Approach

The treatment of Crohn's disease (CD) is highly complex. All pharmacotherapeutic interventions should be managed by specialists who are experts in the condition.

Several agents are available for the medical treatment of CD, including:[106]

  • Locally active corticosteroids (e.g., budesonide)

  • Systemic corticosteroids

  • Thiopurines (e.g., azathioprine, mercaptopurine)

  • Methotrexate

  • Biological therapies (e.g., tumour necrosis factor [TNF]-alpha inhibitors, integrin receptor antagonists, interleukin [IL]-12/23 antagonists)

  • Janus kinase (JAK) inhibitors (e.g., upadacitinib)

Initiating treatment regimens requires frequent monitoring of clinical response, a knowledge of common adverse effects, and expertise in managing potential serious adverse events. In certain areas, evidence for treatment and experience with therapies is limited. The appropriate choice of therapy is best tailored to the individual patient, and decisions on treatment are made by close discussion with the patient.

Specific management of CD in children is beyond the scope of this topic.

Treatment choices are influenced by:[71][106]

  • Patient age and individual risk factors

  • Site and severity of disease

  • Behaviour of the disease (CD is a highly heterogeneous disease with many different phenotypes, such as ileocaecal, colonic, upper gastrointestinal, perianal disease)

  • Previous drug tolerance and response to treatment

  • Previous relapses on treatment

  • The presence of complications, such as perianal or fistulating disease, or abscess formation

  • The presence of extra-intestinal manifestations

Surgical treatment is appropriate for:[71][107]

  • Neoplastic or pre-neoplastic lesions

  • Obstructing stenoses

  • Suppurative complications

  • Fistulating disease

  • Medically intractable disease

Treatment goal

Remission can be categorised as clinical remission, endoscopic remission, histological remission, where the ultimate goal is achievement of all three. In the future, we may also strive to achieve molecular remission, but research continues in this area. Although remission is defined as a Crohn’s Disease Activity Index (CDAI) of <150, in clinical practice, the application of the CDAI is often impractical, and its use is widely confined to that of a research tool.

Patient-reported outcomes may record symptomatic relief more effectively, and endoscopic scoring may help guide treatment by assessing mucosal healing. A Crohn's Disease Endoscopic Index of Severity (CDEIS) score of 0 to 2 can be used for defining remission in terms of mucosal inflammation.[108]

Once remission has been achieved, the choice of drug for the prevention of relapse and maintenance of remission has to be carefully considered.[109]

Disease severity

Prior to initiating treatment, it is important to define the disease activity. The approach to treatment varies according to disease severity. The European Crohn's and Colitis Organisation (ECCO) and the American College of Gastroenterology define disease severity as follows.[71][105]

  • Mild disease: ambulatory and able to tolerate oral alimentation without manifestations of dehydration, systemic toxicity (high fevers, rigors, and prostration), abdominal tenderness, painful mass, intestinal obstruction, or >10% weight loss. It is equivalent to a CDAI of between 150 and 220.

  • Moderate disease: failure of response to treatment for mild disease, or with more prominent symptoms of fever, significant weight loss >10%, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anaemia. It is equivalent to a CDAI of between 220 and 450.

  • Severe disease: persistent symptoms despite the introduction of intensive treatment (e.g., the use of corticosteroids or biological agents [e.g., infliximab, adalimumab, certolizumab pegol]) or evidence of intestinal obstruction or abscess formation (with significant peritoneal signs, such as involuntary guarding or rebound tenderness), or cachexia (body mass index <18 kg/m²). C-reactive protein is increased. It is equivalent to a CDAI of >450.

Presence of fistulating perianal disease or strictures may alter treatment decisions.[105][106][110]

Relapse and recurrence

Relapse is defined as a flare-up of symptoms in a patient with CD who is clinically in remission. This may occur spontaneously, or during or after medical treatment. Clinical trials use a definition of CDAI >150 with an increase of 70 points, although the 2016 ECCO guidelines suggest that it should be an increase of >100 points.[105]

Recurrence is a term best used to define the reappearance of lesions after surgical resection (as opposed to relapse, which refers to the reappearance of symptoms).

