Drug Safety

, Volume 27, Issue 5, pp 307–324

Safety of Tumour Necrosis Factor-α Antagonists

Review Article


Tumour necrosis factor-α (TNFα) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFα plays an adaptive role in immune protection and wound healing at ‘physiological’ levels, excess TNFα production can lead to adverse consequences. TNFα is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFα antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFα antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn’s disease). Worldwide, over half a million patients have been treated with TNFα antagonists and concerns regarding their safety have been raised.

There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin’s lymphoma and treatment with TNFα antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin’s lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFα antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFα antagonists and continued vigilance is warranted in patients on TNFα antagonists for the development of these diseases. At present there is no evidence implicating TNFα antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.


  1. 1.
    Hopkins SJ, Meager A. Cytokines in synovial fluid: II. the presence of tumour necrosis factor and interferon. Clin Exp Immunol 1988; 73: 88–92PubMedCentralPubMedGoogle Scholar
  2. 2.
    Saxne T, Palladino Jr MA, Heinegard D, et al. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 1988; 31: 1041–5PubMedCrossRefGoogle Scholar
  3. 3.
    Arend WP. The mode of action of cytokine inhibitors. J Rheumatol Suppl 2002; 65: 16–21PubMedGoogle Scholar
  4. 4.
    Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423: 356–61PubMedCrossRefGoogle Scholar
  5. 5.
    Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344: 907–16PubMedCrossRefGoogle Scholar
  6. 6.
    Infliximab (Remicade) package insert. 6-1-2002Google Scholar
  7. 7.
    Adalimumab (Humira) package insert. 12-1-2002Google Scholar
  8. 8.
    Etanercept (Enbrel) package insert. 10-1-2003Google Scholar
  9. 9.
    FDA Briefing Document. Update on the TNF-alpha blocking agents [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930b 1.htm [Accessed 2003 Sep 1]Google Scholar
  10. 10.
    Dembic Z, Loetscher H, Gubler U, et al. Two human tumor necrosis factor (TNF) receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 1990; 2: 231–7PubMedCrossRefGoogle Scholar
  11. 11.
    Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993; 151: 1548–61PubMedGoogle Scholar
  12. 12.
    Schall TJ, Lewis M, Koller KJ, et al. Molecular cloning and expression of a receptor for human tumor necrosis factor (TNF). Cell 1990; 61: 361–70PubMedCrossRefGoogle Scholar
  13. 13.
    Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor (TNF) antagonists. J Pharmacol Exp Ther 2002; 301: 418–26PubMedCrossRefGoogle Scholar
  14. 14.
    Korth-Bradley JM, Rubin AS, Hanna RK, et al. The pharmacokinetics of etanercept in healthy volunteers. Ann Pharmacother 2000; 34: 161–4PubMedCrossRefGoogle Scholar
  15. 15.
    Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-tumor necrosis factor (TNF) antibody. Mol Immunol 1993; 30: 1443–53PubMedCrossRefGoogle Scholar
  16. 16.
    den Broeder A, van de PL, Rau R, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-alpha (TNF) antibody adalimumab (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002; 29: 2288–98Google Scholar
  17. 17.
    Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis: Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000; 343: 1594–602PubMedCrossRefGoogle Scholar
  18. 18.
    Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000; 343: 1586–93PubMedCrossRefGoogle Scholar
  19. 19.
    Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor (TNF) alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48: 35–45PubMedCrossRefGoogle Scholar
  20. 20.
    Davis JC, van der Heijde DM, Braun J. Etanercept improves signs and symptoms of ankylosing spondylitis: results of a phase 3 multicenter clinical trial [abstract]. Ann Rheum Dis 2003; 62(1): 65CrossRefGoogle Scholar
  21. 21.
    Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356: 385–90PubMedCrossRefGoogle Scholar
  22. 22.
    Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000; 342: 763–9PubMedCrossRefGoogle Scholar
  23. 23.
    Antoni C, Kavanaugh A, Kirkham B. The one year results of the infliximab multinational psoriatic arthritis controlled trial (IMPACT) [abstract]. Arthritis Rheum 2003; 48(9): S265Google Scholar
  24. 24.
    Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002; 359: 1187–93PubMedCrossRefGoogle Scholar
  25. 25.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9PubMedCrossRefGoogle Scholar
  26. 26.
    Sandborn WJ, Hanauer SB, Katz S, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121: 1088–94PubMedCrossRefGoogle Scholar
  27. 27.
    Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not etanercept induces apoptosis in lamina propria Tlymphocytes from patients with Crohn’s disease. Gastroenterology 2003; 124: 1774–85PubMedCrossRefGoogle Scholar
  28. 28.
    Lugering A, Schmidt M, Lugering N, et al. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology 2001; 121: 1145–57PubMedCrossRefGoogle Scholar
  29. 29.
    Sibilia J, Maillefert JF. Vaccination and rheumatoid arthritis. Ann Rheum Dis 2002; 61: 575–6PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Vautier G, Carty JE. Acute sero-positive rheumatoid arthritis occurring after hepatitis vaccination. Br J Rheumatol 1994; 33: 991PubMedCrossRefGoogle Scholar
  31. 31.
    Iyngkaran P, Limaye V, Hill C, et al. Rheumatoid vasculitis following influenza vaccination. Rheumatology (Oxford) 2003; 42: 907–9CrossRefGoogle Scholar
  32. 32.
    Elkayam O, Yaron M, Caspi D. Safety and efficacy of vaccination against hepatitis B in patients with rheumatoid arthritis. Ann Rheum Dis 2002; 61: 623–5PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Elkayam O, Paran D, Caspi D, et al. Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus. Clin Infect Dis 2002; 34: 147–53PubMedCrossRefGoogle Scholar
  34. 34.
    Elkayam O, Casp D, Paran D, et al. Effect of anti-tumor necrosis factor (TNF) alpha therapies on the immunogenicity of pneumococcal vaccination in patients with rheumatic diseases [abstract]. Arthritis Rheum 2002; 46: S340CrossRefGoogle Scholar
  35. 35.
    Kavanaugh F, Greenwald M, Zizic T, et al. Immune response is not affected by adalimumab therapy [abstract]. Ann Rheum Dis 2003; 62: 169Google Scholar
  36. 36.
    ACR Hotline. FluMist® nasal spray influenza vaccine: implications for rheumatology. Atlanta (GA); American College of Rheumatology, 2003Google Scholar
  37. 37.
    Kavanaugh A, Keenan GF, DeWoody K, et al. Long-term follow-up of patients treated with infliximab in all completed clinical trials category [abstract]. Arthritis Rheum 2002; 46: S535CrossRefGoogle Scholar
  38. 38.
    Singh G, Ramey DR, Rausch PL, et al. Serious infections in rheumatoid arthritis: relationship to immunosuppressive use [abstract]. Arthritis Rheum 1999; 42: S242Google Scholar
  39. 39.
    Doran MF, Crowson CS, Pond GR, et al. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002; 46: 2287–93PubMedCrossRefGoogle Scholar
  40. 40.
    Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002). Ann Rheum Dis 2002; 61Suppl. 2: ii2–7PubMedCentralPubMedGoogle Scholar
  41. 41.
    Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha- neutralizing agent. N Engl J Med 2001; 345: 1098–104PubMedCrossRefGoogle Scholar
  42. 42.
    Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? an update on safety. J Rheumatol Suppl 2002; 65: 33–8PubMedGoogle Scholar
  43. 43.
    Ruderman EM, Markenson J. Granulomatous infections and tumor necrosis factor antagonists therapy: update through June 2002 [abstract]. Arthritis Rheum 2003; 48(9): S241Google Scholar
  44. 44.
    Keane J, Gershon S. Tuberculosis and treatment with infliximab. N Engl J Med 2002; 346: 625–6Google Scholar
  45. 45.
    Global tuberculosis control: WHO report: communicable diseases. Geneva: World Health Organisation, 1999Google Scholar
  46. 46.
    Manadan AM, Mohan AK, Cote TR, et al. Tuberculosis and etanercept treatment [abstract]. Arthritis Rheum 2002; 46: S166Google Scholar
  47. 47.
    Ponce de Leon D, Acevedo EM, Valenzuela G, et al. Inadequate response to tuberculin purified protein (PPD) in patients with rheumatoid arthritis. Study in a population with high prevalence of tuberculosis [abstract]. Arthritis Rheum 2003; 48(9): S108Google Scholar
  48. 48.
    Joven BE, Almodovar R, Galindo M, et al. Could anti-TNFαlpha therapy modify the tuberculin PPD response? [abstract]. Arthritis Rheum 2003; 48(9): S323Google Scholar
  49. 49.
