Circadian rhythms of cellular immunity in rheumatoid arthritis: a hypothesis-generating study

Clin Exp Rheumatol. 2015 Jan-Feb;33(1):34-43. Epub 2014 Dec 22.


Objectives: The circadian rhythm of clinical symptoms in rheumatoid arthritis (RA) has been primarily attributed to circadian variations in humoral factors and hormones. In this study, we investigated circadian rhythms of cellular immunity in RA (CiRA study).

Methods: Peripheral blood of female postmenopausal patients with active RA (DAS 28 ≥ 4.2) (n=5) and female postmenopausal non-RA controls (n=5) was collected every 2 hours for 24 hours and analysed by flow cytometry, cytokine multiplex suspension array and quantitative RT-PCR of clock gene expression in isolated CD14+ monocytes. Endogenous circadian rhythms of macrophages were investigated by BMAL1-luciferase bioluminescence. Significance of circadian rhythms was tested by Cosinor analysis.

Results: We found (i) circadian rhythms in the relative frequency of peripheral blood cell populations that were present in postmenopausal non-RA controls but absent in patients with active RA, (ii) circadian rhythms that were absent in non-RA controls but present in patients with RA and (iii) circadian rhythms that were present in both groups but with differences in peak phase or amplitude or amplitude/magnitude. The circadian rhythm in expression of the clock genes PER2 and PER3 in CD14+ monocytes was lost in patients with RA. The amplitude of BMAL1-luciferase bioluminescence tended to be lower in patients with RA than in non-RA controls.

Conclusions: We conclude that (i) in RA some immune cell populations lose their normal circadian rhythms whereas others establish new 'inflammatory' circadian rhythms and (ii) these findings provide a good basis for further identifying pathophysiological aspects of RA chronobiology with potential therapeutic implications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Aged
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / physiopathology
  • Biomarkers / blood
  • Case-Control Studies
  • Circadian Rhythm* / genetics
  • Cytokines / blood
  • Female
  • Humans
  • Immunity, Cellular*
  • Immunity, Humoral
  • Inflammation Mediators / blood
  • Lipopolysaccharide Receptors / blood
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Period Circadian Proteins / genetics
  • Pilot Projects
  • Postmenopause / immunology
  • RNA, Messenger / blood
  • Time Factors


  • Biomarkers
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharide Receptors
  • PER2 protein, human
  • PER3 protein, human
  • Period Circadian Proteins
  • RNA, Messenger