By Maurizio Cutolo, M.D., Full Professor of Rheumatology, Director Research Laboratories and Academic Unit of Clinical Rheumatology, University of Genova, Italy. Dr. Cutolo is a member of AARDA's Scientific Advisory Board.
General clinical experience supports that disease-related symptoms in patients with chronic inflammatory disorders exhibit circadian, approximately 24- hour rhythms. This has been studied in patients with rheumatoid arthritis (RA) showing that these patients particularly experience morning joint pain and stiffness and functional disability in the early hours of the day. In addition, it is also noteworthy that these daytime variations demonstrate wide ranges, with the patient's condition being very poor in the early morning but with disease activity being mild or moderate in the early evening.
Interestingly, even single cells in the human body, such as cardiomyocytes, peripheral blood mononuclear cells, natural killer cells, liver cells, and most other cells, generate a circadian rhythm of 24 hours, which is controlled by hypothalamic suprachiasmatic nucleus (SCN) activities via hormones and neurotransmitters released into the blood and locally into the area of nerve terminals. Thus, most cells of the body, including immune cells, are controlled by the SCN, leading to coupled cell and organ activities in the periphery with a 24-hour daily cycle.
Such coupling phenomena may be important for the anti-inflammatory cooperation of hormones and neurotransmitters in RA, which has been demonstrated for cortisol and norepinephrine. The cycle of the hypothalamic-pituitary-adrenal axis (HPA axis) shows a maximum in the early morning hours, at 8:00 a.m. and the lowest at midnight.
The cortisol rhythm in patients with RA whose disease activity is relatively low to moderate does not differ from that in health subjects. However, it has been clearly delineated that this rhythm can be highly disturbed in RA patients when disease is very active, leading to a flattening of the response curve; and two peaks appear, in the morning and the afternoon. In addition, RA patients with high disease activity have elevated serum cortisol levels which are, however, inadequately low in relation to ongoing inflammation.
In fact, in patients with RA, the peak level of the pro-inflammatory cytokine tumor necrosis alpha (TNF-alpha) has been reported to appear at 6:00 a.m., and that of interleukin-6 (IL-6), at 7:00 a.m. On the contrary, in healthy subjects, serum levels of TNF and IL-6 have already begun to decrease at 6:00 a.m. and 9:00 a.m. respectively, whereas in RA patients these levels remain elevated until 10:00 a.m. and 11:00 a.m. respectively. The condition in which the amplitude for these pro-inflammatory cytokines in RA patients versus controls is higher and the curve broadened, despite the similarity of the cortisol circadian curves, indicates inadequate cortisol secretion in relation to inflammation in RA, given that cortisol is the strongest endogenous anti-inflammatory substance.
Besides cortisol, two other hormones, melatonin and prolactin, demonstrate a perfect 24-hour rhythm. Both hormones have been linked to stimulation of the immune system, which would lead to an increase in pro-inflammatory conditions in RA. The typical circadian rhythm of melatonin exhibits a maximum at 3:00 a.m., which is quite similar to that of prolactin.
When data from all available studies are combined, the rhythms of these two hormones are not shown to be markedly different in patients with RA as compared with healthy controls. However, one study demonstrated that serum levels of melatonin reached a peak two hours earlier in RA patients than in controls. In RA patients, melatonin levels exhibited a wide plateau lasting two to three hours, an effect not observed in healthy controls.
After the peak was reached, melatonin levels decreased similarly in RA patients and healthy subjects. Furthermore, in a study of subjects from a northern European country (Estonia), serum levels of melatonin appeared to be elevated in patients with RA as compared with controls from South Europe (Italy).
Similarly, serum levels of prolactin during the night were found significantly higher in RA patients compared with controls. Both elevated melatonin and elevated prolactin will probably establish a more pro-inflammatory environment exactly at the time point when cortisol levels are lowest. This is particularly true because the ratio of prolactin to cortisol peaks at 2:00 a.m. in RA patients. Both hormones, prolactin and melatonin, induce a Th1 immune response and may thus lead to an unwanted increase in related cellular immune phenomena in RA patients.
To develop a therapeutic advantage in RA management (and other forms of arthritis) from the respect of circadian rhythms, by considering the short half-life of prednisolone (two hours) and the intense immune activation during the night (2:00 to 3:00 a.m.), it is now clear that the best timing for the corticosteroid replacement should be around 2:00 to 3:00 a.m. when the pro-inflammatory TNF release is increasing. In fact, stronger inhibition of nighttime pro-inflammatory cytokines (i.e., TNF and IL-6) by timed corticosteroid administration seems to lead to a really significant reduction of RA-related symptoms in the early morning.
NOTE TO RESEARCHERS/PHYSICIANS: For a list of complete references, contact AARDA.
