Chronotherapy with modified-release prednisone in patients with rheumatoid arthritis

Abstract

Glucocorticoids are indispensable for the treatment of systemic inflammatory diseases such as rheumatoid arthritis (RA), though their beneficial effects have to be balanced with potential complications arising from high doses, prolonged use or dose splitting. A glucocorticoid formulation (modified-release prednisone) has been developed to be taken in accordance with biological rhythms (chronotherapy). Morning symptoms of RA are caused by elevated nocturnal levels of proinflammatory cytokines, particularly IL-6. Endogenous cortisol levels may be insufficient to counter the inflammatory effects of IL-6. The early morning rise in cortisol can be supplemented with exogenous glucocorticoid replacement therapy if this is given as the recently developed chronotherapy formulation. There is no adverse impact of modified-release prednisone on the hypothalamic–pituitary–adrenal (HPA) axis; indeed, there might be evidence of a beneficial effect on HPA axis function. This review summarizes the development of modified-release prednisone, pharmacokinetic characteristics and clinical experience in patients with RA.

Keywords::

• chronotherapy
• circadian
• HPA axis
• low-dose glucocorticoid
• modified release
• morning stiffness
• prednisone
• rheumatoid arthritis

Financial & competing interests disclosure

R Alten was invited by the journal editor to submit the review. She developed the study program together with Frank Buttgereit, Gisela Döring (formerly of Nitec Pharma), and Achim Schäffler (of Horizon Pharma, formerly Nitec Pharma) and served as a coordinating investigator for the HPA Axis Trial. She was a study investigator in the clinical trial program with modified-release prednisone funded by Horizon Pharma (formerly Nitec Pharma). R Alten received honoraria from Nitec Pharma for advisory board meetings and from Mundipharma International Limited for speaking at meetings. She has served as a consultant for Abbott, BMS, Novartis, USB, MSD and Pfizer. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Diane Storey of DPS Limited prepared the first draft of the manuscript for the author’s review and provided editorial support, with funding provided by Mundipharma Research Limited. Mundipharma Research Limited reviewed the manuscript to check the accuracy of the scientific content.