UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Immunomodulator therapy in Crohn disease

Author
Richard P MacDermott, MD
Section Editor
Paul Rutgeerts, MD, PhD, FRCP
Deputy Editor
Shilpa Grover, MD, MPH

INTRODUCTION

Patients with Crohn disease who remain refractory to therapy with steroids, 5-aminosalicylic acid (5-ASA) agents, and antibiotics, or who depend upon steroids to control the disease are a common and challenging problem. Additional medical therapy is appropriate because surgery is accompanied by a high recurrence rate and many patients have already had previous resections.

Several drugs have shown efficacy in this setting. The best studied and most commonly used are the immunomodulators (azathioprine, its metabolite 6-mercaptopurine, and methotrexate), and the biologics (infliximab, adalimumab, and certolizumab). These medications induce response and remission in a significant number of Crohn disease patients. Furthermore, all are capable of inducing mucosal healing and modifying the disease course in a subset of Crohn disease patients.

The efficacy and toxicities of the commonly used immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) as well as the less frequently used immunomodulator tacrolimus (FK506) and recommendations for their use will be reviewed here.

Conventional and alternative treatments for Crohn disease are discussed elsewhere. (See "Overview of the medical management of mild to moderate Crohn disease in adults" and "Overview of the medical management of severe or refractory Crohn disease in adults" and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease" and "Investigational therapies in the medical management of Crohn disease".)

The role of the anti-tumor necrosis factor (anti-TNF) agents, infliximab (Remicade) and adalimumab (Humira) is discussed separately. (See "Infliximab in Crohn disease" and "Adalimumab for treatment of Crohn disease in adults".)

                        