Typically, patients with CD have intermittent exacerbations followed by periods of remission, with 10% to 20% of patients experiencing a prolonged remission after the initial presentation.[111] To ensure that there is always available scope to step up treatment during relapses, it is important to have a long-term strategy that enables treatment to be stepped down during remission. ​

Physicians should exclude intercurrent infection or other causes of diarrhoea in patients who initially appear to be having a relapse or recurrence of CD.

Cautions concerning medical therapy

To minimise the risk of iatrogenic complications, guidelines recommend baseline blood-test screening prior to initiation of all non-nutritional treatments and regular monitoring, to exclude sepsis and pre-existing renal or liver impairment.[105] Drugs can cause nephrotoxicity or hepatotoxicity.

Immunomodulators

Particular mention should be made of immunomodulators (azathioprine, mercaptopurine, methotrexate), which can produce life-threatening consequences if started without due caution.

Immunomodulators should never be started if there is any indication of sepsis. Before commencing azathioprine or mercaptopurine it is advisable to measure the patient's blood thiopurine S-methyltransferase (TPMT) level to assess susceptibility to toxicity. The patient should also be informed specifically of the risk of serious adverse events (including overwhelming sepsis), and be made aware of the importance of close monitoring of blood counts and liver function tests during treatment. It is advisable to provide information regarding possible adverse effects and specific instructions such as the avoidance of live vaccination (e.g., rubella, bacille Calmette-Guérin, and yellow fever). Certain viruses can be fatal in patients taking azathioprine, due to the drug's immunosuppressive effects. Previous exposure to common viruses, such as varicella zoster (chickenpox), may be checked by antibody testing prior to initiation of azathioprine.[112]

Methotrexate can cause profound myelosuppression, long-term hepatotoxicity, and lung fibrosis. Women of childbearing age should not be started on methotrexate, because of its teratogenic effects.[106]

Tumour necrosis factor (TNF)-alpha inhibitors

TNF-alpha inhibitors are associated with an increased risk of developing opportunistic infections including tuberculosis.[113][114][115]​ Patients should be screened with a combination of history-taking, chest x-rays, an interferon-gamma release assay blood test, and/or a tuberculin skin test if deemed high risk. Reactivation of hepatitis B has been reported, with a theoretical risk of reactivation of hepatitis C; patients with CD should be tested for serological markers of hepatitis B and hepatitis C before treatment is initiated.[116][117]

One study found a small but significant increase in the risk of lymphoma for patients taking TNF-alpha inhibitor monotherapy for inflammatory bowel disease.[118] This risk increased when TNF-alpha inhibitors were taken in combination with thiopurine therapy. Other studies are confounded by thiopurine exposure, making causality difficult to establish.[119]

Those with a history of optic neuritis and demyelinating disorders should avoid receiving TNF-alpha inhibitors. Anaphylactic reactions can occur in response to TNF-alpha inhibitors; hence, initial infusion should always be slow and medically supervised. Septic complications including opportunistic infections increase up to 15-fold if TNF-alpha inhibitors are used in combination with other immunosuppressives.

Vedolizumab and ustekinumab

The biological agents vedolizumab and ustekinumab have strong evidence for induction and maintenance of remission for CD.[120][121][122]​​​ They also favourable safety profiles with low incidence of adverse events.[120][122][123][124][125][126]​​​​​​​​​ 

Biosimilars

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]​ 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. 

Preoperative preparation

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]

Corticosteroids

Corticosteroid use is associated with increased risk of postoperative complications. Preoperative reduction of corticosteroid doses may reduce postoperative complications but should be monitored carefully to avoid increasing disease burden.[107]

Nutritional assessment

Preoperative nutritional assessment should be performed for all patients with CD who need surgery. Nutritional optimisation prior to surgery, with enteral or parenteral nutrition, is recommended for those patients with nutritional deficiencies.[107]

Biological therapy

Evidence suggests that preoperative treatment with a TNF-alpha inhibitor, vedolizumab, or ustekinumab does not increase the risk of postoperative complications in patients with CD having abdominal surgery.[107][131][132][133]​ Cessation of these drugs prior to surgery is not mandatory.[107]

One systematic review found that preoperative treatment with TNF-alpha inhibitors did not increase the risk of postoperative surgical site infection in patients with CD when the preoperative TNF-alpha inhibitor infusion time was within 4, 8, or 12 weeks.[134] Additionally, no significant difference in postoperative complications was observed between preoperative TNF-alpha inhibitor windows of within 4 weeks and more than 4 weeks.[134]

Acute management for induction of remission: ileocaecal disease

Ileocaecal disease refers to disease localised to these areas (<100 cm of bowel affected).

