EDUCATION PRACTICE. Initiating Azathioprine for Crohn s Disease. The Problem. Clinical Scenario. Management Strategies Education

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2012;10: EDUCATION PRACTICE Initiating Azathioprine for Crohn s Disease BARRETT G. LEVESQUE* and EDWARD V. LOFTUS JR *Scripps Clinic, Division of Gastroenterology, Scripps Translational Science Institute, La Jolla, California; Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota Azathioprine (AZA) and 6-mercaptopurine are therapeutic options for patients with moderate to severe inflammatory Crohn s disease. AZA has both a complex metabolism and potential for adverse events that can be clinically challenging. AZA has been shown to maintain remission and reduce corticosteroid use in patients with Crohn s disease. There is heterogeneous thiopurine methyltransferase metabolism among patients, which has implications for clinical dosing and risk for adverse events. Routine thiopurine methyltransferase testing before the initiation of AZA will reduce early leukopenia and is mandatory to avoid potentially life-threatening myelotoxicity. Thiopurine metabolite assays may aid in the assessment of adherence and adverse events. Patients who do not respond to AZA therapy may benefit from the addition of biologic therapy or methotrexate. Keywords: Azathioprine; 6-Mercaptopurine; Thiopurine Methyltransferase; 6-Thioguanine; 6-Methylmercaptopurine; Crohn s Disease. A Clinical Scenario 32-year-old woman with Crohn s disease (CD) presents to her local gastroenterologist to discuss treatment options. She was diagnosed with CD 2 weeks ago when she presented with diarrhea and mild diffuse abdominal pain. She has never had perianal pain, fistula, or abscess. She originally lost 3 kg; however, her weight has stabilized at 65 kg. She does not smoke, and she has not had any extraintestinal manifestations of CD. Ileocolonoscopy revealed multiple discrete ulcers in the terminal ileum and ascending colon. Biopsy specimens revealed moderately active chronic ileitis and colitis. A magnetic resonance enterography showed inflammation of 10 cm of terminal ileum without prestenotic dilatation or penetrating complications. Thiopurine methyltransferase (TPMT) activity level was intermediate (15 U/mL erythrocytes). Her gastroenterologist reviews therapy options for her mild to moderate CD with her, and plans to start a tapering course of oral delayed-release budesonide and initiate azathioprine (AZA). What risks do you discuss before starting AZA? What is the utility of TPMT testing? How do you plan to monitor and manage her for AZA-related adverse events? What if she were to become pregnant? What if she continues to have active CD despite AZA treatment, how could you optimize the AZA or change her medical regimen? The Problem CD represents a spectrum of chronic inflammation, fibrostenosis, and penetrating disease that may affect any segment in the gastrointestinal tract. CD progresses from inflammatory to stricturing or penetrating disease in the majority (60%) of patients. Doctors and patients have several alternative treatments and strategies to consider when choosing therapy. Medication alternatives for mild to moderate Crohn s ileitis include immunosuppressive agents (AZA/6-mercaptopurine [6-MP], methotrexate), biologics (infliximab, adalimumab, certolizumab pegol, natalizumab), or surgery. Therapeutic strategies can be divided into combination vs monotherapy, or top-down (early biologic therapy) vs step-up (immunosuppressive followed by biologic therapy if remission is not obtained). An evidence-based, shared-decision making process involves discussion of the risks and benefits of each strategy, fitting therapy to an individual s disease context, risks for progression, and preferences. In this case, AZA was chosen as a maintenance therapy for mild to moderate inflammatory ileal CD in combination with a tapering course of budesonide induction therapy. Challenges for the physician and patient include an informed discussion of risks and benefits, constructing a plan for monitoring efficacy and side effects, and looking ahead to the next step if therapy fails. The conversion of 6-MP to 6-methylmercaptopurine (6MMP) by TPMT occurs at different rates owing to genetic variation in TPMT activity (Figure 1), and contributes to the variable metabolism, efficacy, and side effects that can be a challenge for the prescribing clinician. Management Strategies Education It is pragmatic to note to patients that approximately 15% of patients cannot tolerate AZA. These dose-independent adverse reactions include drug fever, pancreatitis, arthralgias, nausea, and rash. Drug fever usually presents within 2 weeks of initiating therapy as a flu-like illness, and requires immediately Abbreviations used in this paper: AZA, azathioprine; CBC, complete blood count; CD, Crohn s disease; CI, confidence interval; IBD, inflammatory bowel disease; 6-MMP, 6-methylmercaptopurine; 6-MP, 6-mercaptopurine; 6-TGN, 6-thioguanine nucleotides; RR, relative risk; TPMT, thiopurine methyltransferase by the AGA Institute /$36.00 doi: /j.cgh

