American Gastroenterological Association Institute Medical Position Statement on Corticosteroids, Immunomodulators, and Infliximab in Inflammatory Bowel Disease

Article Outline

• Corticosteroids
  • Recommendations for Corticosteroid Use
    • Mild to moderate IBD
    • Moderate to severe IBD
    • Severe and fulminant IBD
    • Maintenance therapy
    • Dosing and tapering for IBD
    • Monitoring for complications
• AZA/6-MP
  • Recommendations for AZA/6-MP Use
• Methotrexate
  • Recommendations for Methotrexate Use
• Mycophenolate Mofetil
• Cyclosporine
  • Recommendations for Cyclosporine Use
• Infliximab
  • Recommendations for Infliximab Use
• Copyright

The following recommendations were developed to assist physicians in the appropriate use of medications to treat patients with inflammatory bowel disease (IBD). These recommendations represent the results of many years of research and many collaborative efforts. The medications reviewed include corticosteroids, azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, mycophenolate mofetil, cyclosporine, and infliximab.

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Corticosteroids 

Corticosteroids are potent, rapidly acting oral, topical, or parenteral agents used for acute treatment of patients with moderate to severe relapses of IBD. Budesonide (Entocort; AstraZeneca Pharmaceuticals, Wayne, PA) is a poorly absorbed corticosteroid with limited bioavailability due to extensive first-pass metabolism (degraded by the liver and red blood cells) that can produce therapeutic benefit with reduced systemic toxicity in patients with ileocecal Crohn's disease (CD). Topical agents in the form of suppositories or foam have been used to treat patients with proctitis, whereas enemas are effective for application in patients with disease up to the splenic flexure.

Recommendations for Corticosteroid Use 

•Dosages in the range of 40–60 mg/day or 1 mg·kg⁻¹·day⁻¹ of prednisone or equivalent are effective for induction of remission. (Grade A)

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AZA/6-MP 

AZA and 6-MP are chemically related immunomodulators. AZA is nonenzymatically converted to 6-MP. Their onset of full activity is slow and may take 3 months. 6-MP and AZA are members of the thiopurine class of medications and are commonly used to treat patients with CD and UC who are corticosteroid dependent in an attempt to withdraw corticosteroids and maintain patients in remission off corticosteroids. AZA and 6-MP have also been shown in some studies to reduce clinical and endoscopic postoperative recurrence of CD.

Recommendations for AZA/6-MP Use 

•Long-term treatment with corticosteroids is undesirable. Patients with chronic active corticosteroid-dependent disease (either CD or UC) should be treated with AZA 2.0–3.0 mg·kg⁻¹·day⁻¹ or 6-MP 1.0–1.5 mg·kg⁻¹·day⁻¹ in an effort to lower or preferably eliminate corticosteroid use. Infliximab is another option in this situation, as is combination infliximab/antimetabolite therapy. (Grade A)

•Individual patients with either CD or UC who experience a severe flare of disease requiring corticosteroid treatment or require re-treatment during the year with another course of corticosteroids should be considered for initiation of therapy with AZA 2.0–3.0 mg·kg⁻¹·day⁻¹ or 6-MP 1.0–1.5 mg·kg⁻¹·day⁻¹ in an effort to avoid future corticosteroid use (Grade C). Infliximab is another option in this situation, as is combination infliximab/antimetabolite therapy.

•Some studies have shown AZA 2.0–3.0 mg·kg⁻¹·day⁻¹ or 6-MP 1.0–1.5 mg·kg⁻¹·day⁻¹ to have some efficacy in treating and healing perianal and enteric fistulae. (Grade C)

•AZA 2.0–3.0 mg·kg⁻¹·day⁻¹ or 6-MP 1.0–1.5 mg·kg⁻¹·day⁻¹ is effective for maintenance of remission in patients with CD regardless of disease distribution. (Grade A)

•AZA 2.0–3.0 mg·kg⁻¹·day⁻¹ or 6-MP 1.0–1.5 mg·kg⁻¹·day⁻¹ is effective for reducing corticosteroid dose in patients with UC regardless of disease distribution (Grade A). These drugs may also be effective in maintaining remission in patients with UC, but data are conflicting and this has not been confirmed by large well-controlled studies.

