Assessment of the efficacy of different statins in murine collagen‐induced arthritis

Abstract

Objective. Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used lipidlowering agents. In addition to their well-known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen-induced arthritis, a well-described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model.Methods. Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols.Results. Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti-type II collagen IgG production), and biochemical (interleukin-6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels.Conclusion. This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune-mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…T cell proliferation was also significantly suppressed in lymphocyte cultures from simvastatintreated animals. However, a more recent study did not replicate these findings using atorvastatin, rosuvastatin, or simvastatin (139).…”

Simvastatin inhibits cytokine‐stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

“…Previous investigations have shown that statins have a wide range of effects on cells and tissues involved in inflammation (37); however, animal studies on the therapeutic effects of systemically delivered statins in inflammatory arthritis have yielded conflicting results (21)(22)(23). Although the statin doses used in the mouse models (up to 40 mg/kg per day [21,22], equivalent to a daily human dose of 3.25 mg/kg [40]) were higher than those used in standard therapy in humans (0.1-1.0 mg/kg per day) (41), the amount of drug reaching the joints may be low since statins are designed to act primarily in the liver (42). The disparity in the results of animal studies may be due to liverspecific pharmacokinetics and poor distribution of statins to bone and joints.…”

“…However, conflicting results have been obtained from studies using animal models of RA. While Leung et al (21) showed that intraperitoneal simvastatin was effective in alleviating collagen-induced arthritis (CIA) in mice, these findings were not replicated in a later study (22). More recently, Funk and colleagues (23) demonstrated a bone-protective effect of subcutaneous simvastatin in rats with streptococcal cell wall-induced arthritis.…”

Effects of simvastatin on bleomycin-induced pulmonary fibrosis in female rats

“…The dose range for simvastatin in human use is 20-80 mg/day for cardiovascular disease; statinrelated side eff ects such as myopathy are known to be dosagedependent (Escobar et al, 2008). Furthermore, in experimental studies high doses of simvastatin are reported to increase the risk of toxicity and mortality (Palmer et al, 2004). In the study by Palmer et al (2004) of statin eff ect in collagen-induced arthritis, the anti-infl ammatory activity of simvastatin was seen only after administration of 40 mg/kg; serious side eff ects were observed during treatment.…”

“…Furthermore, in experimental studies high doses of simvastatin are reported to increase the risk of toxicity and mortality (Palmer et al, 2004). In the study by Palmer et al (2004) of statin eff ect in collagen-induced arthritis, the anti-infl ammatory activity of simvastatin was seen only after administration of 40 mg/kg; serious side eff ects were observed during treatment. Only 7 of 18 mice completed therapy.…”