2 May 2012 AZATHIOPRINE FOR CD 461 Figure 1. Histogram of 407 patients in New Zealand indicates the number of patients confirmed as homozygous deficient (white), confirmed heterozygous (black), normal genotype (grey), not genotyped (black horizontal stripes), vs TPMT enzyme activity. Reprinted with permission from Sies et al. 3 stopping AZA. The risk of pancreatitis is approximately 3%, typically occurs within the first few weeks of therapy, and requires stopping AZA as well. It is useful to instruct patients to have a low threshold for reporting new symptoms, especially in the first month of therapy. Dose-dependent reactions include leukopenia and hepatotoxicity. Although leukopenia most often occurs within the first month, it may occur at any time during therapy. Thiopurine therapy in CD carries an increased risk of lymphoma. The Cancers et Surrisque Associe aux Maladies inflammatoires intestinales En France (CESAME) Study Group followed up 19,486 patients with inflammatory bowel disease (60% with CD) for a median follow-up period of 35 months (interquartile range, mo). The adjusted hazard ratio for lymphoma in patients treated with thiopurines compared with those treated without thiopurines was 5.28 (95% confidence interval [CI], ). The adjusted hazard ratio for lymphoma among patients who were never treated with thiopurines was not significantly different from patients for whom thiopurines had been discontinued. Incidence rates of lymphoma in patients continuing thiopurines ranged from 0.37 cases per 1000 person-years in patients younger than age 50 years, 2.58 per 1000 person-years in those aged 50 to 65 years, and 5.4 per 1000 person-years in patients older than age 65 years. There have been rare cases of fatal hepatosplenic T-cell lymphoma in primarily young male patients taking a combination of AZA/6-MP and anti tumor necrosis factor therapy, or AZA alone, for inflammatory bowel disease (IBD). A small increased risk of nonmelanoma skin cancers has been found in patients on AZA therapy, with an absolute risk increase of 14% among patients taking thiopurines for more than 1 year. Sunscreen and regular skin checks are recommended for patients on AZA therapy. There may be an increased risk of cervical dysplasia among women with IBD on immunosuppressive therapies, especially if they are cigarette smokers, although the results of studies have been conflicting in this regard. Nevertheless, it would be prudent to recommend annual screening for cervical dysplasia if they are on immunosuppressive therapy. The risks of AZA for CD during pregnancy are weighed against the benefits of medication, and risks of active disease. Active CD during conception and pregnancy has been associated with higher rates of adverse perinatal outcomes. Another study by the Cancers et Surrisque Associe aux Maladies inflammatoires intestinales En France (CESAME) Study Group described the pregnancy outcomes of 204 women with IBD followed up prospectively who were treated with and without thiopurines. The overall rate of congenital malformations in patients receiving medication (3.5%) was not significantly greater than the French general population, although the power of the study may not have been sufficient to detect smaller differences. Overall, it is recommended that risks and benefits of AZA be discussed to enable women to make an informed decision regarding its use during pregnancy. It is reasonable to continue AZA for patients who are tolerating the medication and in remission; however, this decision needs to be made on an individual basis with a discussion of the risks and benefits of therapy. Vaccinations for influenza virus, Streptococcus pneumoniae, and human papillomavirus, if indicated, are recommended for CD patients considering or taking AZA. Live vaccines in immunosuppressed patients generally are contraindicated. Varicella zoster vaccination has been considered by some physicians in patients taking less than 3 mg/kg body weight daily of AZA, but in our practice we have avoided using this live virus vaccine in any patient on any medication with immunosuppressive properties (except oral budesonide). Reactivation of latent hepatitis B virus is a risk for patients treated with AZA, and hepatitis B surface antigen can be checked before starting AZA for patients with any risk factors for the disease. Pharmacology AZA is 55% 6-MP by molecular weight, and the conversion factor of 2.07 is used to convert a dose of 6-MP to a dose of AZA. TPMT, xanthine oxidase, and hypoxanthine phosphoribosyl transferase are the 3 enzyme systems that convert 6-MP to 6-thiouric acid, 6-MMP, and precursors of the active 6-thioguanine nucleotides (6-TGN). 6-TGN are incorporated into nucleic acid and subsequently inhibit synthesis of protein, RNA, and DNA.

