Advertisement

The Evolving Role of Thiopurines in Inflammatory Bowel Disease

  • Saurabh Kapur
  • Stephen B. HanauerEmail author
Inflammatory Bowel Disease (G Lichtenstein, Section Editor)
  • 6 Downloads
Part of the following topical collections:
  1. Topical Collection on Inflammatory Bowel Disease

Abstract

Purpose of review

With the advent of biologic therapies for the treatment of IBD, the roles of thiopurines have continued to evolve. This review will focus on recent advances in pharmacology and the safety and efficacy of thiopurines as maintenance therapies for steroid-induced remissions, post-surgical maintenance of remission, and as combination therapies to reduce immunogenicities of biologic agents.

Recent findings

Due to pharmacogenetics of TPMT, thiopurine dosing is more effectively based on monitoring of thiopurine metabolites rather than weight-based dosing. Thiopurines continue to have a role as maintenance therapy after steroid-induced remissions and in combination with biologics to induce and maintain remission. Safety monitoring includes measurements of blood counts, liver chemistries, as well as dermatologic evaluations and protection from sun exposure.

Summary

Thiopurines appear to be safe during pregnancies and while very uncommon, lymphomas (including hepatosplenic T cell lymphomas) remain a recognized risk, particularly in younger and older males.

Keywords

Inflammatory bowel disease Thiopurines Steroids Immunogenicity TPMT Steroid-induced remission 

