Crohn's disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

ileocaecal disease not fistulating with <100 cm of bowel affected: initial presentation or relapse

mildly active

1st line – observation with monitoring or budesonide

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1st line –

observation with monitoring or budesonide

No active treatment is an option for certain patients with mild symptoms alone, provided that they are monitored closely for disease complications and progression.

Oral budesonide (the delayed-release formulation, which releases the drug into the small bowel and is active particularly at the terminal ileum) is the preferred treatment for inducing remission in mild to moderately active localised ileocaecal Crohn's disease.[106] The dose of budesonide may be tapered once clinical response is achieved. It has been shown to be superior to both placebo and aminosalicylates.[105][135]

The short-term efficacy of budesonide is less than that of systemic corticosteroids and therefore it has a limited role for those with severe disease or more extensive colonic involvement. Budesonide offers a lower likelihood of adverse events and adrenal suppression compared with other corticosteroids.[106][136][137] [ ]

Primary options

budesonide: treatment: 9 mg orally (delayed-release) once daily in the morning for up to 8 weeks, may repeat course for recurrences; remission maintenance: 6 mg orally (delayed-release) once daily in the morning for up to 3 months, followed by a gradual taper to discontinue treatment

Consider – management of extra-intestinal manifestations

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Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Extra-intestinal complications include arthropathies and cutaneous and ocular manifestations. These complications require specific individualised management.[192]

moderately active: initial presentation or non-corticosteroid-dependent/-refractory relapse

1st line – budesonide or oral systemic corticosteroid

Back

1st line –

budesonide or oral systemic corticosteroid

Oral budesonide (the delayed-release formulation, which releases the drug into the small bowel and is active particularly at the terminal ileum) has been shown to be more likely to induce remission than aminosalicylates or placebo, and should be used in preference to systemic corticosteroids (e.g., prednisolone) for limited terminal ileal/ascending colonic Crohn's disease.[105][106][138]

Oral systemic corticosteroids have proven efficacy in inducing remission.[139] However, corticosteroids have a significant adverse-effect profile and may predispose to serious infection, particularly in hospitalised older patients.[140][141][142][143]

Oral corticosteroids may cause profound and varied metabolic effects, including salt and water retention, osteoporosis, and hyperglycaemia. In addition, prolonged use leads to immunosuppression.

Primary options

Secondary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Extra-intestinal complications include arthropathies and cutaneous and ocular manifestations. These complications require specific individualised management, which may be best provided by a multidisciplinary team.[192]

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

2nd line – immunomodulator therapy + oral corticosteroid taper

Back

2nd line –

immunomodulator therapy + oral corticosteroid taper

Immunomodulators (e.g., azathioprine, mercaptopurine, methotrexate) are commonly used in combination with corticosteroids as a corticosteroid-sparing agent to help induce remission in active Crohn's disease (CD), although clinical evidence for their effectiveness has been conflicting and controversial.[144] Corticosteroid dose may be gradually tapered.

Immunomodulators are not recommended as monotherapy for induction of remission.[106][139] Methotrexate may be considered in corticosteroid-dependent patients who do not have alternative options, although evidence regarding induction for remission is weak.[106][145] [ ]

Methotrexate is a first-line immunosuppressant agent in patients with CD-associated arthropathy. Once a clinical response is achieved with intramuscular methotrexate, a switch to oral methotrexate may be made.

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Primary options

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

mercaptopurine: 0.75 to 1.5 mg/kg/day orally

Secondary options

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

and

folic acid: 1 mg orally once daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

3rd line – biological therapy ± azathioprine or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Back

3rd line –

biological therapy ± azathioprine or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Exposure to corticosteroids should be minimised in patients with Crohn's disease (CD). An effective approach is the early introduction of biological agents, such as tumour necrosis factor (TNF)-alpha inhibitors (e.g., infliximab, adalimumab, certolizumab pegol).[106][139]

The TNF-alpha inhibitors infliximab and adalimumab have demonstrated beneficial results in the treatment of CD.[151][152][153][154][155] [156]

The long-term drug safety profile is unclear. They may cause severe immunodeficiency resulting in super-infections, reactivation of tuberculosis, and development of lymphoma.[158] Antibodies to these therapies are a potential concern as they may lead to loss of clinical response and lower serum levels.[159][160]

The effect of this treatment may last for up to 54 weeks and reduces corticosteroid requirements.[161] Corticosteroid dose may be gradually tapered.

During administration and for 30 minutes after, patients may develop fever, chills, pruritus, urticaria, chest pain, hypotension, hypertension, and dyspnoea.

Trials have demonstrated benefits from combination immunomodulator therapy.[152][154][155][156][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

One meta-analysis has shown that infliximab is superior to the immunomodulator azathioprine for inducing corticosteroid-free remission, but importantly that the combination of infliximab and azathioprine is superior to infliximab alone.[145] [ ] Meta-analyses have shown that adalimumab and the combination of infliximab and azathioprine are the most effective therapies for induction and maintenance of remission of CD.[154][155]

Combination treatment is associated with a high degree of immunosuppression, and higher risk of lymphoma; therefore, particular caution is warranted.[153]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by European guidelines.[153] The American Gastroenterology Association recommends combination therapy over adalimumab monotherapy.[139]

Evidence from Cochrane reviews supports the use of adalimumab or certolizumab pegol as effective treatments for the induction of remission and clinical response in people with moderate to severely active CD.[153][157]

Several biosimilars of TNF-alpha inhibitors have been marketed (e.g., biosimilar monoclonal antibody of infliximab, biosimilar monoclonal antibody of adalimumab); however, availability and use varies depending on the location. A biosimilar agent is highly similar, but not identical, to the original biological agent. Biosimilar agents are comparable to the reference agent in terms of quality, safety, and efficacy.[127][128][129][130]

Vedolizumab (an integrin receptor antagonist), ustekinumab (an interleukin [IL]-12 and IL-23 antagonist), or risankizumab (an IL-23 antagonist) may be used instead of TNF-alpha inhibitor therapies for induction of remission in CD in selected patients or where TNF-alpha inhibitor therapy has failed.[106][121][139][164][165][166][167][168][169][170]

Vedolizumab is recommended for patients with moderately to severely active CD who cannot receive or who have previously failed TNF-alpha inhibitor therapy.[71][106][125][165] It has been shown to have a good safety profile, although trials are ongoing.[120][124][125][126]

