Response to 'Statins accelerate the onset of collagen type II-induced arthritis in mice'

Abstract

Statins used to treat hyperlipidemia also exhibit immune-modulatory properties. What is still unclear and a matter of debate, however, is whether these properties are of benefit or are deleterious in collagen type II-induced arthritis (CIA). We read with great interest Vandebriel and colleagues' article about the role of statins in the induction of CIA [1]. According to the authors' conclusion, statins accelerate the onset of CIA in mice. In their study, as previously reported [2], oral atorvastatin and pravastatin had no effect on the arthritis score after CIA induction. Nonetheless, the oral route might be ineffective due to the significant hepatic first-pass metabolism of statins. We performed a study that assessed the effects of simvastatin administrated by subcutaneous and intraperitoneal routes in CIA as previously reported [3]. Of the 60 rats included, 50 developed CIA (83.3%) and were treated by daily intraperitoneal simvastatin (n = 5), subcutaneous simvastatin (n = 9), diluted subcutaneous simvastatin (n = 9), subcutaneous saline (n = 9), and intraperitoneal saline (n = 9) for a total of 15 days. Nine rats received no treatment. A total score was calculated by grading each joint of the four limbs using a scale of 0 to 3 (0 = normal, 1 = erythema, 2 = erythema + swelling, and 3 = loss of function). At baseline, no difference was noted in the arthritis score or weight between groups. We observed a significant weight decrease in each treatment group but no difference in weight loss between groups. After adjusting for weight, there was a significant difference in arthritis scores between intraperitoneal simvastatin and the other groups, with significantly lower arthritis scores obtained in the intraperitoneal simvastatin group (Figure ​(Figure1).1). The difference of the arthritis score between subcutaneous simvastatin and intraperitoneal simvastatin was significant (P = 0.002) (intraperitoneal: 3.67 ± 1.32 at baseline and 4.89 ± 1.69 after 15 days vs. subcutaneous: 4.20 ± 0.84 at baseline and 7.40 ± 1.34 after 15 days). Differences in arthritis scores between the other groups, except for the simvastatin group, were not significant (Figure ​(Figure1).1). These results obtained using linear mixed-models analysis were similar to those obtained when using PROAST, a general program for dose-response modeling, as in Vandebriel and colleagues' article. Figure 1 Arthritis score progression in the different treatment groups. IP, intraperitoneal; SC, subcutaneous. In the intraperitoneal simvastatin group, there was a limitation in the progression of the arthritis score in rats, whereas no effect was noted in the subcutaneous simvastatin group. Statins may therefore be a therapeutic option in CIA, provided that the substantial effects of hepatic first-pass metabolism are avoided. For CIA treatment, it might thus be interesting to administer transdermal statin patches that enhance diffusion, which have been reported to increase bone formation in rats [4]. Perhaps these patches could also be a therapeutic option in human rheumatoid arthritis.