3 462 LEVESQUE AND LOFTUS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 Testing for TPMT activity or genotype before initiating AZA will reduce the risk of severe, life-threatening leukopenia in patients exposed to thiopurine who completely lack TPMT activity, and helps guide initial dosing for patients with intermediate and normal activity. Approximately 0.3% of patients are homozygous for the mutant inactive form of TPMT, 11% are heterozygous with intermediate activity, and 89% have normal activity. A recent systematic review found a sensitivity of genotype testing to be 70% to 83% for low to intermediate TPMT activity, with a specificity approaching 100%. Therefore, TPMT activity testing may assess risk of myelotoxicity more accurately than TPMT genotyping. A recommendation for testing TPMT genotype or activity before initiating AZA has been added to the prescribing information for AZA. It also is stated, however, that TPMT testing does not substitute for complete blood count monitoring for patients receiving AZA or 6-MP. Dosing AZA metabolism has several clinical implications. There is an inverse relationship between TPMT enzyme activity and 6-TGN concentration. For patients with normal genotype or activity level, it is reasonable to start with a dose of 2 to 2.5 mg/kg body weight daily of AZA ( mg/kg/d of 6-MP). Thiopurines at any dose are contraindicated in patients with absent or homozygous-deficient TPMT activity. Starting with low doses will not prevent life-threatening myelosuppression in these patients. For patients with heterozygous genotype or intermediate activity level, the starting dose is reduced by half, but may be increased in time to the full dose in many patients. Starting with low doses (eg, 50 mg/d) of AZA to reduce toxicity, and then increasing this dose over several weeks, will not prevent, but will only delay, dose-dependent toxicity (such as bone marrow suppression) and will not prevent dose-independent reactions (eg, drug fever, pancreatitis, arthralgia, rash). In a patient with a history of drug fever or pancreatitis, it is not recommended to change from AZA to 6-MP or 6-MP to AZA. However, several studies have suggested that 6-MP may be tolerated in up to 60% of patients who develop afebrile flu-like illness, nausea, vomiting, or rash while on AZA. A therapeutic response may take 2 to 4 months for most patients. Efficacy In the ideal setting, AZA therapy serves as a steroidsparing agent that maintains clinical remission and attains mucosal healing. The data supporting these goals have been mixed in clinical trials. In the National Cooperative Crohn s Disease Study, Summers et al did not find a statistically significant difference between AZA (2.5 mg/kg/d) and placebo in rates of relapse over 1 to 2 years. A systematic review by Khan et al in 2011 showed no significant effect in inducing remission of AZA/6-MP vs placebo with a wide CI (relative risk [RR], 0.87; 95% CI, ), and a trend but no significant prevention of relapse, again with a wide CI (RR, 0.64; 95% CI, ). In this review, 3 AZA withdrawal trials showed a significant benefit for patients maintained by AZA in clinical remission (RR, 0.39; 95% CI, ). In comparison, a 2010 Cochrane metaanalysis of the efficacy of AZA or 6-MP for inducing remission in CD showed a significant advantage of AZA over placebo, with a number needed to treat of about 5 to observe benefit in 1 patient. Overall, treatment with AZA may confer a 10% to 25% risk reduction for relapse compared with placebo. In a prospective randomized trial of AZA vs infliximab vs combination therapy, mucosal healing rates at week 26 were significantly lower with AZA therapy than infliximab or combination therapy at 16.5%, 30.1%, and 44%, respectively. In patients without other contraindications who are unable to wean corticosteroids or achieve remission, adding a biologic agent to AZA increases the likelihood of clinical and endoscopic remission. The efficacy of combination therapy compared with AZA alone has been shown to be superior both in patients naive to AZA and in whom AZA has failed in