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

Risankizumab is approved by the FDA and European Medicines Agency (EMA) for the treatment of moderate to severely active CD. It has been found to be more effective than placebo for inducing clinical remission in patients with active CD in clinical trials.[170][172] Risankizumab has a safety profile comparable to other approved biological therapies.[173] It is reported to be safe and effective for maintenance of remission and as induction therapy, although safety trials are ongoing.[174][175][176] NICE recommends risankizumab as an option for treating moderately to severely active CD in patients aged ≥16 years, only if there is an inadequate response to a previous biological treatment, a previous biological treatment was not tolerated, or TNF-alpha inhibitors are not suitable.[177]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Upadacitinib, a JAK inhibitor, is approved by the FDA and EMA for adults with moderately to severely active CD who have had an inadequate response or intolerance to one or more TNF-alpha inhibitors.[178][179][180][181] NICE recommends upadacitinib as an option for moderately to severely active CD only if there is an inadequate response, if a previous biological treatment was not tolerated, or if TNF-alpha inhibitors are contraindicated.[182] It is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin. Upadacitinib may be considered earlier in the treatment cascade if there is co-existing pathology such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, as it is also licensed to treat these conditions. As it is administered orally, upadacitinib is suitable for most patients provided it is not contraindicated.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

and

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

ustekinumab: induction regimen: body weight ≤55 kg: 260 mg intravenous infusion as a single dose over 1 hour; body weight 56-85 kg: 390 mg intravenous infusion as a single dose over 1 hour; body weight >85 kg: 520 mg intravenous infusion as a single dose over 1 hour; maintenance regimen: 90 mg subcutaneously every 8 weeks (starting 8 weeks after induction regimen)

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

moderately active: relapse corticosteroid-dependent/-refractory

1st line – consideration of early initiation of biological therapies or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Back

1st line –

consideration of early initiation of biological therapies or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Exposure to corticosteroids should be minimised in patients with Crohn's disease (CD). An effective approach is the early introduction of biological agents, such as tumour necrosis factor (TNF)-alpha inhibitors, particularly in corticosteroid-dependent, corticosteroid-refractory, or corticosteroid-intolerant patients.[106][139]

The TNF-alpha inhibitors infliximab and adalimumab have demonstrated beneficial results in the treatment of CD.[151][152][153][154][155][156]

The long-term drug safety profile is unclear. They may cause severe immunodeficiency resulting in superinfections, reactivation of tuberculosis, and development of lymphoma.[158] Antibodies to these therapies are a potential concern as they may lead to loss of clinical response and lower serum levels.[159][160] The effect of this treatment may last for up to 54 weeks and reduce corticosteroid requirements.[161]

Vedolizumab (an integrin receptor antagonist), ustekinumab (an interleukin [IL]-12 and IL-23 antagonist), or risankizumab (an IL-23 antagonist) may be used instead of TNF-alpha inhibitor therapies in selected patients or where TNF-alpha inhibitor therapy has failed.[106][121][139][164][165][166][167][168][169][170]

Ustekinumab has been approved in Europe and the UK to treat patients with moderately to severely active CD who have an inadequate response or lost response to, are intolerant of, or are contraindicated to conventional therapy or TNF-alpha inhibitor therapy.[106][169] The FDA has approved ustekinumab for the treatment of moderately to severely active CD in adults who have an inadequate response to, or are intolerant of immunomodulators or corticosteroids, or who failed or were intolerant to treatment with one or more TNF-alpha inhibitors. Upadacitinib may be considered earlier in the treatment cascade if there is co-existing pathology such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, as it is also licensed to treat these conditions. As it is administered orally, upadacitinib is suitable for most patients provided it is not contraindicated.

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

Risankizumab is approved by the FDA and EMA for the treatment of moderate to severely active CD. It has been found to be more effective than placebo for inducing clinical remission in patients with active CD in clinical trials.[170][172] Risankizumab has a safety profile comparable to other approved biological therapies.[173] It is reported to be safe and effective for maintenance of remission and as induction therapy, although safety trials are ongoing.[174][175][176] NICE recommends risankizumab as an option for treating moderately to severely active CD in patients aged ≥16 years, only if there is an inadequate response to a previous biological treatment, a previous biological treatment was not tolerated, or TNF-alpha inhibitors are not suitable.[177]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Corticosteroid dose may be gradually tapered.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

2nd line – methotrexate

Back

2nd line –

methotrexate

Methotrexate may be considered in corticosteroid-dependent patients who do not have alternative options if it was not used initially, although evidence regarding induction for remission is weak.[106][145] [ ]

Methotrexate must be stopped in those planning pregnancy.[106][149][150]

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Primary options

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

3rd line – surgery

Back

3rd line –

surgery

Patients should be considered for surgery when medical therapy alone does not work or the symptoms worsen.[71][184][185] If there are obstructive symptoms, surgery may be considered early.

Although patients may respond to oral corticosteroids, 80% will require surgery within 5 years of diagnosis.

Limited ileocaecal resection has shown 35% to 40% recurrence rates at 10 years, with 50% not having symptoms of similar severity at 15 years. There are no similar data available for medical therapy.[186][187][188][189]

Due to the high success rate of limited ileocaecal resection for patients with Crohn's disease (CD) limited to this area, surgery is recommended as a reasonable alternative to infliximab treatment in this patient group.[107] It is also recommended as an alternative to medical escalation in this group.[190]

Preoperative optimisation is a key element in successful management of complex situations and chronic disease. Many aspects of perioperative care are common to all abdominal procedures, although some are particularly important in the context of CD.[107] Preoperative reduction of corticosteroid doses may reduce postoperative complications but should be monitored carefully to avoid increasing disease burden.[107] Nutritional optimisation prior to surgery, with enteral or parenteral nutrition, is recommended for those patients with nutritional deficiencies.[107] Evidence suggests that preoperative treatment with tumour necrosis factor-alpha inhibitor, vedolizumab, or ustekinumab does not increase the risk of postoperative complications in patients with CD having abdominal surgery.[107][131][132]

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

severely active: initial presentation or non-corticosteroid-dependent/-refractory relapse

1st line – hospitalisation + oral or intravenous corticosteroid + consideration of surgery

Back

1st line –

hospitalisation + oral or intravenous corticosteroid + consideration of surgery

Hospitalisation, resuscitation, and urgent surgical review are required in patients with the following signs and symptoms: high fever; abdominal mass; signs of intestinal obstruction; frequent vomiting. The possibility of an intra-abdominal abscess or perforation requires exclusion.

Patients with severely active disease can be treated initially with oral or intravenous corticosteroids.[71]

Primary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

hydrocortisone sodium succinate: 100 mg intravenously every 8 hours

methylprednisolone: 12-15 mg intravenously every 6 hours

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

Consider – immunomodulator therapy + oral corticosteroid taper

Back

Consider –

immunomodulator therapy + oral corticosteroid taper

Additional treatment recommended for SOME patients in selected patient group

Oral corticosteroids are an effective therapy, with the addition of immunomodulators, such as azathioprine, mercaptopurine, or methotrexate, for patients who have relapsed.[144][160]

Immunomodulators inhibit DNA and RNA synthesis, causing cell proliferation to arrest. This results in suppression of the immune system.

