The 70th Anniversary of Glucocorticoids in Rheumatic Diseases

The Second Youth of an Old Friend

Yannick Palmowski; Thomas Buttgereit; Frank Buttgereit


Rheumatology. 2019;58(4):580-587. 

In This Article

Modified-release Prednisone

Of all these new substances, modified- or delayed-release prednisone is the only one that has already made its way into the market. The development of this new GC formulation was inspired by the observation that in patients with RA, clinical symptoms like pain, stiffness and functional disability are often worst in the early morning hours. The reason for this lies in an increase in pro-inflammatory cytokines like IL-6 or TNF-α late at night and early in the morning.[39–45] Consequently, prevention of this cytokine peak, for example, by the intake of anti-inflammatory agents right at that time, should result in relief of morning symptoms. This hypothesis was supported by the promising results of a study published in 1997 where the time of prednisone administration was shifted to the night time instead of morning hours.[40] However, getting up at night in order to take the medication at the right time is evidently not an optimal solution. The seemingly easiest solution, the administration of the daily GC dose in the evening before going to bed, bears a high risk for sleep disturbances and an increased negative impact on circadian rhythms.[46] Modified-release prednisone was designed as a solution to this dilemma. It is composed of conventional prednisone encapsulated in a way that delays its liberation by 4 h, thereby allowing for convenient administration at bedtime while preserving the optimized benefit–risk profile of an effect onset late at night. The efficacy of this concept was confirmed by two large clinical studies, the Circadian Administration of Prednisone in Rheumatoid Arthritis 1 and 2 studies. While the first one showed a significant reduction of morning stiffness under a bedtime dose of modified-release prednisone compared with a morning dose of conventional prednisone for 12 weeks,[47] the second one demonstrated an improvement of signs and symptoms of RA for low-dose (5 mg) modified-release prednisone added to existing DMARD treatment compared with a placebo, confirming the efficacy and safety of additional prednisone chronotherapy.[48] The results of these trials led to global approval of the drug under the trade names Lodotra and Rayos.