Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine

Abstract

Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

Cardiovascular Risk Factors and the Risk of Discontinuation of Advanced Therapies Due to Treatment Failure in Rheumatoid Arthritis: Results From the Ontario Best Practices Research Initiative

“…It is hypothesized that risk factors such as DM, obesity, and smoking can induce immune dysregulation and disrupt the balance between pro‐inflammatory and anti‐inflammatory responses and increase the risk of developing ADAs 10 . CVD risk comorbidities can also impact organ function, leading to altered drug metabolism contributing to increased immunogenicity 11 . Furthermore, a higher burden of comorbidities has been associated with nonadherence or intermittent use of RA treatment 12 .…”

Therapeutic Drug Monitoring: A Tool to Optimize Treatment of Inflammatory Joint Diseases

“…An important reason for the large individual variation in drug metabolism of TNFi is development of neutralizing anti‐drug antibodies, a common phenomenon in patients treated with biologic therapies 7,8 . Although anti‐drug antibody formation almost never occurs in patients on etanercept and tocilizumab, a prevalence of 10% to 60% has been reported across diagnoses for the more immunogenic adalimumab and infliximab 7,8 . Neutralizing anti‐drug antibodies block and inactivate the target binding site of the drug and accelerate drug clearance, with subsequent loss of response 7,9 .…”

“…12,13 By implementing TDM, adverse events related to anti-drug antibody formation (eg, infusion reactions) can be avoided by change of therapy. 6,7,9,11 In NOR-DRUM A, 16 patients (8%) in the standard therapy group compared to 5 patients (2.5%) in the TDM group experienced an infusion-related reaction (hazard ratio 17.02, 95% CI 6.98-41.47]). 9,11 It is still not known whether infections and other adverse events are dependent on serum drug levels of TNFi.…”

“…Assays for serum drug levels and anti‐drug antibodies exist for use in clinical practice for nearly all biologics used in rheumatology (TNFi, interleukin [IL] 6 receptor, T cell costimulatory, and IL‐17 inhibitors), but the access to these assays vary widely. Assays and guidance regarding the interpretation of results are most widely available for TNFi 5,7 . By implementing the results from both these analyses in treatment decisions through TDM, rheumatologists can tailor drug dosages to individual patients and maximize therapeutic response while reducing risk of adverse events and unnecessary costs.…”

HLA‐DQ2 is associated with anti‐drug antibody formation to infliximab in patients with immune‐mediated inflammatory diseases

“…Still, lack or loss of treatment response resulting in reduced quality of life and potential irreversible organ damage and disability is a significant clinical problem. Formation of antidrug antibodies (ADAb) is a leading cause of TNFi treatment failure and is also related to adverse events [1,2].…”