Etanercept (Enbrel) induces a rapid and sustained decline in disease activity in the majority of patients with refractory juvenile idiopathic arthritis (JIA). For unknown reasons, however, a number of JIA patients fail to respond to this therapy. During this treatment neutralisation of tumour necrosis factor (TNF, previously termed TNF alpha) and lymphotoxin (LT, previously termed TNF beta) may be mediated by etanercept itself as well as by naturally occurring soluble TNF receptors. In light of this, it was of interest to study the total TNF neutralizing capacity in plasma before and during treatment with etanercept.
In initial experiments plasma samples from healthy individuals were incubated with etanercept, and spiked with TNF or LT to a final concentration of 1000 pg/mL. Detection of TNF and LT by ELISA was found to be reduced by approximately 50% and 80% respectively, at a concentration of etanercept of 5-500 ng/mL, which is close to the pharmacological plasma concentrations. Plasma samples (n = 80) were then collected from 12 JIA patients (5 with pauciarticular, 5 with polyarticular and 2 with the systemic onset type) during treatment with etanercept (0.4 mg/kg twice weekly) for a period of 20.8 (15.6-23.9) months (median, range). The plasma samples were spiked with LT, and the inhibition of LT detection in ELISA was measured. In samples obtained 3 months after the start of etanercept, the inhibition of LT detection was augmented [72% (60-85)] compared with pre-treatment samples [16% (0.32)] (p = 0.0039). These findings were confirmed in binding assays using radiolabelled TNF. Among patients who responded insufficiently to therapy, reduced LT binding capacity, coinciding with flares of disease activity, was observed.
We have developed an assay by which LT binding capacity, reflecting the level of free, pharmacologically active etanercept, may be monitored in the blood of patients treated with etanercept. This assay may prove to be useful in guiding dose adjustments in patients with an incomplete response to etanercept.