Notes

Compliance with Ethical Standards

Conflict of Interest

Saurabh Kapur declares that he has no conflict of interest. Stephen B. Hanauer declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Hindorf U, Lindqvist M, Peterson C, Söderkvist P, Ström M, Hjortswang H, et al. Pharmacogenetics during standardised initiation of thiopurine treatment in inflammatory bowel disease. Gut. 2006;55:1423–31.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Eklund BI, Moberg M, Bergquist J, Mannervik B. Divergent activities of human glutathione transferases in the bioactivation of azathioprine. Mol Pharmacol. 2006;70:747–54.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Amin J, Huang B, Yoon J, Shih DQ. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–52.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32:651–62.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al. 6-Thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology. 2003;125:298–303.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Derijks LJ, Gilissen LP, Engels LG, Bos LP, Bus PJ, Lohman JJ, et al. Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy. Ther Drug Monit. 2004;26:311–8.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Gardiner SJ, Gearry RB, Begg EJ, et al. Thiopurine dose in intermediate and normal metabolizers of thiopurine methyltransferase may differ three-fold. Clin Gastroenterol Hepatol. 2008;6:654–60 quiz 604.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    •• Walker GJ, Harrison JW, Heap GA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA. 2019;321:773–85 Identification of a new genetic variant in thiopurine metabolism associated with an increased risk of myelosuppression with thiopurine use.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. Thiopurine methyltransferase activity influences clinical response to azathioprine in inflammatory bowel disease. Clin Gastroenterol Hepatol. 2004;2:410–7.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Dassopoulos T, Dubinsky MC, Bentsen JL, Martin CF, Galanko JA, Seidman EG, et al. Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn’s disease. Aliment Pharmacol Ther. 2014;39:163–75.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    •• Yarur AJ, Gondal B, Hirsch A, et al. Higher thioguanine nucleotide metabolite levels are associated with better long-term outcomes in patients with inflammatory bowel diseases. J Clin Gastroenterol. 2018;52:537–44 Updated confirmation of thioguanine metabolite levels as predictor of response than weight-based dosing.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med. 1980;302:981–7.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    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;117:527–35.Google Scholar
  14. 14.
    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;145:766–74.e1.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Chande N, Townsend CM, Parker CE, et al. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2016;10:Cd000545.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Jewell DP, Truelove SC. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J. 1974;4:627–30.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106:630–42.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2013:Cd000545.Google Scholar
  19. 19.
    D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc. 1999;50:667–71.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Cosnes J, Nion-Larmurier I, Beaugerie L, Afchain P, Tiret E, Gendre JP. Impact of the increasing use of immunosuppressants in Crohn’s disease on the need for intestinal surgery. Gut. 2005;54:237–41.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Vernier-Massouille G, Balde M, Salleron J, Turck D, Dupas JL, Mouterde O, et al. Natural history of pediatric Crohn’s disease: a population-based cohort study. Gastroenterology. 2008;135:1106–13.PubMedCrossRefGoogle Scholar
  22. 22.
    Gisbert JP, Linares PM, McNicholl AG, Maté J, Gomollón F. Meta-analysis: the efficacy of azathioprine and mercaptopurine in ulcerative colitis. Aliment Pharmacol Ther. 2009;30:126–37.PubMedCrossRefGoogle Scholar
  23. 23.
    Cohen RD, Stein R, Hanauer SB. Intravenous cyclosporin in ulcerative colitis: a five-year experience. Am J Gastroenterol. 1999;94:1587–92.PubMedCrossRefGoogle Scholar
  24. 24.
    Miyake N, Ando T, Ishiguro K, Maeda O, Watanabe O, Hirayama Y, et al. Azathioprine is essential following cyclosporine for patients with steroid-refractory ulcerative colitis. World J Gastroenterol. 2015;21:254–61.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Singh H, Bernstein CN. Sorting through the risks and benefits of thiopurine therapy for inflammatory bowel diseases. Clin Gastroenterol Hepatol 2019.Google Scholar
  26. 26.
    • Eriksson C, Rundquist S, Cao Y, et al. Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study. Gut. 2019;68:623–32 Additional supoprt for efficacy of thiopurines to prevent long-term complications of ulcerative colitis.PubMedCrossRefGoogle Scholar
  27. 27.
