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Shortly after Anti-TNFα agents became available, safety concerns surrounding increased risk for opportunistic infection and lymphoma were raised.1 Lichtenstein and others have previously examined Anti-TNFα "class" safety in very large retrospective meta-analysis studies.2 Their results suggested no significant increase in risk for non-Hodgkin's lymphoma (NHL). However, many have since published contrary conclusions.1,3,4,5 In this edition of VHJOE, we reviewed two very important articles that examine safety issues surrounding Anti-TNFα agents in the treatment of inflammatory disorders.6,7
Siegel, et al, carefully culled the published literature to identify a select group of studies that included long term follow up of Crohn's disease patients treated with any of the three FDA approved Anti-TNF agents [Infliximab (IFX), Adalimumab (ADA), and Certolizumab (CTZ)] for the evolution of NHL.6 While Burmester, et al, looked at a very large collective cohort of patients with 6 different inflammatory disorders (Rheumatoid arthritis, Psoriatic arthritis, Psoriasis, Crohn's disease, Juvenile Idiopathic Arthritis, and Ankylosing Spondylitis ) treated with a single Anti-TNFα agent, ADA.7 Each of these studies have inherent strengths and weaknesses. The large number of patients and the "collective" longitudinal follow up in both of these meta-analyses provide the statistical power to give strong support to the conclusion that long-term Anti-TNFα therapy for Crohn's disease or a number of inflammatory disorders is associated with an increased risk for NHL. The risk for NHL appears to be about 3 times increased over that of the general US population as reported by National Cancer Institute, SEER database, Figure 1.8
Unfortunately, the evolution of Anti-TNFα therapy has been influenced by the development of neutralizing antibodies to Anti-TNFα agents, especially Infliximab.9 To prevent this development, it has become common place to use an immunomodulator drug such as 6-mercaptopurine, imuran or methotrexate in conjunction with Anti-TNFα therapy.10,11 Chronic treatment with an immunomodulator alone has been shown to independently increase the risk for lymphoma.12 In both the Burmester and Siegel studies many of the subjects included (46 and 77%, respectively) received "combination" Anti-TNFα and immunomodulator therapy.6,7 Hence, the calculated increased risk for NHL is a reflection of "combination" Anti-TNFα and Immunomodulator therapy NOT "mono" Anti-TNFα therapy.
The recent published results of the SONIC trial indicated that combination therapy of immunomodulator plus IFX exhibited greater efficacy than monotherapy in Crohn's disease patients.12 These results have supported the convention of "combination" therapy for Crohn's patients with moderate to severe disease.13 We should ask ourselves, should we commit all patients with inflammatory disorders to the "combination" therapy and a multiplied risk of NHL, when use of a less antigenic "mono"Anti-TNFα therapy with ADA or CTZ may be as effective for most patients with potentially less risk for NHL.14,15,16 Perhaps, we should save "combination" Anti-TNFα and Immunomodulator therapy for those failing "mono" Anti-TNFα therapy.
We know that the intrinsic risk for lymphoma (see figures 2 & 3) among patients with inflammatory disorders such as, rheumatoid arthritis and Crohn's disease is different. This makes it difficult to translate safety data from one patient group to another. However, JIR and Psoriasis are two inflammatory disorders where "mono" Anti-TNFα therapy is the current convention. Perhaps, selected longitudinal of these two groups will provide important safety data for "mono" Anti-TNFα therapy.
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1. Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results and safety. Inflamm Bowel Dis. 1999;5:119-133.
2. Lichtenstein GR, Cohen RD, Feagan BG, et al. Safety of infliximab and other Crohn's disease therapies - TREAT (TM) registry data with nearly 20,000 patient-years of follow up. Gastroenterology. 20087;132:A178.
3. Loftus EV jr, Tremaine WJ, Habermann TM, et al. Risk of lymphoma in inflammatory bowel disease. Am J Gastroenterol. 2000;95:2308-2312.
4. Lewis JD, Bilker WB, Brensinger C, et al. Inflammatory bowel disease is not associated with increased risk of lymphoma. Gastroenterology. 2001;121:1080-1087.
5. Ljung T, Karlen P, Schmidt D, et al. Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849-853.
6. Siegel CA, Marden SM, Persing SM, Larson RJ, Sands BE. Risk of Lymphoma Associated with Combination of Anti-Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn's Disease: A Meta-Analysis. Clin Gastroenterol and Hepatol. 2009;7:874-881.
7. Burmester GR, Mease P, Dijkmas BAC, Gordon K, Lovell D, Panaccione R, Perez J, Pangan AL. Adalimumab Safety and Mortality Rates from Global Clinical Trials of Six Immune-Mediated Inflammatory Diseases. Ann Rheum Dis. Ann Rheum Dis. 2009;68:1863-9. Epub 2009 Jan 15.
8. SEER. Surveillance, Epidemiology, and End Results Database.
9. Rutgeers P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease. Gastroenterology. 2004;126:402-413.
10. Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn's disease. Gastroenterology. 2005;128:862-869.
11. Kandeil A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut. 2005;54:1121-1125.
12. D'Haens G, Baert F, van Assche G,et al. Belgian Inflammatory Bowel Disease Research Group; North-Holland Gut Club. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomized trial. Lancet. 2008;371(9613):660-7.
13. Sandborn WJ. Initial combination therapy in early Crohn's disease. Lancet. 2008;371(9613):635-6.
14. Hanauer S, Sandborn W, Rutgeerts, et al. Human Anti-Tumor Necrosis Factor Monoclonal Antibody (Adalimumab) in Crohn's Disease: the CLASSIC-I Trial. Gastroenterology. 2006;130:323-333.
15. Schreiber S, Khaliq-Kareemi M, Lawrence IC, et al. Maintenance Therapy with Certolizumab Pegol for Crohn's Disease. N Engl J Med. 2007;357:239-250.
16. Hanauer SB. Risks and benefits of combining immunosuppressives and biological agents in inflammatory bowel disease: is the synergy worth the risk? Gut 2007;56:1181-1183.
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