Antiinflammatory therapy for rheumatoid arthritis? (2007)

Glucocorticoids, since their spectacular introduction into clinical medicine in 1948 (1), remain a classically efficient treatment for arthritis and other inflammatory conditions (2). Indeed, the discoverers of this therapy were awarded an immediate Nobel Prize. Since then, glucocorticoids have remained a cornerstone in the treatment of chronic inflammation, and despite the introduction of novel therapies such as tumor necrosis factor–blocking agents (3), we have lately witnessed the increased use of glucocorticoids in arthritis. Recent studies confirm the capacity of glucocorticoids both to diminish inflammation and to reduce the pace of joint destruction (4–8), particularly when these agents are used at high doses and in the early phases of arthritis (6–8). Unfortunately, glucocorticoids are equally well known for their undesirable side effects, particularly with long-term use and systemic administration (2). A major problem has been achieving effective concentrations of active drug at the site of chronic inflammation and while avoiding too-high concentrations systemically and in uninflamed sites. The first attempt to reduce the undesirable effects of glucocorticoids on the rest of the body involved injecting them directly into the inflamed joints (9,10). This route of administration is still frequently used in practice, and it offers an efficient complement to other currently used therapies, despite the obvious drawbacks of repeated joint needling and the problem of polyarthritis involving small and inaccessible joints. Nevertheless, there is convincing evidence that glucocorticoids delivered in sufficiently high concentrations to an inflamed joint are beneficial. An attractive way to guide glucocorticoid treatment selectively to affected joints is to attach them to molecular delivery vehicles that, following systemic administration, accumulate in inflamed tissues to a relatively greater degree than they do in healthy tissues. Because of increased blood flow and vascular permeability at inflamed sites, liposomes could theoretically carry glucocorticoid drugs to arthritic joints (11). Despite efforts over the years, and some reports of success (12), liposome delivery of glucocorticoids has not been developed into a clinically useful therapy; this may be due, at least in part, to insufficient encapsulation of the drug into the liposomes and to lack of controlled release at the diseased joints. In this issue of Arthritis & Rheumatism, Avnir and colleagues report the engineering of a novel glucocorticoid-loaded liposome preparation, with promising results (13). The authors devised stabilized liposomes of !80 nm that could be loaded with relatively large amounts of an amphipathic weak acid glucocorticoid. This preparation manifested controlled release of the glucocorticoid in the circulation and especially in the swollen paws of rats with adjuvant-induced arthritis. This special liposome–glucocorticoid preparation produced a clinical effect on the rat arthritis much superior to that obtained with free glucocorticoid drug (13). The hope is that such glucocorticoid-loaded liposomes will safely work in humans to release sufficient amounts of drug into inflamed joints without exposing other body tissues to the hazards of too-high levels of the glucocorticoid. In view of the evidence that timely systemic administration of glucocorticoids can both ameliorate inflammation and prevent joint destruction (14), it is of great interest to explore the liposome formulation used by Avnir and colleagues in controlled clinical trials.