    Furst DE, Cush J, Kaufmann S, et al. Preliminary guidelines for diagnosing and treating tuberculosis in patients with rheumatoid arthritis in immunosuppressive trials or being treated with biological agents. Ann Rheum Dis 2002; 61Suppl. 2: ii62–3PubMedCentralPubMedGoogle Scholar
  50. 50.
    Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. Lancet Infect Dis 2003; 3: 148–55PubMedCrossRefGoogle Scholar
  51. 51.
    Slifman NR, Gershon SK, Lee JH, et al. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 2003; 48: 319–24PubMedCrossRefGoogle Scholar
  52. 52.
    FDA Briefing Document. Safety update on TNF-alpha antagonists: infliximab and etanercept. FDA 8-1-2001Google Scholar
  53. 53.
    ACR Hotline. FDA Advisory Committee Reviews Safety of TNF Inhibitors. Atlanta (GA); American College of Rheumatology, 2001Google Scholar
  54. 54.
    Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002; 46: 2565–70PubMedCrossRefGoogle Scholar
  55. 55.
    Centeno-Lima S, Silveira H, Casimiro C, et al. Kinetics of cytokine expression in mice with invasive aspergillosis: lethal infection and protection. FEMS Immunol Med Microbiol 2002; 32: 167–73PubMedCrossRefGoogle Scholar
  56. 56.
    Bergstrom L, Yocum D, Tesser JR, et al. Coccidiomycosis (valley fever) occurring during infliximab therapy [abstract]. Arthritis Rheum 2002; 46: S169Google Scholar
  57. 57.
    Giron-Gonzalez JA, Lopez-Sanchez A, Elvira J, et al. Effect of patient adherence to antiretroviral therapy on CD4+ cell count, HIV-1 RNA, and serum concentrations of tumor necrosis factor and its soluble receptors. Eur J Clin Microbiol Infect Dis 2000; 19: 852–8PubMedCrossRefGoogle Scholar
  58. 58.
    Wong GH, Goeddel DV. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. Nature 1986; 323: 819–22PubMedCrossRefGoogle Scholar
  59. 59.
    Smith D, Letendre S. Viral pneumonia as a serious complication of etanercept therapy [letter]. Ann Intern Med 2002; 136: 174PubMedCrossRefGoogle Scholar
  60. 60.
    Mohan AK, Cote TR, Siegel JN, et al. Infectious complications of biologic treatments of rheumatoid arthritis. Curr Opin Rheumatol 2003; 15: 179–84PubMedCrossRefGoogle Scholar
  61. 61.
    Reddy MM, Sorrell SJ, Lange M, et al. Tumor necrosis factor and HIV P24 antigen levels in serum of HIV-infected populations. J Acquir Immune Defic Syndr 1988; 1: 436–40PubMedGoogle Scholar
  62. 62.
    Roux-Lombard P, Modoux C, Cruchaud A, et al. Purified blood monocytes from HIV 1-infected patients produce high levels of TNF alpha and IL-1. Clin Immunol Immunopathol 1989; 50: 374–84PubMedCrossRefGoogle Scholar
  63. 63.
    Aboulafia DM, Bundow D, Wilske K, et al. Etanercept for the treatment of human immunodeficiency virus-associated psoriatic arthritis. Mayo Clin Proc 2000; 75: 1093–8PubMedCrossRefGoogle Scholar
  64. 64.
    Walker RE, Spooner KM, Kelly G, et al. Inhibition of immunoreactive tumor necrosis factor-αlpha by a chimeric antibody in patients infected with human immunodeficiency virus type 1. J Infect Dis 1996; 174: 63–8PubMedCrossRefGoogle Scholar
  65. 65.
    Gaylis N. Infliximab in the treatment of an HIV positive patient with Reiter’s syndrome. J Rheumatol 2003; 30: 407–11PubMedGoogle Scholar
  66. 66.
    Peterson JR, Hsu FC, Simkin PA, et al. Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 2003; 62: 1078–82PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Zien NN. Abstract 101808. Presented at the 53rd Annual Meeting of the American Association for the Study of Liver Diseases, Nov 1-5; Boston (MA), 2002Google Scholar
  68. 68.
    Schlaak JF, Tully G, Lohr HF, et al. HBV-specific immune defect in chronic hepatitis B (CHB) is correlated with a dysregulation of pro- and anti-inflammatory cytokines. Clin Exp Immunol 1999; 115: 508–14PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Ostuni P, Botsios C, Punzi L, et al. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003; 62: 686–7PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Michel M, Duvoux C, Hezode C, et al. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still’s disease. J Rheumatol 2003; 30: 1624–5PubMedGoogle Scholar
  71. 71.