Methotrexate is a first-line immunosuppressant agent in patients with Crohn's disease-associated arthropathy. Once a clinical response is achieved with intramuscular methotrexate, a switch to oral methotrexate may be made.

The clinician should refer to the specific cautions concerning the use of immunomodulators.

Corticosteroid dose may be gradually tapered.

Primary options

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

mercaptopurine: 0.75 to 1.5 mg/kg/day orally

Secondary options

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

and

folic acid: 1 mg orally once daily

2nd line – biological therapy or Janus kinase (JAK) inhibitor or surgery

Back

2nd line –

biological therapy or Janus kinase (JAK) inhibitor or surgery

Tumour necrosis factor (TNF)-alpha inhibitors, with or without an immunomodulator, are an appropriate option for patients with severely active disease, objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[71][106][139][160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Combination treatment is associated with a high degree of immunosuppression, and higher risk of lymphoma; therefore, it should only be used by experts experienced in managing this patient group.[153]

Combination treatment with infliximab and a thiopurine is recommended to induce remission in patients with moderately to severely active Crohn's disease (CD) who have had inadequate response to conventional therapy.[154] This combination is an option for patients with objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by the European Crohn's and Colitis Organisation guideline on CD.[153] However, the American Gastroenterological Association recommends combination therapy over adalimumab monotherapy.[139]

Meta-analyses have shown that adalimumab and the combination of infliximab and azathioprine are the most effective therapies for induction and maintenance of remission of CD.[154][155]

Vedolizumab (an integrin receptor antagonist), ustekinumab (an interleukin [IL]-12 and IL-23 antagonist), or risankizumab (an IL-23 antagonist) may be used instead of TNF-alpha inhibitor therapies for induction of remission in CD in selected patients, or where conventional therapy and/or TNF-alpha inhibitor therapy has failed.[106][121][139][164][165][166][167][168][169][170]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Upadacitinib, a JAK inhibitor, is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for adults with moderately to severely active CD who have had an inadequate response or intolerance to one or more TNF-alpha inhibitors.[178][179][180][181] NICE recommends upadacitinib as an option for moderately to severely active CD only if there is an inadequate response, if a previous biological treatment was not tolerated, or if TNF-alpha inhibitors are contraindicated.[182] It is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin. Upadacitinib may be considered earlier in the treatment cascade if there is co-existing pathology such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, as it is also licensed to treat these conditions. As it is administered orally, upadacitinib is suitable for most patients provided it is not contraindicated.

Patients should be considered for surgery when medical therapy alone does not work or the symptoms worsen.[71][184][185] Surgery is a reasonable alternative for some patients in preference to biological agents, although opinions differ as to the optimal timing. Some experts recommend surgery after 2-6 weeks of ineffective medical therapy, whereas other experts advocate immediate surgery.[184] Patients with severe symptoms despite corticosteroids or biological therapy require practical treatment that is individualised according to the presentation.

Preoperative optimisation is a key element in successful management of complex situations and chronic disease. Many aspects of perioperative care are common to all abdominal procedures, although some are particularly important in the context of CD.[107] Preoperative reduction of corticosteroid doses may reduce postoperative complications but should be monitored carefully to avoid increasing disease burden.[107] Nutritional optimisation prior to surgery, with enteral or parenteral nutrition, is recommended for those patients with nutritional deficiencies.[107] Evidence suggests that preoperative treatment with TNF-alpha inhibitor, vedolizumab, or ustekinumab does not increase the risk of postoperative complications in patients with CD having abdominal surgery.[107][131][132]

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

-- AND --

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 120 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – gradual tapered dose reduction of corticosteroids

Back

Consider –

gradual tapered dose reduction of corticosteroids

Additional treatment recommended for SOME patients in selected patient group

Corticosteroids may be gradually tapered.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

severely active: relapse corticosteroid-dependent/-refractory

1st line – hospitalisation + consideration of early initiation of biological therapy or Janus kinase (JAK) inhibitor or surgery

Back

1st line –

hospitalisation + consideration of early initiation of biological therapy or Janus kinase (JAK) inhibitor or surgery

Patients with severe symptoms require hospitalisation.

Increasingly a top-down approach to treatment is being advocated. This strategy involves initiating more potent treatments (e.g., tumour necrosis factor [TNF]-alpha inhibitor therapies) early in the disease process. The potential merits of this approach are a reduction in the need for repeated courses of corticosteroids, thus avoiding the side effects and risks of corticosteroid dependence. It has been postulated that a more aggressive approach may reduce the need for future surgery. Clinical criteria and patient factors are used on a patient-by-patient basis to determine the threshold at which TNF-alpha inhibitor or immunomodulator therapy are commenced, depending on predicted disease course.[105]

TNF-alpha inhibitors, with or without an immunomodulator, is an appropriate option for patients with severely active disease, objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[71][106][139][160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Combination treatment with infliximab and a thiopurine is recommended to induce remission in patients with moderately to severely active Crohn's disease (CD) who have had inadequate response to conventional therapy.[153] This combination is an option for patients with objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Meta-analyses have shown that adalimumab and the combination of infliximab and azathioprine are the most effective therapies for induction and maintenance of remission of CD.[154][155]

Combination treatment is associated with a high degree of immunosuppression, and higher risk of lymphoma; therefore, it should only be used by experts experienced in managing this patient group.[153]

Vedolizumab (an integrin receptor antagonist), ustekinumab (an interleukin [IL]-12 and IL-23 antagonist), or risankizumab (an IL-23 antagonist) may be used in those who have relapsed on other therapy, which may include TNF-alpha inhibitor therapy.[106][121][139][164][165][166][167][168][169][170]

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

Risankizumab is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of moderate to severely active CD. It has been found to be more effective than placebo for inducing clinical remission in patients with active CD in clinical trials.[170][172] Risankizumab has a safety profile comparable to other approved biological therapies.[173] It is reported to be safe and effective for maintenance of remission and as induction therapy, although safety trials are ongoing.[174][175][176] NICE recommends risankizumab as an option for treating moderately to severely active CD in patients aged ≥16 years, only if there is an inadequate response to a previous biological treatment, a previous biological treatment was not tolerated, or TNF-alpha inhibitors are not suitable.[177]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Upadacitinib, a JAK inhibitor, is approved by the FDA and EMA for adults with moderately to severely active CD who have had an inadequate response or intolerance to one or more TNF-alpha inhibitors.[178][179][180][181] NICE recommends upadacitinib as an option for moderately to severely active CD only if there is an inadequate response, if a previous biological treatment was not tolerated, or if TNF-alpha inhibitors are contraindicated.[182] It is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin. It is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin. Upadacitinib may be considered earlier in the treatment cascade if there is co-existing pathology such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis, as it is also licensed to treat these conditions. As it is administered orally, upadacitinib is suitable for most patients provided it is not contraindicated.