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Methotrexate 

Methotrexate has been used in clinical medicine for nearly half a century. This agent induces clinical response more rapidly than 6-MP or AZA in patients with IBD. Over the course of the past decade, evidence has shown that methotrexate has an emerging role for the treatment of patients with CD.

Recommendations for Methotrexate Use 

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Mycophenolate Mofetil 

Mycophenolate mofetil inhibits lymphocyte proliferation by selectively blocking the synthesis of guanosine nucleotide in T cells. Its use in IBD was first proposed as an alternative immunosuppressive in patients intolerant to AZA or 6-MP. Early enthusiasm over the use of mycophenolate mofetil has been tempered by studies that showed lower efficacy rates and a higher incidence of patient intolerance.

This lack of convincing evidence of efficacy, coupled with concerning safety data, make it difficult to justify the use of mycophenolate mofetil in the treatment of patients with IBD at this time.

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Cyclosporine 

Cyclosporine has a rapid onset of action (more rapid than AZA, 6-MP, or methotrexate) and when administered intravenously has been shown to be effective in the management of patients with severe UC. It often demonstrates clinical efficacy within 1 week when administered intravenously. Oral cyclosporine has a possible role in the induction of a clinical response in UC and shortterm in the maintenance of an intravenous cyclosporine-induced response, allowing time for the slow-acting purine analogues to become effective. Its efficacy in patients with luminal CD has only been shown for higher doses, and the risks of therapy may not warrant its use. Intravenous cyclosporine is effective for the treatment of patients with fistulizing CD; however, toxicity has limited its applicability, and when administered orally, disease often reflares.

Recommendations for Cyclosporine Use 

•Intravenous cyclosporine at 2–4 mg·kg⁻¹·day⁻¹ or colectomy should be considered if a patient with severe UC has failed to respond to medical therapy with 7–10 days of high-dose oral or parenteral corticosteroids. (Grade B)

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Infliximab 

Infliximab is a chimeric monoclonal antibody to human tumor necrosis factor α that was introduced into clinical practice in the United States in 1998. Infliximab is effective for the treatment of patients with inflammatory and fistulizing CD that has failed to respond to other therapies. Several recent studies have shown efficacy of infliximab in the treatment of patients with UC.

Indications for infliximab use include the following:

Recommendations for Infliximab Use 

The recommended initial dose of infliximab for all IBD indications is 5 mg/kg body wt, administered by intravenous infusion over 2 hours in an induction regimen of 3 doses at weeks 0, 2, and 6. This should be followed by maintenance therapy every 8 weeks in patients who respond. For patients with CD who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. The treatment should be administered under the supervision and control of a specialized health care deliverer, with emergency equipment for severe infusion reactions available. A follow-up observation period of approximately 1 hour is advocated. Current indications for infliximab include the following:

1. Treatment of moderately to severely active CD or UC in patients who have not responded despite complete and adequate therapy with a corticosteroid or an immunosuppressive agent (AZA, 6-MP, or methotrexate). These patients are individuals who are resistant to medical therapy (complete and adequate therapy with a corticosteroid or an immunosuppressive agent) or who cannot receive such therapies due to intolerance to medications (corticosteroids or medical contraindications [therapy intolerant]).

2. Treatment of CD with fistulas in patients who have not responded despite complete and adequate therapy with conventional treatments (including antibiotics, surgical drainage with examination under anesthesia, and/or immunosuppressive therapy): the use of infliximab should be avoided in patients with known hypersensitivity to infliximab, active infections, demyelinating disorders, severe congestive heart failure, and current or recent malignancy. Appropriate screening for latent and active tuberculosis should be performed on all patients before administration of infliximab.

Although there is evidence-based data to support the use of corticosteroids, immunomodulators, and infliximab in the treatment of patients with IBD, there are many aspects of therapy with these agents for which the data are lacking or inadequate. Additional prospective data are needed to resolve the areas of controversy. The gastroenterologist who uses these agents must have a clear understanding of the proven benefits and risks of these therapies to provide optimal care to the patient with IBD.