the past. Monitoring and Optimization Myelosuppression is a dose-dependent adverse reaction that may occur at any time during AZA therapy. Frequent monitoring of complete blood count (CBC), as well as liver transaminase level for hepatotoxicity, is recommended. A genetic analysis of patients with myelosuppression on AZA therapy showed that only 27% carried mutant alleles, and therefore normal TPMT testing does not exclude the possibility of future leukopenia. A large retrospective cohort study showed that most severe neutropenia and thrombocytopenia occurs during the first 8 weeks of therapy; however, myelosuppression has been found even a decade after starting therapy, which supports intercurrent illness as an alternative etiology of leukopenia. Leukopenia (defined as below the normal limit for the testing laboratory) warrants stopping the medication and restarting at a lower dose once leukopenia has resolved. Even mild increases in liver transaminase levels are concerning, and if other etiologies are excluded, warrant discontinuing the medication owing to rare but present risks of nodular hyperplasia and fibrosis. Assays for 6-TGN and 6-MMP are commercially available. Levels of 6-TGN greater than 235 to 250 pmol/ erythrocytes and 6-MMP levels greater than 5700 pmol/ erythrocytes have been found to correlate with therapeutic response and hepatotoxicity, respectively. Data on the utility of measuring metabolites are mixed. Nonresponders may have low or high 6-TGN levels and there are few safety data for doses greater than 2.5 mg/kg/d of AZA in CD. A meta-analysis examining the utility of 6-TGN levels in IBD showed that median levels were 66 pmol/ red blood cells higher among responders than nonresponders, but there was significant heterogeneity. Patients with levels above and below a threshold of 230 to 260 pmol/ erythrocytes had remission rates of 62% and 36%, respectively. Patients with and without hepatoxicity may have high 6-MMP levels; however, an increase in the alanine aminotransferase level in a patient on AZA without other liver disease warrants decreasing the AZA dose. AZA metabolite assessment is probably most useful in assessing patients with no or incomplete response, when nonadherence is suspected, and in finding a therapeutic dose in patients who are TPMT heterozygotes. Allopurinol competes with xanthine oxidase, shunts metabolism away from 6-MMP production, and increases levels of 6-TGN. The addition of allopurinol may correct an unfavorable ratio of 6-TGN to 6-MMP by reducing 6-MMP concentrations and increasing 6-TGN concentrations. The addition of allopurinol to AZA, and subsequent substantial dose reduction of AZA, has been suggested in patients with hepatoxicity, arthralgias, or nausea to correct an unfavorable ratio of 6-TGN to 6-MMP. This is controversial and has been associated with high rates of opportunistic infections, despite small prospective studies

4 May 2012 AZATHIOPRINE FOR CD 463 Figure 2. Algorithm: initiating AZA in CD 11. showing safety of long-term use. If this is to be undertaken, we suggest an allopurinol dose of 100 mg/d, a reduction in the thiopurine dose to 25% of the original dose, and frequent CBC monitoring thereafter. Monitoring of 6-TGN metabolites should be performed after 1 to 3 months of therapy. Therapy with 6-TGN has been shown to be associated with early hepatic nodular hyperplasia disease of the liver and is not recommended in our clinical practice. Areas of Uncertainty There is significant uncertainty around predicting which patients will respond to therapy with thiopurines. Further research into the genomics and proteonomics of CD is needed to help make these predictions. In addition, it remains unclear from a policy perspective if initial treatment with AZA, biologic, or combination therapy is the most cost-effective strategy, and on what disease factors the value of these initial treatments options depend. Published Guidelines The AGA Institute Medical Position Statement recommends a CBC at least every other week while adjusting the dose of AZA, and thereafter at least every 3 months