Patients should be considered for surgery when medical therapy alone does not work or the symptoms worsen.[71][184][185] Surgery is a reasonable alternative for some patients in preference to biological therapy, although opinions differ as to the optimal timing. Some experts recommend surgery after 2-6 weeks of ineffective medical therapy, whereas other experts advocate immediate surgery.[184]

Preoperative optimisation is a key element in successful management of complex situations and chronic disease. Many aspects of perioperative care are common to all abdominal procedures, although some are particularly important in the context of CD.[107] Preoperative reduction of corticosteroid doses may reduce postoperative complications but should be monitored carefully to avoid increasing disease burden.[107] Nutritional optimisation prior to surgery, with enteral or parenteral nutrition, is recommended for those patients with nutritional deficiencies.[107] Evidence suggests that preoperative treatment with TNF-alpha inhibitor, vedolizumab, or ustekinumab does not increase the risk of postoperative complications in patients with CD having abdominal surgery.[107][131][132]

Patients with severe symptoms despite corticosteroids or biological therapy require practical treatment that is individualised according to the presentation.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

-- AND --

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – gradual tapered dose reduction of corticosteroids

Back

Consider –

gradual tapered dose reduction of corticosteroids

Additional treatment recommended for SOME patients in selected patient group

If the patient is already taking existing corticosteroid therapy, the dose may be gradually tapered depending on clinical response.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

colonic disease not fistulating: initial presentation or relapse

mildly active

1st line – oral corticosteroid

Back

1st line –

oral corticosteroid

Oral corticosteroids are recommended as initial treatment. Colonic-release budesonide may be considered as it has a more distal distribution than other budesonide formulations.

Corticosteroids may cause profound and varied metabolic effects, including salt and water retention, osteoporosis, and hyperglycaemia. In addition, prolonged use leads to immunosuppression.

Primary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

Consider – immunomodulator therapy

Back

Consider –

immunomodulator therapy

Additional treatment recommended for SOME patients in selected patient group

Immunomodulators (azathioprine, mercaptopurine, methotrexate) are commonly used in combination with corticosteroids to help induce remission in active Crohn's disease, although clinical evidence for their effectiveness has been conflicting and controversial.[144]

Immunomodulators inhibit DNA and RNA synthesis, causing cell proliferation to arrest. This results in suppression of the immune system. Immunomodulators should never be started if there is any indication of sepsis.

Immunomodulators are not recommended as monotherapy for induction of remission.[106] In corticosteroid-dependent patients who do not have alternative options, methotrexate may be considered as a monotherapy, although evidence for induction of remission is weak.[106][145] [ ]

Clinicians should refer to the specific cautions concerning the use of immunomodulators. When initiated, the therapeutic response to immunosuppressants is slow, with improvement usually observed within 3-6 months, during which time corticosteroids should be tapered slowly.[145][146][147][148]

Methotrexate must be stopped in those planning pregnancy.[106][149][150]

Primary options

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

and

folic acid: 1 mg orally once daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

2nd line – surgery

Back

2nd line –

surgery

Surgery should be considered early for colonic disease if there is no improvement with initial therapies, and patients should be managed on an individual basis by a multidisciplinary team.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

moderately or severely active: initial presentation or non-corticosteroid-dependent/-refractory relapse

1st line – oral or intravenous corticosteroid + immunomodulator therapy + consideration for surgery

Back

1st line –

oral or intravenous corticosteroid + immunomodulator therapy + consideration for surgery

Immunomodulators (azathioprine, mercaptopurine, methotrexate) are commonly used in combination with oral corticosteroids to help induce remission in active Crohn's disease (CD), although clinical evidence for their effectiveness has been conflicting and controversial.[144] This combination is also effective for patients who have relapsed.[144]

Immunomodulators inhibit DNA and RNA synthesis, causing cell proliferation to arrest. This results in suppression of the immune system.

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Surgery should be considered, and patients should be managed on an individual basis by a multidisciplinary team. Preoperative optimisation of corticosteroid use, nutrition, and biological therapy should be considered in all patients having surgery.[107][131][132]

Primary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

hydrocortisone sodium succinate: 100 mg intravenously every 8 hours

methylprednisolone: 12-15 mg intravenously every 6 hours

-- AND --

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

mercaptopurine: 0.75 to 1.5 mg/kg/day orally

Secondary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

hydrocortisone sodium succinate: 100 mg intravenously every 8 hours

methylprednisolone: 12-15 mg intravenously every 6 hours

-- AND --

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

-- AND --

folic acid: 1 mg orally once daily

Consider – topical rectal hydrocortisone

Back

Consider –

topical rectal hydrocortisone

Additional treatment recommended for SOME patients in selected patient group

There are no data from randomised controlled trials on topical therapy for left-sided Crohn's disease, although hydrocortisone enemas or suppositories are often recommended.

Primary options

hydrocortisone rectal: 100 mg/60 mL enema twice daily

hydrocortisone rectal: 90 mg (one applicatorful) once or twice daily

hydrocortisone rectal: 25-30 mg suppository twice daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

2nd line – biological therapy or Janus kinase (JAK) inhibitor + consideration for surgery

Back

2nd line –

biological therapy or Janus kinase (JAK) inhibitor + consideration for surgery

It may be appropriate in some patients with severe and aggressive colonic disease (often when combined with perianal infection associated with systemic signs [sepsis]) to rest the bowel with a diverting stoma before tumour necrosis factor (TNF)-alpha inhibitor therapy can be used safely.

TNF-alpha inhibitors (infliximab, adalimumab, certolizumab pegol) can be considered to treat severely active Crohn's disease (CD) with or without an immunomodulator such as azathioprine.[71][106][139][155] Combination treatment is associated with a high degree of immunosuppression, and higher risk of lymphoma; therefore, it should only be used by experts experienced in managing this patient group.[153]

Combination treatment with infliximab and a thiopurine is recommended to induce remission in patients with moderately to severely active CD who have had inadequate response to conventional therapy.[154] This combination is an option for patients with objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by the European Crohn's and Colitis Organisation guideline on CD.[153] However, the American Gastroenterology Association recommends combination therapy over adalimumab monotherapy.[139]

Meta-analyses have shown that adalimumab and the combination of infliximab and azathioprine are the most effective therapies for induction and maintenance of remission of CD.[154][155]

The long-term drug safety profile of TNF-alpha inhibitor therapies is unclear. They may cause severe immunodeficiency resulting in superinfections, reactivation of tuberculosis, and development of lymphoma.[158] Furthermore, antibodies to these therapies are a potential concern as they may lead to loss of clinical response and lower serum levels.[159][160] The effect of this treatment may last up to 54 weeks and reduces corticosteroid requirements.[161]

Patients may be able to gradually taper the dose of any existing corticosteroid therapy.

