ARTHRITIS & RHEUMATISM Vol. 50, No. 12, December 2004, pp 4051–4059 DOI 10.1002/art.20673 © 2004, American College of Rheumatology Assessment of the Efficacy of Different Statins in Murine Collagen-Induced Arthritis Gaby Palmer, 1 Ve ´ ronique Chobaz, 2 Dominique Talabot-Ayer, 1 Sophia Taylor, 3 Alexander So, 2 Cem Gabay, 1 and Nathalie Busso 2 Objective. Hydroxymethylglutaryl-coenzyme A re- ductase inhibitors (statins) are widely used lipid- lowering 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 therapeu- tic effects of simvastatin were recently demonstrated in mouse collagen-induced arthritis, a well-described ex- perimental 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 adminis- tration 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 (syno- vial hyperplasia, exudate, and cartilage damage), immu- nologic (anti–type II collagen IgG production), and biochemical (interleukin-6, serum amyloid A, and glu- cocorticoid 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 treat- ment, 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 in- flammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA. The hydroxymethylglutaryl-coenzyme A (HMG- CoA) reductase inhibitors (statins) constitute a family of chemically related molecules, selected for their lipid- lowering effects. Statins are extensively used in medical practice, and large clinical trials have demonstrated their efficacy in reducing cardiovascular-related morbidity and mortality (1,2). Increasing clinical and experimental evidence indicates that some beneficial effects of statins may result from antiinflammatory mechanisms indepen- dent of their lipid-lowering effects (3–5). Such mecha- nisms include the inhibition of proinflammatory cyto- kine and chemokine production, adhesion molecule expression, and matrix metalloproteinase (MMP) secre- tion (6–11). In addition, statins have been reported to suppress interferon- (IFN)–inducible expression of class II major histocompatibility complex (MHC) mole- cules on nonprofessional antigen-presenting cells, as well as class II MHC–dependent activation of T lympho- cytes in vitro (12,13). Statins also decrease CD40 and CD40 ligand expression in various cell types, such as endothelial cells, smooth muscle cells, and macrophages (14–16). Finally, some of the statins, which are com- monly used for the treatment of hypercholesterolemia, block lymphocyte function–associated antigen 1–mediated cell adhesion and costimulation of T lym- phocytes (17). These observations, which strongly suggest that Dr. Gabay’s work was supported by grants from the Swiss National Science Foundation (3231-54954.98 and 3200-54955.98) and from the Department of Internal Medicine, University Hospital of Geneva. Dr. Busso’s work was supported by a grant from the Swiss National Science Foundation (3200-067231.01) and from AstraZeneca Pharmaceuticals (London, UK). 1 Gaby Palmer, PhD, Dominique Talabot-Ayer, MSc, Cem Gabay, MD: University Hospital and University of Geneva School of Medicine, Geneva, Switzerland; 2 Ve ´ronique Chobaz, Alexander So, MD, PhD, Nathalie Busso, PhD: University Hospital, Lausanne, Switzerland; 3 Sophia Taylor, MD: University Hospital, Geneva, Swit- zerland. Address correspondence and reprint requests to Cem Gabay, MD, Division of Rheumatology, University Hospital, 26 Avenue Beau-Se ´jour, 1211 Geneva 14, Switzerland. E-mail: Cem.Gabay@ hcuge.ch. Submitted for publication May 11, 2004; accepted in revised form August 23, 2004. 4051