Mildly active disease: ileocaecal disease

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

Budesonide

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 CD. The dose of budesonide may be tapered once clinical response is achieved. It has been shown to be superior to both placebo and aminosalicylates such as mesalazine.[105][106][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] [ Cochrane Clinical Answers logo ]

Moderately active disease: ileocaecal disease

Medical treatments for moderately active ileocaecal CD include oral or systemic corticosteroids, immunomodulators in combination with a TNF-alpha inhibitor, an integrin receptor antagonist, or an IL-12/23 antagonist.

Corticosteroids

Oral budesonide (delayed-release formulation) has been shown to be more likely to induce remission than aminosalicylates or placebo, and should be used preferably over systemic corticosteroids for limited terminal ileal/ascending colonic CD.[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]

Immunomodulators plus corticosteroids

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

They 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] [ Cochrane Clinical Answers logo ]

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 to 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]

TNF-alpha inhibitors

Exposure to corticosteroids should be minimised in patients with CD. An effective approach is the early introduction of biological drugs, such as TNF-alpha inhibitor therapies (e.g., infliximab, adalimumab, certolizumab pegol), 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]​​ One meta-analysis demonstrated that infliximab is superior to azathioprine for inducing corticosteroid-free remission, but importantly that the combination of azathioprine and infliximab was superior to infliximab alone.[145] [ Cochrane Clinical Answers logo ] ​ 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][156]​​ 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]

The long-term drug safety profile of TNF-alpha inhibitors 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]

TNF-alpha inhibitor with or without an immunomodulator

Trials have demonstrated benefits from combination therapy with TNF-alpha inhibitor plus an immunomodulator.[152][154][155][156][162][163]​​​​​​ One meta-analysis concluded 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] [ Cochrane Clinical Answers logo ] ​​​​ Another meta-analysis confirmed that combination therapy with infliximab and azathioprine is more effective at inducing remission compared with a TNF-alpha inhibitor alone.[155] 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]​ 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.[106][153]​ The American Gastroenterology Association (AGA) guidelines recommend combination therapy over adalimumab monotherapy.[139]

Integrin receptor antagonists or IL-12/23 antagonists

Vedolizumab (an integrin receptor antagonist), ustekinumab (an 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]​​

Ustekinumab has been approved in Europe and the UK to treat:[106][169]

  • Patients with moderately to severely active CD who have an inadequate response, lost response to, are intolerant to, or are contraindicated to conventional therapy or TNF-alpha inhibitor therapy.

The US Food and Drug Administration (FDA) has approved ustekinumab for the treatment of moderately to severely active CD in adults who have:

  • failed or were intolerant to treatment with immunomodulators or corticosteroids but never failed treatment with a TNF-alpha inhibitor therapy, or

  • failed or were intolerant to treatment with one or more TNF-alpha inhibitors.

Ustekinumab has demonstrated a good safety profile, although trials are ongoing.[171]

Risankizumab is approved by the FDA and the 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]

JAK inhibitors

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. Common adverse effects include upper respiratory tract infections, anaemia, fever, acne, herpes zoster, and headache. As upadacitinib is administered orally, it is suitable for most patients provided it is not contraindicated.

Antibiotics

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.[71][106][139][183]

Surgery

Patients should be considered for surgery when medical therapy alone does not work or the symptoms worsen from mildly active disease to moderate or severe disease.[71][184][185]​​​ If there are obstructive symptoms, surgery may be considered early. Surgery is also an acceptable option as an alternative to biologics in those with limited ileocaecal disease. This is because, 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.[186][187][188][189]

Due to the high success rate of limited ileocaecal resection for patients with 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]

Severely active disease: ileocaecal disease

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.