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

Risankizumab is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of moderate to severely active CD. It has been found to be more effective than placebo for inducing clinical remission in patients with active CD in clinical trials.[170][172] Risankizumab has a safety profile comparable to other approved biologic therapies.[173] It is reported to be safe and effective for maintenance of remission and as induction therapy, although safety trials are ongoing.[174][175][176] NICE recommends risankizumab as an option for treating moderately to severely active CD in patients aged ≥16 years, only if there is an inadequate response to a previous biological treatment, a previous biological treatment was not tolerated, or TNF-alpha inhibitors are not suitable.[177]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

-- AND --

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – topical rectal hydrocortisone

Back

Consider –

topical rectal hydrocortisone

Additional treatment recommended for SOME patients in selected patient group

There are no data from randomised controlled trials on topical therapy for left-sided Crohn's disease, although hydrocortisone enemas or suppositories are often recommended.

Primary options

hydrocortisone rectal: 100 mg/60 mL enema twice daily

hydrocortisone rectal: 90 mg (one applicatorful) once or twice daily

hydrocortisone rectal: 25-30 mg suppository twice daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

3rd line – surgery

Back

3rd line –

surgery

Surgery may be required. There is a risk of perforation, obstruction, and development of a toxic megacolon.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

moderately or severely active: relapse corticosteroid-dependent/-refractory

1st line – early initiation of biological therapy or Janus kinase (JAK) inhibitor or consideration for surgery

Back

1st line –

early initiation of biological therapy or Janus kinase (JAK) inhibitor or consideration for surgery

Increasingly a top-down approach to treatment is being advocated. This strategy involves initiating more potent treatments (e.g., tumour necrosis factor [TNF]-alpha inhibitor therapies) early in the disease process. The potential merits of this approach are a reduction in the need for repeated courses of corticosteroids, thus avoiding the side effects and risks of corticosteroid dependence. It has been postulated that a more aggressive approach may reduce the need for future surgery. The benefits of this versus a standard approach have not been extensively studied.

TNF-alpha inhibitor drug treatment, with or without an immunomodulator, is an appropriate option for patients with severely active disease, objective evidence of active disease that has relapsed, or for people who are non-responsive to initial therapy.[71][106][139][160][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by the European Crohn's and Colitis Organisation guideline on CD.[153] However, the American Gastroenterology Association recommends combination therapy over adalimumab monotherapy.[139]

Meta-analyses have shown that adalimumab and the combination of infliximab and azathioprine are the most effective therapies for induction and maintenance of remission of CD.[154][155]

Combination treatment is associated with a high degree of immunosuppression, and higher risk of lymphoma; therefore, it should only be used by experts experienced in managing this patient group.[153]

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

Risankizumab is approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of moderate to severely active CD. It has been found to be more effective than placebo for inducing clinical remission in patients with active CD in clinical trials.[170][172] Risankizumab has a safety profile comparable to other approved biologic therapies.[173] It is reported to be safe and effective for maintenance of remission and as induction therapy, although safety trials are ongoing.[174][175][176] NICE recommends risankizumab as an option for treating moderately to severely active CD in patients aged ≥16 years, only if there is an inadequate response to a previous biological treatment, a previous biological treatment was not tolerated, or TNF-alpha inhibitors are not suitable.[177]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

There is a risk of perforation, obstruction, and development of a toxic megacolon.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

-- AND --

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

upadacitinib: 45 mg orally once daily for 12 weeks, followed by 15-30 mg once daily

Consider – topical rectal hydrocortisone

Back

Consider –

topical rectal hydrocortisone

Additional treatment recommended for SOME patients in selected patient group

There are no data from randomised controlled trials on topical therapy for left-sided Crohn's disease, although hydrocortisone enemas or suppositories are often recommended.

Primary options

hydrocortisone rectal: 100 mg/60 mL enema twice daily

hydrocortisone rectal: 90 mg (one applicatorful) once or twice daily

hydrocortisone rectal: 25-30 mg suppository twice daily

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

2nd line – surgery

Back

2nd line –

surgery

Surgery may be required. There is a risk of perforation, obstruction, and development of a toxic megacolon.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

Consider – antibiotics

Back

Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics can be added if septic complications are suspected.[106][139]

Routine use of antibiotics in the absence of suspected sepsis is not supported by evidence from controlled clinical trials.[71][106][139][183]

extensive small bowel disease (>100 cm of bowel affected) not fistulating: initial presentation or relapse

1st line – oral corticosteroid + early introduction of immunomodulators

Back

1st line –

oral corticosteroid + early introduction of immunomodulators

Treatment with corticosteroids and the early introduction of immunomodulators (azathioprine, mercaptopurine, and methotrexate) for their corticosteroid-sparing effect are considered appropriate as first-line therapies in this group.

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Primary options

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

mercaptopurine: 0.75 to 1.5 mg/kg/day orally

-- AND --

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

Secondary options

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

and

folic acid: 1 mg orally once daily

-- AND --

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

Consider – nutritional therapy

Back

Consider –

nutritional therapy

Additional treatment recommended for SOME patients in selected patient group

In extensive disease (>100 cm of bowel affected) there is a larger inflammatory burden and patients are at risk of nutritional deficiencies. Nutritional therapy can be considered both as an adjunct and as primary therapy in patients with mild disease.[199] Nutrition approaches include a trial of exclusive enteral feeding with an elemental or polymeric diet. The aim of this is to suppress intestinal inflammation and promote mucosal healing. Trials of enteral feeding are often limited by poor patient tolerability.

Consider – early consideration of biological therapy

Back

Consider –

early consideration of biological therapy

Additional treatment recommended for SOME patients in selected patient group

Biological treatment with tumour necrosis factor (TNF)-alpha inhibitor therapy should be considered early, as evidence has demonstrated that early intervention is beneficial in these patients, who have a poorer long-term prognosis compared with people with more localised disease.[193][194] However, the long-term safety profile of TNF-alpha inhibitors is unclear. Furthermore, antibodies to these therapies are a potential concern as they may lead to loss of clinical response and lower serum levels.[159][160]

The use of certolizumab pegol in Crohn's disease (CD) has been approved in the US and other countries, but the European Medicines Agency has refused a marketing authorisation for this indication.

