OP-0042 – New Modified-Release Prednisone Tablet Shows Sustained Reduction of Morning Stiffness and Interleukin-6 in Patients with Rheumatoid Arthritis
Buttgereit, Doering, Schaeffler, Witte, Szechinski, Alten; Berlin, Germany
Objectives
Although their use has decreased, glucocorticoids remain frequently used in RA. Because patients often have their worst symptoms in the morning, glucocorticoid activity peaking in the A.M. may be beneficial. To have maximal morning efficacy of currently available glucocorticoids, users would have to take them at 3 or 4 in the morning. The authors present the efficacy of a modified-release (MR) prednisone formulation that can be taken before bedtime, but not released in active form for four hours.
Methods
In the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-1) trial, 288 RA patients with active RA were randomized equally to receive immediate release (IR) vs. MR prednisone in a double-blinded fashion. Enrolled patients were on stable DMARDs without biologics, and were maintained on a stable dose of 2.5 to 10 mg of prednisone equivalent for at least three months. The primary outcome measure was change in duration of morning stiffness from baseline to 12 weeks of therapy. After 12 weeks of double-blind therapy, all patients were invited to continue in a 9 month open-label extension phase, with outcomes assessed 12 months after randomization.
Results
The double-blind portion of the study has previously been published (Buttgereit et al. Lancet 2008; 371: 205). At entry, the 288 randomized patients were mostly female (86%) with a mean age of 55 years. The mean duration of RA was 10 years, mean DAS28 was 5.8, and mean HAQ was 1.5. Mean duration of morning stiffness was approximately 170 minutes. The mean entry dose of prednisone was 6.5 mg per day. Approximately 87% completed the study. For the double-blind phase, morning stiffness did not change in users of IR prednisone compared to a 28% relative reduction in AM stiffness in those using MR prednisone. There was no significant difference in DAS28 or inflammatory markers between the preparations. Sleep quality was not different in those using MR prednisone.
During the open-label phase, IR patients crossed over to MR demonstrated the similar efficacy in morning stiffness reduction after crossover to MR as those initially randomized to MR. There was a correlation between IL-6 reduction and reduction in morning stiffness for the combined groups. There was no difference in safety or sleep quality associated with the cross-over.
Conclusions
MR prednisone may be more efficacious at alleviating morning stiffness than IR prednisone in patients with moderate to severe RA.
Editorial Comment
Engineering prednisone for a very specific effect on one symptom in RA seems somewhat regressive in the current era of aggressive, goal-oriented therapy. For most RA patients, maximally controlling synovitis with DMARDs would be considered the most effective means of improving morning stiffness, given the known risks associated with chronic glucocorticoid therapy and their lack of disease modifying properties past the earliest phases of disease. However, for patients with continued morning stiffness symptoms who are on aggressive therapy that includes prednisone, then MR prednisone may have a legitimate application. Doubtless, the cost of MR prednisone will likely be orders of magnitude higher than currently available prednisone.
