Skip to main content

Concomitant Use of Immunosuppressive Therapy with Tumor Necrosis Factor (TNF) Antagonists in Inflammatory Bowel Disease

  • Chapter
  • First Online:
Treatment of Inflammatory Bowel Disease with Biologics

Abstract

The treatment paradigm of ulcerative colitis (UC) and Crohn’s disease (CD) has shifted considerably over the past decade. Despite the advancements in our understanding of treatment monitoring and optimization, one of the key questions that continues to be debated is the optimal approach to using concomitant immunosuppressive agents. Well-designed randomized controlled trials have suggested that a clear treatment benefit exists; however, the external validity and applicability of these findings to the general population, and the personalization of treatment decisions based on individual factors and safety, remain to be clarified. In this review, we will discuss the evidence available for treatment efficacy, the impact safety may have on treatment decisions, and opportunities available to optimize the potential application and personalization of concomitant immunosuppressive therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. 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;108:40–7.

    Article  CAS  PubMed  Google Scholar 

  2. Colombel JF, Sandborn WJ, Allez M, et al. Association between plasma concentrations of certolizumab pegol and endoscopic outcomes of patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2013;12(3):423–31.

    Article  PubMed  Google Scholar 

  3. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology. 2005;129:807–18.

    Article  CAS  PubMed  Google Scholar 

  4. Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease. Clin Gastroenterol Hepatol. 2004;2:542–53.

    Article  CAS  PubMed  Google Scholar 

  5. Vermeire S, Noman M, Van Assche G, et al. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56:1226–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dulai PS, Siegel CA, Colombel JF, et al. Systematic review: monotherapy with antitumour necrosis factor alpha agents versus combination therapy with an immunosuppressive for IBD. Gut. 2014;63:1843–53.

    Article  CAS  PubMed  Google Scholar 

  7. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010;362:1383–95.

    Article  CAS  PubMed  Google Scholar 

  8. Panaccione R, Ghosh S, Middleton S, et al. Infliximab, azathioprine, or infliximab and azathioprine for treatment of moderate to severe ulcerative colitis: the UC success trial. Gastroenterology. 2011;140:A–202.

    Google Scholar 

  9. 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. 2013;146(3):681–8.

    Article  PubMed  Google Scholar 

  10. 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;130:1054–61.

    Article  CAS  PubMed  Google Scholar 

  11. Billioud V, Sandborn WJ, Peyrin-Biroulet L. Loss of response and need for adalimumab dose intensification in Crohn’s disease: a systematic review. Am J Gastroenterol. 2011;106:674–84.

    Article  CAS  PubMed  Google Scholar 

  12. Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology. 2003;124:917–24.

    Article  CAS  PubMed  Google Scholar 

  13. Lichtenstein GR, Diamond RH, Wagner CL, et al. Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials. Aliment Pharmacol Ther. 2009;30:210–26.

    Article  CAS  PubMed  Google Scholar 

  14. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial. Gut. 2007;56:1232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn’s disease. N Engl J Med. 2007;357:228–38.

    Article  CAS  PubMed  Google Scholar 

  16. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:96–109.e1.

    Article  CAS  PubMed  Google Scholar 

  17. Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146:85–95; quiz e14-5.

    Article  CAS  PubMed  Google Scholar 

  18. Dulai PS, Siegel CA, Peyrin-Biroulet L. Anti-tumor necrosis factor-alpha monotherapy versus combination therapy with an immunomodulator in IBD. Gastroenterol Clin N Am. 2014;43:441–56.

    Article  Google Scholar 

  19. Kopylov U, Al-Taweel T, Yaghoobi M, Bitton A, Lakatos PL, Ben-Horin S, Seidman EG, Afif W. Adalimumab monotherapy versus combination therapy with adalimumab and immunomodulators for Crohn’s disease: a meta-analysis. J Crohns Colitis. 2014;8(12):1632–41.

    Article  PubMed  Google Scholar 

  20. Jones JL, Kaplan GG, Peyrin-Biroulet L, et al. Effects of concomitant immunomodulator therapy on efficacy and safety of anti-tumor necrosis factor therapy for Crohn’s disease: a meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. 2015;13:2233–40.e1-2; quiz e177-8.

    Article  CAS  PubMed  Google Scholar 

  21. D’Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn’s disease: an open randomised trial. Lancet. 2008;371:660–7.

    Article  PubMed  Google Scholar 

  22. Khanna R, Bressler B, Levesque BG, et al. Early combined immunosuppression for the management of Crohn’s disease (REACT): a cluster randomised controlled trial. Lancet. 2015;386:1825–34.

