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Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases

Klaus Bendtzen, MD, DMSc
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD


Targeted inhibitors of tumor necrosis factor-alpha (TNF) are widely used in the treatment of a number of inflammatory conditions, including rheumatoid arthritis (RA), axial and peripheral spondyloarthritis, inflammatory bowel disease, and psoriasis (with or without arthritis). However, use of these agents has been associated in some patients with the development of anti-drug antibodies, which may promote adverse effects and diminish drug efficacy. Induction of autoimmunity, including both autoantibodies and, much less often, clinically evident autoimmune disease, may also occur during treatment.

Adverse effects associated with the use of biologic agents that inhibit TNF include injection site and infusion reactions, cytopenias, infections, autoimmune and demyelinating diseases, heart failure, malignancy, and pulmonary, liver, and skin disease. These potentially serious risks are among the factors included in the risk/benefit assessment made when deciding whether to use one of these agents in an individual patient.

TNF inhibitor-related anti-drug antibody formation, autoantibody formation, and the development of autoimmune diseases are reviewed here. Other major complications of anti-TNF therapy, such as injection site and infusion reactions, tuberculosis and other infections, malignancy, and other adverse effects, are described separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)


The formation of anti-drug antibodies, especially drug-neutralizing antibodies, is a concern with biologic TNF inhibitors, particularly the monoclonal antibody agents, infliximab and adalimumab, and, most likely, biosimilars to these original drugs. Hence, anti-drug antibodies may cause allergic reactions, loss of responsiveness, and increased cost of therapy. The risk of developing antibodies appears least common with use of etanercept, a receptor fusion protein, and most common with infliximab, a chimeric (mouse/human) antibody construct.

The five biologic TNF inhibitors that are widely available for the treatment of a variety of inflammatory illnesses (eg, rheumatoid arthritis [RA], Crohn disease), their composition, and their association with anti-drug antibody induction include:

