The role and advances of immunomodulator therapy for inflammatory bowel disease

References

• Hitchings GH, Elion GB. The chemistry and biochemistry of purine analogs. Ann N Y Acad Sci 1954;60(2):195-9
   PubMedGoogle Scholar
• Present DH, Korelitz BI, Wisch N, et al. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980;302(18):981-7
   PubMed Web of Science ®Google Scholar
• Case JP. Old and new drugs used in rheumatoid arthritis: a historical perspective. Part 1: the older drugs. Am J Ther 2001;8(2):123-43
   PubMedGoogle Scholar
• Kozarek RA, Patterson DJ, Gelfand MD, et al. Methotrexate induces clinical and histologic remission in patients with refractory inflammatory bowel disease. Ann Intern Med 1989;110(5):353-6
   PubMed Web of Science ®Google Scholar
• Domenech E, Nos P, Papo M, et al. 6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine. Scand J Gastroenterol 2005;40(1):52-5
   PubMed Web of Science ®Google Scholar
• McGovern DP, Travis SP, Duley J, et al. Azathioprine intolerance in patients with IBD may be imidazole-related and is independent of TPMT activity. Gastroenterology 2002;122(3):838-9
   PubMed Web of Science ®Google Scholar
• Nielsen OH, Bjerrum JT, Herfarth H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol 2013;53(6):575-88
   PubMed Web of Science ®Google Scholar
• Derijks LJ, Gilissen LP, Hooymans PM, Hommes DW. Review article: thiopurines in inflammatory bowel disease. Aliment Pharmacol Ther 2006;24(5):715-29
   PubMed Web of Science ®Google Scholar
• Neurath MF, Kiesslich R, Teichgraber U, et al. 6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn’s disease. Clin Gastroenterol Hepatol 2005;3(10):1007-14
   PubMed Web of Science ®Google Scholar
• Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130(3):935-9
   PubMed Web of Science ®Google Scholar
• Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol 2010;63(4):288-95
   PubMed Web of Science ®Google Scholar
• Relling MV, Gardner EE, Sandborn WJ, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-91
   PubMed Web of Science ®Google Scholar
• Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 2013;93(4):324-5
   PubMed Web of Science ®Google Scholar
• Dignass A, Lindsay JO, Sturm A, et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management. J Crohns Colitis 2012;6(10):991-1030
   PubMed Web of Science ®Google Scholar
• Dignass A, Van AG, Lindsay JO, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010;4(1):28-62
   PubMed Web of Science ®Google Scholar
• Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60(5):571-607
   PubMed Web of Science ®Google Scholar
• Lennard L. TPMT in the treatment of Crohn’s disease with azathioprine. Gut 2002;51(2):143-6
   PubMed Web of Science ®Google Scholar
• Thompson AJ, Newman WG, Elliott RA, et al. The cost-effectiveness of a pharmacogenetic test: a trial-based evaluation of TPMT genotyping for azathioprine. Value Health 2014;17(1):22-33
   PubMed Web of Science ®Google Scholar
• 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(12):814-23
   PubMed Web of Science ®Google Scholar
• Haines ML, Ajlouni Y, Irving PM, et al. Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease. Inflamm Bowel Dis 2011;17(6):1301-7
   PubMed Web of Science ®Google Scholar
• Moreau AC, Paul S, Del TE, et al. Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis. Inflamm Bowel Dis 2014;20(3):464-71
   PubMed Web of Science ®Google Scholar
• Gonzalez-Lama Y, Bermejo F, Lopez-Sanroman A, et al. Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients. Aliment Pharmacol Ther 2011;34(5):544-54
   PubMed Web of Science ®Google Scholar
• Lowry PW, Franklin CL, Weaver AL, et al. Measurement of thiopurine methyltransferase activity and azathioprine metabolites in patients with inflammatory bowel disease. Gut 2001;49(5):665-70
   PubMed Web of Science ®Google Scholar
