TNF-α neutralization in cytokine-driven diseases: A mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome

Objectives. Neutralization of TNF-α with either monoclonal antibodies or soluble receptors, although not curative, has significant clinical benefit in patients with rheumatoid arthritis (RA). In contrast, blockade of TNF-α has little clinical benefit in the majority of patients with systemic inflammatory response syndrome (SIRS) in spite of the identification of TNF-α as a key factor in its pathology. It is not clear why there is such a significant difference in the responses to TNF-α neutralization in these two conditions. Here we use mathematical modelling to investigate this discrepancy. Methods. Using the known pharmacokinetic and pharmacodynamic properties of TNF-α-blocking biological agents, we constructed a mathematical model of the biological actions of soluble (s)TNFR2, Etanercept and Infliximab. Results. Our model predicts that all three inhibitors, but especially Etanercept, are effective at controlling TNF-α levels in RA, which we propose is a condition in which TNF-α production and inhibition are in equilibrium. However, when free TNF-α drops to a low level, as can occur in SIRS, which we propose is a non-equilibrium condition, the sequestered TNF-α can act as a slow-release reservoir, thereby sabotaging its effectiveness. Conclusions. These results may explain the effectiveness of TNF-α blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.