Initial treatment for severely active ileocaecal disease

Patients with severely active disease can be treated initially with oral or intravenous corticosteroids.[71] 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.[71][106][139][183]

TNF-alpha inhibitor with or without an immunomodulator

TNF-alpha inhibitors (e.g., infliximab, adalimumab, certolizumab pegol) can be considered to treat severely active 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]​ Infliximab combined with a thiopurine 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][163]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by the ECCO guideline on CD.[153] However, the AGA 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]

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]

Integrin receptor antagonists or IL-12/-23 antagonists

Vedolizumab (an integrin receptor antagonist), ustekinumab (an 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]

Immunomodulator plus oral corticosteroid

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

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.

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

Corticosteroid dose may be gradually tapered.

JAK inhibitors

Upadacitinib 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. It 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. Upadacitinib is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin. As upadacitinib is administered orally, it is suitable for most patients provided it is not contraindicated.

Antibiotics

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.[71][106][139][183]

Surgery

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 TNF-alpha inhibitors, although opinions differ as to the optimal timing.[107] 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 TNF-alpha inhibitor therapy require practical treatment that is individualised according to the presentation.

Acute management for induction of remission: colonic disease

Colonic CD can involve the entire colon (pancolonic) or part of the colon (segmental), and is often associated with skip areas of normal histology.[191]

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]

Mildly active colonic disease

Treatments for mildly active colonic disease include an oral corticosteroid alone or in combination with an immunomodulator. Patients should be managed on an individual basis by a multidisciplinary team.

Corticosteroids

Oral systemic corticosteroids (e.g., prednisolone) are recommended as initial treatment. However, budesonide is not recommended unless the disease is primarily affecting the ileum or ascending colon.[106]

Hydrocortisone enemas or suppositories are often used, although there are no data from randomised trials on topical therapy for left-sided CD.

Immunomodulator plus an oral corticosteroid

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

They 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] [ Cochrane Clinical Answers logo ]

Immunomodulators should never be started if there is any indication of sepsis.

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 to 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]

Antibiotics

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.[71][106][183]

Surgery

Surgery should be considered early for colonic disease if there is no improvement with initial therapies.

Moderately or severely active colonic disease

Treatment is similar for moderately and severely active disease, although surgery must be considered early for patients with severe disease due to the risk of perforation, obstruction, and development of a toxic megacolon.

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.

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 biological therapies such as TNF-alpha inhibitor therapy can be used safely.

Increasingly, a top-down approach to treatment is being advocated for patients with moderately active disease. This strategy involves initiating more potent treatments (e.g., TNF-alpha inhibitor therapies) early in the disease process. The potential merit of this approach is 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.

Immunomodulator plus an oral corticosteroid

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

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

Topical corticosteroids

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

JAK inhibitors

Upadacitinib 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. It 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. Upadacitinib is not recommended for use in combination with other JAK inhibitors, with biological therapies, or with strong immunosuppressants such as azathioprine and ciclosporin.

Antibiotics

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.[71][106][139][183]

TNF-alpha inhibitor with or without an immunomodulator

TNF-alpha inhibitors (e.g., infliximab, adalimumab, certolizumab pegol) can be considered to treat severely active 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]​ Infliximab combined with a thiopurine 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][163]

Combination therapy with adalimumab is not recommended over adalimumab monotherapy by the ECCO guideline on CD.[153] However, the AGA 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 moderate-to-severe CD.[154][155]

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]

Antibodies to TNF-alpha inhibitors may lead to loss of clinical response and lower serum TNF-alpha inhibitor levels.[159][160]

Integrin receptor antagonists or IL-12/-23 antagonists

Vedolizumab (an integrin receptor antagonist), ustekinumab (an 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]

Acute management for induction of remission: extensive small bowel disease

Treatment for the induction of remission in patients with extensive small bowel disease (>100 cm of bowel affected) includes nutritional therapy, corticosteroids with immunomodulators, TNF-alpha inhibitors, integrin receptor antagonists, IL-12/23 antagonists, or surgical resection.

Corticosteroids and 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.

TNF-alpha inhibitor therapy

Biological treatment with TNF-alpha inhibitor therapy (e.g., infliximab, adalimumab, or certolizumab pegol) should be considered early because these patients have a poorer long-term prognosis compared with people with more localised disease.[139][193][194] However, the long-term drug safety profile is unclear. Furthermore, the development of antibodies to these drugs is a potential concern as this may lead to loss of clinical response and lower serum levels.[159][160] The use of certolizumab pegol in CD has been approved in the US and other countries, but not in Europe.

