Plasma TNF binding capacity profiles during treatment with etanercept in rheumatoid arthritis

Abstract

Background: Etanercept (Enbrel<formula>®</formula>) induces a rapid and sustained decline in disease activity in the majority of patients with refractory rheumatoid arthritis (RA). In these patients neutralization of TNFα and lymphotoxin (LT), previously termed TNFβ is mediated by etanercept itself, as well as by naturally occurring soluble TNF receptors. However, the clinical response to treatment with etanercept may vary. Previously, pharmacokinetic studies have focused on the molar concentrations of etanercept, but very little is known about the kinetics of bioactive etanercept in patients treated with etanercept. The purpose of this study was to evaluate kinetics, including inter- and intraindividual variations of the total TNF binding capacity, in RA patients who were on a standard treatment schedule with etanercept. Methods: Plasma samples were collected daily from 16 RA patients who were in the steady-state phase during treatment with etanercept 25 mg subcutaneous once (n=2) or twice (n=14) weekly. The inflammatory activity, including Health Assessment Questionnaire (HAQ) score, numbers of painful and swollen joints, and ESR, was assessed at inclusion; CRP was measured on a daily basis. The samples were incubated with human recombinant LT to a concentration of 1000 pg/mL and the levels of detectable LT were measured by ELISA specific for free LT. The LT binding capacity (LTBC) was expressed in arbitrary units (AU) as the percentage value of bound LT to added LT. Results: The median LTBC values measured during the treatment schedule from Day 1 (before the injection) to Day 4 (before the next injection) were 47 AU. The LTBC values in each individual patient generally remained fairly stable through the treatment schedule, and there were no significant differences in LTBC levels in samples obtained on a daily basis during the treatment schedule. However, a pronounced variation between the patients was noticed with LTBC values ranging from 10-82 AU (coefficient of variation=38%). No significant association was found between LTBC levels and clinical measures of disease activity, including HAQ and numbers of swollen or painful joints. However, among patients with high LTBC levels (≥65 AU), elevated levels of ESR and CRP were less frequent (0%) compared with patients who had lower LTBC levels, in which the frequencies of elevated ESR and CRP were 53% and 37%, respectively. Soluble TNF receptor 1 (sTNFR1) remained stable between the injections and correlated with the number of swollen joints, but did not correlate with LTBC values. Conclusion: LTBC levels appeared stable in each individual RA patient who was on the standard treatment schedule with weekly injections of etanercept, but the inter-individual variations were considerable.