Circadian rhythms in rheumatology - a glucocorticoid perspective

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in regulating and controlling immune responses. Dysfunction of the HPA axis has been implicated in the pathogenesis of rheumatoid arthritis (RA) and other rheumatic diseases. The impact of glucocorticoid (GC) therapy on HPA axis function also remains a matter of concern, particularly for longer treatment duration. Knowledge of circadian rhythms and the influence of GC in rheumatology is important: on the one hand we aim for optimal treatment of the daily undulating inflammatory symptoms, for example morning stiffness and swelling; on the other, we wish to disturb the HPA axis as little as possible. This review describes circadian rhythms in RA and other chronic inflammatory diseases, dysfunction of the HPA axis in RA and other rheumatic diseases and the recent concept of the hepato-hypothalamic-pituitary-adrenal-renal axis, the problem of adrenal suppression by GC therapy and how it can be avoided, and evidence that chronotherapy with modified release prednisone effective at 02:00 a.m. can inhibit proinflammatory sequelae of nocturnal inflammation better compared with GC administration in the morning but does not increase the risk of HPA axis insufficiency in RA.

The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond

“…Consequently, the diurnal profile of cortisol helps entrain peripheral tissue clocks. The HPA axis can also be activated by circulating cytokines such as IL-1, IL-6 or TNF, leading to a physiological negative feedback loop created by the immunomodulatory and anti-inflammatory properties of cortisol 34,35 . Importantly, cortisol and cytokines both have strong circadian profiles, supporting an integral crosstalk between the circadian timing system and the HPA axis.…”

Low-dose modified-release prednisone in axial spondyloarthritis: 3-month efficacy and tolerability

“…Modern trials have confirmed that the efficacy of GCs can be significantly improved by administration as chronotherapy 28. In particular, low-dose MR prednisone effective at 02.00 am inhibits the proinflammatory sequelae of nocturnal inflammation better than GC administration in the morning, alleviating signs and symptoms related to pathways of circadian cytokines without increasing the risk of hypothalamus–pituitary–adrenal axis insufficiency in rheumatoid arthritis 29…”

Co-morbidity of PTSD and immune system dysfunction: opportunities for treatment

“…Low salivary and urinary cortisol immediately following trauma have been reported to be predictors of PTSD suggesting that low cortisol concentrations may in fact be a preexisting vulnerability for developing PTSD rather than a consequence of PTSD [11]. Interestingly, inadequate cortisol secretion in relation to the chronic inflammation observed in rheumatoid arthritis, suggests that the suboptimal production of cortisol may be involved in onset and/or progression of autoimmune disease [12,13]. Hence, overlap may exist between the mechanisms by which low cortisol concentrations may precipitate both psychiatric and somatic diseases and disorders.…”