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]

Antibodies to TNF-alpha inhibitors may lead to loss of clinical response and lower serum TNF-alpha inhibitor levels.[159][160]

Integrin receptor antagonists or interleukin IL-12/23 antagonists

Vedolizumab (an integrin receptor antagonist), ustekinumab (an 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]

Surgical resection

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.[198]

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

Nutrition

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. An elemental diet provides the nutritional requirements for individuals in the smallest constituent form, such as amino acids. A polymeric diet provides the nutritional requirements as whole proteins, carbohydrates, or fats (or as polymers). The aim of this is to suppress intestinal inflammation and promote mucosal healing. Trials of enteral feeding are often limited by poor patient tolerability.

Acute management for induction of remission: upper gastrointestinal (GI) disease (oesophageal and/or gastroduodenal)

This particular subtype of CD is being increasingly diagnosed on upper GI endoscopy.

Evidence for treatment is mainly based on case series, but most experts agree that a proton-pump inhibitor is necessary with therapeutic doses of systemic corticosteroids, and methotrexate, azathioprine, or mercaptopurine, as described in other disease phenotypes.[200]

TNF-alpha inhibitor therapy

Upper GI CD is thought to be associated with a worse prognosis. Therefore, TNF-alpha inhibitor therapy must be considered early.[106] 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 drug safety profile is unclear. Furthermore, the development of antibodies to these drugs is a potential concern as this may lead to loss of clinical response and lower serum levels.[159][160]

Surgery

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

Acute management for induction of remission: perianal and fistulating disease

Fistulae are tracts that connect two epithelial-lined organs. These include:

  • Enteroenteric fistulae (connecting two bowel loops)

  • Enterovesical fistulae (bowel to bladder), presenting with recurrent urinary tract infections and pneumaturia

  • Enterovaginal fistulae, presenting with passage of gas or faeces through the vagina

  • Enterocutaneous fistulae, manifesting with bowel contents draining to the surface of the skin

  • Cologastric fistulae, manifesting as feculent vomiting

  • Fistulae to other organs

Fistulae may require surgical management.​[91][201]

Perianal fistulae

A combined medical/surgical approach to control potential sepsis and luminal activity is recommended.[91][107]​​[202][203]

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 immunomodulator therapy.

Seton placement with biological therapy

Seton placement is recommended, with a TNF-alpha inhibitor.[91][106][139]​​

Infliximab or adalimumab is recommended to treat perianal fistulae.[106][204]​​ 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 CD, although on discontinuation of antibiotic therapy the initial benefit was not maintained.[206]​ This therapy may be combined with a surgical approach if the fistulae are amenable.[207]​ 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]

Ustekinumab or vedolizumab are not currently recommended first-line to treat complex perianal fistula, although trials show promising results.[208]​ There also may be benefit with these agents in patients where TNF-alpha inhibitors are ineffective or contraindicated and there are no treatment options, especially when concomitant luminal disease is present.[106][139]

Antibodies to TNF-alpha inhibitors may lead to loss of clinical response and lower serum TNF-alpha inhibitor levels.[159][160]

The use of certolizumab pegol in CD has been approved in the US and other countries, but not in Europe.

Anal fistula plugs should not be routinely considered for ano-perineal fistula closure in CD, seton removal alone is equally effective.[107]

Antibiotics

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

Non-perianal fistulae

Enterocutaneous fistulae, ano- and rectogenital fistulae related to CD 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]

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 CD, and is recommended to control inflammation or maintain remission.[70][203]

Antibodies to TNF-alpha inhibitors may lead to loss of clinical response and lower serum TNF-alpha inhibitor levels.[159][160]

Perianal abscess

In the case of abscess formation with or without fistulating disease, the first line of treatment is antibiotic therapy 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]​ 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.

Abscess elsewhere in the GI tract

Collections may form at any point where CD is active in the GI tract, but most often occur at the site of fistulating disease. Drainage of collections in small bowel or large bowel may need interventional radiology input with insertion of pigtail drains under ultrasound or CT guidance to drain the pus. Some may also require a surgical approach. As with perianal abscesses, the focus then shifts to treating the underlying problem of fistulating disease with immunosuppressive drugs. Antibiotics treatment and drainage of infection should precede commencing these drugs.