    Hawthorne AB, Logan RF, Hawkey CJ, Foster PN, Axon AT, Swarbrick ET, et al. Randomised controlled trial of azathioprine withdrawal in ulcerative colitis. Bmj. 1992;305:20–2.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Bouhnik Y, Lemann M, Mary JY, et al. Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996;347:215–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Treton X, Bouhnik Y, Mary JY, Colombel JF, Duclos B, Soule JC, et al. Azathioprine withdrawal in patients with Crohn’s disease maintained on prolonged remission: a high risk of relapse. Clin Gastroenterol Hepatol. 2009;7:80–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Boyapati RK, Torres J, Palmela C, et al. Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn’s disease. Cochrane Database Syst Rev. 2018;5:Cd012540.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Sandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876–85.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    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;146:392–400.e3.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    • Colombel JF, Adedokun OJ, Gasink C, et al. Combination therapy with infliximab and azathioprine improves infliximab pharmacokinetic features and efficacy: a post hoc analysis. Clin Gastroenterol Hepatol. 2019;17(8):1525–32 Post hoc analysis of SONIC study suggesting that azathioprine may be efficacious in combination with infliximab by raising blood levels of the biologic in contrast to mechanistic synergy.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Yarur AJ, Kubiliun MJ, Czul F, et al. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin Gastroenterol Hepatol. 2015;13:1118–24.e3.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Matsumoto T, Motoya S, Watanabe K, Hisamatsu T, Nakase H, Yoshimura N, et al. Adalimumab monotherapy and a combination with azathioprine for Crohn’s disease: a prospective, randomized trial. J Crohns Colitis. 2016;10:1259–66.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Kopylov U, Al-Taweel T, Yaghoobi M, et al. Adalimumab monotherapy versus combination therapy with immunomodulators in patients with Crohn’s disease: a systematic review and meta-analysis. J Crohns Colitis. 2014;8:1632–41.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Feagan BG, Chande N, MacDonald JK. Are there any differences in the efficacy and safety of different formulations of Oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? Evidence from Cochrane reviews. Inflamm Bowel Dis. 2013;19:2031–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Al-Bawardy B, Ramos GP, Willrich MAV, et al. Vedolizumab drug level correlation with clinical remission, biomarker normalization, and mucosal healing in inflammatory bowel disease. Inflamm Bowel Dis. 2019;25(3):580–6.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106:685–98.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Baert F, Noman M, Vermeire S, van Assche G, D’ Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601–8.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    • Ungar B, Kopylov U, Engel T, et al. Addition of an immunomodulator can reverse antibody formation and loss of response in patients treated with adalimumab. Aliment Pharmacol Ther. 2017;45:276–82 Additional evidence that thiopurines reduce immunogenicity to biologic therapies.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Ben-Horin S, Waterman M, Kopylov U, et al. Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2013;11:444–7.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    van Schaik T, Maljaars JP, Roopram RK, Verwey MH, Ipenburg N, Hardwick JC, et al. Influence of combination therapy with immune modulators on anti-TNF trough levels and antibodies in patients with IBD. Inflamm Bowel Dis. 2014;20:2292–8.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Strik AS, van den Brink GR, Ponsioen C, Mathot R, Löwenberg M, D’Haens GR. Suppression of anti-drug antibodies to infliximab or adalimumab with the addition of an immunomodulator in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2017;45:1128–34.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    van Assche G, Magdelaine-Beuzelin C, D’Haens G, et al. Withdrawal of immunosuppression in Crohn’s disease treated with scheduled infliximab maintenance: a randomized trial. Gastroenterology. 2008;134:1861–8.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Louis E, Mary JY, Vernier-Massouille G, et al. Maintenance of remission among patients with Crohn’s disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142:63–70 e5 quiz e31.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and anti-TNF-alpha drugs during pregnancy in patients with inflammatory bowel disease. Am J Gastroenterol. 2013;108:433–40.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Akbari M, Shah S, Velayos FS, Mahadevan U, Cheifetz AS. Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:15–22.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Kanis SL, de Lima-Karagiannis A, de Boer NKH, et al. Use of thiopurines during conception and pregnancy is not associated with adverse pregnancy outcomes or health of infants at one year in a prospective study. Clin Gastroenterol Hepatol. 2017;15:1232–1241.e1.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Peyrin-Biroulet L, Oussalah A, Roblin X, Sparrow MP. The use of azathioprine in Crohn’s disease during pregnancy and in the post-operative setting: a worldwide survey of experts. Aliment Pharmacol Ther. 2011;33:707–13.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    • Nguyen GC, Seow CH, Maxwell C, et al. The Toronto consensus statements for the management of inflammatory bowel disease in pregnancy. Gastroenterology. 2016;150:734–757.e1 Review of safety of thiopurine use in pregnancy.