Tumor necrosis factor-alpha inhibitors: Risk of malignancy
- Kimme Hyrich, MD, PhD, FRCPC
Kimme Hyrich, MD, PhD, FRCPC
- Professor of Epidemiology and Honorary Consultant in Rheumatology
- Centre for Musculoskeletal Research
- Institute of Inflammation and Repair
- The University of Manchester
- Section Editor
- Daniel E Furst, MD
Daniel E Furst, MD
- Section Editor — Treatment Issues in Rheumatology
- Professor of Rheumatology, University of Washington, Seattle
- Professor of Rheumatology, Washington University of Florence, Florence, Italy
- Professor of Rheumatology, University of California in Los Angeles (Emeritus)
- Director of Research, Pacific
Inhibitors of tumor necrosis factor (TNF)-alpha represent important treatment advances for a number of inflammatory conditions, including rheumatoid arthritis (RA), the seronegative spondyloarthropathies, inflammatory bowel disease (IBD), and psoriasis. TNF-alpha inhibitors offer a targeted strategy that contrasts with the nonspecific immunosuppressive agents traditionally used to treat most inflammatory diseases.
However, multiple potential adverse effects of TNF-alpha inhibition have been reported through both clinical trials and postmarketing surveillance. These include:
●Injection site reactions
- Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975; 72:3666.
- National Cancer Institute: Surveillance Epidemiology and End Results Program. http://seer.cancer.gov/ (Accessed on January 22, 2013).
- Askling J, van Vollenhoven RF, Granath F, et al. Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment? Arthritis Rheum 2009; 60:3180.
- Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum 1997; 26:794.
- Gridley G, McLaughlin JK, Ekbom A, et al. Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 1993; 85:307.
- Collins PD, Mpofu C, Watson AJ, Rhodes JM. Strategies for detecting colon cancer and/or dysplasia in patients with inflammatory bowel disease. Cochrane Database Syst Rev 2006; :CD000279.
- Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 2008; 10:R45.
- Symmons D. Excess mortality in rheumatoid arthritis--is it the disease or the drugs? J Rheumatol 1995; 22:2200.
- Cibere J, Sibley J, Haga M. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum 1997; 40:1580.
- Greenstein AJ, Mullin GE, Strauchen JA, et al. Lymphoma in inflammatory bowel disease. Cancer 1992; 69:1119.
- Ebeo CT, Girish MR, Byrd RP, et al. Methotrexate-induced pulmonary lymphoma. Chest 2003; 123:2150.
- Wolfe F, Michaud K. The effect of methotrexate and anti-tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum 2007; 56:1433.
- Bongartz T, Sutton AJ, Sweeting MJ, et al. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006; 295:2275.
- Askling J, Fored CM, Baecklund E, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis 2005; 64:1414.
- Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis 2011; 70:1895.
- Askling J, Fahrbach K, Nordstrom B, et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf 2011; 20:119.
- Dommasch ED, Abuabara K, Shin DB, et al. The risk of infection and malignancy with tumor necrosis factor antagonists in adults with psoriatic disease: a systematic review and meta-analysis of randomized controlled trials. J Am Acad Dermatol 2011; 64:1035.
- Thompson AE, Rieder SW, Pope JE. Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Arthritis Rheum 2011; 63:1479.
- Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46:3151.
- Early communication about an ongoing safety review of tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, and Cimzia). 6/4/2008 www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070725.htm (Accessed on January 27, 2010).
- Follow-up to the June 4, 2008 early communication about the ongoing safety review of tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). August 4, 2009. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174449.htm (Accessed on January 27, 2010).
- Information for healthcare professionals: tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). FDA Alert (8/4/2009). www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm174474.htm (Accessed on January 27, 2010).
- Questions and answers - TNF blockers 8/25/2009. www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm180694.htm (Accessed on January 27, 2010).
- Dreyer L, Mellemkjær L, Andersen AR, et al. Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry. Ann Rheum Dis 2013; 72:79.
- Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 2012; 308:898.
- Nyboe Andersen N, Pasternak B, Basit S, et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014; 311:2406.
- Haynes K, Beukelman T, Curtis JR, et al. Tumor necrosis factor α inhibitor therapy and cancer risk in chronic immune-mediated diseases. Arthritis Rheum 2013; 65:48.
- Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol 2012; 107:1051.
- Williams CJ, Peyrin-Biroulet L, Ford AC. Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-α therapy in inflammatory bowel disease. Aliment Pharmacol Ther 2014; 39:447.
- Baecklund E, Iliadou A, Askling J, et al. Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis. Arthritis Rheum 2006; 54:692.
- FDA Arthritis Advisory Committee Meeting, 3/04. http://www.fda.gov/ohrms/dockets/ac/cder03.html#Arthritis (Accessed on July 17, 2005).
- Geborek P, Bladström A, Turesson C, et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 2005; 64:699.
- Everitt, DE. Important drug warning. www.fda.gov/medwatch/SAFETY/2004/remicade_dearhcp.pdf (Accessed on January 18, 2004).
- Askling J, Baecklund E, Granath F, et al. Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register. Ann Rheum Dis 2009; 68:648.
- Mariette X, Tubach F, Bagheri H, et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis 2010; 69:400.
- Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum 2006; 54:1608.
- Leombruno JP, Einarson TR, Keystone EC. The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events. Ann Rheum Dis 2009; 68:1136.
- Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis 2005; 64:1421.
- 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.
- Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351.
- Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum 2007; 56:2886.
- 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.
- 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.
- Raaschou P, Simard JF, Holmqvist M, et al. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden. BMJ 2013; 346:f1939.
- Dixon WG, Watson KD, Lunt M, et al. Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register. Arthritis Care Res (Hoboken) 2010; 62:755.
- Phillips C, Zeringue AL, McDonald JR, et al. Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis. PLoS One 2015; 10:e0143286.
- Raaschou P, Frisell T, Askling J, ARTIS Study Group. TNF inhibitor therapy and risk of breast cancer recurrence in patients with rheumatoid arthritis: a nationwide cohort study. Ann Rheum Dis 2015; 74:2137.
- Raaschou P, Simard JF, Neovius M, et al. Does cancer that occurs during or after anti-tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologic agents. Arthritis Rheum 2011; 63:1812.
- GENERAL ISSUES
- Inhibitors of TNF-alpha
- TNF-alpha biology
- Measures of risk
- - Standardized incidence ratios
- - Relative risk
- CHALLENGES IN ESTABLISHING MALIGNANCY RISK
- STUDIES OF OVERALL CANCER RISK
- Evidence of increased risk
- Evidence of no increased long-term risk
- LYMPHOMA RISK
- Studies suggesting increased lymphoma risk
- Studies suggesting no increased lymphoma risk
- SOLID MALIGNANCY RISK
- Cyclophosphamide and TNF inhibitor combination
- - Etanercept label warning
- SKIN CANCER RISK
- Non-melanoma skin cancer
- Malignant melanoma
- CANCER RISK IN PATIENTS WITH PRIOR MALIGNANCY
- SUMMARY AND RECOMMENDATIONS