Mathematical modelling of cytokine-mediated inflammation in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments.

Integrated Inflammatory Stress (ITIS) Model

“…Two illustrative examples of simple models describing the acute inflammatory response developed for studying and understanding the systemic behavior are presented by Baker et al (2013) and Reynolds et al (2006). The model proposed by Baker et al (2013) is a two-dimensional model classifying all cytokines into proand anti-inflammatory, respectively.…”

“…The model proposed by Baker et al (2013) is a two-dimensional model classifying all cytokines into proand anti-inflammatory, respectively. The simplicity of the model permits an analytical investigation and illustrates possible dynamics in general, although it was not compared to data.…”

“…The simplicity of the model permits an analytical investigation and illustrates possible dynamics in general, although it was not compared to data. This model is analyzed by bifurcation theory in order to investigate the involvement of the pro-and anti-inflammatory cytokines in the disease rheumatoid arthritis (Baker et al 2013). The aim of the work by Reynolds et al (2006) was to investigate the importance of the anti-inflammatory mediators for restoring homeostasis after an infection.…”

“…The elimination of endotoxin is proportional to the product of the number of activated phagocytic cells and the amount of endotoxin (Asachenkov et al 1994;Copeland et al 2005;Harrison et al 2011;Herald 2010;Loosbroock and Hunter 2014;Reynolds et al 2006;Vedder et al 1999;Zuev et al 2006). Thus, there will be no elimination of endotoxin if there is none of the activated phagocytic cells by this modeling choice.…”

Depression Phenotype, Inflammation, and the Brain

“…Furthermore, chemokines and colony-stimulating factors have also been linked to cognitive dysfunction and the pathophysiology of psychiatric symptom clusters (46). Given the complex interplay between these factors sophisticated modeling using techniques such as principal component analysis, hierarchical or other advanced clustering techniques are likely to be required to fully capture how changes in networks of interacting inflammatory markers act on the brain to induce associated changes in behavior and cognition (47).…”