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Orlando A, Mocciaro F, Renna S, Scimeca D, Rispo A, Lia Scribano M, et al. Early post-operative endoscopic recurrence in Crohn’s disease patients: data from an Italian group for the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter cohort. J Crohns Colitis. 2014;8:1217–21.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    • Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG clinical guideline: management of Crohn’s disease in adults. Am J Gastroenterol. 2018;113:481–517 Current US Society guideline on treatment of Crohn’s disease including role of thiopurines.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Gionchetti P, Dignass A, Danese S, Magro Dias FJ, Rogler G, Lakatos PL, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 2: surgical management and special situations. J Crohns Colitis. 2017;11:135–49.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Hanauer SB, Korelitz BI, Rutgeerts P, Peppercorn MA, Thisted RA, Cohen RD, et al. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology. 2004;127:723–9.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Papay P, Reinisch W, Ho E, Gratzer C, Lissner D, Herkner H, et al. The impact of thiopurines on the risk of surgical recurrence in patients with Crohn’s disease after first intestinal surgery. Am J Gastroenterol. 2010;105:1158–64.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    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;104:2089–96.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Jewel Samadder N, Valentine JF, Guthery S, Singh H, Bernstein CN, Wan Y, et al. Colorectal cancer in inflammatory bowel diseases: a population-based study in Utah. Dig Dis Sci. 2017;62:2126–32.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Rutter M, Saunders B, Wilkinson K, Rumbles S, Schofield G, Kamm M, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology. 2004;126:451–9.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    van Schaik FD, van Oijen MG, Smeets HM, van der Heijden G, Siersema PD, Oldenburg B. Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease. Gut. 2012;61:235–40.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Jess T, Lopez A, Andersson M, et al. Thiopurines and risk of colorectal neoplasia in patients with inflammatory bowel disease: a meta-analysis. Clin Gastroenterol Hepatol. 2014;12:1793–1800.e1.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Zhu Z, Mei Z, Guo Y, Wang G, Wu T, Cui X, et al. Reduced risk of inflammatory bowel disease-associated colorectal neoplasia with use of thiopurines: a systematic review and meta-analysis. J Crohns Colitis. 2018;12:546–58.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Bernheim O, Colombel JF, Ullman TA, Laharie D, Beaugerie L, Itzkowitz SH. The management of immunosuppression in patients with inflammatory bowel disease and cancer. Gut. 2013;62:1523–8.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Shelton E, Laharie D, Scott FI, et al. Cancer recurrence following immune-suppressive therapies in patients with immune-mediated diseases: a systematic review and meta-analysis. Gastroenterology. 2016;151:97–109.e4.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mehta F. Report: economic implications of inflammatory bowel disease and its management. Am J Manag Care. 2016;22:s51–60.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Kappelman MD, Rifas-Shiman SL, Porter CQ, Ollendorf DA, Sandler RS, Galanko JA, et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology. 2008;135:1907–13.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Wu N, Lee YC, Shah N, et al. Cost of biologics per treated patient across immune-mediated inflammatory disease indications in a pharmacy benefit management setting: a retrospective cohort study. Clin Ther. 2014;36:1231–41 1241.e1–3.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Sewell JL, Velayos FS. Systematic review: the role of race and socioeconomic factors on IBD healthcare delivery and effectiveness. Inflamm Bowel Dis. 2013;19:627–43.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Yao Q, Altman RD. Thiopurine methyltransferase measurement may not predict azathiopurine-associated non-myelotoxicity. Clin Exp Rheumatol. 2013;31:156.PubMedGoogle Scholar
  74. 74.
    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;19:1404–10.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Godat S, Fournier N, Safroneeva E, Juillerat P, Nydegger A, Straumann A, et al. Frequency and type of drug-related side effects necessitating treatment discontinuation in the Swiss inflammatory bowel disease cohort. Eur J Gastroenterol Hepatol. 2018;30:612–20.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Teich N, Mohl W, Bokemeyer B, Bündgens B, Büning J, Miehlke S, et al. Azathioprine-induced acute pancreatitis in patients with inflammatory bowel diseases--a prospective study on incidence and severity. J Crohns Colitis. 2016;10:61–8.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Dubinsky MC, Feldman EJ, Abreu MT, Targan SR, Vasiliauskas EA. Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol. 2003;98:1058–63.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Broekman M, Coenen MJH, Wanten GJ, et al. Risk factors for thiopurine-induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype. Aliment Pharmacol Ther. 2017;46:953–63.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohn’s disease. Eur J Gastroenterol Hepatol. 2004;16:207–12.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–800.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Kopylov U, Battat R, Benmassaoud A, et al. Hematologic indices as surrogate markers for monitoring thiopurine therapy in IBD. Dig Dis Sci. 2015;60:478–84.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367–73.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Vogelin M, Biedermann L, Frei P, et al. The impact of azathioprine-associated lymphopenia on the onset of opportunistic infections in patients with inflammatory bowel disease. PLoS One. 2016;11:e0155218.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Predictors of infection in rheumatoid arthritis. Arthritis Rheum. 2002;46:2294–300.CrossRefGoogle Scholar