    Article  PubMed  Google Scholar 

  23. Toruner M, Loftus EV Jr, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology. 2008;134:929–36.

    Article  PubMed  Google Scholar 

  24. Marehbian J, Arrighi HM, Hass S, et al. Adverse events associated with common therapy regimens for moderate-to-severe Crohn’s disease. Am J Gastroenterol. 2009;104:2524–33.

    Article  PubMed  Google Scholar 

  25. Deepak P, Stobaugh DJ, Ehrenpreis ED. Infectious complications of TNF-alpha inhibitor monotherapy versus combination therapy with immunomodulators in inflammatory bowel disease: analysis of the Food and Drug Administration Adverse Event Reporting System. J Gastrointestin Liver Dis. 2013;22:269–76.

    PubMed  Google Scholar 

  26. Dulai PS, Thompson KD, Blunt HB, et al. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol. 2014;12:1443–51; quiz e88-9.

    Article  PubMed  Google Scholar 

  27. Kopylov U, Afif W. Risk of infections with biological agents. Gastroenterol Clin N Am. 2014;43:509–24.

    Article  Google Scholar 

  28. Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn’s disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107:1409–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brassard P, Bitton A, Suissa A, et al. Oral corticosteroids and the risk of serious infections in patients with elderly-onset inflammatory bowel diseases. Am J Gastroenterol. 2014;109:1795–802; quiz 1803.

    Article  CAS  PubMed  Google Scholar 

  30. Cottone M, Kohn A, Daperno M, et al. Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2011;9:30–5.

    Article  CAS  PubMed  Google Scholar 

  31. Ananthakrishnan AN, McGinley EL. Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases. J Crohns Colitis. 2013;7:107–12.

    Article  PubMed  Google Scholar 

  32. Buckley JP, Cook SF, Allen JK, et al. Prevalence of chronic narcotic use among children with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;13(2):310–5.

    Article  PubMed  Google Scholar 

  33. Buckley JP, Kappelman MD, Allen JK, et al. The burden of comedication among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:2725–36.

    Article  PubMed  Google Scholar 

  34. Long MD, Barnes EL, Herfarth HH, et al. Narcotic use for inflammatory bowel disease and risk factors during hospitalization. Inflamm Bowel Dis. 2012;18:869–76.

    Article  PubMed  Google Scholar 

  35. Long MD, Martin C, Sandler RS, et al. Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol. 2013;108:240–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–68.

    Article  CAS  PubMed  Google Scholar 

  37. Loras C, Saro C, Gonzalez-Huix F, et al. Prevalence and factors related to hepatitis B and C in inflammatory bowel disease patients in Spain: a nationwide, multicenter study. Am J Gastroenterol. 2009;104:57–63.

    Article  CAS  PubMed  Google Scholar 

  38. Gisbert JP, Chaparro M, Esteve M. Review article: prevention and management of hepatitis B and C infection in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011;33:619–33.

    Article  CAS  PubMed  Google Scholar 

  39. Ananthakrishnan AN, McGinley EL, Binion DG. Excess hospitalisation burden associated with Clostridium difficile in patients with inflammatory bowel disease. Gut. 2008;57:205–10.

    Article  CAS  PubMed  Google Scholar 

  40. Ananthakrishnan AN, McGinley EL, Saeian K, et al. Temporal trends in disease outcomes related to Clostridium difficile infection in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2011;17:976–83.

    Article  PubMed  Google Scholar 

  41. Biancone L, Onali S, Petruzziello C, et al. Cancer and immunomodulators in inflammatory bowel diseases. Inflamm Bowel Dis. 2015;21:674–98.

    Article  PubMed  Google Scholar 

  42. Pedersen N, Duricova D, Elkjaer M, et al. Risk of extra-intestinal cancer in inflammatory bowel disease: meta-analysis of population-based cohort studies. Am J Gastroenterol. 2010;105:1480–7.

    Article  PubMed  Google Scholar 

  43. Jess T, Horvath-Puho E, Fallingborg J, et al. Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: a Danish population-based cohort study. Am J Gastroenterol. 2013;108:1869–76.

    Article  CAS  PubMed  Google Scholar 

  44. Kappelman MD, Farkas DK, Long MD, et al. Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation. Clin Gastroenterol Hepatol. 2014;12(2):265–73

    Google Scholar 

  45. Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med. 2015;372:1441–52.

    Article  CAS  PubMed  Google Scholar 

  46. Nyboe Andersen N, Pasternak B, Basit S, et al. Association between tumor necrosis factor-alpha antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA. 2014;311:2406–13.

    Article  PubMed  Google Scholar 

  47. 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;7:874–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Osterman MT, Sandborn WJ, Colombel JF, et al. Increased risk of malignancy with adalimumab combination therapy, compared to monotherapy, for Crohn’s disease. Gastroenterology. 2014;146(4):941–9.

    Google Scholar 

  49. 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;374:1617–25.

