disease

The use of immunomodulators in the induction of remission of mild-to-moderate ulcerative colitis is not recommended. There is some evidence on methotrexate but it did not show a clear benefit and was therefore not included as a recommendation in this update. Tacrolimus is no longer recommended as a treatment option in the guideline for any extent of disease.³

New Biological Treatments Available for IBD Including anti-TNF Biosimilars

In addition to costs associated with hospital admissions, biologics remain one of the biggest cost pressures for clinical commissioning groups in the management of people with IBD. Many patients with IBD receive a biologic as maintenance treatment, including people who have had surgery.¹⁴ The use of biologics and other drugs that modulate the immune response will continue to increase, particularly as more options become available to those who lose response.

Biologics should only be started by clinicians with experience of their use in IBD and their clinical benefit should be reviewed regularly.^2,3

Since the publication of the original guidelines, further biologics and other drugs which target different molecules in the inflammatory process to modulate the immune response have become licensed and formally appraised by NICE. Where these treatments are indicated, they are referred to in the relevant guideline updates with an embedded link to the relevant technology appraisals. Box 4 summarises the relevant NICE Technology appraisals for IBD.

Both infliximab and adalimumab are now available as biosimilars, which can provide significant cost savings for the NHS. Collaborative working with commissioners in the development of treatment pathways for IBD, particularly the use of biologics and biosimilars, is essential to ensure optimal cost-effective use of available treatments.

When GPs Should Refer to Secondary Care

The management of IBD poses a challenge to the multidisciplinary team both clinically and economically. In practice, complex cases and those prescribed biologics are increasingly managed by specialist hospital centres. Patients whose disease is less severe are still managed predominantly by gastroenterologists and IBD specialist nurses with support from primary care doctors.

Situations when primary care doctors should refer patients to secondary care include failure to respond to oral treatment for acute exacerbations and toxicity to immunomodulators or biologics. It is essential that primary care doctors and pharmacists recognise signs of an acute severe exacerbation and refer patients to hospital promptly for intensive treatment. 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 UK.¹

General practitioner responsibilities within a shared-care protocol for treatments such as immunomodulators could include:

• prescribing immunomodulators once the dose of immunomodulators is stable. The first month of treatment should generally be prescribed under secondary care
• advising the hospital consultant/specialist IBD nurse of any clinical deteriorations and monitoring for adverse effects as appropriate
• checking bloods weekly for the first month, then every 2–3 months
• providing vaccinations (i.e. seasonal influenza, pneumococcal polysaccharide vaccine, human papillomavirus according to national guidance, hepatitis B for selected patients); live vaccines should be avoided.

Summary

The care of people diagnosed with Crohn’s disease and ulcerative colitis requires a multidisciplinary team approach across primary and secondary care. NICE has updated its management guidelines for these conditions (NG129 and NG130) with the aim of improving the consistency, quality, and evidence-based care throughout the UK. It is important that GPs are familiar with the recommendations when reviewing patients who have inflammatory bowel disease, particularly as many people are not routinely followed up by secondary care, and they are prescribed medication that requires close monitoring.

Sarah Cripps

Consultant Pharmacist, Oxford University Hospitals NHS Foundation Trust

Member of the guideline development group for NG129 and NG130