• Reinshagen M, Schutz E, Armstrong VW, et al. 6-thioguanine nucleotide-adapted azathioprine therapy does not lead to higher remission rates than standard therapy in chronic active Crohn disease: results from a randomized, controlled, open trial. Clin Chem 2007;53(7):1306-14
   PubMed Web of Science ®Google Scholar
• Chouchana L, Narjoz C, Beaune P, et al. Review article: the benefits of pharmacogenetics for improving thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2012;35(1):15-36
   PubMed Web of Science ®Google Scholar
• 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(6):734-41
   PubMed Web of Science ®Google Scholar
• Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther 2005;22(5):441-6
   PubMed Web of Science ®Google Scholar
• 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(2):209-14
   PubMed Web of Science ®Google Scholar
• Sparrow MP. IBD: switching metabolism-can two drugs be better than one? Nat Rev Gastroenterol Hepatol 2010;7(8):420-2
   PubMed Web of Science ®Google Scholar
• Smith MA, Blaker P, Marinaki AM, et al. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis 2012;6(9):905-12
   PubMed Web of Science ®Google Scholar
• Leong RW, Gearry RB, Sparrow MP. Thiopurine hepatotoxicity in inflammatory bowel disease: the role for adding allopurinol. Expert Opin Drug Saf 2008;7(5):607-16
   PubMed Web of Science ®Google Scholar
• Goldman ID, Matherly LH. The cellular pharmacology of methotrexate. Pharmacol Ther 1985;28(1):77-102
   PubMed Web of Science ®Google Scholar
• Morgan SL, Oster RA, Lee JY, et al. The effect of folic acid and folinic acid supplements on purine metabolism in methotrexate-treated rheumatoid arthritis. Arthritis Rheum 2004;50(10):3104-11
   PubMed Web of Science ®Google Scholar
• Grim J, Chladek J, Martinkova J. Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet 2003;42(2):139-51
   PubMed Web of Science ®Google Scholar
• Jacobs SA, Adamson RH, Chabner BA, et al. Stoichiometric inhibition of mammalian dihydrofolate reductase by the gamma-glutamyl metabolite of methotrexate, 4-amino-4-deoxy-N-10-methylpteroylglutamyl-gamma-glutamate. Biochem Biophys Res Commun 1975;63(3):692-8
   PubMed Web of Science ®Google Scholar
• Louis E, ElYafi FAN, Belaiche J. High doses of azathioprine but not 6-mercaptopurine inhibit the production of pro-inflammatory cytokines in inflammatory bowel diseases: an in vitro study. Gastroenterology 2000;118(Suppl 2):4204
   Google Scholar
• Almer S. Novel strategies in the thiopurine treatment of inflammatory bowel disease. Nucleosides Nucleotides Nucleic Acids 2010;29(4-6):267-77
   PubMed Web of Science ®Google Scholar
• Chande N, Tsoulis DJ, Macdonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2013;4:CD000545
   PubMed Web of Science ®Google Scholar
• Dassopoulos T, Sultan S, Falck-Ytter YT, et al. American Gastroenterological Association Institute technical review on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013;145(6):1464-78
   PubMed Web of Science ®Google Scholar
• Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013;145(6):1459-63
   PubMed Web of Science ®Google Scholar
• Prefontaine E, Sutherland LR, Macdonald JK, Cepoiu M. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009(1):CD000067
   PubMed Web of Science ®Google Scholar
• Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut 1995;37(5):674-8
   PubMed Web of Science ®Google Scholar
• D’Haens GR, Vermeire S, Van AG, et al. Therapy of metronidazole with azathioprine to prevent postoperative recurrence of Crohn’s disease: a controlled randomized trial. Gastroenterology 2008;135(4):1123-9
   PubMed Web of Science ®Google Scholar
• Hanauer SB, Korelitz BI, Rutgeerts P, et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004;127(3):723-9
   PubMed Web of Science ®Google Scholar
• Lemann M, Mary JY, Colombel JF, et al. A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine. Gastroenterology 2005;128(7):1812-18
