Monotherapy

1.2.1.

Offer monotherapy with a conventional glucocorticosteroid (prednisolone, methylprednisolone or intravenous hydrocortisone) to induce remission in people with a first presentation or a single inflammatory exacerbation of Crohn’s disease in a 12-month period. [2012]

1.2.2.

Consider enteral nutrition as an alternative to a conventional glucocorticosteroid to induce remission for:

• children in whom there is concern about growth or side effects and
• young people in whom there is concern about growth. [2012]

1.2.3.

Consider budesonide^[2] for a first presentation or a single inflammatory exacerbation in a 12-month period for people:

• who have one or more of distal ileal, ileocaecal or right-sided colonic disease^[3] and
• if conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them.

Explain that budesonide is less effective than a conventional glucocorticosteroid, but may have fewer side effects. [2012]

1.2.4.

Consider aminosalicylate treatment^[4] for a first presentation or a single inflammatory exacerbation in a 12-month period if conventional glucocorticosteroids are contraindicated, or if the person declines or cannot tolerate them. Explain that aminosalicylates are less effective than a conventional glucocorticosteroid or budesonide but may have fewer side effects than a conventional glucocorticosteroid. [2012]

1.2.5.

Do not offer budesonide or aminosalicylate treatment for severe presentations or exacerbations. [2012]

1.2.6.

Do not offer azathioprine, mercaptopurine or methotrexate as monotherapy to induce remission. [2012]

Add-on treatment

1.2.7.

Consider adding azathioprine or mercaptopurine^[5] to a conventional glucocorticosteroid or budesonide^[2] to induce remission of Crohn’s disease if:

• there are 2 or more inflammatory exacerbations in a 12-month period or
• the glucocorticosteroid dose cannot be tapered. [2012]

1.2.8.

Assess thiopurine methyltransferase (TPMT) activity before offering azathioprine or mercaptopurine. Do not offer azathioprine or mercaptopurine if TPMT activity is deficient (very low or absent). Consider azathioprine or mercaptopurine^[5] at a lower dose if TPMT activity is below normal but not deficient (according to local laboratory reference values). [2012]

1.2.9.

Consider adding methotrexate^[6],[7] to a conventional glucocorticosteroid or budesonide^[2] to induce remission in people who cannot tolerate azathioprine or mercaptopurine, or in whom TPMT activity is deficient, if:

• there are 2 or more inflammatory exacerbations in a 12-month period or
• the glucocorticosteroid dose cannot be tapered. [2012]

1.2.10.

Monitor the effects of azathioprine, mercaptopurine^[5] and methotrexate^[6],[7] as advised in the British national formulary (BNF) or British national formulary for children (BNFC)^[8]. Monitor for neutropenia in people taking azathioprine or mercaptopurine even if they have normal TPMT activity. [2012]

1.2.11.

Ensure that there are documented local safety monitoring policies and procedures (including audit) for people receiving treatment that needs monitoring. Nominate a member of staff to act on abnormal results and communicate with GPs, people with Crohn’s disease and their family members or carers (as appropriate). [2012]

Infliximab and adalimumab

The recommendations in the following section (1.2.12, 1.2.13, and 1.2.15 to 1.2.20) are from the NICE technology appraisal guidance on infliximab and adalimumab for the treatment of Crohn’s disease.

1.2.12.

Infliximab and adalimumab, within their licensed indications, are recommended as treatment options for adults with severe active Crohn’s disease (see recommendation 1.2.18) whose disease has not responded to conventional therapy (including immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate. [2010]

1.2.13.

Treatment as described in recommendation 1.2.12 should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). This may need to be varied for individuals because of differences in the method of administration and treatment schedules. [2010]

1.2.14.

When a person with Crohn’s disease is starting infliximab or adalimumab (in line with recommendations 1.2.12, 1.2.15, 1.2.17 and 1.2.20), discuss options of:

• monotherapy with one of these drugs oror
• combined therapy (either infliximab or adalimumab, combined with an immunosuppressant).

