Mathematical modeling of the circadian rhythm of key neuroendocrine-immune system players in rheumatoid arthritis: a systems biology approach

Arthritis Rheum. 2009 Sep;60(9):2585-94. doi: 10.1002/art.24797.


Objective: Healthy subjects and patients with rheumatoid arthritis (RA) exhibit circadian rhythms of the neuroendocrine-immune system. Understanding circadian dynamics is complex due to the nonlinear behavior of the neuroendocrine-immune network. This study was undertaken to seek and test a mathematical model for studying this network.

Methods: We established a quantitative computational model to simulate nonlinear interactions between key factors in the neuroendocrine-immune system, such as plasma tumor necrosis factor (TNF), plasma cortisol (and adrenal cholesterol store), and plasma noradrenaline (NA) (and presynaptic NA store).

Results: The model was nicely fitted with measured reference data on healthy subjects and RA patients. Although the individual circadian pacemakers of cortisol, NA, and TNF were installed without a phase shift, the relative phase shift between these factors evolved as a consequence of the modeled network interactions. Combined long-term and short-term TNF increase (the "RA model") increased cortisol plasma levels for only a few days, and cholesterol stores started to become markedly depleted. This nicely demonstrated the phenomenon of inadequate cortisol secretion relative to plasma TNF levels, as a consequence of adrenal deficiency. Using the RA model, treatment with glucocorticoids between midnight and 2:00 AM was found to have the strongest inhibitory effect on TNF secretion, which supports recent studies on RA therapy. Long-term reduction of TNF levels by simulation of anti-TNF therapy normalized cholesterol stores under "RA" conditions.

Conclusion: These first in silico studies of the neuroendocrine-immune system in rheumatology demonstrate that computational biology in medicine, making use of large collections of experimental data, supports understanding of the pathophysiology of complex nonlinear systems.

MeSH terms

  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / physiopathology*
  • Cholesterol / blood
  • Circadian Rhythm / physiology*
  • Glucocorticoids / therapeutic use
  • Humans
  • Hydrocortisone / blood
  • Immune System / physiology*
  • Models, Theoretical*
  • Neurosecretory Systems / physiology*
  • Norepinephrine / blood
  • Time Factors
  • Tumor Necrosis Factor-alpha / blood


  • Glucocorticoids
  • Tumor Necrosis Factor-alpha
  • Cholesterol
  • Hydrocortisone
  • Norepinephrine