    Zeltser R, Valle L, Tanck C, et al. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol 2001; 137: 893–9PubMedGoogle Scholar
  72. 72.
    Wells AF, Kupper H, Fischoff S, et al. Incidence of injectionsite reactions association with adalimumab (D2E7) given subcutaneously for at least 6 months: a retrospective analysis of 4 phase 2/3 clinical trials [abstract]. Arthritis Rheum 2002; 46: S171Google Scholar
  73. 73.
    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: 601–8PubMedCrossRefGoogle Scholar
  74. 74.
    Selmaj K, Raine CS, Cross AH. Anti-tumor necrosis factor therapy abrogates autoimmune demyelination. Ann Neurol 1991; 30: 694–700PubMedCrossRefGoogle Scholar
  75. 75.
    van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 1996; 47: 1531–4PubMedCrossRefGoogle Scholar
  76. 76.
    The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999; 53: 457–65Google Scholar
  77. 77.
    FDA Briefing Document. Safety update on TNF-alpha antagonists: infliximab and etanercept. FDA. 8-1-2001Google Scholar
  78. 78.
    Seta Y, Shan K, Bozkurt B, et al. Basic mechanisms in heart failure: the cytokine hypothesis. J Card Fail 1996; 2: 243–9PubMedCrossRefGoogle Scholar
  79. 79.
    Mann DL. Inflammatory mediators and the failing heart: past, present, and the foreseeable future. Circ Res 2002; 91: 988–98PubMedCrossRefGoogle Scholar
  80. 80.
    Deswal A, Bozkurt B, Seta Y, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99: 3224–6PubMedCrossRefGoogle Scholar
  81. 81.
    Coletta AP, Clark AL, Banarjee P, et al. Clinical trials update: RENEWAL (RENAISSANCE and RECOVER) and ATTACH. Eur J Heart Fail 2002; 4: 559–61PubMedCrossRefGoogle Scholar
  82. 82.
    Chung ES, Packer M, Lok H, et al. Randomized, double-blind, placebo-controlled pilot trial of infliximab, a chimeric monoclonal antibody to TNFα in patients with moderate-to-severe heart failure: results of the ATTALH trial. Circulation 2003; 107: 3133–40PubMedCrossRefGoogle Scholar
  83. 83.
    Kwon HJ, Cote TR, Cuffe MS, et al. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med 2003; 138: 807–11PubMedCrossRefGoogle Scholar
  84. 84.
    Gordon C, Ranges GE, Greenspan JS, et al. Chronic therapy with recombinant tumor necrosis factor-αlpha in autoimmune NZB/NZW F1 mice. Clin Immunol Immunopathol 1989; 52: 421–34PubMedCrossRefGoogle Scholar
  85. 85.
    Stichweh DS, Punaro M, Pascual V. Infliximab-induced doublestranded DNA antibodies in children with rheumatological diseases [abstract]. Arthritis Rheum 2003; 48(9): S100Google Scholar
  86. 86.
    Shakoor N, Michalska M, Harris CA, et al. Drug-induced systemic lupus erythematosus associated with etanercept therapy. Lancet 2002; 359: 579–80PubMedCrossRefGoogle Scholar
  87. 87.
    Mohan AK, Edwards ET, Cote TR, et al. Drug-induced systemic lupus erythematosus and TNF-alpha blockers [letter]. Lancet 2002; 360: 646PubMedCrossRefGoogle Scholar
  88. 88.
    Prior P, Symmons DP, Hawkins CF, et al. Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 1984; 43: 128–31PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Myllykangas-Luosujarvi R, Aho K, Isomaki H. Mortality from cancer in patients with rheumatoid arthritis. Scand J Rheumatol 1995; 24: 76–8PubMedCrossRefGoogle Scholar
  90. 90.
    Baecklund E, Sundstrom C, Ekbom A, et al. Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum 2003; 48: 1543–50PubMedCrossRefGoogle Scholar
  91. 91.
    Isomaki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis 1978; 31: 691–6PubMedCrossRefGoogle Scholar
  92. 92.
    Baecklund E, Ekbom A, Sparen P, et al. Disease activity and risk of lymphoma in patients with rheumatoid arthritis: nested case-control study. BMJ 1998; 317: 180–1PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Surveillance, epidemiology, and end results program. National Cancer Institute, 2003 [online]. Available from URL: http://www.seer.cancer.gov [Accessed 2003 Jan]Google Scholar
  94. 94.
