title: Statins accelerate the onset of collagen type II-induced arthritis in mice.
abstract: BACKGROUND
  Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are effective in reducing the risk of cardiovascular morbidity and mortality in patients with hyperlipidemia, hypertension, or type II diabetes. Next to their cholesterol-lowering activity, statins have immunomodulatory properties. Based on these properties, we hypothesized that statin use may eventually lead to dysregulation of immune responses, possibly resulting in autoimmunity. We have recently shown in an observational study that statin use was associated with an increased risk of developing rheumatoid arthritis. Our objective was to investigate whether a causal relationship could be established for this finding.
  
  
  METHODS
  The mouse collagen type II (CII)-induced arthritis (CIA) model was used, with immunization, challenge, and euthanasia at days 0, 21, and 42, respectively. Statins were given orally before (day -28 until day 21) or after (day 21 until day 42) CIA induction. Atorvastatin (0.2 mg/day) or pravastatin (0.8 mg/day) was administered. Arthritis was recorded three times a week. Serum anti-CII autoantibodies and cytokines in supernatants from Concanavalin-A-stimulated lymph node cells and CII-stimulated spleen cells were measured.
  
  
  RESULTS
  Statin administration accelerated arthritis onset and resulted in 100% arthritic animals, whereas only seven out of 12 nonstatin control animals developed arthritis. Atorvastatin administration after CIA induction resulted in earlier onset than atorvastatin administration before induction, or than pravastatin administration before or after induction. The arthritic score of animals given pravastatin before CIA induction was similar to that of the nonstatin controls, whereas the other groups that received statins showed higher arthritic scores. Atorvastatin administration, especially before CIA induction, increased anti-CII autoantibody production. IL-2 and IL-17 production by lymph node and spleen cells was higher in CIA animals than in PBS controls, but was not affected by statin administration. While IFNγ production was not affected by CIA induction, atorvastatin administration before CIA induction increased the production of this cytokine.
  
  
  CONCLUSIONS
  These data support previous results from our observational studies, indicating a role for statins in the induction of autoimmunity.
authors.affiliation: Laboratory for Health Protection Research, National Institute for Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, PO Box 1, 3720 BA Bilthoven, The Netherlands. rob.vandebriel@rivm.nl
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Vandebriel
authors.forename: Hilda J I
authors.initials: HJ
authors.lastname: De Jong
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gremmer
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.forename: Jan-Willem Cohen
authors.initials: JW
authors.lastname: Tervaert
authors.forename: Wout
authors.initials: W
authors.lastname: Slob
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Van Der Laan
authors.forename: Henk
authors.initials: H
authors.lastname: Van Loveren
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology*; D002417:Cattle; D024043:Collagen Type II / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA
chemical_list: D024043:Collagen Type II; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors