Low-Dose Prednisone Chronotherapy for Rheumatoid Arthritis
Glucocorticoids (GCs) were first introduced into the therapeutic armamentarium in 1948, with the successful treatment of a 28-year-old patient with crippling rheumatoid arthritis (RA).1 As the awareness of adverse events emerged, the "two-edged sword" of GC therapy began to spark more debate about its long-term safety.1 Nevertheless, GCs have remained the mainstay of RA treatment due to their strong anti-inflammatory, immunosuppressive, and disease-modifying benefits.2 They are particularly effective in treating RA when used in conjunction with a regimen of disease-modifying antirheumatic drugs (DMARDs); a meta-analysis of 15 studies involving 1,414 patients found convincing evidence that, even according to the most conservative estimates, GCs given in addition to standard therapy can substantially reduce the rate of erosion progression in RA. But the authors note that concern remains about potential long-term adverse reactions.3
An increasing body of evidence suggests that low-dose treatment minimizes the risk of side effects and toxicities associated with higher doses, is well-tolerated, and is efficacious.4 Given the important role that low-dose GC therapy can play in improving RA outcomes, it is essential to continue improving its efficacy so that it can be used as a viable alternative to higher-dose treatment.5 Chronotherapy—delivery of treatment that is coordinated with circadian biological rhythms—has shown promise in management of several conditions, including hypertension, allergic rhinitis, and bronchial asthma,5 and a low-dose chronotherapeutic GC has been formulated for treatment of RA.
Chronotherapy is particularly appropriate for RA because RA symptoms follow circadian rhythms. For example, joint pain and stiffness are commonly most severe in the early morning.5 These morning symptoms can be attributed to overnight increases in serum levels of interleukin 6 (IL-6), tumor necrosis factor a (TNFa), and other proinflammatory cytokines. In healthy individuals, nocturnal secretion of cortisol counterbalances effects of increased IL-6 levels, but the mechanism of cortisol secretion is impaired in patients with RA.5 Thus, it seems plausible that the optimal time for delivery of GC treatment would be during the night, to mimic the ordinary balancing out of pro- and anti-inflammatory secretions. A modified-release (MR) oral formulation of low-dose prednisone has been developed to deliver prednisone during the night. This novel chronotherapeutic agent uses a programmed-release mechanism to release prednisone approximately four hours after ingestion (ie, at approximately 2:00 AM, if the patient has taken the tablet at 10:00 PM).
Buttgereit et al5 reported on results of the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA-2) trial that investigated the efficacy and safety of this agent in 350 patients with active RA, who were randomized on a 2:1 ratio basis to receive either MR prednisone (5 mg) or placebo (n=231 and 119 respectively) after their evening meal for a 12-week period. Study participants had been taking DMARDs for at least six months prior to their first screening. Additionally, patients were required to have had a duration of morning stiffness of at least 45 minutes on at least four days within the seven days of screening; a swollen joint count and a tender joint count of >4 each; and no use of GCs within six weeks of the screening visit. The primary endpoint was the percentage of patients achieving a 20% improvement in RA signs and symptoms, according to the American College of Rheumatology (ACR) criteria (ie, an ACR20 response) at week 12.