Treatment based on the behaviour of the disease

There are a number of factors associated with a poorer prognosis, such as:

  • Presentation at a young age

  • Extensive disease, requiring initial treatment with corticosteroid

  • Perianal disease at diagnosis

Patients with corticosteroid-refractory CD that remains clinically active should be considered as a distinct group who need to be treated more intensively and sooner than corticosteroid-responsive groups. These patients should be given TNF-alpha inhibitor treatment, with or without other immunomodulators (e.g., azathioprine, mercaptopurine, and methotrexate).[106]

It has been suggested that patients presenting with poor prognostic factors (e.g., fistulising perianal disease, extensive disease, deep ulcerations, complicated phenotype) would benefit from the early introduction of TNF-alpha inhibitor to achieve a reduced risk of surgery, hospitalisation, or development of disease-related complications.[106][139]

Maintenance of remission

Considerations on choosing the right long-term treatment for remission include:

  • The course of the disease (initial presentation, frequency, and severity of flare-ups)

  • The extent of the disease (localised or extensive)

  • The effectiveness and tolerance of treatments that have previously been used to induce or maintain remission

  • The presence of biological or endoscopic signs of inflammation and the potential for complications

Patient preference and logistical constraints may also influence the treatment options. Smoking cessation reduces the complications experienced by patients and the risk of disease recurrence.[213][214][215][216]​​​ There is insufficient evidence to determine the role of probiotics in maintenance of remission.[217][218][219][220]

Maintenance of medically induced remission: localised ileocaecal or colonic disease

Thiopurines are effective for maintenance of remission in established CD and are recommended in those with corticosteroid-dependent disease.[106] 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.

Biological therapy

Patients who achieve remission with TNF-alpha inhibitors, vedolizumab, or ustekinumab should continue the same drug for maintenance of remission.[106][125][139]​​[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][223][224][225] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ]

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]

Systemic corticosteroids

Systemic corticosteroids are not effective in maintaining remission and can cause unwanted adverse effects such as acne, round face, body hair growth, insomnia, weight gain, and osteoporosis.[139]

Budesonide is not effective for maintenance of remission beyond 3 months following induction of remission.[135]

Maintenance of remission: other clinical scenarios

Corticosteroid-dependent disease

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]

Combination treatment of infliximab with azathioprine may be more effective than infliximab alone for maintaining corticosteroid-free remission.[162][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.

Relapse on thiopurines

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]

Thiopurine metabolites can also be used to:[228]

  • Assess compliance to therapy

  • Detect sub/supra therapeutic dosing

  • Identify resistance to thiopurines or the need to add allopurinol (in patients who are hypermethylators of thiopurines), or

  • Investigate possible thiopurine side effects

The British Society of Gastroenterology suggests checking metabolites in patients with newly abnormal liver function tests or myelotoxicity, and using results to alter dosing (or stop the drug) as necessary.[70] However, routine measurement of metabolites has not been shown to be beneficial, due to wide variations in levels reported.[229] Prospective studies show a lack of clinical benefit.[230][231][232]

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 this setting, or surgery if disease is localised.[71]

Following intestinal resection

Postoperative recurrence rates are significant, and medical prophylaxis is recommended.[233][234][235]​ In those with surgically induced remission on medical therapy, endoscopic surveillance is recommended 6 to 12 months postoperatively to assess disease activity.[236]

Immunomodulators

One Cochrane review found both azathioprine and mercaptopurine to be superior to placebo for maintenance of surgically induced remission.[237]

Azathioprine with or without metronidazole

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, in particular peripheral neuropathy.[239] If metronidazole is not tolerated, NICE recommends azathioprine alone post ileocaecal resection.[238]

TNF-alpha inhibitors

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; 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]

Budesonide

Budesonide is not recommended to maintain remission in people with ileocolonic CD who have had complete macroscopic resection.[238]

Therapeutic monitoring of TNF-alpha inhibitors

Antibodies to TNF-alpha inhibitors may lead to loss of clinical response and lower serum TNF-alpha inhibitor 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). This may allow dose adjustment if levels are too high. If levels are too low, additional testing for anti-TNF antibody levels can be done, where their presence may render any dose escalation futile and inadvisable and may encourage a switch to an alternative agent. This can be done in two groups of patients, those who lose response to TNF-alpha inhibitor treatment, and those who are maintained on treatment and could benefit from sustained treatment.

