Circadian Use of Glucocorticoids in Rheumatoid Arthritis

Abstract

A clear temporal relationship exists in rheumatoid arthritis (RA) patients between increased nocturnal levels of pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-6, pro-inflammatory hormones (i.e. melatonin, prolactin) and insufficient night production of the anti-inflammatory cortisol (circadian rhythm). Under long-standing chronic stress of disease, insufficient cortisol is available to inhibit an ongoing nocturnal immune/inflammatory reaction. Clinical RA symptoms follow the same circadian rhythm with highest morning severity. Chronotherapy with nighttime glucocorticoid (GC) availability optimizes the treatment of RA patients with low-dose GCs through more efficient targeting of mediators of the immune/inflammatory reaction during the night to be available on arising. Circadian use of low-dose, long-term prednisone, by using night-release formulations (ingested at 10 to 11 p.m.) especially in early RA patients, appears characterized by a significantly superior efficacy on decreasing morning stiffness and IL-6 serum levels, compared to conventional daytime immediate-release prednisone. Shift from medium-dose, immediate-release prednisone (over 7.5-10 mg/day) to night-release formulations GC low-dose, long-term chronotherapy requires a gradual passage, since the hypothalamic-pituitary-adrenal axis of the treated RA patients, potentially altered by a negative feedback induced by the medium/high daily exogenous GC administration, needs time to re-synchronize control of endogenous GC production into a circadian and more physiological nocturnal hormone availability/optimized efficacy.