The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences

Abstract

Biologic therapies, predominantly TNF-α inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies – those that hinder bioactivity by preventing drug molecules from binding to TNF – are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies.

Keywords::

• abatacept
• adalimumab
• antidrug antibodies
• biologic therapies
• etanercept
• immunogenicity
• infliximab
• rheumatoid arthritis
• rituximab
• TNF antagonists

Acknowledgements

Medical writing support was provided by Susanne Gilbert of ACUMED and was funded by Pfizer Inc.

Financial & competing interest disclosure

M Keiserman has participated in Advisory Boards and/or lectures for Pfizer, Abbott, Actelion, AstraZeneca, Amgen, Roche, Bristol Myers Squibb, and Janssen and has received clinical trial honoraria from Pfizer, Amgen, AstraZeneca, Anthera Pharmaceuticals, Bristol-Myers Squibb, Biogen Idec Inc, Celltrion Inc., Eli Lilly, Human Genome Sciences, Novartis, Roche, Sanofi, UCB Inc. C Codreanu has received speaker fees from AbbVie, Amgen, Angellini, AstraZeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme, Pfizer, Richter, Roche, Sanofi, Servier, Teva, UCB and Zentiva; and consulting fees from AbbVie, Amgen, Egis, Merck Sharpe & Dohme, Pfizer, Roche, Sanofi and UCB. R Handa has received honoraria as a speaker, consultant and advisory board member for Abbott India, Pfizer, Ranbaxy, IPCA, Glaxo SmithKline, Dr Reddy’s Laboratories Ltd, Bristol-Myers Squibb India, Janssen, Piramal Life Sciences, Panasonic Health Care, Roche and Sanofi. D Xibillé-Friedmann has received speaker fees from Pfizer; and support for clinical trials from Pfizer and UCB. E Mysler has received honoraria as an investigator, speaker and advisor for AbbVie, Bristol-Myers Squibb, Pfizer and Roche. F Briceño has received honoraria as a speaker and advisor for Bristol-Myers Squibb, Lilly and Pfizer. S Akar has received honoraria as a speaker and advisor for AbbVie, Pfizer and Merck Sharp & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Although the principles of targeted treatment in rheumatoid arthritis are accepted internationally, there are many barriers to implementation, particularly in developing regions such as Central and Eastern Europe, Russia, India, Turkey and Latin America.

• Barriers include clinician inexperience and limited access to treatment, especially for relatively costly therapies such as biologic agents.

• Even when biologic therapies are accessible to patients, their clinical utility can be limited by the development of neutralizing antidrug antibodies, which prevent drug molecules from binding to TNF-α.

• Neutralizing antidrug antibodies are significantly correlated with reduced serum drug concentrations, diminished therapeutic response, adverse events and treatment discontinuation.

• Among the TNF-α inhibitors, immunogenicity may be more common with mAbs than with etanercept, a soluble TNF receptor–Fc immunoglobulin fusion protein. However, direct comparisons are lacking.

• Concomitant administration of immunomodulators such as methotrexate or azathioprine may reduce the immunogenicity of therapeutic antibodies, although the mechanism is unclear.

• Cost–effective use of anti-TNF agents will depend on further research into drug and antidrug antibody assays and how they should be used to guide dose reduction or switching strategies.

• Better understanding and monitoring of the immunogenic effects of biologic therapies and their clinical consequences will help to individualize therapy and achieve the goals of low disease activity or full remission.