Review Article | Published:

Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment

Nature Reviews Rheumatology volume 13, pages 707718 (2017) | Download Citation


The availability of monoclonal antibodies has revolutionized the treatment of an increasingly broad spectrum of diseases. Inflammatory diseases are among those most widely treated with protein-based therapeutics, termed biologics. Following the first large-scale clinical trials with monoclonal antibodies performed in the 1990s by rheumatologists and clinical immunologists, the approval of these agents for use in daily clinical practice led to substantial progress in the treatment of rheumatic diseases. Despite this progress, however, only a proportion of patients achieve a long-term clinical response. Data on the use of agents blocking TNF, which were among the first biologics introduced into clinical practice, provide ample evidence of primary and secondary treatment inefficacy in patients with rheumatoid arthritis (RA). Important issues relevant to primary and secondary failure of these agents in RA include immunogenicity, methodological problems for the detection of antidrug antibodies and trough drug levels, and the implications for treatment strategies. Although there is no strong evidence to support the routine estimation of antidrug antibodies or serum trough levels during anti-TNF therapy, these assessments might be helpful in a few clinical situations; in particular, they might guide decisions on switching the therapeutic biologic in certain instances of secondary clinical failure.

Key points

  • Monoclonal antibodies and fusion proteins induce the formation of antidrug antibodies (ADAs), the occurrence and magnitude of which differs between chimeric antibodies, fully humanized antibodies and fusion proteins

  • The clinical implication of ADAs are unclear, although ADAs are known to cause secondary drug failure

  • Consensus definitions of primary and secondary non-response are lacking, as are evidence-based recommendations on how to guide biologic therapy on the basis of drug level and immunogenicity

  • Testing for ADAs or serum trough drug levels might be indicated in some situations of primary and secondary treatment failure and could prompt changes in dosing or therapeutic agent

  • When switching from an anti-TNF drug (originator) to a biosimilar of that originator, one has to take into consideration that ADAs against the originator will crossreact with the biosimilar, causing treatment failure

  • More information regarding the immunogenicity of the different TNF antagonists and improved ADA testing systems could lead to the development of an immune-pharmacologic strategy for the individualized treatment of rheumatoid arthritis

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The authors sincerely thank Martina Seidel for instrumental help with the preparation of the manuscript.

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  1. Friedrich-Alexander University Erlangen-Nürnberg, Division of Molecular Immunology, Nikolaus-Fiebiger Center, Glückstraße 6, D-91054 Erlangen, Germany.

    • Joachim R. Kalden
  2. Ludwig-Maximilians-University, Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Pettenkoferstraße 8a, D-80336 Munich, Germany.

    • Hendrik Schulze-Koops


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