The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the HPA axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema progression. Notably, our model also predicts that an increase in mean secretion of CST after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators our model is able to simulate important features of rheumatoid arthritis pathophysiology.