Association of Pharmacologic Markers of Anti-Tumor Necrosis Factor-α Activity and Etanercept Effectiveness in Juvenile Idiopathic Arthritis

Abstract

Therapies targeting tumor necrosis factor-α (TNFα), including etanercept (ETN), have become a mainstay in the treatment of juvenile idiopathic arthritis (JIA). As a result, this work seeks to evaluate the relationship between pharmacologic markers of ETN activity and clinical effectiveness in a cohort of patients with JIA. This is a single-centered, open-label, prospective, cross-sectional study of patients with JIA (n = 26) receiving maintenance ETN. Determination of ETN effectiveness was based on the absence of active arthritis in any joint at the time of sample collection. Patient plasma samples were collected and analyzed for ETN concentrations, anti-ETN antibodies, anti-TNFα activity, and TNFα concentrations. ETN was effective in 46% (n = 12) of patients assessed at the time of sampling. No differences in baseline demographics were observed between patients based on effectiveness. Median [IQR] plasma ETN concentrations were 2094 [1384, 2680] ng/mL. Anti-ETN antibodies were undetectable in all patients. Plasma anti-TNFα activity varied 32-fold and was directly proportionate to plasma ETN concentrations (ρ = 0.75, p = 3.8 × 10^-3). Plasma TNFα concentrations were 9-fold higher than previous measurements in patients with JIA not receiving anti-TNFα therapy (p = 3.6 × 10^-9). ETN effectiveness was associated with 21% higher ETN concentrations (p = 0.36), 52% higher plasma anti-TNFα activity (p = 0.14), and 84% higher plasma TNFα concentrations (p = 0.008). Among pharmacologic markers of ETN activity measured, plasma TNFα concentrations are most strongly associated with ETN effectiveness in JIA.

Keywords: etanercept; juvenile idiopathic arthritis; pharmacokinetics; tumor necrosis factorbiomarkers.

FIGURE 1

Plasma ETN concentrations and anti‐ETN ADAs in patients with JIA treated with ETN. (A) The distribution of plasma ETN (ng/mL) concentrations measured is displayed as a histogram. (B) Anti‐ETN ADA detection by immunoassay with signal measured in absorbance units (A.U.). Blank plasma was used as a negative control, and blank plasma spiked with anti‐ETN ADAs was used as a positive control. Data points are presented as box and whisker plots.

FIGURE 2

Anti‐TNFα activity in patients with JIA receiving ETN. (A) Anti‐TNFα activity was measured in plasma samples from children with JIA receiving ETN using a gene‐reporter assay and is presented as a histogram. (B) The correlation between ETN plasma concentrations and anti‐TNFα activity was evaluated by Spearman's correlation analysis. The Spearman correlation coefficient (ρ) and p‐value are provided.

FIGURE 3

Plasma TNFα concentrations in children with JIA receiving ETN. TNFα concentrations were measured in plasma samples by immunoassay and compared to concentrations from a previous study comparing plasma TNFα concentrations in anti‐TNFα therapy naïve and ETN‐treated JIA patients [5]. Data is plotted as box and whisker plots and assessed by unpaired analysis using the Wilcoxon rank sum test; the resulting p‐values are provided.

FIGURE 4

Relationship of pharmacologic markers of ETN response with ETN effectiveness in patients with JIA. Plasma (A) ETN concentrations, (B) anti‐TNFα activity, and (C) TNFα concentrations in patients with JIA based on the presence of active or inactive disease at the time of sampling. Data is plotted as box and whisker plots and assessed by unpaired analysis using the Wilcoxon rank sum test; resulting p‐values are provided.