    Article  CAS  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. Selvaraj SA, Chairez E, Wilson LM, et al. Use of case reports and the Adverse Event Reporting System in systematic reviews: overcoming barriers to assess the link between Crohn’s disease medications and hepatosplenic T-cell lymphoma. Syst Rev. 2013;2:53.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Deepak P, Sifuentes H, Sherid M, et al. T-cell non-Hodgkin’s lymphomas reported to the FDA AERS with tumor necrosis factor-alpha (TNF-alpha) inhibitors: results of the REFURBISH study. Am J Gastroenterol. 2013;108:99–105.

    Article  CAS  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. 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;54:1121–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Long MD, Herfarth HH, Pipkin CA, et al. Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease. Clin Gastroenterol Hepatol. 2010;8:268–74.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Long MD, Martin CF, Pipkin CA, et al. Risk of melanoma and nonmelanoma skin cancer among patients with inflammatory bowel disease. Gastroenterology. 2012;143:390–399.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Melmed GY, Spiegel BM, Bressler B, et al. The appropriateness of concomitant immunomodulators with anti-tumor necrosis factor agents for Crohn’s disease: one size does not fit all. Clin Gastroenterol Hepatol. 2010;8:655–9.

    Article  PubMed  Google Scholar 

  58. Khan N, Abbas AM, Lichtenstein GR, et al. Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study. Gastroenterology. 2013;145:1007–1015.e3.

    Article  CAS  PubMed  Google Scholar 

  59. 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.

    Article  PubMed  Google Scholar 

  60. 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.

    Article  CAS  PubMed  Google Scholar 

  61. Torres J, Boyapati RK, Kennedy NA, et al. Systematic review of effects of withdrawal of immunomodulators or biologic agents from patients with inflammatory bowel disease. Gastroenterology. 2015;149:1716–30.

    Article  CAS  PubMed  Google Scholar 

  62. Pariente B, Laharie D. Review article: why, when and how to de-escalate therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2014;40:338–53.

    Article  CAS  PubMed  Google Scholar 

  63. Warner B, Johnston E, Arenas-Hernandez M, et al. A practical guide to thiopurine prescribing and monitoring in IBD. Front Gastroenterol. 2016.

    Google Scholar 

  64. Sokol H, Beaugerie L, Maynadie M, et al. Excess primary intestinal lymphoproliferative disorders in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2063–71.

    Article  PubMed  Google Scholar 

  65. Moreau AC, Paul S, Del Tedesco E, et al. Association between 6-thioguanine nucleotides levels and clinical remission in inflammatory disease: a meta-analysis. Inflamm Bowel Dis. 2014;20:464–71.

    Article  PubMed  Google Scholar 

  66. Smith M, Blaker P, Patel C, et al. The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic. Int J Clin Pract. 2013;67:161–9.

    Article  CAS  PubMed  Google Scholar 

  67. 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;36:449–58.

    Article  CAS  PubMed  Google Scholar 

  68. van Schaik T, Maljaars JP, Roopram RK, 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.

    Article  PubMed  Google Scholar 

  69. 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.

    Article  CAS  PubMed  Google Scholar 

  70. Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–13.

    Article  CAS  PubMed  Google Scholar 

  71. Bouguen G, Sninsky C, Tang KL, et al. Change in erythrocyte mean corpuscular volume during combination therapy with azathioprine and infliximab is associated with mucosal healing: a post hoc analysis from SONIC. Inflamm Bowel Dis. 2015;21:606–14.

    Article  PubMed  Google Scholar 

  72. Hirten R, Longman RS, Bosworth BP, et al. Vedolizumab and infliximab combination therapy in the treatment of Crohn’s disease. Am J Gastroenterol. 2015;110:1737–8.

    Article  CAS  PubMed  Google Scholar 

  73. Siegel CA, Siegel LS, Hyams JS, et al. Real-time tool to display the predicted disease course and treatment response for children with Crohn’s disease. Inflamm Bowel Dis. 2011;17:30–8.

    Article  PubMed  Google Scholar 

  74. Siegel CA, Horton H, Siegel LS, et al. A validated web-based patient communication tool to display individualized Crohn’s disease predicted outcomes based on clinical, serological and genetic variables. Gastroenterology. 2014;146(5):S–433.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Corey A. Siegel .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Cite this chapter

Dulai, P.S., Siegel, C.A. (2018). Concomitant Use of Immunosuppressive Therapy with Tumor Necrosis Factor (TNF) Antagonists in Inflammatory Bowel Disease. In: Cheifetz, A., Feuerstein, J. (eds) Treatment of Inflammatory Bowel Disease with Biologics . Springer, Cham. https://doi.org/10.1007/978-3-319-60276-9_7

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-60276-9_7

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-60275-2

  • Online ISBN: 978-3-319-60276-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics