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Editorial
Circadian rhythms of nocturnal hormones in rheumatoid arthritis: translation from bench to bedside
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  1. Maurizio Cutolo1,
  2. Rainer H Straub2,
  3. Frank Buttgereit3
  1. 1
    Research Laboratories and Clinical Academic Unit of Rheumatology, University of Genova Italy
  2. 2
    Neuroendocrinoimmunology Laboratory, Department of Internal Medicine I, University Hospital, Regensburg, Germany
  3. 3
    Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany
  1. Maurizio Cutolo, Research Laboratories and Clinical Academic Unit of Rheumatology, University of Genova Italy, Viale Benedetto XV, 6, 16132 Genova Italy; mcutolo{at}unige.it

https://doi.org/10.1136/ard.2008.088955

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    Translation from basic research to clinical medicine is complex and needs to be carefully performed. In addition, translational research is needed using human subjects who meet current diagnostic criteria.

    Recently, circadian rhythm science has pointed the way to rational intervention on nocturnal hormone production to modulate the immune/inflammatory reactions in patients suffering from rheumatoid arthritis (RA).1 2 These approaches have been introduced into practice with increasing degrees of interest.3

    We will discuss two recent examples of therapeutically modulating melatonin (MLT) and cortisol as nocturnal hormones implicated in RA clinical circadian rhythms.

    CIRCADIAN RHYTHMS AND MORNING STIFFNESS IN RHEUMATOID ARTHRITIS

    It has been known for many decades that disease symptoms in RA follow obvious circadian rhythms, with an increase of activity in the early morning hours, abatement during the day, and a smaller new increase in the early evening (fig 1A).3 4

    Figure 1 Circadian rhythm of symptoms and interleukin (IL)-6. A. The graph depicts the circadian rhythm of joint stiffness, pain and functional disability. B. The circadian rhythm of IL6 secretion in healthy subjects (black line) and patients with rheumatoid arthritis (red line). The data are given as percentages of the 24-h mean value of the respective variable.

    A number of papers have reported a temporal relationship between elevated levels of pro-inflammatory cytokines and symptoms of RA, such as morning stiffness. 4–9 Several of these cytokines are highly elevated in patients with active RA in the early hours of the day but after noon they are almost non-existent. Their release pattern and serum concentrations, respectively—possibly triggered by MLT and other hormones or a subordinate neuroendocrine centre in the hypothalamus4—follow a strict 24-h daily cycle (fig 1B).

    The closest similarity with the daily pattern of RA symptoms, such as morning stiffness, joint pain and functional disability, seems to exist for interleukin (IL)-6.

    Pro-inflammatory hormones start to rise before the onset of RA symptoms and before endogenous cortisol in these patients is activated to counteract the inflammatory cascade of disease symptoms. It should be also noted that rhythmic fluctuations of the nocturnal secretion and the peripheral metabolism of endogenous cortisol, as well as changes in the activation of …

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