Tell the person there is uncertainty about the comparative effectiveness and long-term adverse effects of monotherapy and combined therapy. [2016]

1.2.15.

Infliximab, within its licensed indication, is recommended as a treatment option for people with active fistulising Crohn’s disease whose disease has not responded to conventional therapy (including antibiotics, drainage and immunosuppressive treatments), or who are intolerant of or have contraindications to conventional therapy. Infliximab should be given as a planned course of treatment until treatment failure (including the need for surgery) or until 12 months after the start of treatment, whichever is shorter. People should then have their disease reassessed (see recommendation 1.2.16) to determine whether ongoing treatment is still clinically appropriate. [2010]

1.2.16.

Treatment with infliximab or adalimumab (see recommendations 1.2.12 and 1.2.15) should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary. Specialists should discuss the risks and benefits of continued treatment with patients and consider a trial withdrawal from treatment for all patients who are in stable clinical remission. People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again. [2010]

1.2.17.

Infliximab, within its licensed indication, is recommended for the treatment of people aged 6 to 17 years with severe active Crohn’s disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months. [2010]

1.2.18.

For the purposes of this guidance, severe active Crohn’s disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3 to 4 or more) diarrhoeal stools daily. People with severe active Crohn’s disease may or may not develop new fistulae or have extra-intestinal manifestations of the disease. This clinical definition normally, but not exclusively, corresponds to a Crohn’s Disease Activity Index (CDAI) score of 300 or more, or a Harvey-Bradshaw score of 8 to 9 or above. [2010]

1.2.19.

When using the CDAI and Harvey-Bradshaw Index, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the scores and make any adjustments they consider appropriate. [2010]

1.2.20.

Treatment with infliximab or adalimumab should only be started and reviewed by clinicians with experience of TNF inhibitors and of managing Crohn’s disease. [2010]

Ustekinumab and vedolizumab

1.2.21.

For guidance on using ustekinumab, see the NICE technology appraisal guidance on ustekinumab for moderately to severely active Crohn’s disease after previous treatment. [2019]

1.2.22.

For guidance on using vedolizumab, see the NICE technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn’s disease after prior therapy. [2019]

Follow-up during remission for people who choose not to have maintenance treatment

1.3.3.

When people choose not to receive maintenance treatment:

• discuss and agree with them and their family members or carers (as appropriate) plans for follow-up, including the frequency of follow-up and who they should see
• ensure they know which symptoms may suggest a relapse and should prompt a consultation with their healthcare professional (most frequently, unintended weight loss, abdominal pain, diarrhoea, general ill-health)
• ensure they know how to access the healthcare system if they experience a relapse
• discuss the importance of not smoking. [2012]

Maintenance treatment for people who choose this option

1.3.4.

Offer azathioprine or mercaptopurine^[5] as monotherapy to maintain remission when previously used with a conventional glucocorticosteroid or budesonide to induce remission. [2012]

1.3.5.

Consider azathioprine or mercaptopurine^[5] to maintain remission in people who have not previously received these drugs (particularly people with adverse prognostic factors such as early age of onset, perianal disease, glucocorticosteroid use at presentation and severe presentations). [2012]

1.3.6.

Consider methotrexate^[6],[7] to maintain remission only in people who:

• needed methotrexate to induce remission oror
• have tried but did not tolerate azathioprine or mercaptopurine for maintenance or
• have contraindications to azathioprine or mercaptopurine (for example, deficient thiopurine methyltransferase [TPMT] activity or previous episodes of pancreatitis).
• [2012]

1.3.7.

Do not offer a conventional glucocorticosteroid or budesonide to maintain remission. [2012]

See recommendations 1.2.10 and 1.2.11 for guidance on monitoring the effects of azathioprine, mercaptopurine and methotrexate.

See recommendation 1.2.16 for when to continue infliximab or adalimumab during remission.

Crohn’s disease limited to the distal ileum

1.5.1.