   PubMed Web of Science ®Google Scholar
• O’Donoghue DP, Dawson AM, Powell-Tuck J, et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet 1978;2(8097):955-7
   PubMed Web of Science ®Google Scholar
• Rosenberg JL, Levin B, Wall AJ, Kirsner JB. A controlled trial of azathioprine in Crohn’s disease. Am J Dig Dis 1975;20(8):721-6
   PubMedGoogle Scholar
• Summers RW, Switz DM, Sessions JTJr, et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology 1979;77(4 Pt 2):847-69
   PubMed Web of Science ®Google Scholar
• Willoughby JM, Beckett J, Kumar PJ, Dawson AM. Controlled trial of azathioprine in Crohn’s disease. Lancet 1971;2(7731):944-7
   PubMed Web of Science ®Google Scholar
• Cosnes J, Bourrier A, Laharie D, et al. Early administration of azathioprine vs conventional management of Crohn’s Disease: a randomized controlled trial. Gastroenterology 2013;145(4):758-65
   PubMed Web of Science ®Google Scholar
• Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterology 2013;145(4):766-74
   PubMed Web of Science ®Google Scholar
• de Boer NK, van Bodegraven AA. Get the best out of thiopurine therapy. Gastroenterology 2014;146(3):865
   PubMed Web of Science ®Google Scholar
• Hawthorne AB, Probert CS, Sanderson JD. Early use of azathioprine in Crohn’s disease. Gastroenterology 2014;146(3):865-6
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Peyrin-Biroulet L. Azathioprine in early Crohn’s disease: time to revisit patient selection and end points for clinical trials and/or azathioprine efficacy? Gastroenterology 2014;146(3):867-8
   PubMed Web of Science ®Google Scholar
• Rammohan H, Pai CG. Shrinking indications for azathioprine in Crohn’s disease: a conclusion too premature? Gastroenterology 2014;146(3):866-7
   PubMed Web of Science ®Google Scholar
• Jones GR, Kennedy NA, Lees CW, et al. Systematic review: the use of thiopurines or anti-TNF in post-operative Crohn’s disease maintenance - progress and prospects. Aliment Pharmacol Ther 2014;39(11):1253-65
   PubMed Web of Science ®Google Scholar
• Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol 2009;104(8):2089-96
   PubMed Web of Science ®Google Scholar
• Reinisch W, Angelberger S, Petritsch W, et al. Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn’s disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial. Gut 2010;59(6):752-9
   PubMed Web of Science ®Google Scholar
• Chatu S, Subramanian V, Saxena S, Pollok RC. The role of thiopurines in reducing the need for surgical resection in Crohn’s disease: a systematic review and meta-analysis. Am J Gastroenterol 2014;109(1):23-34
   PubMed Web of Science ®Google Scholar
• Lakatos PL, Golovics PA, David G, et al. Has there been a change in the natural history of Crohn’s disease? Surgical rates and medical management in a population-based inception cohort from Western Hungary between 1977-2009. Am J Gastroenterol 2012;107(4):579-88
   PubMed Web of Science ®Google Scholar
• Ramadas AV, Gunesh S, Thomas GA, et al. Natural history of Crohn’s disease in a population-based cohort from Cardiff (1986-2003): a study of changes in medical treatment and surgical resection rates. Gut 2010;59(9):1200-6
   PubMed Web of Science ®Google Scholar
• Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J 1974;4(5945):627-30
   PubMed Web of Science ®Google Scholar
• Sood A, Midha V, Sood N, Kaushal V. Role of azathioprine in severe ulcerative colitis: one-year, placebo-controlled, randomized trial. Indian J Gastroenterol 2000;19(1):14-16
   PubMedGoogle Scholar
• 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(4):630-42
   PubMed Web of Science ®Google Scholar
• Timmer A, McDonald JW, Tsoulis DJ, Macdonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;9:CD000478
   PubMed Web of Science ®Google Scholar
