What are the treatment options for moderate to severe inflammatory bowel disease (IBD)?

Treatment Options for Moderate to Severe Inflammatory Bowel Disease (IBD)

For patients with moderate to severe inflammatory bowel disease, biologic agents and small molecules are strongly recommended as the most effective treatment options, with infliximab and vedolizumab being preferred first-line options for ulcerative colitis, while anti-TNF agents, vedolizumab, or ustekinumab are all reasonable first-line options for Crohn's disease. 1

First-Line Treatment Options for Moderate to Severe Ulcerative Colitis

Recommended Biologic Agents

• The American Gastroenterological Association (AGA) strongly recommends infliximab, golimumab, vedolizumab, tofacitinib, upadacitinib, ustekinumab, ozanimod, etrasimod, risankizumab, and guselkumab over no treatment for moderate to severe UC (strong recommendation, moderate to high certainty of evidence) 1
• The AGA conditionally recommends adalimumab, filgotinib, or mirikizumab over no treatment (conditional recommendation, moderate certainty of evidence) 1
• In biologic-naïve patients, infliximab is ranked highest for induction of clinical remission and endoscopic improvement 2

Combination Therapy Considerations

• The AGA suggests combining TNF antagonists with immunomodulators rather than TNF antagonist monotherapy or immunomodulator monotherapy alone (conditional recommendation, low to moderate certainty of evidence) 1
• For non-TNF antagonist biologics, there is insufficient evidence to recommend for or against combination with immunomodulators 1

Important Safety Considerations

• JAK inhibitors (tofacitinib, filgotinib, upadacitinib) have restricted use in biologic-naïve patients in the US, with FDA recommendations to use these agents only after failure of or intolerance to TNF antagonists 1
• Vedolizumab has the lowest risk of infections in maintenance trials, followed by ustekinumab 2

Second-Line Treatment Options (After TNF Antagonist Failure)

• In patients with prior exposure to TNF antagonists, ustekinumab and tofacitinib rank highest for induction of clinical remission and are superior to vedolizumab and adalimumab (moderate certainty of evidence) 2
• JAK inhibitors (tofacitinib, filgotinib, upadacitinib) are specifically recommended for patients with prior failure or intolerance to TNF antagonists 1
• The effectiveness of anti-TNF therapy does not seem to be significantly impacted by prior vedolizumab therapy, suggesting potential benefit of using vedolizumab as a first-line biologic 3

Treatment Options for Crohn's Disease

• For moderate to severe Crohn's disease with a penetrating phenotype or with multiple extraintestinal manifestations, infliximab or adalimumab are preferred first-line agents 4
• For moderate to severe Crohn's disease with an inflammatory phenotype, anti-TNF agents, vedolizumab, and ustekinumab are all reasonable options 4
• Infliximab (5 mg/kg) should be reserved for patients with moderate to severe CD who are refractory to or intolerant of treatment with steroids, mesalazine, azathioprine/mercaptopurine, and methotrexate, and where surgery is considered inappropriate 1

Immunomodulator Therapy

• The AGA suggests against using thiopurine monotherapy for inducing remission in patients with active disease (conditional recommendation; very low certainty of evidence) 1
• Thiopurine monotherapy may be considered for maintaining remission typically induced with corticosteroids (conditional recommendation; low certainty of evidence) 1
• The AGA suggests against using methotrexate monotherapy for inducing or maintaining remission (conditional recommendation; low certainty of evidence) 1
• Azathioprine (1.5–2.5 mg/kg/day) or mercaptopurine (0.75–1.25 mg/kg/day) are first-line agents of choice for steroid-dependent disease 1
• Regular monitoring of full blood count is advisable to detect neutropenia, although profound neutropenia and sepsis can develop rapidly 1

De-escalation of Therapy

• In patients who have escalated to therapy with immunomodulators or advanced therapies after failing 5-aminosalicylates, the AGA suggests stopping 5-aminosalicylates (conditional recommendation, low certainty of evidence) 1
• For patients in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA suggests against withdrawal of TNF antagonists (conditional recommendation; very low certainty of evidence) 1

Special Considerations

Pregnancy

• Adalimumab crosses the placenta, with cord blood concentrations higher than maternal serum in most cases 5
• Adalimumab can be detected in infant serum for at least 3 months after birth 5
• The safety of administering live or live-attenuated vaccines in infants exposed to biologics in utero is unknown; risks and benefits should be considered prior to vaccinating 5

COVID-19 Risk Stratification

• Patients on immunomodulators or biologics with moderate to severely active disease may be at higher risk for severe COVID-19 outcomes 1
• Patients on anti-TNF monotherapy, biologic plus immunomodulator in stable patients, ustekinumab, vedolizumab, thiopurines, methotrexate, calcineurin inhibitors, JAK inhibitors, or prednisolone <20 mg are considered at moderate risk 1

Surgical Considerations

• For ulcerative colitis, surgery should be advised for disease not responding to intensive medical therapy 1
• For Crohn's disease, surgery should only be undertaken for symptomatic rather than asymptomatic, radiologically identified disease, as it is potentially panenteric and usually recurs following surgery 1
• Resections in Crohn's disease should be limited to macroscopic disease 1
• The decision to operate is best taken by the gastroenterologist and colorectal surgeon in conjunction with the patient 1

Treatment Algorithm for Moderate to Severe IBD

1. For Ulcerative Colitis:

   • First-line: Infliximab or vedolizumab (strongest evidence) 1, 2
   • Alternative first-line: Golimumab, ustekinumab 1
   • After TNF failure: Ustekinumab, tofacitinib, or JAK inhibitors 1, 2

2. For Crohn's Disease:

   • Penetrating phenotype/extraintestinal manifestations: Infliximab or adalimumab 4
   • Inflammatory phenotype: Anti-TNF, vedolizumab, or ustekinumab 4
   • After TNF failure: Ustekinumab or vedolizumab 3

3. Consider combination therapy with immunomodulators for TNF antagonists 1

4. Monitor response closely and switch therapy promptly if inadequate response 3