along with periodic liver chemistries. A TPMT genotype or phenotype is suggested before starting AZA/6-MP. The guidelines suggest AZA/6-MP as a steroid-sparing, long-term treatment for patients with chronic active disease, who have a severe flare requiring steroids, or multiple steroid treatments during a year. Biologic therapy or combination biologic/antimetabolite therapy is an alternative for chronic, active, steroiddependent disease. Recommendations The patient began therapy with a tapering course of budesonide (9 mg/d 8 wk, 6 mg/d 4 wk, 3 mg/d 4 wk) and AZA at 75 mg/d (1.1 mg/kg). Methotrexate was avoided because of the patient s interest in becoming pregnant when her CD is in remission. Budesonide was chosen as an induction agent because the patient preferred to reduce her chances of the systemic side effects of prednisone. Laboratory tests were scheduled as a CBC weekly for the first month, every other week for 2 months, and then monthly to every other month thereafter, along with hepatic biochemistries at week 4 and then every 3 months. At approximately 8 weeks into treatment, 6-TGN and 6-MMP metabolites would be checked, with a goal of slowly escalating her dose of AZA until her 6-TGN was found to be greater than 230 to 260 pmol/ erythrocytes. If she were to develop dose-dependent complications such as leukopenia or transaminase increases, 6-TGN and 6-MMP metabolites would be checked to help inform a next step in management (Figure 2). A plan was made to add biologic therapy if she did not respond within the first month of budesonide therapy, or if disease is persistent or progressing endoscopically or radiologically despite therapeutic doses of AZA. Suggested Reading 1. Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn s disease. Inflamm Bowel Dis 2002;8: Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associated with progression to intestinal complications of Crohn s disease in a population-based cohort. Gastroenterology 2010;139: Sies C, Florkowski C, George P, et al. Measurement of thiopurine methyl transferase activity guides dose-initiation and prevents toxicity from azathioprine. N Z Med J 2005;118:U Sandborn WJ. A review of immune modifier therapy for inflammatory bowel disease: azathioprine, 6-mercaptopurine, cyclosporine, and methotrexate. Am J Gastroenterol 1996;91: Weersma RK, Peters FT, Oostenbrug LE, et al. Increased incidence of azathioprine-induced pancreatitis in Crohn s disease compared with other diseases. Aliment Pharmacol Ther 2004; 20: Bermejo F, Lopez-Sanroman A, Taxonera C, et al. Acute pancreatitis in inflammatory bowel disease, with special reference to azathioprine-induced pancreatitis. Aliment Pharmacol Ther 2008; 28: Hindorf U, Johansson M, Eriksson A, et al. Mercaptopurine treatment should be considered in azathioprine intolerant patients with

5 464 LEVESQUE AND LOFTUS CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 10, No. 5 inflammatory bowel disease. Aliment Pharmacol Ther 2009;29: Lewis JD, Abramson O, Pascua M, et al. Timing of myelosuppression during thiopurine therapy for inflammatory bowel disease: implications for monitoring recommendations. Clin Gastroenterol Hepatol 2009;7: ; quiz, Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet 2009; 374: Mackey AC, Green L, Liang LC, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr 2007;44: Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for nonmelanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2010;8: Long MD, Kappelman MD, Pipkin CA. Nonmelanoma skin cancer in inflammatory bowel disease: a review. Inflamm Bowel Dis 2011;17: Bhatia J, Bratcher J, Korelitz B, et al. Abnormalities of uterine cervix in women with inflammatory bowel disease. World J Gastroenterol 2006;12: Kane S, Khatibi B, Reddy D. Higher incidence of abnormal pap smears in women with inflammatory bowel disease. Am J Gastroenterol 2008;103: Lees CW, Critchley J, Chee N, et al. Lack of association between cervical dysplasia and IBD: a large case-control study. Inflamm Bowel Dis 2009;15: Baiocco PJ, Korelitz BI. The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 1984;6: Bush MC, Patel S, Lapinski RH, et al. Perinatal outcomes in inflammatory bowel disease. J Matern Fetal Neonatal Med 2004; 15: Coelho J, Beaugerie L, Colombel JF, et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME study. Gut 2011;60: Melmed GY, Ippoliti AF, Papadakis KA, et al. Patients with inflammatory bowel disease are at risk for vaccine-preventable illnesses. Am J Gastroenterol 2006;101: Wasan SK, Baker SE, Skolnik PR, et al. