Chronotherapy with Glucorticoids in Rheumatoid Arthritis

A third successful and recent approach to improve the risk–benefit ratio is to refine treatment with conventional glucocorticoids. One option is to combine a very low dose of prednisolone with dipyridamole, which can enhance antiinflammatory activities in immune cells.8 Another interesting approach is the targeted delivery of glucocorticoids to sites of inflammation using liposomes such as a polyethylene glycol (PEG) carrier system. In this delivery technique, the glucocorticoid is enclosed in small vesicles (~100 nm in size) that accumulate at the site of inflammation. As a consequence, very high local concentrations are achieved for increased periods of time. Animal studies have demonstrated that, in terms of clinical effectiveness, liposomal glucocorticoids are superior to conventional high-dose glucocorticoid therapy delivered intravenously.^9,10 Because of the encapsulation of the drug and correspondingly lower plasma levels, liposomal administration is expected to have lower adverse effects than that of conventional glucocorticoid therapy. Recently, it has been reported that the use of larger liposomes (~295 nm in size) using non-PEGylated liposomal dexamethasone phosphate is effective and allows persistent therapeutic effects with separation of risks and benefits in animal arthritis models.^11,12

The fourth and by far the most advanced approach to optimize treatment with current glucocorticoids involves the programmed delivery of glucocorticoids using MR prednisone. This specific formulation changes the timing of active drug release. The clinical relevance of the timing of glucocorticoid administration, (i.e., of chronotherapy with MR prednisone) is assessed here.

Chronotherapy with MR Prednisone

A circadian rhythm of pain, stiffness, and functional disability, as well as the underlying cyclic variations in hormone levels and cytokine concentrations, are well-known phenomena in patients with RA.13 Similar diurnal variations have been described for other rheumatic diseases such as polymyalgia rheumatica and ankylosing spondylitis.14 Although data for the latter conditions are limited, the mechanisms underlying the development of morning symptoms in RA are increasingly well understood. In this disease, major symptoms such as pain, inflammation, and stiffness vary as a function of the time of day, usually with the highest severity in the morning hours. These symptoms are preceded by elevated levels of interleukin-6 (IL-6) and other proinflammatory cytokines.^13,15–18 A causal and not only a temporal relationship between these cytokines and symptoms has been suggested since the pathogenesis of RA involves complex humoral and cellular reactions including immune complex formation, vascular reactions, and infiltration of lymphocytes and monocytes into the synovium.¹⁹