Vedolizumab (an integrin receptor antagonist), ustekinumab (an interleukin [IL]-12 and IL-23 antagonist), or risankizumab (an IL-23 antagonist) may be used instead of TNF-alpha inhibitor therapies for induction of remission in CD in selected patients, or where conventional therapy and/or TNF-alpha inhibitor therapy has failed.[106][121][139][164][165][166][167][168][169][170]

Data show that vedolizumab and ustekinumab have favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]

The same precautions are taken as with TNF-alpha inhibitors until results of longer-term data are known.

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Secondary options

vedolizumab: 300 mg intravenous infusion at weeks 0, 2, and 6 initially, then every 8 weeks thereafter; 108 mg subcutaneously every 2 weeks

risankizumab: 600 mg intravenously given at weeks 0, 4, and 8 initially, followed by 180-360 mg subcutaneously every 8 weeks starting at week 12

Consider – consideration of surgical resection

Back

Consider –

consideration of surgical resection

Additional treatment recommended for SOME patients in selected patient group

Surgical resection needs to be considered very carefully in this patient group, as there is a risk of developing short bowel syndrome.

Strictureplasty for strictured segments <10 cm may be performed to preserve small bowel length and is considered safe, but where there is extensive disease, the risk of perforation and bleeding are increased.[195][196]

Longer segments have been successfully treated with non-conventional strictureplasty, particularly where short-bowel syndrome is likely to become a problem.[197]

Long-term recurrence rates remain unclear and there have been reports of carcinomas occurring at strictureplasty sites.

Deferred surgery is the preferred option in adult patients with Crohn's disease presenting with acute small-bowel obstruction without bowel ischaemia or peritonitis.[107]

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

upper gastrointestinal disease (oesophageal and/or gastroduodenal disease) not fistulating: initial presentation or relapse

1st line – proton-pump inhibitor

Back

1st line –

proton-pump inhibitor

This particular subtype of Crohn's disease is being increasingly diagnosed on upper gastrointestinal endoscopy.

Evidence for treatment is mainly based on case series, but most experts agree that a proton-pump inhibitor is necessary.[200]

Primary options

lansoprazole: 30 mg orally once daily

omeprazole: 40 mg orally once daily

Consider – oral corticosteroid

Back

Consider –

oral corticosteroid

Additional treatment recommended for SOME patients in selected patient group

Most experts agree that therapeutic doses of systemic corticosteroids should be combined with proton pump inhibitors and methotrexate, azathioprine, or mercaptopurine, as described in other disease phenotypes.[200]

Primary options

prednisolone: 0.5 to 0.75 mg/kg/day orally, taper gradually according to response

Consider – immunomodulator therapy

Back

Consider –

immunomodulator therapy

Additional treatment recommended for SOME patients in selected patient group

Oral corticosteroids are an effective therapy, with the addition of immunomodulators, such as azathioprine, mercaptopurine, or methotrexate, for patients who have relapsed.

Immunomodulators inhibit DNA and RNA synthesis, causing cell proliferation to arrest. This results in suppression of the immune system.

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Primary options

azathioprine: 1 to 2.5 mg/kg/dose orally once daily

mercaptopurine: 0.75 to 1.5 mg/kg/day orally

Secondary options

methotrexate: 25 mg orally/subcutaneously/intramuscularly once weekly

and

folic acid: 1 mg orally once daily

Consider – early consideration of tumour necrosis factor (TNF)-alpha inhibitor therapy

Back

Consider –

early consideration of tumour necrosis factor (TNF)-alpha inhibitor therapy

Additional treatment recommended for SOME patients in selected patient group

Upper gastrointestinal Crohn's disease (CD) is thought to be associated with a worse prognosis. Therefore, TNF-alpha inhibitors must be considered early.[106]

Evidence has demonstrated that early intervention is beneficial in patients who have a poorer long-term prognosis compared with people with more localised disease.[193][194] However, the long-term safety profile of TNF-alpha inhibitors is unclear. Furthermore, antibodies to these therapies are a potential concern as they may lead to loss of clinical response and lower serum levels.[159][160]

Evidence from Cochrane reviews support the use of adalimumab and certolizumab pegol as effective treatments for the induction of remission and clinical response in people with moderate to severely active CD.[153][157]

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

certolizumab pegol: 400 mg subcutaneously given at weeks 0, 2, and 4, followed by 400 mg every 4 weeks beginning at week 8

Consider – surgery or dilation

Back

Consider –

surgery or dilation

Additional treatment recommended for SOME patients in selected patient group

Surgery or dilation is appropriate treatment for those with obstructive symptoms.

Consider – management of extra-intestinal manifestations

Back

Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

perianal or fistulating disease: initial presentation or relapse

perianal fistulae

1st line – seton placement + drainage of abscess if present

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1st line –

seton placement + drainage of abscess if present

Perianal or intra-abdominal abscess should be excluded clinically. If there is clinical suspicion of an abscess, then imaging with computed tomography scan for intra-abdominal sepsis, or with magnetic resonance imaging for pelvic/perianal sepsis, will be necessary. Any abscess should be treated surgically or radiologically drained prior to commencement of immunosuppressant or immunomodulation therapy.

Seton placement is recommended alongside antibiotics and tumour necrosis factor-alpha inhibitors as initial treatment.[91][106][139]

Consider – antibiotics

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Consider –

antibiotics

Additional treatment recommended for SOME patients in selected patient group

Antibiotics should be added in as initial medical therapy if there is evidence of perianal infection.[91][106][139][209] Antibiotic protocols vary locally.

Consider – tumor necrosis factor (TNF)-alpha inhibitor therapy ± surgery

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Consider –

tumor necrosis factor (TNF)-alpha inhibitor therapy ± surgery

Additional treatment recommended for SOME patients in selected patient group

Infliximab or adalimumab is recommended to treat perianal fistulae.[106] One randomised controlled trial found that fistula healing was sustained for up to 2 years in an open-label extension with adalimumab.[205] The conclusion of one study suggests that combination therapy of adalimumab and ciprofloxacin may be more effective than adalimumab alone to achieve fistula closure in Crohn's disease (CD), although on discontinuation of antibiotic therapy the initial benefit was not maintained.[206]

TNF-alpha inhibitor therapy may be combined with surgery if patients are amenable. One patient preference randomised trial reported improved healing with short-term TNF-alpha inhibitor therapy plus surgery compared with TNF-alpha inhibitor therapy alone in patients with CD with perianal fistulae.[207]

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

Consider – management of extra-intestinal manifestations

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Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

non-perianal fistulae

1st line – multidisciplinary input + supportive care

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1st line –

multidisciplinary input + supportive care

Enterocutaneous fistulae, ano- and rectogenital fistulae related to Crohn's disease are very complex and rare; they should be treated by an experienced multidisciplinary team.[107] Studies are needed to assess the efficacy of combined surgical and medical therapy for better achievement of complete response in this challenging patient group.