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105: Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol 1992;43: Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet 1980;32: Booth RA, Ansari MT, Loit E, et al. Assessment of thiopurine S-methyltransferase activity in patients prescribed thiopurines: a systematic review. Ann Intern Med 2011;154: , W Sandborn WJ, Van OE, Zins BJ, et al. An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn s disease. Gastroenterology 1995;109: Lees CW, Maan AK, Hansoti B, et al. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther 2008;27: Sandborn WJ, Tremaine WJ, Wolf DC, et al. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn s disease. North American Azathioprine Study Group. Gastroenterology 1999;117: Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995;123: Summers RW, Switz DM, Sessions JT Jr, et al. National cooperative Crohn s disease study: results of drug treatment. Gastroenterology 1979;77: Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol 2011;106: Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn s disease. Cochrane Database Syst Rev 2010;6:CD Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn s disease. N Engl J Med 2010;362: Lémann M, Mary JY, Duclos B, et al. Infliximab plus azathioprine for steroid-dependent Crohn s disease patients: a randomized placebo-controlled trial. Gastroenterology 2006;130: Connell WR, Kamm MA, Ritchie JK, et al. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34: Colombel JF, Ferrari N, Debuysere H, et al. Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn s disease and severe myelosuppression during azathioprine therapy. Gastroenterology 2000;118: Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118: Cuffari C, Hunt S, Bayless T. Utilisation of erythrocyte 6-thioguanine metabolite levels to optimise azathioprine therapy in patients with inflammatory bowel disease. Gut 2001;48: Osterman MT, Kundu R, Lichtenstein GR, et al. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology 2006;130: Gardiner SJ, Gearry RB, Burt MJ, et al. Allopurinol might improve response to azathioprine and 6-mercaptopurine by correcting an unfavorable metabolite ratio. J Gastroenterol Hepatol 2011;26: Sparrow MP, Hande SA, Friedman S, et al. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol 2007;5: Ansari A, Elliott T, Baburajan B, et al. Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease. Aliment Pharmacol Ther 2008;28: Ansari A, Patel N, Sanderson J, et al. Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease. Aliment Pharmacol Ther 2010;31: Govani SM, Higgins PD. Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD. J Crohns Colitis 2010;4: Leung Y, Sparrow MP, Schwartz M, et al. Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease. J Crohns Colitis 2009; 3: Geller SA, Dubinsky MC, Poordad FF, et al. Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 2004;28:

6 May 2012 AZATHIOPRINE FOR CD Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130: Reprint requests Address requests for reprints to: Edward V. Loftus Jr, MD, Division of Gastroenterology, Mayo Clinic, 200 First Street SW, Rochester, Minnesota fax: (507) Conflicts of interest The authors disclose the following: Barrett Levesque is a consultant for Castlight Health, and is a member of the speaker s bureau for UCB, Warner Chilcott, Abbott Labs, and Salix. Edward Loftus is a consultant for Abbott Labs, UCB, Bristol-Myers Squibb, and Pfizer, and provides research support for Abbott Labs, UCB, Shire, Bristol-Myers Squibb, GlaxoSmithKline, Millenium-Takeda, Amgen, Braintree Labs, Pfizer, Janssen Biotech, and Genentech.