• Ardizzone S, Maconi G, Russo A, et al. Randomised controlled trial of azathioprine and 5-aminosalicylic acid for treatment of steroid dependent ulcerative colitis. Gut 2006;55(1):47-53
   PubMed Web of Science ®Google Scholar
• McDonald JW, Tsoulis DJ, Macdonald JK, Feagan BG. Methotrexate for induction of remission in refractory Crohn’s disease. Cochrane Database Syst Rev 2012;12:CD003459
   PubMed Web of Science ®Google Scholar
• Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med 2000;342(22):1627-32
   PubMed Web of Science ®Google Scholar
• Mate-Jimenez J, Hermida C, Cantero-Perona J, Moreno-Otero R. 6-mercaptopurine or methotrexate added to prednisone induces and maintains remission in steroid-dependent inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12(11):1227-33
   PubMed Web of Science ®Google Scholar
• Oren R, Moshkowitz M, Odes S, et al. Methotrexate in chronic active Crohn’s disease: a double-blind, randomized, Israeli multicenter trial. Am J Gastroenterol 1997;92(12):2203-9
   PubMed Web of Science ®Google Scholar
• Patel V, Macdonald JK, McDonald JW, Chande N. Methotrexate for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2009(4):CD006884
   Google Scholar
• Oren R, Arber N, Odes S, et al. Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial. Gastroenterology 1996;110(5):1416-21
   PubMed Web of Science ®Google Scholar
• Chande N, Macdonald JK, McDonald JW. Methotrexate for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2007(4):CD006618
   Google Scholar
• Herfarth HH, Osterman MT, Isaacs KL, et al. Efficacy of methotrexate in ulcerative colitis: failure or promise. Inflamm Bowel Dis 2010;16(8):1421-30
   PubMed Web of Science ®Google Scholar
• Comparison of methotrexate vs placebo in steroid-refractory ulcerative colitis (METEOR). Available from: http://clinicaltrials.gov/show/NCT00498589
   Google Scholar
• Methotrexate in induction and maintenance of steroid free remission in ulcerative colitis (Merit-UC). Available from: http://clinicaltrials.gov/show/NCT01393405
   Google Scholar
• Onuk MD, Kaymakoglu S, Demir K. Low-dosage weekly methotrexate therapy in remission maintenance in ulcerative colitis. Gut 1996;39:A75
   Google Scholar
• Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med 2013;369(8):754-62
   PubMed Web of Science ®Google Scholar
• Hanauer SB. Risks and benefits of combining immunosuppressives and biological agents in inflammatory bowel disease: is the synergy worth the risk? Gut 2007;56(9):1181-3
   PubMed Web of Science ®Google Scholar
• Lichtenstein GR, Hanauer SB, Sandborn WJ. Management of Crohn’s disease in adults. Am J Gastroenterol 2009;104(2):465-83
   PubMed Web of Science ®Google Scholar
• Travis SP, Stange EF, Lemann M, et al. European evidence based consensus on the diagnosis and management of Crohn’s disease: current management. Gut 2006;55(Suppl 1):i16-35
   Google Scholar
• Siegel CA, Marden SM, Persing SM, et al. Risk of lymphoma associated with combination anti-tumor necrosis factor and immunomodulator therapy for the treatment of Crohn’s disease: a meta-analysis. Clin Gastroenterol Hepatol 2009;7(8):874-81
   PubMed Web of Science ®Google Scholar
• Van Assche G, Lewis JD, Lichtenstein GR, et al. The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organisation: safety. Am J Gastroenterol 2011;106(9):1594-602
   PubMed Web of Science ®Google Scholar
• Lichtenstein GR, Feagan BG, Cohen RD, et al. Drug therapies and the risk of malignancy in Crohn’s disease: results from the TREAT Registry. Am J Gastroenterol 2014;109(2):212-23
   PubMed Web of Science ®Google Scholar
• Targownik LE, Bernstein CN. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol 2013;108(12):1835-42. quiz
   PubMed Web of Science ®Google Scholar
• Lemann 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(4):1054-61
   PubMed Web of Science ®Google Scholar