Consider surgery as an alternative to medical treatment early in the course of the disease for people whose disease is limited to the distal ileum, taking into account the following:

• benefits and risks of medical treatment and surgery
• risk of recurrence after surgery^[11]
• individual preferences and any personal or cultural considerations.

Record the person’s views in their notes. [2012]

1.5.2.

Consider surgery early in the course of the disease, or before or early in puberty, for children and young people whose disease is limited to the distal ileum and who have:

• growth impairment despite optimal medical treatment and/orand/or
• refractory disease.

Discuss treatment options with the child or young person and their family members or carers (as appropriate), and within the multidisciplinary team. [2012]

Managing strictures

1.5.3.

Consider balloon dilation, particularly for people with a single stricture that is short, straight and accessible by colonoscopy. [2012]

1.5.4.

Discuss the benefits and risks of balloon dilation and surgical interventions for managing strictures^[12] with:

• the person with Crohn’s disease and their family members or carers (as appropriate) and
• a surgeon and
• a gastroenterologist. [2012]

1.5.5.

Take into account the following factors when assessing options for managing a stricture:

• whether medical treatment has been optimised
• the number and extent of previous resections
• the rapidity of past recurrence (if appropriate)
• the potential for further resections
• the consequence of short bowel syndrome
• the person’s preference, and how their lifestyle and cultural background might affect management. [2012]

1.5.6.

Ensure that abdominal surgery is available for managing complications or failure of balloon dilation. [2012]

Complete macroscopic resection

The surgical removal of the section of bowel with visible (rather than microscopic) disease.

Why the committee made the recommendations

The recommendations apply to people with ileocolonic Crohn’s disease who have had complete macroscopic resection and who have no residual active disease. This is the population covered in the studies the committee reviewed. The committee was aware that a proportion of people could still have residual active disease after surgery. It agreed that in these people, their disease is not in remission and the recommendations for inducing remission in section 1.2 would apply.

The evidence showed that azathioprine in combination with up to 3 months’ metronidazole was effective in maintaining endoscopic remission. While there was some evidence of clinical benefit with azathioprine on its own, the effect was less certain. However, the committee included it as an option because some people have trouble tolerating metronidazole. The committee did not recommend metronidazole alone because, based on the evidence and their clinical experience, the potential benefits did not outweigh the potential harms (or adverse effects). Azathioprine can also be difficult to tolerate, and can cause adverse effects, so the committee looked at mercaptopurine as an alternative. However, mercaptopurine is not cost effective for maintaining remission because it has a high cost relative to the limited benefits it provides. The committee also reviewed the evidence for aminosalicylates (such as mesalazine). The evidence on relapse rates (assessed endoscopically) showed that aminosalicylates were not clinically or cost effective. Because of this, the 2012 recommendation on aminosalicylates was removed.

The committee made a recommendation on monitoring because of the tolerability issues and potential adverse effects of azathioprine and metronidazole. This is based on the 2012 recommendation on monitoring azathioprine when using it to induce remission.

There was limited evidence available for biologics, and a lot of uncertainty around how much benefit they provide. Biologics are also expensive, and all these factors together mean that they are not currently cost effective when compared with the other options for maintaining remission. To avoid unnecessarily changing treatments for people who started taking biologics before this guideline was published, the committee made a recommendation to cover this group.

The committee made a recommendation against offering budesonide because evidence shows that it is not beneficial in maintaining remission after surgery.

None of the included studies looked specifically at maintaining remission for children and young people after surgery, so the committee did not make separate recommendations for this population. In their experience children and young people are offered the same post-surgery treatment as adults.

There was no randomised controlled trial evidence on enteral nutrition. The committee recommended further research on this because it is sometimes used alone or with other maintenance therapy for maintaining remission after surgery.

How the recommendations might affect practice

The committee noted that the recommendations made are in line with current practice. There is variation across the UK in whether people receive 3 months of metronidazole after surgery.

The committee believe that the recommendation to not start biologics after surgery could potentially result in cost savings and maintain consistency in clinical practice.

Full details of the evidence and the committee’s discussion are in the evidence review: Crohn’s disease management – post surgical maintenance of remission.

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