Effect of the soluble TNF-antagonist etanercept on tumor necrosis factor bioactivity and stability.
BACKGROUND
Targeted anti-tumor necrosis factor (TNF) strategies in patients with rheumatoid arthritis have resulted in new and/or worsening heart failure in individuals who were free of cardiovascular disease.


RESULTS
To determine the mechanism of new and/or worsening heart failure in patients who were receiving the soluble TNF-antagonist etanercept, we analyzed frozen plasma samples from a previous clinical trial with etanercept in heart failure patients, and conducted complimentary mechanistic in vitro studies. Analysis of the clinical trial data showed that use of etanercept resulted in a significant 70-fold increase in the level of immunoreactive TNF. Complimentary in vitro studies using an L929 bioassay showed that at low concentrations of etanercept relative to TNF there was an unexpected 1.5- to 1.75-fold increase in the absolute level of TNF bioactivity. We also examined the effect of etanercept on TNF stability and the results showed that there was a two-fold increase in the mass of bioactive homotrimeric TNF when the molar ratio of TNF to etanercept was approximately 200:1.


CONCLUSIONS
Etanercept increases the immunoreactive mass of TNF in heart failure patients, as well as augments TNF cytotoxicity in certain settings, thus suggesting one potential mechanism for the worsening heart failure in some patients who were receiving this agent.
Mann
Douglas L
DL
Winters Center for Heart Failure Research, Texas Heart Institute at St. Luke's Episcopal Hospital, Department of Medicine, Baylor College of Medicine, Houston, USA. dmann@bcm.edu <dmann@bcm.edu>
Bozkurt
Biykem
B
Torre-Amione
Guillermo
G
Soran
Ozlem Z
OZ
Sivasubramanian
Natarajan
N
D000068800:Etanercept; D006333:Heart Failure / Q000097:blood; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor; D012995:Solubility / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*
D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept