AGA Reviews the Use of Corticosteroids, Immunomodulators, and Infliximab in IBD
Am Fam Physician. 2007 Feb 1;75(3):410-416.
Guideline source: American Gastroenterological Association
Literature search described? Yes
Evidence rating system used? Yes
Published source: Gastroenterology, March 2006
Inflammatory bowel disease (IBD) encompasses gastrointestinal tract disorders, including Crohn's disease and ulcerative colitis. These disorders are common, affecting almost 1 million persons in the United States and Europe. Their presentation is varied, and a number of complications can occur. To help develop a more consistent care plan, the American Gastroenterological Association Institute issued a clinical position statement on corticosteroids, immunomodulators, and infliximab (Remicade) use in managing IBD.
Corticosteroids are used for treating patients with a moderate to severe relapse of IBD. Topical agents like suppositories or foam have been used to treat proctitis, and enemas have been effective for patients with disease up to the splenic flexure. Budesonide (Rhinocort), which has limited bioavailability and is poorly absorbed, can provide therapeutic benefit with reduced toxicity in patients with ileocecal Crohn's disease.
For patients with mild to moderate IBD, ileal-release forms of budesonide can be used to treat ileal and right-sided colonic Crohn's disease; however, they are not effective in treating ulcerative colitis. Conventional corticosteroids (e.g., prednisone) typically are used only in patients with moderate to severe IBD who do not respond to other first-line treatments (e.g., mesalamine [Rowasa] for ulcerative colitis, budesonide for Crohn's disease). For distal colonic inflammation, a topical solution of hydrocortisone or budesonide is effective.
For patients with moderate to severe IBD, corticosteroids are effective in managing Crohn's disease and ulcerative colitis; however, they are not effective in treating perianal fistulas.
Hospitalization for parenteral corticosteroids is needed for patients with severe and fulminant IBD who do not respond to oral corticosteroids and for those with severe IBD with Crohn's disease or ulcerative colitis.
Conventional corticosteroids are not effective for use as maintenance therapy in patients with Crohn's disease or ulcerative colitis. Budesonide is effective as a maintenance therapy in patients with mild to moderate ileocecal Crohn's disease who are in short-term (three months) remission; it is not effective for long-term (one year) remission.
For the initiation of remission, a prednisone (or equivalent medication) dosage ranging from 40 to 60 mg per day or 1 mg per kg per day is effective. Induction of response can average seven to 14 days. Gradually tapering the dosage by 5 mg per week to a dose of 20 mg per day and then tapering the dosage again by 2.5 to 5.0 mg per week until the dosage is below 20 mg per day is recommended. Budesonide also can be tapered gradually from the initial dose of 9 mg to 6-mg and 3-mg doses. Budesonide suppresses the adrenocortical axis, so physicians should monitor patient symptoms and evaluate for adrenal insufficiency. If a corticosteroid dose cannot be tapered, antimetabolite or infliximab therapy is needed. If a patient does not respond to therapy with high doses of prednisone (or equivalent medication) in seven to 14 days, parenteral corticosteroids are indicated; the dosage usually ranges from 40 to 60 mg per day of methylprednisolone (Medrol) or 200 to 300 mg per day of hydrocortisone.
Patients taking corticosteroids are at an increased risk of infectious complications and should be monitored for glucose intolerance and other metabolic abnormalities. Occasional bone mineral density assessment and yearly ophthalmologic examinations also are recommended for patients on long-term (more than three months) corticosteroid therapy. Those who have taken corticosteroids in the past year have a higher risk of adrenal insufficiency; stress-dose corticosteroids may be needed if the patient undergoes surgery.
Azathioprine and 6-Mercaptopurine
Azathioprine (Imuran) and 6-mercaptopurine (6-MP; Purinethol) are immunomodulators; azathioprine is converted to 6-MP nonenzymatically. They often are used to withdraw the corticosteroids and maintain remission in corticosteroid-dependent patients who have Crohn's disease or ulcerative colitis. Some studies show that azathioprine and 6-MP are effective in reducing clinical and endoscopic postoperative recurrence of Crohn's disease.
While azathioprine and 6-MP doses are being adjusted, a complete blood count with differential should be taken at least every other week. Once the doses stabilize, a complete blood count should be performed at least once every three months for as long as it is clinically appropriate. Periodic measurement of liver-associated chemistries also is recommended. Currently, the U.S. Food and Drug Administration recommends that, to avoid adverse effects, all persons should have a thiopurine methyltransferase (TPMT) genotype or phenotype assessment before undergoing azathioprine or 6-MP therapy. Persons with intermediate or normal TPMT activity also will need frequent complete blood count measurements because of the possibility of developing myelosuppression.
Because long-term corticosteroid use is undesirable, patients who have chronic, active, corticosteroid-dependent disease (i.e., Crohn's disease or ulcerative colitis) should be treated with 2 to 3 mg per kg per day of azathioprine or 1.0 to 1.5 mg per kg per day of 6-MP. Another option would be to use infliximab or infliximab combined with antimetabolites. In an attempt to avoid future corticosteroid use, those patients who have a severe flare-up of IBD also should be considered for this treatment.
6-MP is modestly effective in decreasing postoperative recurrence in Crohn's disease; its use should be an option for patients who are at high risk of postoperative recurrence or those in whom recurrence would be harmful.
An azathioprine dosage of 2 to 3 mg per kg per day or a 6-MP dosage of 1.0 to 1.5 mg per kg per day has been shown to be effective for treating perianal and enteric fistulas.
When trying to determine medical noncompliance, it is useful to monitor thiopurine metabolites in patients using 6-MP or azathioprine. Metabolites also may be useful to help optimize dosing and monitor for toxicity.
