An altered functioning of the hypothalamic-pituitary-adrenal/gonadal axis seems to be an important factor in the perpetuation and circadian symptoms of rheumatoid arthritis (RA). As a matter of fact, the clinical symptoms of RA show a circadian variation with joint stiffness and pain being more prominent in the early morning. Consistently, human pro-inflammatory cytokine production exhibits a diurnal rhythmicity with peak levels during the night and early morning at a time when plasma cortisol is lower. An inappropriate low secretion of cortisol is a further typical feature of the inflammatory disease in patients with RA.
However, cortisol may not be the only hormone affecting cytokine rhythms; a strong candidate is the pineal indoleamine melatonin, the circadian hormone "par excellence," whose synthesis and secretion is regulated by the photoperiod with peak levels during the night, darkness hours. The circadian nocturnal release of melatonin exerts a profound influence on the internal environment of the organism with diverse physiological effects.
The main function of melatonin seems to be that of synchronizing the organism in the photoperiod and may play a role in reproduction, metabolism, seasonality, and thermoregulation; but important effects are evident also on immunity and inflammation. In peripheral blood mononuclear cells, melatonin has been reported to stimulate the production of pro-inflammatory interleukin-2, interferon-gamma, and interleukin-6 but not that of interleukin-4. Physiologically, the nocturnal melatonin peak has been associated with high IFN-interleukin-10 ratio, i.e., the melatonin rhythm positively correlated with the rhythmicity of T helper cell type 1 / T helper cell type 2 ratio. Maurizio Cutolo and Alberto Sulli at the Rheumatology Division of the University of Genova (Italy), together with Georges Maestroni at the Centre for Experimental Pathology, Locarno (Switzerland), are evaluating the roles of melatonin in inflammation.
Relevant to RA, melatonin can promote collagen-induced arthritis in mice and stimulate primary cultures of synovial macrophages from RA patients to produce interleukin-12 as well as nitric oxide. Recent studies by Cutolo and Maestroni indicate that melatonin production in RA patients seems to be higher than in healthy controls at the beginning of the night and in early morning. Interestingly, the melatonin increase in the early morning correlated with the typical peaking of joint stiffness and pain.
In a recent study evaluating circadian melatonin levels in RA patients from North Europe Countries during winter time, much higher serum concentrations and longer duration of peak levels of the pineal hormone were found when compared with both age-matched healthy controls and RA patients from South Europe (manuscript in preparation). These results seem related to the prolonged daily darkness characterizing the North Europe in winter time as more intensive inducer of melatonin production. Of interest, both frequency and severity of RA in North Europe is higher that in the South.
Most interesting, melatonin has been found to be present at a rather high concentration in synovial fluid from RA patients. In general, melatonin in body fluids is believed to originate from the blood. In the present study, it is noteworthy that the synovial fluid was collected in the late morning when the serum melatonin concentration is possibly much lower both in RA patients and controls. This might indicate that synovial melatonin is produced in situ. It has been, in fact, recently reported that human immunocompetent cells may synthesize melatonin; and Cutolo and Maestroni have found melatonin receptors on human synovial macrophages. Therefore, whatever the origin, melatonin can bind specific binding sites in activated synovial macrophages with a binding affinity consistent with both its serum and synovial fluid concentration. Due to its peculiar ability to enhance pro-inflammatory cytokine production, melatonin might thus play a pathogenic role in RA and possibly drive the circadian rhythm of the RA clinical symptoms (i.e., morning stiffness and gelling).
In addition, lower than expected early morning cortisol levels in RA patients might reduce the endogenous anti-inflammatory activities exerted by the adrenal steroid leading to uncontrolled pro-inflammatory activities exerted by melatonin. Inhibitors of melatonin synthesis or melatonin antagonists might therefore be of therapeutic value in RA patients, together with the usual early morning administration of low dose corticosteroids.
NOTE TO RESEARCHERS/PHYSICIANS: For copy of Dr. Cutolo article with complete references, please contact AARDA.