The patient's nutritional state needs to be optimised and any sepsis controlled with antibiotics. The decision to operate should be made by a multidisciplinary team of colorectal surgeons and gastroenterologists.[202]

Consider – surgery

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Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

The decision to operate should be made by a multidisciplinary team of colorectal surgeons and gastroenterologists.[202]

Management of fistulae to other organs may require surgical diversion of the bowel with an -ostomy, and any active intestinal inflammation should be treated prior to surgery.

Consider – antibiotic

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Consider –

antibiotic

Additional treatment recommended for SOME patients in selected patient group

When managing enterocutaneous fistulae, any sepsis should be controlled with antibiotics as per hospital guidelines.

Consider – tumor necrosis factor (TNF)-alpha inhibitor therapy

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Consider –

tumor necrosis factor (TNF)-alpha inhibitor therapy

Additional treatment recommended for SOME patients in selected patient group

The role of infliximab in the treatment of non-perianal fistulae is not well-established. Some studies have suggested that closure of fistulae or complete cessation of fistula drainage following infliximab is less likely among patients with non-perianal (rectovaginal or mixed fistulae) compared with perianal fistulae.[210][211]

However, TNF-alpha inhibitor therapy is still used for non-perianal fistulating Crohn's disease, and is recommended to control inflammation or maintain remission.[70][203]

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

Consider – management of extra-intestinal manifestations

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Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

perianal abscess

1st line – antibiotics

Back

1st line –

antibiotics

Antibiotics are the mainstay of treatment in perianal abscesses.[91][106][139][209] Antibiotic protocols vary locally.

Consider – seton placement + drainage

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Consider –

seton placement + drainage

Additional treatment recommended for SOME patients in selected patient group

Antibiotic therapy may be often combined with drainage of the collection, depending on the size of abscess and response to antibiotics.[91][106][139] Perianal abscesses may need incision and drainage under anaesthesia with washout of the cavity, and a seton suture may be placed where the abscess is associated with a perianal fistula.[212]

Consider – tumor necrosis factor (TNF)-alpha inhibitor therapy

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Consider –

tumor necrosis factor (TNF)-alpha inhibitor therapy

Additional treatment recommended for SOME patients in selected patient group

Where the abscess has originated from perianal fistulating disease, the focus then becomes more on treatment of the fistula itself, with use of immunosuppressants such as TNF-alpha inhibitors. However, wherever possible, the infection should be cleared before commencing these drugs.

However, TNF-alpha inhibitor therapy is still used for non-perianal fistulating Crohn's disease, and is recommended to control inflammation or maintain remission.[70][203]

Primary options

infliximab: 5 mg/kg/dose intravenously given at weeks 0, 2, and 6 initially, followed by 5 mg/kg/dose every 8 weeks; 120 mg subcutaneously every 2 weeks

adalimumab: 160 mg subcutaneously at week 0, 80 mg at week 2, followed by 40 mg every other week beginning at week 4

Consider – management of extra-intestinal manifestations

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Consider –

management of extra-intestinal manifestations

Additional treatment recommended for SOME patients in selected patient group

ONGOING

in remission

1st line – maintenance therapy

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1st line –

maintenance therapy

Considerations on choosing long-term treatment for remission include: course and extent of Crohn's disease (CD); effectiveness and tolerance of treatments previously used; presence of biological or endoscopic signs of inflammation; and potential for complications.

For localised ileocaecal or colonic CD, azathioprine is the preferred immunomodulator for those who have had corticosteroid-induced remission. Mercaptopurine can be tried in patients who are intolerant of azathioprine (except in cases of pancreatitis or cytopenia). Corticosteroids can be tapered and then discontinued when established in these therapies.[106]

Parenteral methotrexate is recommended for the maintenance of remission in patients with corticosteroid-dependent CD.[106] Given orally, low-dose methotrexate does not appear to be effective for maintenance of remission, and further large-scale studies are required to support the use of methotrexate given orally at higher doses.[221]

Clinicians should refer to the specific cautions concerning the use of immunomodulators.

Patients who achieve remission with tumour necrosis factor (TNF)-alpha inhibitors, vedolizumab, or ustekinumab should continue the same drug for maintenance of remission.[106][139][125][222]

Infliximab and adalimumab have been shown to be effective in maintaining remission, although larger studies and longer follow-up periods are required to assess their long-term safety profile.[152][162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[223][224][225] [ ]

Meta-analysis has shown the combination therapy of infliximab and immunosuppressives is more effective than monotherapy in the maintenance of remission of CD. However, larger clinical trials with longer follow-up are warranted to further assess the efficacy and safety profile of combination therapy.[226]

Antibodies to TNF-alpha inhibitor therapies may lead to loss of clinical response and lower serum levels.[159][160] Therapeutic monitoring of TNF-alpha inhibitors can be done by testing the serum level of circulating drug (trough level, taken before the next dose is due). Currently, guidelines do not recommend proactive therapeutic drug monitoring in those in clinical remission or for those who have lost response to a TNF-alpha inhibitor.[106][244]

Patients who are corticosteroid-dependent should be treated with thiopurines or methotrexate, although if they have limited ileocaecal disease, ileal resection may be useful. Once established on these treatments, corticosteroids can be tapered or discontinued.[106]

Early use of biological therapies such as TNF-alpha inhibitors in patients with corticosteroid dependency may be useful in maintaining remission depending on previous exposure to other drugs, such as immunomodulators.[106]

It has been established that a combination treatment of infliximab and azathioprine may be more effective than infliximab alone for maintaining corticosteroid-free remission.[162]Colombel JF, Rutgeerts P, Reinisch W, et al. P087: SONIC: a randomized, double-blind, controlled trial comparing infliximab and infliximab plus azathrioprine to azathioprine in patients with Crohn’s disease naive to immunomodulators and biologic therapy. Abstracts of the 4th Congress of ECCO - the European Crohn’s and Colitis Organisation; Hamburg, Germany, 5-7 February 2009. J Crohns Colitis. 2009 Feb 1;3(1):S45-6.[163] However, this combination approach should only be used by experts who are experienced at managing these patients. Particular caution is required because of the associated risks of the high degree of immunosuppression with the combination of these two drugs.

In patients who relapse on thiopurine maintenance therapy, thiopurine metabolite testing (6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine [6-MMP]) can guide dose optimisation and likelihood of side effects.[227]

If thiopurine dose optimisation does not maintain remission, methotrexate is an alternative option.