Regardless of disease distribution, a dosage of 2 to 3 mg per kg per day of azathioprine or 1.0 to 1.5 mg per kg per day of 6-MP is effective in maintaining remission in persons with Crohn's disease and for corticosteroid dose reduction in persons with ulcerative colitis. This dosage may be effective in maintaining remission in those with ulcerative colitis; however, data are conflicting and not supported by larger well-controlled trials.
Before considering surgery or other treatments, 6-MP may be tried carefully in persons with gastrointestinal intolerance (not including fever, pancreatitis, hypersensitivity reaction) to azathioprine. Azathioprine can be tried in patients with intolerance to 6-MP.
Methotrexate has been used in clinical settings for almost 50 years. It produces a more rapid response in persons with IBD than 6-MP or azathioprine, and it has been shown to have a possible role in managing Crohn's disease.
Parenteral methotrexate is used for inducing remission in persons with active Crohn's disease and for maintenance of remission in those with inactive Crohn's disease. It also can be used to initiate remission with corticosteroid withdrawal in corticosteroid-dependent patients with Crohn's disease. Currently, there is insufficient evidence to support its use for inducing or maintaining remission in persons with active ulcerative colitis.
Maintenance therapy of weekly 15- to 25-mg intra-muscular injections is effective in persons with active Crohn's disease that is responsive to intramuscular methotrexate. For those with chronic active Crohn's disease, 25 mg intramuscularly per week for 16 weeks and then 15 mg per week thereafter is effective.
Regular monitoring of laboratory results, including blood counts and liver-associated chemistries, is suggested for persons treated with methotrexate. Those with persistent abnormal liver-associated test results should have a liver biopsy or discontinue treatment. Methotrexate is contraindicated in pregnancy.
Mycophenolate mofetil (Cellcept) slows down lymphocyte proliferation by blocking the synthesis of guano-sine nucleotide in T cells. It was first used in IBD as an alternate immunosuppressant for persons intolerant to azathioprine or 6-MP. However, studies have shown that mycophenolate mofetil is less effective and has a higher incidence of patient intolerance, making it difficult to justify its use at this time.
Cyclosporine (Sandimmune) has a more rapid onset of action than azathioprine, 6-MP, or methotrexate. Intravenous cyclosporine is effective in managing severe ulcerative colitis and typically works within one week. Intravenous cyclosporine also can be effective for man-aging fistulizing Crohn's disease, but it may have toxic effects, and the disease often flares up again with use of the oral formulation. In persons with luminal Crohn's disease, it has only been effective at higher doses, which may not justify its use.
An intravenous cyclosporine dosage of 2 to 4 mg per kg per day or a colectomy should be considered for patients with severe ulcerative colitis in whom seven to 10 days of high-dose oral or parenteral corticosteroids failed. It also can help patients with severe corticosteroid-refractory ulcerative colitis avoid surgery.
To provoke a response in persons with severe ulcerative colitis who are already receiving intravenous cyclosporine, combined use of intravenous corticosteroids is recommended. Response or remission induced by intravenous cyclosporine in persons with IBD usually requires continuing therapy with oral cyclosporine for a few months. It also requires corticosteroid dose reduction, initiation of azathioprine or 6-MP treatment, and prophylaxis againstPneumocystis carinii. Continued purine analogue use is recommended for maintenance.
Although azathioprine or 6-MP therapy is required for maintenance of remission, oral cyclosporine is effective for managing corticosteroid-refractory ulcerative colitis.
High-dose oral cyclosporine has short-term effectiveness in treating luminal Crohn's disease, whereas low-dose cyclosporine (i.e., oral and intravenous) has not been proven effective.
Intravenous cyclosporine is effective for managing fistulizing Crohn's disease and should be followed with azathioprine or 6-MP therapy for maintenance of fistula closure.
Infliximab is a chimeric monoclonal antibody to human tumor necrosis factor α that has been used in clinical practice in the United States since 1998. It is effective in managing inflammatory and fistulizing Crohn's disease that has not responded to other treatments. Recent trials have shown that infliximab also is effective in managing ulcerative colitis.
Indications for infliximab use include fistulizing Crohn's disease as well as Crohn's disease and ulcerative colitis in persons who do not respond to conventional therapy. Patients who respond to induction therapy also should receive maintenance therapy.
An initial dose of 5 mg per kg, given by intravenous infusion over two hours, with three doses at weeks 0, 2, and 6 is recommended. It should be followed by maintenance therapy every eight weeks in those persons who are responsive. A health care practitioner should supervise treatment and observe the patient for approximately one hour after treatment. In patients with Crohn's disease who initially respond to treatment and then lose responsiveness, 10 mg per kg of infliximab may be tried.
Infliximab can be used to manage moderately to severely active Crohn's disease or ulcerative colitis in persons who do not respond to adequate corticosteroid or immunosuppressive treatment. Those who respond to induction therapy should continue with maintenance therapy every eight weeks. If the patient is nonresponsive after three infusions, treatment should be discontinued. If the patient achieves remission with infliximab, any concomitant corticosteroid should be withdrawn or tapered.
Infliximab also can be used to treat fistulizing Crohn's disease in persons who are nonresponsive to conventional therapies (e.g., antibiotics, immunosuppressives); however, it should not be used in persons with hypersensitivity to infliximab or those who have active infections, demyelinating disorders, severe congestive heart failure, or current or recent malignancy. Patients should be screened for latent or active tuberculosis before receiving infliximab.
Although the use of corticosteroids, immunomodulators, and infliximab for treating IBD is supported by well-designed clinical trials, many of the data are insufficient, and additional research is needed. Physicians who use these medications should clearly understand their benefits and risks so they can provide the best possible care.
Copyright © 2007 by the American Academy of Family Physicians.
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