?Fig.2].2]. of a recent systematic literature review of the immunogenicity of 11 biological/biosimilar agents, we conducted an ancillary qualitative review of a subset of randomized controlled trials and observational studies of the monoclonal antibodies against anti\TNF factor adalimumab and infliximab. Among studies sAJM589 of adalimumab and infliximab, the immunoassay method?used to detect antibodies was reported in 91 of 111 (82%) and 154 of 206 (75%) adalimumab and infliximab studies, respectively. In most adalimumab and infliximab studies, an enzyme\linked immunosorbent assay or radioimmunoassay was used [85 of 91 (93%) and 134 of 154 (87%), respectively]. ADA incidence varied widely among assays and inflammatory diseases (adalimumab, 0C87%; infliximab, 0C79%). Pharmacokinetic and clinical outcomes were only reported for ADA\positive patients in 38 of 91 (42%) and 61 of 154 (40%) adalimumab and infliximab studies, respectively. Regardless of assay format or biological used, ADA formation was associated with lower serum concentrations, reduced efficacy and elevated rates of infusion\related reactions. Consistent with previous recommendations to improve interpretation of immunogenicity data for biologicals, greater consistency in reporting of assay methods and clinical consequences of ADA formation may prove useful. Additional standardization in immunogenicity testing and reporting, application of modern, robust assays that satisfy current regulatory expectations and implementation of international standards for marketed products may help to improve our understanding of the impact of immunogenicity to biologics. Keywords: adalimumab, anti\drug antibody, anti\tumour necrosis factor monoclonal antibody, immunoassay, infliximab Introduction Up\regulation of the proinflammatory cytokine tumour necrosis factor (TNF)\ is a common pathogenic mechanism in a wide array of chronic immune\mediated inflammatory diseases 1. In clinical sAJM589 trials conducted over nearly two decades, biological agents that block inflammatory responses activated by TNF\ have been shown to be clinically effective in treating such diseases. However, sAJM589 a substantial proportion of patients do not achieve a response to anti\TNF therapy, fail to maintain their response after initial improvement and/or develop therapy\limiting adverse events. In patients with chronic inflammatory diseases who receive anti\TNF agents, anti\drug antibodies (ADA) have been associated with loss of response, because of inadequate therapeutic levels caused by increased clearance and/or neutralization of the agent’s biological activity and hypersensitivity reactions 2, 3, 4, 5. Given the possible adverse clinical sequelae of treatment\induced ADA formation, evaluation of ADA and associated outcomes is a critical aspect of patient care in those who receive biological therapy and is required for biological approval by regulatory bodies 6. Historically, reported ADA prevalence has been inconsistent among studies due, in part, to the various assay formats used to monitor immunogenicity in clinical trials of biologicals in chronic inflammatory diseases 7, sAJM589 8. Each of the available formats has limitations that can reduce its utility in clinical and research settings and complicate interpretation of findings 9. Some assays have a poor dynamic range and may generate false\negative results because of interfering interaction with active drug or false\positive results due to other antibodies, such as rheumatoid factor. Although the various immunoassay platforms have been used successfully to detect and quantify ADA in discrete study populations, few studies have directly assessed findings based on the different methods. Important recommendations for immunoassay validation and alignment of terms, definitions and concepts involving biological immunogenicity have been published in the past decade 6, 10, but the continuing lack of a unified approach to ADA testing throughout trials prohibits a meaningful comparison of the immunogenicity in studies of the same biological or different biologicals. In the present review, we examined the assay formats used in assessing ADA in patients with chronic inflammatory disease treated with the anti\TNF monoclonal antibodies adalimumab and infliximab, as well as the pharmacokinetic and clinical outcomes reported, to characterize the impact of ADA assessment in clinical studies. Methods Tap1 A systematic literature review (SLR) was conducted previously to evaluate the available data on the immunogenicity of 10 biological agents and one approved biosimilar agent in studies of autoimmune diseases 11. The search strategy and other methodological aspects of the original SLR, conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta\Analyses (PRISMA) guidelines 12, are presented in detail elsewhere 11 and are summarized briefly below. Using findings of the original SLR, we conducted an ancillary qualitative.