LAUSR

Biologic agents have become a core component of therapeutic strategies for many inflammatory rheumatic diseases. However, perhaps reflecting the specificity and generally high affinity of biologic agents, these therapeutics have been used by rheumatologists with less consideration of their pharmacokinetics than that of conventional synthetic DMARDs. Immunogenicity was recognized as a potential limitation to the use of biologic agents at an early stage in their development, although regulatory guidance was relatively limited and assays to measure immunogenicity were less sophisticated than today. The advent of biosimilars has sparked a renewed interest in immunogenicity that has resulted in the development of increasingly sensitive assays, an enhanced appreciation of the pharmacokinetic consequences of immunogenicity and the development of comprehensive and specific guidance from regulatory authorities. As a result, rheumatologists have a greatly improved understanding of the field in general, including the factors responsible for immunogenicity, its potential clinical consequences and the implications for everyday treatment. In some specialties, immunogenicity testing is becoming a part of routine clinical management, but definitive evidence of its cost-effectiveness in rheumatology is awaited. The immunogenicity of a biologic agent can have clinical consequences in terms of response to therapy and risk of adverse events. In this Review, the authors summarize the latest data on the immunogenicity of biologic agents for various rheumatic indications. All biologic agents are immunogenic and many pathways influence their bioavailability, including patient-specific factors, disease-specific features and genetic background. The potential consequences of immunogenicity range from no clinical consequences to reduced therapeutic efficacy, infusion reactions and, rarely, serum sickness or anaphylaxis. Group level pharmacokinetic models have consistently shown that anti-drug antibodies (ADAs) result in decreased serum drug concentrations and reduced efficacy. The most important difference between available immunogenicity assays is the degree to which the assay is drug tolerant. Coadministration of anti-proliferative and/or immunosuppressive agents such as methotrexate decreases ADA formation and maintains serum drug concentrations via various mechanisms. Regular monitoring of serum drug and ADA levels has been proposed but not yet instigated into rheumatological practice, mainly owing to a lack of cost-effectiveness data.