With over 60 years of experience with glucocorticoids (GC), the number of patients treated and the range of clinical applications is more extensive than with other treatments. GC are still widely used in clinical medicine today. For example, they form a mainstay of therapy for rheumatoid arthritis (RA) since they are cost-effective drugs which exert strong anti-inflammatory, immunosuppressive and disease-modifying therapeutic effects. However, there is increasing awareness of the potential for these drugs to produce adverse effects. Therefore, the improvement of their benefit-risk ratio represents both a current need and an ongoing challenge. The increasingly detailed knowledge on their mechanism of action has initiated a variety of approaches to optimise treatments with these important drugs.
Interesting and recent approaches to optimize GC treatment include the development of innovative GCs or GC receptor ligands. One example is the development of selective GR agonists (SEGRAs). This approach is based on the suggestion that some GC actions (the so called transrepression effects) are to a greater extent responsible for desirable anti-inflammatory and immunomodulating effects than the other actions (the so called transactivation effects) that are associated with frequently occurring side effects (but also with some immunosuppressive activities). The idea of developing SEGRAs is, therefore, to use transrepression-mediated GC effects almost exclusively thereby inducing potent GC therapeutic activity with reduced side effects. This concept, however, has recently been challenged by experimental observations. And indeed, convincing data are still missing to demonstrate clinical efficacy and safety; but clinical studies are currently underway.
Treatment with conventional GCs already available to clinicians may also be improved, for example by the targeted delivery of GC using liposomal formulations. Additional work is needed to gauge the ultimate clinical utility of these interesting drug development concepts.
Far more advanced, however, is a chronotherapeutic prednisone formulation that is referred to in the EU as “modified-release prednisone” (MR prednisone) and in the United States as “delayed-release prednisone” (DR prednisone); these are interchangeable terms that refer to the same drug. The efficacy and safety of MR/DR prednisone at low dosages were investigated in the CAPRA (Circadian Administration of Prednisone in Rheumatoid Arthritis) studies. In CAPRA-1, the new formulation was shown to be clinically superior to the conventional immediate-release preparation with respect to reducing morning joint stiffness and clinical control of the disease. The safety profile showed no differences between the two preparations. Further safety and efficacy data were obtained from the CAPRA-2 study, a 12-week, double-blind, placebo-controlled trial. MR/DR prednisone 5 mg once daily plus DMARD therapy resulted in higher response rates for ACR20 and ACR50, and a greater median relative reduction from baseline in morning stiffness at week 12 compared with placebo plus DMARD therapy. Significantly greater reductions in severity of RA and fatigue, as well as a greater improvement in physical function were seen at week 12 with MR/DR prednisone compared with placebo. The incidence of adverse events was similar for MR/DR prednisone and placebo.
Disclosure of Interest F. Buttgereit Grant/Research support from: Horizon, Consultant for: Horizon, Mundipharma, Pfizer, Conflict with: Horizon, Mundipharma