gastrointestinal disorders
Medications for Inflammatory Bowel Disease
Immunomodulating Medications
 are also used in combination therapy with Biologic Agents . Azathioprineand its metabolite 6-mercaptopurineinhibit T-cell function and may induce T-cell apoptosis. They are effective long-term and may diminish corticosteroid requirements and maintain remission for years. These drugs often require 1 to 3 months to produce clinical benefits, so corticosteroids cannot be completely withdrawn until at least the 2nd month. Dosage varies depending on individual metabolism. The dose ofazathioprineor 6-mercaptopurineshould be reduced by 50% and adjusted accordingly based on clinical response and hematologic monitoring in patients who are intermediate metabolizers. Themost common adverse effectsare nausea, vomiting, and malaise. Signs of bone marrow suppression must be monitored with regular white blood cell counts (biweekly for 1 month, then every 1 to 2 months). Pancreatitis or high fever occurs in about 3 to 5% of patients; either is an absolute contraindication to rechallenge. Hepatotoxicity is rarer and can be screened for by blood tests every 6 to 12 months. These drugs are associated with increased risk of lymphoma and nonmelanoma skin cancers. Before starting these medications, patients should have tests to measure the activity of thiopurine methyltransferase (TPMT), an enzyme that convertsazathioprineand 6-mercaptopurineto their active metabolites 6-thioguanine(6-TG) and 6-methylmercaptopurine (6-MMP). Patients should also have genotype testing for known low-activity variants of this enzyme. After starting these drugs, it is useful to measure levels of 6-TG and 6-MMP to help ensure safe and effective drug dosages. Therapeutic efficacy correlates with 6-TG levels between 230 and 450 picomoles per 8 × 108red blood cells (RBCs). Myelotoxicity can occur when 6-TG levels are > 450. Hepatotoxicity can occur when 6-MMP levels are > 5700 picomoles per 8 × 108RBCs. The concentrations of metabolites are also useful in nonresponding patients to distinguish lack of adherence from resistance. Methotrexateis of benefit to many patients with corticosteroid-refractory or corticosteroid-dependent Crohn disease, even those who have not responded toazathioprineor 6-mercaptopurine. Adverse effectsinclude nausea, vomiting, and asymptomatic liver test abnormalities. Folate 1 mg orally once a day may diminish some of the adverse effects. Both women and men takingmethotrexateshould ensure the female partner uses an effective contraceptive method such as an intrauterine device, a contraceptive implant, or an oral contraceptive. Less effective methods of contraception, such as condoms, spermicides, diaphragms, cervical caps, and periodic abstinence, should be discouraged. Additionally, women and perhaps men should stopmethotrexatefor at least 3 months before trying to conceive. Monthly complete blood counts and liver tests withalbuminshould be done for the first 3 months of therapy then every 8 to 12 weeks during therapy. Alcohol use, hepatitis B and C, obesity, diabetes, and possibly psoriasis are risk factors for hepatotoxicity. Preferably, patients with these conditions should not be treated withmethotrexate. Pretreatment liver biopsies are not recommended; liver biopsies are done if the results of 6 of 12 tests done in a 1-year period show elevated levels of aspartate aminotransferase (AST). Myelosuppression, pulmonary toxicity, and nephrotoxicity can also occur withmethotrexatetherapy. Cyclosporine,which blocks lymphocyte activation, may benefit patients with severe ulcerative colitis unresponsive to corticosteroids and biologic agents and who may otherwise require colectomy. Its only well-documented use in Crohn disease is for patients with refractory fistulas or pyoderma. Long-term use (>6 months) is contraindicated by multiple adverse effects (eg, renal toxicity, seizures, opportunistic infections, hypertension, neuropathy). Generally, patients with severe ulcerative colitis unresponsive to corticosteroids and biologics are not offeredcyclosporineunless there is a reason to avoid the safer curative option of colectomy. If the drug is used, trough blood levels should be kept between 200 to 400 ng/mL (166 to 333 nmol/L) andPneumocystis jiroveciiprophylaxis should be considered during the period of concomitant corticosteroid,cyclosporine, and antimetabolite treatment. Tacrolimus,an immunosuppressant also used in patients who have had transplants, seems as effective ascyclosporineand may be considered for use in patients with severe or refractory ulcerative colitis who do not require hospitalization. The trough blood levels should be kept between 10 to 15 ng/mL (12 to 25 nmol/L).Tacrolimuscan be given for short-term treatment of perianal and cutaneous fistulas in Crohn disease. 