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Rheumatology Advance Access published online on December 7, 2004
Rheumatology, doi:10.1093/rheumatology/keh491
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British Society for Rheumatology; all rights reserved
Received June 2, 2004
Accepted October 22, 2004

Original Papers

TNF-{alpha} neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome

M. Jit 1, B. Henderson 2, M. Stevens 3, and R. M. Seymour 1*

1 Department of Mathematics, Eastman Dental Institute, University College London, London
2 Cellular Microbiology Research Group, Eastman Dental Institute, University College London, London
3 European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

* To whom correspondence should be addressed.
R. M. Seymour, E-mail: rms{at}math.ucl.ac.uk


  Abstract

Objectives. Neutralization of TNF-{alpha} 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-{alpha} has little clinical benefit in the majority of patients with systemic inflammatory response syndrome (SIRS) in spite of the identification of TNF-{alpha} as a key factor in its pathology. It is not clear why there is such a significant difference in the responses to TNF-{alpha} neutralization in these two conditions. Here we use mathematical modelling to investigate this discrepancy.

Methods. Using the known pharmacokinetic and pharmacodynamic properties of TNF-{alpha}-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-{alpha} levels in RA, which we propose is a condition in which TNF-{alpha} production and inhibition are in equilibrium. However, when free TNF-{alpha} drops to a low level, as can occur in SIRS, which we propose is a non-equilibrium condition, the sequestered TNF-{alpha} can act as a slow-release reservoir, thereby sabotaging its effectiveness.

Conclusions. These results may explain the effectiveness of TNF-{alpha} blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.

Keywords: Rheumatoid arthritis; SIRS; TNF-{alpha}; Enbrel; Remicade; Cytokine networks; Mathematical modelling.
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