• D’Haens G, Baert F, Van AG, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet 2008;371(9613):660-7
   PubMed Web of Science ®Google Scholar
• Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362(15):1383-95
   PubMed Web of Science ®Google Scholar
• Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterology 2014;146(2):392-400
   PubMed Web of Science ®Google Scholar
• Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med 2003;348(7):601-8
   PubMed Web of Science ®Google Scholar
• Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol 2013;108(1):40-7
   PubMed Web of Science ®Google Scholar
• Vermeire S, Noman M, Van AG, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut 2007;56(9):1226-31
   PubMed Web of Science ®Google Scholar
• Feagan BG, McDonald JW, Panaccione R, et al. Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn’s disease. Gastroenterology 2014;146(3):681-8
   PubMed Web of Science ®Google Scholar
• Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 2007;132(1):52-65
   PubMed Web of Science ®Google Scholar
• Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359(9317):1541-9
   PubMed Web of Science ®Google Scholar
• Moss AC, Kim KJ, Fernandez-Becker N, et al. Impact of concomitant immunomodulator use on long-term outcomes in patients receiving scheduled maintenance infliximab. Dig Dis Sci 2010;55(5):1413-20
   PubMed Web of Science ®Google Scholar
• Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004;350(9):876-85
   PubMed Web of Science ®Google Scholar
• Sokol H, Seksik P, Carrat F, et al. Usefulness of co-treatment with immunomodulators in patients with inflammatory bowel disease treated with scheduled infliximab maintenance therapy. Gut 2010;59(10):1363-8
   PubMed Web of Science ®Google Scholar
• Armuzzi A, Pugliese D, Danese S, et al. Long-term combination therapy with infliximab plus azathioprine predicts sustained steroid-free clinical benefit in steroid-dependent ulcerative colitis. Inflamm Bowel Dis 2014. [Epub ahead of print]
   Web of Science ®Google Scholar
• McLean LP, Cross RK. Adverse events in IBD: to stop or continue immune suppressant and biologic treatment. Expert Rev Gastroenterol Hepatol 2014;8(3):223-40
   PubMed Web of Science ®Google Scholar
• Thomas A, Lodhia N. Advanced therapy for inflammatory bowel disease: a guide for the primary care physician. J Am Board Fam Med 2014;27(3):411-20
   PubMed Web of Science ®Google Scholar
• Salliot C, van der HD. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009;68(7):1100-4
   PubMed Web of Science ®Google Scholar
• Kane S. Preparing the patient for immunosuppressive therapy. Curr Gastroenterol Rep 2010;12(6):502-6
   PubMedGoogle Scholar
• Hindorf U, Lindqvist M, Hildebrand H, et al. Adverse events leading to modification of therapy in a large cohort of patients with inflammatory bowel disease. Aliment Pharmacol Ther 2006;24(2):331-42
   PubMed Web of Science ®Google Scholar
• Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2009(4):CD000545
   Google Scholar
• Kennedy NA, Rhatigan E, Arnott ID, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther 2013;38(10):1255-66
   PubMed Web of Science ®Google Scholar
• Kennedy NA, Lees CW. Azathioprine-induced pancreatitis and subsequent tolerance of mercaptopurine. Aliment Pharmacol Ther 2014;39(4):440-1
   PubMed Web of Science ®Google Scholar
• Shih DQ, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther 2012;36(5):449-58
   PubMed Web of Science ®Google Scholar
• Chaparro M, Ordas I, Cabre E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis 2013;19(7):1404-10
   PubMed Web of Science ®Google Scholar
• Glazier KD, Palance AL, Griffel LH, Das KM. The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease. J Clin Gastroenterol 2005;39(1):21-6
   PubMed Web of Science ®Google Scholar
• de Boer NK, van Bodegraven AA, Jharap B, et al. Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol 2007;4(12):686-94
   PubMedGoogle Scholar
• Grassia R, Paolo CG, Staiano T. Severe muscular weakness as an isolated symptom of azathioprine hypersensitivity. Inflamm Bowel Dis 2011;17(6):E61
   Web of Science ®Google Scholar
• Present DH, Meltzer SJ, Krumholz MP, et al. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989;111(8):641-9
   PubMed Web of Science ®Google Scholar
• Connell WR, Kamm MA, Dickson M, et al. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet 1994;343(8908):1249-52
   PubMed Web of Science ®Google Scholar
• Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology 2000;118(4):705-13
   PubMed Web of Science ®Google Scholar
• 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(6):1025-30
   PubMed Web of Science ®Google Scholar
• Ardizzone S, Cassinotti A, Manes G, Porro GB. Immunomodulators for all patients with inflammatory bowel disease? Therap Adv Gastroenterol 2010;3(1):31-42
   PubMedGoogle Scholar
• Gluck T, Kiefmann B, Grohmann M, et al. Immune status and risk for infection in patients receiving chronic immunosuppressive therapy. J Rheumatol 2005;32(8):1473-80
   PubMed Web of Science ®Google Scholar
• Lee WM. Drug-induced hepatotoxicity. N Engl J Med 2003;349(5):474-85
   PubMed Web of Science ®Google Scholar
• Bokemeyer B. Asymptomatic elevation of serum lipase and amylase in conjunction with Crohn’s disease and ulcerative colitis. Z Gastroenterol 2002;40(1):5-10
   PubMed Web of Science ®Google Scholar
• Floyd A, Pedersen L, Nielsen GL, et al. Risk of acute pancreatitis in users of azathioprine: a population-based case-control study. Am J Gastroenterol 2003;98(6):1305-8
   PubMed Web of Science ®Google Scholar
• Wahed M, Louis-Auguste JR, Baxter LM, et al. Efficacy of methotrexate in Crohn’s disease and ulcerative colitis patients unresponsive or intolerant to azathioprine/mercaptopurine. Aliment Pharmacol Ther 2009;30(6):614-20
   PubMed Web of Science ®Google Scholar
• Warman JI, Korelitz BI, Fleisher MR, Janardhanam R. Cumulative experience with short- and long-term toxicity to 6-mercaptopurine in the treatment of Crohn’s disease and ulcerative colitis. J Clin Gastroenterol 2003;37(3):220-5
   PubMed Web of Science ®Google Scholar
• Vernier-Massouille G, Cosnes J, Lemann M, et al. Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut 2007;56(10):1404-9
   PubMed Web of Science ®Google Scholar
• Seiderer J, Zech CJ, Diebold J, et al. Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy. Eur J Gastroenterol Hepatol 2006;18(5):553-5
   PubMed Web of Science ®Google Scholar
• Khan N, Abbas AM, Whang N, et al. Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials. Inflamm Bowel Dis 2012;18(2):359-67
   PubMed Web of Science ®Google Scholar
• Kotlyar DS, Lewis JD, Beaugerie L, et al. Risk of Lymphoma in Patients with Inflammatory Bowel Disease Treated with Azathioprine and 6-Mercaptopurine: a Meta-Analysis. Clin Gastroenterol Hepatol 2014. [ Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• Kotlyar DS, Gisbert JP, Lewis JD, et al. Overall incidence of hepatosplenic T cell lymphoma in patients with inflammatory bowel disease on thiopurines. Gastroenterology 2011;140:S775
   Web of Science ®Google Scholar
• Kotlyar DS, Osterman MT, Diamond RH, et al. A systematic review of factors that contribute to hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol 2011;9(1):36-41
   PubMed Web of Science ®Google Scholar
• Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut 2005;54(8):1121-5
   PubMed Web of Science ®Google Scholar
• Kotlyar D, Gisbert J, Chaparro M, et al. Systematic review: Duration of exposure to azathiopurine/6-mercaptopurine as a risk factor for lymphoma. Gastroenterology 2012;142(Suppl 1):S250
   Google Scholar
• Sokol H, Beaugerie L, Maynadie M, et al. Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis 2012;18(11):2063-71
