Circadian rhythms and rheumatoid arthritis.

Circadian rhythms (Nobel prize for Medicine 2017) regulate, under action of biological clocks located both at the level of central nervous system and inside peripheral cells, several daily activities, embracing sleep, feeding times, energy metabolism, endocrine and immune functions with related pathological conditions, including rheumatoid arthritis (RA). In RA the circadian rhythms impact on cellular functions, involving night synthesis and release of pro-inflammatory cytokines and chemokines, cell migration to inflamed tissues, phagocytosis, proliferative cell response and all are peaking at late night. In chronic inflammatory conditions such as RA, the amplitude of the circadian rhythm of the anti-inflammatory endogenous cortisol availability is not increased as expected and requested, which indicate a reduced night cortisol secretion under the adrenal chronic stress induced by the disease. Therefore, the prevention/treatment of the immune cell night hyperactivity, with related flare of cytokine synthesis and morning RA clinical symptoms, has been shown more effective when the availability of the exogenous glucocorticoids is obtained in the middle of the night (night release). The impressive positive results observed in RA patients treated with modified-night release prednisone with a low-dose chronotherapy, seem applicable even for other agents such as conventional NSAIDs and DMARDs, including the positive experimental and clinical results obtained by the night time daily administration of methotrexate. Interestingly, a very recent study showed that methotrexate upregulates important cell circadian genes, resulting in induction of apoptosis in synovial fibroblasts. The link between the circadian rhythms of the disease and the chronotherapy of RA is promising.