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Literature review current through: Nov 2017. | This topic last updated: Oct 08, 2017.
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  1. Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor infliximab. Arthritis Rheum 2006; 54:3782.
  2. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006; 54:711.
  3. 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.
  4. Steenholdt C, Brynskov J, Thomsen OØ, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut 2014; 63:919.
  5. Schaeverbeke T, Truchetet ME, Kostine M, et al. Immunogenicity of biologic agents in rheumatoid arthritis patients: lessons for clinical practice. Rheumatology (Oxford) 2016; 55:210.
  6. Kelly OB, Donnell SO, Stempak JM, et al. Therapeutic Drug Monitoring to Guide Infliximab Dose Adjustment is Associated with Better Endoscopic Outcomes than Clinical Decision Making Alone in Active Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23:1202.
  7. Hindryckx P, Novak G, Vande Casteele N, et al. Incidence, Prevention and Management of Anti-Drug Antibodies Against Therapeutic Antibodies in Inflammatory Bowel Disease: A Practical Overview. Drugs 2017; 77:363.
  8. Vincent FB, Morand EF, Murphy K, et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013; 72:165.
  9. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007; 66:921.
  10. Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009; 68:1739.
  11. Bartelds GM, Krieckaert CL, Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011; 305:1460.
  12. l'Ami MJ, Kneepkens EL, Nurmohamed MT, et al. Long-term treatment response in rheumatoid arthritis patients starting adalimumab or etanercept with or without concomitant methotrexate. Clin Exp Rheumatol 2017; 35:431.
  13. Colombel JF, Jharap B, Sandborn WJ, et al. Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn's disease or ulcerative colitis who had failed conventional therapy. Aliment Pharmacol Ther 2017; 45:50.
  14. Sandborn WJ, Wolf DC, Kosutic G, et al. Effects of Transient and Persistent Anti-drug Antibodies to Certolizumab Pegol: Longitudinal Data from a 7-Year Study in Crohn's Disease. Inflamm Bowel Dis 2017; 23:1047.
  15. Vande Casteele N, Khanna R. Therapeutic Drug Monitoring of Golimumab in the Treatment of Ulcerative Colitis. Pharm Res 2017; 34:1556.
  16. Zhou H, Jang H, Fleischmann RM, et al. Pharmacokinetics and safety of golimumab, a fully human anti-TNF-alpha monoclonal antibody, in subjects with rheumatoid arthritis. J Clin Pharmacol 2007; 47:383.
  17. Bendtzen K. Anti-TNF-α biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy 2012; 4:1167.
  18. Bendtzen K. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. Discov Med 2013; 15:201.
  19. Kay J. Biosimilars: a regulatory perspective from America. Arthritis Res Ther 2011; 13:112.
  20. Kay J, Feagan BG, Guirguis MS, et al. Health Canada/BIOTECanada Summit on regulatory and clinical topics related to subsequent entry biologics (biosimilars), Ottawa, Canada, 14 May 2012. Biologicals 2012; 40:517.
  21. Minghetti P, Rocco P, Cilurzo F, et al. The regulatory framework of biosimilars in the European Union. Drug Discov Today 2012; 17:63.
  22. Smits LJ, Derikx LA, de Jong DJ, et al. Clinical Outcomes Following a Switch from Remicade® to the Biosimilar CT-P13 in Inflammatory Bowel Disease Patients: A Prospective Observational Cohort Study. J Crohns Colitis 2016; 10:1287.
  23. Benucci M, Gobbi FL, Bandinelli F, et al. Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: a 6-month real-life observational study. Immunol Res 2017; 65:419.
  24. Feagan BG, Choquette D, Ghosh S, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals 2014; 42:177.
  25. Braun J, Kudrin A. Progress in biosimilar monoclonal antibody development: the infliximab biosimilar CT-P13 in the treatment of rheumatic diseases. Immunotherapy 2015; 7:73.
  26. Vital EM, Kay J, Emery P. Rituximab biosimilars. Expert Opin Biol Ther 2013; 13:1049.
  27. Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis. JAMA Intern Med 2013; 173:1416.
  28. Prado MS, Bendtzen K, Andrade LEC. Biological anti-TNF drugs: immunogenicity underlying treatment failure and adverse events. Expert Opin Drug Metab Toxicol 2017; 13:985.
  29. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41:1552.
  30. Ollendorf DA, Massarotti E, Birbara C, Burgess SM. Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis. J Manag Care Pharm 2005; 11:383.
  31. St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46:1451.
  32. Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994; 344:1125.
  33. Atzeni F, Talotta R, Salaffi F, et al. Immunogenicity and autoimmunity during anti-TNF therapy. Autoimmun Rev 2013; 12:703.
  34. Ramos-Casals M, Roberto-Perez-Alvarez, Diaz-Lagares C, et al. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev 2010; 9:188.
  35. Perez-Alvarez R, Pérez-de-Lis M, Ramos-Casals M, BIOGEAS study group. Biologics-induced autoimmune diseases. Curr Opin Rheumatol 2013; 25:56.
  36. Visvanathan S, Wagner C, Smolen J, et al. IgG and IgM anticardiolipin antibodies following treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis. Arthritis Rheum 2006; 54:2840.
  37. Charles PJ, Smeenk RJ, De Jong J, et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000; 43:2383.
  38. Benucci M, Saviola G, Baiardi P, et al. Anti-nucleosome antibodies as prediction factor of development of autoantibodies during therapy with three different TNFalpha blocking agents in rheumatoid arthritis. Clin Rheumatol 2008; 27:91.
  39. Brito-Zerón P, Perez-Alvarez R, Ramos-Casals M, BIOGEAS Study Group. Etanercept and uveitis: friends or foes? Curr Med Res Opin 2015; 31:251.
  40. Boyman O, Comte D, Spertini F. Adverse reactions to biologic agents and their medical management. Nat Rev Rheumatol 2014; 10:612.
  41. Brunasso AM, Aberer W, Massone C. New onset of dermatomyositis/polymyositis during anti-TNF-α therapies: a systematic literature review. ScientificWorldJournal 2014; 2014:179180.
  42. Stübgen JP. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve 2008; 37:281.
  43. Czaja AJ. Drug-induced autoimmune-like hepatitis. Dig Dis Sci 2011; 56:958.
  44. Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine (Baltimore) 2007; 86:242.
  45. De Bandt M, Sibilia J, Le Loët X, et al. Systemic lupus erythematosus induced by anti-tumour necrosis factor alpha therapy: a French national survey. Arthritis Res Ther 2005; 7:R545.
  46. Adalimumab (Humira) package insert.
  47. De Bandt M. Lessons for lupus from tumour necrosis factor blockade. Lupus 2006; 15:762.
  48. Stokes MB, Foster K, Markowitz GS, et al. Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 2005; 20:1400.
  49. Williams EL, Gadola S, Edwards CJ. Anti-TNF-induced lupus. Rheumatology (Oxford) 2009; 48:716.
  50. Soforo E, Baumgartner M, Francis L, et al. Induction of systemic lupus erythematosus with tumor necrosis factor blockers. J Rheumatol 2010; 37:204.
  51. Wetter DA, Davis MD. Lupus-like syndrome attributable to anti-tumor necrosis factor alpha therapy in 14 patients during an 8-year period at Mayo Clinic. Mayo Clin Proc 2009; 84:979.
  52. Williams VL, Cohen PR. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol 2011; 50:619.
  53. Beigel F, Schnitzler F, Paul Laubender R, et al. Formation of antinuclear and double-strand DNA antibodies and frequency of lupus-like syndrome in anti-TNF-α antibody-treated patients with inflammatory bowel disease. Inflamm Bowel Dis 2011; 17:91.
  54. Moulis G, Sommet A, Lapeyre-Mestre M, et al. Is the risk of tumour necrosis factor inhibitor-induced lupus or lupus-like syndrome the same with monoclonal antibodies and soluble receptor? A case/non-case study in a nationwide pharmacovigilance database. Rheumatology (Oxford) 2014; 53:1864.
  55. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40:1725.
  56. Ramos-Casals M, Perez-Alvarez R, Perez-de-Lis M, et al. Pulmonary disorders induced by monoclonal antibodies in patients with rheumatologic autoimmune diseases. Am J Med 2011; 124:386.
  57. Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum 2011; 41:256.
  58. Wendling D, Paccou J, Berthelot JM, et al. New onset of uveitis during anti-tumor necrosis factor treatment for rheumatic diseases. Semin Arthritis Rheum 2011; 41:503.
  59. Lim LL, Fraunfelder FW, Rosenbaum JT. Do tumor necrosis factor inhibitors cause uveitis? A registry-based study. Arthritis Rheum 2007; 56:3248.
  60. Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology 2014; 121:785.