Abstract
Tumor necrosis factor (TNF)-alpha has been established in the innate and acquired immune response in various disease processes, including both Crohn’s disease (CD) and ulcerative colitis (UC). This has led to the development and widespread use of anti-TNF therapies for the management of inflammatory bowel diseases (IBD). Infection, malignancy, antibody development, and infusion reactions are some of the major adverse reactions associated with anti-TNF agents. This review summarizes the evidence, including the limitations of the currently available literature, on various types of malignancy that have been associated with IBD therapies, with a focus upon anti-TNF agents. We highlight the association of anti-TNF agents with melanoma, while thiopurines in combination with anti-TNF agents are more strongly associated with non-melanoma skin cancer (NMSC). Additionally, we discuss the compounded risk of anti-TNFs with immunomodulators in the development of lymphoma and, in particular, the risk of hepatosplenic T-cell lymphoma (HSTCL) in younger patients. We also summarize the limited data on risks of solid tumors and cervical cancer associated with anti-TNF agents. In contrast, we highlight the established reduction in colorectal cancer risk with the use of immunosuppressive agents in IBD that treat inflammatory activity. Finally, we provide recommendations on how to discuss the risks and benefits of anti-TNF agents with patients, emphasizing methods of preventing complications of immunosuppressive medications in IBD. A shared decision-making process in selection of therapies, with appropriate follow-up, monitoring, and continued discussions of risks and benefits, will allow us to effectively and safely treat our patients with IBD.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Weinberg JM, Buchholz R. TNF-alpha inhibitors. Basel; Boston: Birkhäuser Verlag; 2006.
Van Deventer SJ. Tumour necrosis factor and Crohn's disease. Gut. 1997;40:443–8.
Mielke ME, Rosen H, Brocke S, et al. Protective immunity and granuloma formation are mediated by two distinct tumor necrosis factor alpha- and gamma interferon-dependent T cell-phagocyte interactions in murine listeriosis: dissociation on the basis of phagocyte adhesion mechanisms. Infect Immun. 1992;60:1875–82.
Amiri P, Locksley RM, Parslow TG, et al. Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature. 1992;356:604–7.
Kindler V, Sappino AP, Grau GE, et al. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989;56:731–40.
Flynn JL, Goldstein MM, Triebold KJ, et al. IL-12 increases resistance of BALB/c mice to mycobacterium tuberculosis infection. J Immunol. 1995;155:2515–24.
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;12:265–73.e1.
Buoy AG, Yoo S, Alam M, et al. Distribution of skin type and skin cancer in organ transplant recipients. Arch Dermatol. 2010;146:344–6.
Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol. 2010;146:283–7.
Jensen P, Hansen S, Moller B, et al. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 1999;40:177–86.
Lindelof B, Sigurgeirsson B, Gabel H, et al. Incidence of skin cancer in 5356 patients following organ transplantation. Br J Dermatol. 2000;143:513–9.
Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Engl J Med. 2003;348:1681–91.
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.
Ekbom A, Helmick C, Zack M, et al. Extracolonic malignancies in inflammatory bowel disease. Cancer. 1991;67:2015–9.
Mellemkjaer L, Olsen JH, Frisch M, et al. Cancer in patients with ulcerative colitis. Int J Cancer. 1995;60:330–3.
Long MD, Kappelman MD, Pipkin CA. Nonmelanoma skin cancer in inflammatory bowel disease: a review. Inflamm Bowel Dis. 2011;17:1423–7.
O’Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 2005;309:1871–4.
Kopylov U, Vutcovici M, Kezouh A, et al. Risk of lymphoma, colorectal and skin cancer in patients with IBD treated with immunomodulators and biologics: a quebec claims database study. Inflamm Bowel Dis. 2015;21:1847–53.
Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol. 2005;32:2130–5.
Amari W, Zeringue AL, McDonald JR, et al. Risk of non-melanoma skin cancer in a national cohort of veterans with rheumatoid arthritis. Rheumatology (Oxford). 2011;50:1431–9.
Mercer LK, Green AC, Galloway JB, et al. The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology biologics register. Ann Rheum Dis. 2012;71:869–74.
Singh S, Nagpal SJ, Murad MH, et al. Inflammatory bowel disease is associated with an increased risk of melanoma: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:210–8.
