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.


Jit, M; Henderson, B; Stevens, M; Seymour, RM; (2005) 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. Rheumatology (Oxford, England), 44 (3). pp. 323-31. ISSN 1462-0324 DOI: https://doi.org/10.1093/rheumatology/keh491

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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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
PubMed ID: 15585509
Web of Science ID: 227241400011
URI: http://researchonline.lshtm.ac.uk/id/eprint/111578

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