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Thu Dec 04 00:00:00 GMT+00:00 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Elion GB. The purine path to chemotherapy. Science 1989; 244:41.
  2. Huskisson EC. Azathioprine. Clin Rheum Dis 1984; 10:325.
  3. Nyhan WL, Sweetman L, Carpenter DG, et al. Effects of azathiprine in a disorder of uric acid metabolism and cerebral function. J Pediatr 1968; 72:111.
  4. 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; 106:630.
  5. Chande N, Tsoulis DJ, MacDonald JK. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2013; :CD000545.
  6. Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology 2013; 145:1459.
  7. 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; 145:758.
  8. Panés J, López-Sanromán A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn's disease. Gastroenterology 2013; 145:766.
  9. Rayner CK, Hart AL, Hayward CM, et al. Azathioprine dose escalation in inflammatory bowel disease. Aliment Pharmacol Ther 2004; 20:65.
  10. Candy S, Wright J, Gerber M, et al. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37:674.
  11. Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology 1979; 77:847.
  12. Willoughby JM, Beckett J, Kumar PJ, Dawson AM. Controlled trial of azathioprine in Crohn's disease. Lancet 1971; 2:944.
  13. Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119:895.
  14. 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; 2:955.
  15. Rosenberg JL, Levin B, Wall AJ, Kirsner JB. A controlled trial of azathioprine in Crohn's disease. Am J Dig Dis 1975; 20:721.
  16. Vilien M, Dahlerup JF, Munck LK, et al. Randomized controlled azathioprine withdrawal after more than two years treatment in Crohn's disease: increased relapse rate the following year. Aliment Pharmacol Ther 2004; 19:1147.
  17. 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; :CD000067.
  18. 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.
  19. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2009; :CD000545.
  20. Korelitz BI, Present DH. Favorable effect of 6-mercaptopurine on fistulae of Crohn's disease. Dig Dis Sci 1985; 30:58.
  21. Jeshion WC, Larsen KL, Jawad AF, et al. Azathioprine and 6-mercaptopurine for the treatment of perianal Crohn's disease in children. J Clin Gastroenterol 2000; 30:294.
  22. 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; 302:981.
  23. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995; 123:132.
  24. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010; 362:1383.
  25. 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; 348:601.
  26. Egan LJ, Sandborn WJ. Methotrexate for inflammatory bowel disease: pharmacology and preliminary results. Mayo Clin Proc 1996; 71:69.
  27. Morabito L, Montesinos MC, Schreibman DM, et al. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 1998; 101:295.
  28. Cronstein BN. Molecular therapeutics. Methotrexate and its mechanism of action. Arthritis Rheum 1996; 39:1951.
  29. Genestier L, Paillot R, Fournel S, et al. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells. J Clin Invest 1998; 102:322.
  30. Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med 1995; 332:292.
  31. 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; 92:2203.
  32. Arora S, Katkov W, Cooley J, et al. Methotrexate in Crohn's disease: results of a randomized, double-blind, placebo-controlled trial. Hepatogastroenterology 1999; 46:1724.
  33. Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev 2005; :CD003459.
  34. McDonald JW, Wang Y, Tsoulis DJ, et al. Methotrexate for induction of remission in refractory Crohn's disease. Cochrane Database Syst Rev 2014; :CD003459.
  35. Nathan DM, Iser JH, Gibson PR. A single center experience of methotrexate in the treatment of Crohn's disease and ulcerative colitis: a case for subcutaneous administration. J Gastroenterol Hepatol 2008; 23:954.
  36. Lémann M, Zenjari T, Bouhnik Y, et al. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol 2000; 95:1730.
  37. Chong RY, Hanauer SB, Cohen RD. Efficacy of parenteral methotrexate in refractory Crohn's disease. Aliment Pharmacol Ther 2001; 15:35.
  38. Domènech E, Mañosa M, Navarro M, et al. Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practice. J Clin Gastroenterol 2008; 42:395.
  39. Din S, Dahele A, Fennel J, et al. Use of methotrexate in refractory Crohn's disease: the Edinburgh experience. Inflamm Bowel Dis 2008; 14:756.
  40. 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; 342:1627.
  41. Patel V, Wang Y, MacDonald JK, et al. Methotrexate for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev 2014; :CD006884.
  42. Hausmann J, Zabel K, Herrmann E, Schröder O. Methotrexate for maintenance of remission in chronic active Crohn's disease: long-term single-center experience and meta-analysis of observational studies. Inflamm Bowel Dis 2010; 16:1195.
  43. 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; 146:681.
  44. Seinen ML, Ponsioen CY, de Boer NK, et al. Sustained clinical benefit and tolerability of methotrexate monotherapy after thiopurine therapy in patients with Crohn's disease. Clin Gastroenterol Hepatol 2013; 11:667.
  45. Te HS, Schiano TD, Kuan SF, et al. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000; 95:3150.
  46. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006; 130:940.
  47. Brynskov J, Freund L, Rasmussen SN, et al. A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 1989; 321:845.
  48. Stange EF, Modigliani R, Peña AS, et al. European trial of cyclosporine in chronic active Crohn's disease: a 12-month study. The European Study Group. Gastroenterology 1995; 109:774.
  49. Jewell D, Lennard-Jones J, Cyclosporine Study Group of Great Britain and Ireland. Oral cyclosporine for chronic active Crohn's disease: A multicentre controlled trial. Eur J Gastroenterol Hepatol 1994; 6:499.
  50. Feagan BG, McDonald JW, Rochon J, et al. Low-dose cyclosporine for the treatment of Crohn's disease. The Canadian Crohn's Relapse Prevention Trial Investigators. N Engl J Med 1994; 330:1846.
  51. McDonald JW, Feagan BG, Jewell D, et al. Cyclosporine for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2005; :CD000297.
  52. Lazarev M, Present DH, Lichtiger S, et al. The effect of intravenous cyclosporine on rates of colonic surgery in hospitalized patients with severe Crohn's colitis. J Clin Gastroenterol 2012; 46:764.
  53. Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn's disease with intravenous cyclosporine. Am J Gastroenterol 1998; 93:442.
  54. Santos JV, Baudet JA, Casellas FJ, et al. Intravenous cyclosporine for steroid-refractory attacks of Crohn's disease. Short- and long-term results. J Clin Gastroenterol 1995; 20:207.
  55. Hanauer SB, Smith MB. Rapid closure of Crohn's disease fistulas with continuous intravenous cyclosporin A. Am J Gastroenterol 1993; 88:646.
  56. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn's disease. Dig Dis Sci 1994; 39:374.
  57. Banks PA, Present DH. Is there any value in using cyclosporine in the treatment of Crohn's disease-to use or not to use? Inflamm Bowel Dis 1995; 1:340.
  58. Sandborn WJ. A critical review of cyclosporine therapy in inflammatory bowel disease. Inflamm Bowel Dis 1995; 1:48.
  59. Sandborn WJ. Preliminary report on the use of oral tacrolimus (FK506) in the treatment of complicated proximal small bowel and fistulizing Crohn's disease. Am J Gastroenterol 1997; 92:876.
  60. van Dieren JM, Kuipers EJ, Samsom JN, et al. Revisiting the immunomodulators tacrolimus, methotrexate, and mycophenolate mofetil: their mechanisms of action and role in the treatment of IBD. Inflamm Bowel Dis 2006; 12:311.
  61. Baumgart DC, Pintoffl JP, Sturm A, et al. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up. Am J Gastroenterol 2006; 101:1048.
  62. Ierardi E, Principi M, Francavilla R, et al. Oral tacrolimus long-term therapy in patients with Crohn's disease and steroid resistance. Aliment Pharmacol Ther 2001; 15:371.
  63. Ng SC, Arebi N, Kamm MA. Medium-term results of oral tacrolimus treatment in refractory inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:129.
  64. Benson A, Barrett T, Sparberg M, Buchman AL. Efficacy and safety of tacrolimus in refractory ulcerative colitis and Crohn's disease: a single-center experience. Inflamm Bowel Dis 2008; 14:7.
  65. Ierardi E, Principi M, Rendina M, et al. Oral tacrolimus (FK 506) in Crohn's disease complicated by fistulae of the perineum. J Clin Gastroenterol 2000; 30:200.
  66. González-Lama Y, Abreu L, Vera MI, et al. Long-term oral tacrolimus therapy in refractory to infliximab fistulizing Crohn's disease: a pilot study. Inflamm Bowel Dis 2005; 11:8.
  67. Sandborn WJ, Present DH, Isaacs KL, et al. Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial. Gastroenterology 2003; 125:380.
  68. Massey DC, Bredin F, Parkes M. Use of sirolimus (rapamycin) to treat refractory Crohn's disease. Gut 2008; 57:1294.
  69. Reinisch W, Panés J, Lémann M, et al. A multicenter, randomized, double-blind trial of everolimus versus azathioprine and placebo to maintain steroid-induced remission in patients with moderate-to-severe active Crohn's disease. Am J Gastroenterol 2008; 103:2284.