    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: 3151–8PubMedCrossRefGoogle Scholar
  95. 95.
    ACR Hotline. FDA Meeting March 2003: update on the safety of new drugs for rheumatoid arthritis. Atlanta (GA); American College of Rheumatology, 2003Google Scholar
  96. 96.
    Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis associated with anti-tumor necrosis factor (TNF) therapy [abstract]. Arthritis Rheum 2002; 46: S165CrossRefGoogle Scholar
  97. 97.
    Stone JH, Uhlfelder ML, Hellmann DB, et al. Etanercept combined with conventional treatment in Wegener’s granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum. 2001 May; 44(5): 1149–54PubMedCrossRefGoogle Scholar
  98. 98.
    Tartakovsky B, Ben Yair E. Cytokines modulate preimplantation development and pregnancy. Dev Biol 1991; 146: 345–52PubMedCrossRefGoogle Scholar
  99. 99.
    Wallace DJ. The use of etanercept and other tumor necrosis factor-αlpha blockers in infertility: it’s time to get serious. J Rheumatol 2003; 30: 1897–9PubMedGoogle Scholar
  100. 100.
    Munno I, Chiechi LM, Lacedra G, et al. Evaluation of nonspecific immunity and plasma levels of interferon-gamma, interleukin-6 and tumor necrosis factor-αlpha in preeclampsia. Immunopharmacol Immunotoxicol 1999; 21: 551–64PubMedCrossRefGoogle Scholar
  101. 101.
    Murakami T, Okamura C, Matsuzaki S, et al. Prediction of pregnancy in infertile women with endometriosis. Gynecol Obstet Invest 2002; 53Suppl. 1: 26–32PubMedCrossRefGoogle Scholar
  102. 102.
    Daher S, Fonseca F, Ribeiro OG, et al. Tumor necrosis factor during pregnancy and at the onset of labor and spontaneous abortion. Eur J Obstet Gynecol Reprod Biol 1999; 83: 77–9PubMedCrossRefGoogle Scholar
  103. 103.
    Berman J, Girardi G, Salmon J. Tumor necrosis factor-α is an important effector in antiphospholipid-induced pregnancy loss in mice [abstract]. Arthritis Rheum 2003; 48(9): S446Google Scholar
  104. 104.
    Imseis HM, Zimmerman PD, Samuels P, et al. Tumour necrosis factor-αlpha induces cyclo-oxygenase-2 gene expression in first trimester trophoblasts: suppression by glucocorticoids and NSAIDs. Placenta 1997; 18: 521–6PubMedCrossRefGoogle Scholar
  105. 105.
    Arslan A, Zingg HH. Regulation of COX-2 gene expression in rat uterus in vivo and in vitro. Prostaglandins 1996; 52: 463–81PubMedCrossRefGoogle Scholar
  106. 106.
    Sookvanichsilp N, Pulbutr P. Anti-implantation effects of indomethacin and celecoxib in rats. Contraception 2002; 65: 373–8PubMedCrossRefGoogle Scholar
  107. 107.
    Vioxx (Rofecoxib) package insert. 8-2-0003Google Scholar
  108. 108.
    Sills ES, Perloe M, Tucker MJ, et al. Successful ovulation induction, conception, and normal delivery after chronic therapy with etanercept: a recombinant fusion anti-cytokine treatment for rheumatoid arthritis. Am J Reprod Immunol 2001; 46: 366–8PubMedCrossRefGoogle Scholar
  109. 109.
    Burt MJ, Frizelle FA, Barbezat GO. Pregnancy and exposure to infliximab (anti-tumor necrosis factor-αlpha monoclonal antibody). J Gastroenterol Hepatol 2003; 18: 465–6PubMedCrossRefGoogle Scholar
  110. 110.
    Antoni C, Furst D, Manger B, et al. Outcome of pregnancy in women receiving infliximab for the treatment of Crohn’s disease or rheumatoid arthritis [abstract]. Arthritis Rheum 2001; 44: S152Google Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Dinesh Khanna
    • 1
  • Maureen McMahon
    • 1
  • Daniel E. Furst
    • 1
  1. 1.Division of Rheumatology, Carl Pearson Professor of MedicineDavid Geffen School of Medicine at UCLALos AngelesUSA

Personalised recommendations