   PubMed Web of Science ®Google Scholar
• Armstrong RG, West J, Card TR. Risk of cancer in inflammatory bowel disease treated with azathioprine: a UK population-based case-control study. Am J Gastroenterol 2010;105(7):1604-9
   PubMed Web of Science ®Google Scholar
• 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(9701):1617-25
   PubMed Web of Science ®Google Scholar
• Vos AC, Bakkal N, Minnee RC, et al. Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study. Inflamm Bowel Dis 2010;17:1837-45
   PubMed Web of Science ®Google Scholar
• Sokol H, Beaugerie L. Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle. Gut 2009;58(10):1427-36
   PubMed Web of Science ®Google Scholar
• Ariyaratnam J, Subramanian V. Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis. Am J Gastroenterol 2014;109(2):163-9
   PubMed Web of Science ®Google Scholar
• Beigel F, Steinborn A, Schnitzler F, et al. Risk of malignancies in patients with inflammatory bowel disease treated with thiopurines or anti-TNF alpha antibodies. Pharmacoepidemiol Drug Saf 2014. [ Epub ahead of print]
   PubMed Web of Science ®Google Scholar
• Magro F, Peyrin-Biroulet L, Sokol H, et al. Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (III). J Crohns Colitis 2014;8(1):31-44
   PubMed Web of Science ®Google Scholar
• Hsiao SC, Ichinohasama R, Lin SH, et al. EBV-associated diffuse large B-cell lymphoma in a psoriatic treated with methotrexate. Pathol Res Pract 2009;205(1):43-9
   PubMed Web of Science ®Google Scholar
• French H, Mark DA, Srinivasan R, El-Matary W. Relapse rate following azathioprine withdrawal in maintaining remission for Crohn’s disease: a meta-analysis. Dig Dis Sci 2011;56(7):1929-36
   PubMed Web of Science ®Google Scholar
• Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut 2002;50(4):485-9
   PubMed Web of Science ®Google Scholar
• Kim PS, Zlatanic J, Korelitz BI, Gleim GW. Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease. Am J Gastroenterol 1999;94(11):3254-7
   PubMed Web of Science ®Google Scholar
• Lobel EZ, Korelitz BI, Xuereb MA, Panagopoulos G. A search for the optimal duration of treatment with 6-mercaptopurine for ulcerative colitis. Am J Gastroenterol 2004;99(3):462-5
   PubMed Web of Science ®Google Scholar
• Clarke K, Regueiro M. Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission. Inflamm Bowel Dis 2012;18:174-9
   PubMed Web of Science ®Google Scholar
• Hawthorne AB, Logan RF, Hawkey CJ, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. BMJ 1992;305(6844):20-2
   PubMed Web of Science ®Google Scholar
• Cassinotti A, Actis GC, Duca P, et al. Maintenance treatment with azathioprine in ulcerative colitis: outcome and predictive factors after drug withdrawal. Am J Gastroenterol 2009;104(11):2760-7
   PubMed Web of Science ®Google Scholar
• Fournier MR, Klein J, Minuk GY, Bernstein CN. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol 2010;105(7):1620-6
   PubMed Web of Science ®Google Scholar
• Hawthorne AB. Methotrexate: a useful alternative in Crohn’s disease? Gut 2001;49(1):9-10
   PubMed Web of Science ®Google Scholar
• Rogler G, Sandborn WJ. Is there still a role for thiopurines in Crohn’s disease? Gastroenterology 2013;145(4):714-16
   PubMed Web of Science ®Google Scholar
• Narula N, Peyrin-Biroulet L, Colombel JF. Combination therapy with methotrexate in inflammatory bowel disease: time to COMMIT? Gastroenterology 2014;146(3):608-11
   PubMed Web of Science ®Google Scholar
• Pedersen J, Coskun M, Soendergaard C, et al. Inflammatory pathways of importance for management of inflammatory bowel disease. World J Gastroenterol 2014;20(1):64-77
   PubMed Web of Science ®Google Scholar
• Mosli MH, Sandborn WJ, Kim RB, et al. Toward a Personalized Medicine Approach to the Management of Inflammatory Bowel Disease. Am J Gastroenterol 2014. [ Epub ahead of print]
   PubMed Web of Science ®Google Scholar