Evidence from a single large randomised trial suggests that intramuscular methotrexate provides a benefit for induction of remission and complete withdrawal from corticosteroids in patients with refractory CD.[144]

TNF-alpha inhibitors should also be considered in patients who relapse on thiopurine maintenance, or surgery if disease is localised.[71]

Following intestinal resection, postoperative recurrence rates are significant and medical prophylaxis is recommended.[233][234][235]

To maintain remission in people with ileocolonic CD who have had complete macroscopic resection within the past 3 months, the National Institute for Health and Care Excellence (NICE) recommends that azathioprine with up to 3 months' postoperative metronidazole should be considered.[238]

Metronidazole has been shown to be more effective than placebo in preventing postoperative recurrence of CD, but long-term use is limited due to side effects (i.e., peripheral neuropathy).[236][239] If metronidazole is not tolerated, NICE recommends azathioprine alone post ileocaecal resection.[238]

There is some evidence to show that infliximab and adalimumab are more effective than azathioprine and mesalazine in preventing endoscopic and clinical recurrence of CD.[240][241] Both treatment regimens have been shown to aid remission maintenance postoperatively.[242][243] However, this evidence is insufficient to draw firm conclusions; hence, the choice between TNF-alpha inhibitors and thiopurines should be a risk versus benefit decision based on the individual patient and their risk of disease recurrence.[236]

If the patient is already on biological agents, guidance suggests continuation of treatment until it is appropriate to stop; however, commencing new biological therapy in those with complete macroscopic resection of ileocolonic CD is not recommended as routine.[238]

Plus – smoking cessation advice

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Plus –

smoking cessation advice

Treatment recommended for ALL patients in selected patient group

Smoking cessation reduces the complications experienced by patients and the risk of disease recurrence.[213][214][215][216]

Consider – antispasmodic agent

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Consider –

antispasmodic agent

Additional treatment recommended for SOME patients in selected patient group

Used in the treatment of pain caused by spasms of the gastrointestinal (GI) tract.

These drugs block the action of acetylcholine in secretory glands, smooth muscle, and the central nervous system.

Caution should be exercised when administering to patients with hepatic or renal insufficiency, cardiovascular disease, urinary tract obstruction, or hypertension.

Should not be given to patients with possible GI obstruction.

Primary options

dicycloverine: 20-40 mg orally three times daily when required

hyoscyamine: 0.125 mg orally every 4-6 hours when required, maximum 1.5 mg/day

Consider – anti-diarrhoeal agent

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Consider –

anti-diarrhoeal agent

Additional treatment recommended for SOME patients in selected patient group

Treatment may be initiated at any time when patients have symptomatic diarrhoea, except when active colitis is present, as the risk of toxic megacolon is increased.

Reduce frequency of diarrhoea by inhibiting peristalsis and slowing intestinal motility. This increases the transit time of electrolytes and fluid through the bowel, thereby increasing their absorption.

Colestyramine forms a non-absorbable complex with bile acids and may be useful in patients with terminal ileum disease.

Primary options

loperamide: 4 mg orally initially, followed by 2 mg after each unformed stool, maximum 16 mg/day

diphenoxylate/atropine: 5/0.05 mg orally three to four times daily initially, reduced to 2.5/0.025 mg twice to three times daily if needed, maximum 20/0.20 mg/day

colestyramine: 4 g orally once daily initially, increase by 4 g increments every week up to 12-24 g daily in a suitable liquid given in 1-4 divided doses according to response, maximum 36 g/day

Consider – chronic pain management

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Consider –

chronic pain management

Additional treatment recommended for SOME patients in selected patient group

Chronic abdominal pain may be a feature of patients with chronic inflammatory bowel disease due to a number of reasons including ongoing inflammation, presence of non-obstructing stricturing disease, or neuropathic type pain which can overlap with an irritable bowel syndrome picture. Management strategies are guided by aetiology and individualised to the patient, particularly given that pain may be complex and multifactorial.

Neuromodulators for the treatment of chronic pain include low-dose tricyclic antidepressants (e.g., amitriptyline), serotonin noradrenaline-reuptake inhibitors (SNRIs) such as venlafaxine or duloxetine, and mirtazapine.[257] In combination with self-management interventions such as exercise, mindfulness, and brain-gut behaviour therapies (cognitive behaviour therapy), pain can be effectively managed.

Primary options

amitriptyline: 10-100 mg orally once daily at bedtime

venlafaxine: 37.5 to 225 mg orally (extended-release) once daily

duloxetine: 30-120 mg orally once daily

mirtazapine: 15-45 mg orally once daily

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Crohn's disease

Treatment algorithm

ileocaecal disease not fistulating with <100 cm of bowel affected: initial presentation or relapse

observation with monitoring or budesonide

Primary options

management of extra-intestinal manifestations

budesonide or oral systemic corticosteroid

Primary options

Secondary options

management of extra-intestinal manifestations

antibiotics

immunomodulator therapy + oral corticosteroid taper

Primary options

Secondary options

management of extra-intestinal manifestations

antibiotics

biological therapy ± azathioprine or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Primary options

Secondary options

management of extra-intestinal manifestations

antibiotics

consideration of early initiation of biological therapies or Janus kinase (JAK) inhibitor + oral corticosteroid taper

Primary options

Secondary options

management of extra-intestinal manifestations

antibiotics

methotrexate

Primary options

management of extra-intestinal manifestations

antibiotics

surgery

management of extra-intestinal manifestations

antibiotics

hospitalisation + oral or intravenous corticosteroid + consideration of surgery

Primary options

management of extra-intestinal manifestations

antibiotics

immunomodulator therapy + oral corticosteroid taper

Primary options

Secondary options

biological therapy or Janus kinase (JAK) inhibitor or surgery

Primary options

Secondary options

gradual tapered dose reduction of corticosteroids

management of extra-intestinal manifestations

antibiotics

hospitalisation + consideration of early initiation of biological therapy or Janus kinase (JAK) inhibitor or surgery

Primary options

Secondary options

gradual tapered dose reduction of corticosteroids

management of extra-intestinal manifestations

antibiotics

colonic disease not fistulating: initial presentation or relapse

oral corticosteroid

Primary options

immunomodulator therapy

Primary options

management of extra-intestinal manifestations

antibiotics

surgery

management of extra-intestinal manifestations

antibiotics

oral or intravenous corticosteroid + immunomodulator therapy + consideration for surgery

Primary options

Secondary options

topical rectal hydrocortisone

Primary options

management of extra-intestinal manifestations

antibiotics

biological therapy or Janus kinase (JAK) inhibitor + consideration for surgery

Primary options

Secondary options

topical rectal hydrocortisone

Primary options

management of extra-intestinal manifestations

antibiotics

surgery

management of extra-intestinal manifestations

antibiotics

early initiation of biological therapy or Janus kinase (JAK) inhibitor or consideration for surgery