  85. 85.
    Kirchgesner J, Lemaitre M, Carrat F, et al. Risk of serious and opportunistic infections associated with treatment of inflammatory bowel diseases. Gastroenterology. 2018;155:337–346.e10.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Rahier JF, Ben-Horin S, Chowers Y, Conlon C, de Munter P, D’Haens G, et al. European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2009;3:47–91.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine. Gastroenterology. 2002;122:72–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    •• Lemaitre M, Kirchgesner J, Rudnichi A, et al. Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease. JAMA. 2017;318:1679–86 Large data base demonstrating small but significant risk of lymphoma with thiopurines alone or in combination with TNF inhibitors.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    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. 2015;13:847–58.e4 quiz e48–50.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    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;9:36–41 e1.PubMedCrossRefGoogle Scholar
  91. 91.
    Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED. Hepatosplenic T-cell lymphoma in patients receiving TNF-alpha inhibitor therapy: expanding the groups at risk. Eur J Gastroenterol Hepatol. 2011;23:1150–6.PubMedCrossRefGoogle Scholar
  92. 92.
    Virdis F, Tacci S, Messina F, et al. Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn’s disease. World J Gastrointest Surg. 2013;5:306–8.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    de Francisco R, Castano-Garcia A, Martinez-Gonzalez S, et al. Impact of Epstein-Barr virus serological status on clinical outcomes in adult patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2018;48:723–30.PubMedCrossRefGoogle Scholar
  94. 94.
    Gordon J, Ramaswami A, Beuttler M, et al. EBV status and thiopurine use in pediatric IBD. J Pediatr Gastroenterol Nutr. 2016;62:711–4.PubMedCrossRefGoogle Scholar
  95. 95.
    Abbas AM, Almukhtar RM, Loftus EV Jr, et al. Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort. Am J Gastroenterol. 2014;109:1781–93.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    • Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG clinical guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112:241–58 Relevance of preventive health maintenance for IBD patients receiving immune suppression.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    • Rubin DT, Ananthakrishnan AN, Siegel CA, et al. ACG clinical guideline: ulcerative colitis in adults. Am J Gastroenterol. 2019;114:384–413 Current US Society guideline on management of ulcerative colitis including role of thiopurines.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, et al. Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: Current management. J Crohns Colitis. 2017;11:769–84.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Dassopoulos T, Cohen RD, Scherl EJ, et al. Ulcerative colitis care pathway. Gastroenterology. 2015;149:238–45.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Gomollon F, Dignass A, Annese V, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: Part 1: Diagnosis and medical management. J Crohns Colitis. 2017;11:3–25.PubMedCrossRefGoogle Scholar
  101. 101.
    Sandborn WJ. Crohn’s disease evaluation and treatment: clinical decision tool. Gastroenterology. 2014;147:702–5.PubMedCrossRefGoogle Scholar
  102. 102.
    Hanauer SB, Sandborn WJ, Lichtenstein GR. Evolving considerations for thiopurine therapy for inflammatory bowel diseases-a clinical practice update: commentary. Gastroenterology. 2019;156:36–42.PubMedCrossRefGoogle Scholar
  103. 103.
    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;145:1464–78 e1–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Hyams JS, Dubinsky M, Rosh J, et al. The effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in paediatric patients with Crohn’s disease: a post hoc analysis. Aliment Pharmacol Ther. 2019;49:155–64.PubMedCrossRefGoogle Scholar
  105. 105.
    Colombel JF, Jharap B, Sandborn WJ, Feagan B, Peyrin-Biroulet L, Eichner SF, et al. Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn’s disease or ulcerative colitis who had failed conventional therapy. Aliment Pharmacol Ther. 2017;45:50–62.PubMedCrossRefGoogle Scholar
  106. 106.
    Khanna R, Jairath V, Feagan BG. The evolution of treatment paradigms in Crohn’s disease: beyond better drugs. Gastroenterol Clin N Am. 2017;46:661–77.CrossRefGoogle Scholar
  107. 107.
    Ungaro R, Colombel JF, Lissoos T, Peyrin-Biroulet L. A treat-to-target update in ulcerative colitis: a systematic review. Am J Gastroenterol. 2019 Jun;114(6):874–83.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Kansas University Medical CenterKansasUSA
  2. 2.Northwestern UniversityChicagoUSA

Personalised recommendations