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.
de La Forest DM, Gottenberg JE, Salliot C. Safety of biologic DMARDs in RA patients in real life: a systematic literature review and meta-analyses of biologic registers. Joint Bone Spine. 2016;84(2):133–40.
Olsen CM, Hyrich KL, Knight LL, et al. Melanoma risk in patients with rheumatoid arthritis treated with tumour necrosis factor alpha inhibitors: a systematic review and meta-analysis. Melanoma Res. 2016;26:517–23.
Herrinton LJ, Liu L, Weng X, et al. Role of thiopurine and anti-TNF therapy in lymphoma in inflammatory bowel disease. Am J Gastroenterol. 2011;106:2146–53.
Weidmann E. Hepatosplenic T cell lymphoma. A review on 45 cases since the first report describing the disease as a distinct lymphoma entity in 1990. Leukemia. 2000;14:991–7.
Mackey AC, Green L, Liang LC, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2007;44:265–7.
Mackey AC, Green L, Leptak C, et al. Hepatosplenic T cell lymphoma associated with infliximab use in young patients treated for inflammatory bowel disease: update. J Pediatr Gastroenterol Nutr. 2009;48:386–8.
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.
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.
Mercer LK, Lunt M, Low AL, et al. Risk of solid cancer in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology biologics register for rheumatoid arthritis. Ann Rheum Dis. 2015;74:1087–93.
Lebrec H, Ponce R, Preston BD, et al. Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk. Curr Med Res Opin. 2015;31:557–74.
Solomon DH, Kremer JM, Fisher M, et al. Comparative cancer risk associated with methotrexate, other non-biologic and biologic disease-modifying anti-rheumatic drugs. Semin Arthritis Rheum. 2014;43:489–97.
Viens LJ, Henley SJ, Watson M, et al. Human papillomavirus-associated cancers – United States, 2008–2012. MMWR Morb Mortal Wkly Rep. 2016;65:661–6.
Rungoe C, Simonsen J, Riis L, et al. Inflammatory bowel disease and cervical neoplasia: a population-based nationwide cohort study. Clin Gastroenterol Hepatol. 2015;13:693–700.e1.
Kane S, Khatibi B, Reddy D. Higher incidence of abnormal pap smears in women with inflammatory bowel disease. Am J Gastroenterol. 2008;103:631–6.
Singh H, Demers AA, Nugent Z, et al. Risk of cervical abnormalities in women with inflammatory bowel disease: a population-based nested case-control study. Gastroenterology. 2009;136:451–8.
Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–16.
Triantafillidis JK, Nasioulas G, Kosmidis PA. Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res. 2009;29:2727–37.
Mellemkjaer L, Johansen C, Gridley G, et al. Crohn's disease and cancer risk (Denmark). Cancer Causes Control. 2000;11:145–50.
Sachar DB. Cancer in Crohn's disease: dispelling the myths. Gut. 1994;35:1507–8.
Rubin DT, Huo D, Kinnucan JA, et al. Inflammation is an independent risk factor for colonic neoplasia in patients with ulcerative colitis: a case-control study. Clin Gastroenterol Hepatol. 2013;11:1601–8.e1-4.
Carrat F, Seksik P, Colombel JF, et al. The effects of aminosalicylates or thiopurines on the risk of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2016;45(4):533–41.
van Schaik FD, van Oijen MG, Smeets HM, et al. Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease. Gut. 2012;61:235–40.
Axelrad J, Bernheim O, Colombel JF, et al. Risk of new or recurrent cancer in patients with inflammatory bowel disease and previous cancer exposed to immunosuppressive and anti-tumor necrosis factor agents. Clin Gastroenterol Hepatol. 2016;14:58–64.
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(1):97–109.e4.
Siegel CA. Lost in translation: helping patients understand the risks of inflammatory bowel disease therapy. Inflamm Bowel Dis. 2010;16:2168–72.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG
About this chapter
Cite this chapter
Hughes, J.T., Long, M.D. (2018). Tumor Necrosis Factor-Alpha Inhibitors and Risks of Malignancy. 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_13
Download citation
DOI: https://doi.org/10.1007/978-3-319-60276-9_13
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-60275-2
Online ISBN: 978-3-319-60276-9
eBook Packages: MedicineMedicine (R0)