Glucocorticoid management in rheumatoid arthritis: morning or night low dose?

Abstract

Morning symptoms of rheumatoid arthritis (RA) are linked to circadian increase of night inflammation, supported by inadequate cortisol secretion in active disease. Therefore, exogenous glucocorticoid administration in RA is recommended by EULAR and ACR from the beginning of the diagnosis, since may partially act like a "replacement therapy". In addition, the prevention/treatment of the night up-regulation of the immune/inflammatory reaction has been shown more effective when exogenous glucocorticoid administration is managed with a night-time-release formulation. Despite a considerably higher cost than conventional prednisone (immediate release), chronotherapy with night-time-release prednisone has been recognized a cost-effective option for RA patients not on glucocorticoids who are eligible for therapy with biologic disease-modifying antirheumatic drugs (DMARDs). Interestingly, since different cell populations involved in the inflammatory process are particularly activated during the night (i.e. monocytes, macrophages), other therapeutical approaches used in RA, such as conventional DMARDs and non-steroidal anti-inflammatory drugs (NSAIDs) should follow the same concepts of glucocorticoid chronotherapy. Therefore, bedtime methotrexate chronotherapy was found to better manage RA symptoms, and several available NSAIDs (i.e. indomethacin, aceclofenac, ketoprofen, flurbiprofen, lornoxicam) have been recently modified in their formulation, in order to obtain more focused night action.

Keywords: chronotherapy; circadian rhythms; disease-modifying antirheumatic drugs; glucocorticoids; non-steroidal anti-inflammatory drugs; rheumatic diseases; rheumatoid arthritis.

Fig. 1

The circadian sequence of nocturnal hormone secretion that induce activation (melatonin, prolactin) and/or down regulation (cortisol) of the immune inflammatory response, during the night, determine the clinical consequences that include morning symptoms such as joint stiffness and pain.

Fig. 2

The daily neuroimmunoendocrine rhythms (gonadal, adrenal, pituitary hormones) are controlled by a central pacemaker, which is found in a hypothalamic region called the suprachiasmatic nucleus (SCN) of the central nervous system (CNS). Basically melatonin increases and cortisol reduces the Immune/inflammatory reaction following a circadian rhythm.