Prednisone chronotherapy

Abstract

Glucocorticoids (GCs) are widely used in clinical medicine because of their anti-inflammatory and immunosuppressive effects. However, these agents have a considerable potential for adverse effects, especially if used in high doses. The currently most advanced approach to improve the risk-benefit ratio of GCs is low-dose prednisone chronotherapy with modified release (MR) prednisone timing drug release to chronobiological rhythms. In RA, the circadian rhythms of pain, stiffness and functional disability show maximum symptoms in the early morning hours, which is preceded by elevated levels of pro-inflammatory cytokines, in particular interleukin 6. It was hypothesised that preventing the nocturnal rise of pro-inflammatory cytokines by GC therapy is more effective than treating established symptoms in the morning. As waking in the night for tablet intake is impracticable, modified release (MR) prednisone was developed, which releases prednisone approximately four hours after ingestion (i.e. at approximately 2 am if taken at 10 pm bedtime). Data from two large-scale trials in rheumatoid arthritis (RA) (CAPRA-1 and 2) document that MR prednisone has greater efficacy for long-term, low-dose glucocorticoid treatment in patients with RA, with a significant reduction in morning joint stiffness, in addition to all known therapeutic effects with conventional prednisone and a similar safety profile without additional suppression of hypothalamic-pituitary-adrenal (HPA) axis. For patients with RA on low to medium doses of prednisone, especially those who continue to experience a long duration of morning stiffness, MR prednisone appears a valuable additional treatment option.