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] Further research is required regarding the best method to measure TNF-alpha inhibitor levels, the reference standards, the accuracy for predicting clinical state, and clinically meaningful thresholds.[245] One trial compared proactive therapeutic drug monitoring (individualised, scheduled monitoring of serum drug levels) with standard infliximab therapy in patients with immune-mediated inflammatory diseases, including CD. Patients who received therapeutic drug monitoring were more likely to sustain disease remission compared with patients who received standard care (73.6% vs. 55.9%).[246] NICE in the UK has evaluated a commercially available enzyme-linked immunosorbent assay (ELISA) as a technology for this purpose for centres where TNF levels and antibody levels are performed.[247]

Duration of maintenance treatments

The optimal duration of immunomodulator or biological therapy for maintenance of remission is unclear.

Immunomodulators

Cessation of treatment for patients maintained in remission on azathioprine has been studied, and may be considered after 4 years of remission.[248]

The risks and benefits of long-term azathioprine need to be considered, including the risk of lymphoma development.

Long-term treatment with methotrexate does not increase the risk of severe hepatotoxicity. Therefore, patients can be maintained on this drug provided that the risk of withdrawing the drug is greater than that of being on long-term treatment.[249]

Biological therapy

There is insufficient evidence to recommend either continuation or withdrawal of TNF-alpha inhibitor therapy in patients with CD after achieving long-term remission. The decision to continue treatment should be individualised and potential consequences should always be discussed with the patient.[106][250]

In patients who achieve long-term remission with infliximab or adalimumab plus immunosuppressant, monotherapy with infliximab or adalimumab is recommended for maintenance treatment.[106][251][252]​​ However, this should be a case-by-case decision weighing up the risks of infection with dual immunosuppression versus risk of anti-drug antibody formation if the immunomodulator is withdrawn.

Complications: managing extra-intestinal manifestations

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]

Arthropathy

Treatment of arthropathy associated with CD supports the short-term use of non-steroidal anti-inflammatory drugs (NSAIDs), local corticosteroid injections, and physiotherapy for peripheral arthritis, although the emphasis should be on treating the underlying CD.[202]

Patients with CD-associated arthropathy should be considered for treatment with methotrexate. The treatment is initiated intramuscularly, with an overlapping corticosteroid taper. Once a clinical response is achieved, methotrexate may be given orally, with an attempt to lower the dose gradually over several months. In addition, all patients should take folic acid in order to minimise the adverse effects of methotrexate.[145][161]

With axial arthropathy associated with CD, infliximab has been demonstrated to be effective in those with ankylosing spondylitis refractory to or intolerant of NSAIDs.[253]

Cutaneous manifestations

Treatment of erythema nodosum is based on the treatment of the underlying CD.

Pyoderma gangrenosum is typically treated with corticosteroids, although intravenous ciclosporin and tacrolimus have been shown to have proven benefit.[254] Other studies have demonstrated a response induced with infliximab in 69% of patients and remission in 31% patients at week 6. Therefore, infliximab is recommended for use in patients who do not rapidly respond to corticosteroids.[255]

Corticosteroids and TNF-alpha inhibitors can also be used for peristomal pyoderma gangrenosum.[256]

Ocular manifestations

Seek expert opinion from an ophthalmologist when a diagnosis of uveitis is suspected. It may be necessary to treat with topical and systemic corticosteroids.

Episcleritis may be self-limiting, but will usually respond to topical corticosteroids.

Symptomatic therapy

Symptomatic treatment includes managing diarrhoea, abdominal pain, and malabsorption. Anti-diarrhoeal agents should be avoided in patients with active colitis, given the risk of developing toxic megacolon. Abdominal cramps can be effectively treated with oral antispasmodics.

Patients with terminal ileal disease develop secretory diarrhoea due to inability to absorb bile acids. Bile acid sequestrants are helpful in this situation.

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, serotonin noradrenaline-reuptake inhibitors (SNRIs), 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.

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