Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases?
Pleiotropic effects are now described for the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (or statins) that might have utility in the context of chronic inflammatory autoimmune disease. Here we discuss the pharmacology and established uses of statins and in this context describe potential anti-inflammatory and immune-modulatory effects. An extensive in vitro data set defines roles for statins in modifying endothelial function, particularly with respect to adhesion molecule expression and apoptosis. Broader effects on leukocyte function have now emerged including altered adhesion molecule expression, cytokine and chemokine release and modulation of development of adaptive immune responses via altered MHC class II upregulation. In vivo data in several inflammatory models, including collagen-induced inflammatory arthritis and experimental autoimmune encephalomyelitis, suggest that such effects might have immune-modulatory potential. Finally, a recent clinical trial has demonstrated immunomodulatory effects for statins in patients with rheumatoid arthritis. Together with their known vasculoprotective effects, this growing body of evidence provides compelling support for longer-term trials of statin therapy in human disease such as rheumatoid arthritis.
McCarey
David W
DW
Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK.
Sattar
Naveed
N
McInnes
Iain B
IB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002986:Clinical Trials as Topic; D016207:Cytokines / Q000378:metabolism; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D016030:Kidney Transplantation; D051379:Mice; D015394:Molecular Structure; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D015815:Cell Adhesion Molecules; D018925:Chemokines; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007155:Immunologic Factors
N Engl J Med. 1995 Nov 16;333(20):1301-7
7566020
J Immunol. 2003 Feb 1;170(3):1524-30
12538717
Transplantation. 1996 May 27;61(10):1469-74
8633373
J Immunol. 2004 Mar 1;172(5):2903-8
14978092
J Atheroscler Thromb. 2002;9(4):178-83
12226549
Atherosclerosis. 2002 May;162(1):179-85
11947912
Nature. 2002 Nov 7;420(6911):78-84
12422218
JAMA. 1996 Jan 10;275(2):128-33
8531308
Biochem Pharmacol. 2004 Jan 15;67(2):303-13
14698043
Clin Chim Acta. 2003 Dec;338(1-2):17-24
14637261
Biochemistry (Mosc). 2002 Jan;67(1):85-91
11841343
JAMA. 2001 Jul 4;286(1):64-70
11434828
Lancet. 2004 Jun 19;363(9426):2015-21
15207950
Kidney Int. 2003 Jan;63(1):96-106
12472772
Atherosclerosis. 2004 Jan;172(1):85-93
14709361
J Am Coll Cardiol. 2001 Mar 1;37(3):800-7
11693755
N Engl J Med. 2004 Apr 1;350(14):1387-97
15070788
Thromb Res. 2002 Feb 15;105(4):285-90
12031821
Trends Pharmacol Sci. 1998 Jan;19(1):26-37
9509899
Nat Immunol. 2002 Apr;3(4):360-5
11896391
Curr Control Trials Cardiovasc Med. 2001;2(5):205-207
11806796
Int J Clin Pharmacol Ther. 2003 Sep;41(9):397-401
14518599
J Pharmacol Exp Ther. 2002 Aug;302(2):601-5
12130721
Nat Med. 2001 Jun;7(6):687-92
11385505
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):115-21
11145942
Am J Nephrol. 2003 Jan-Feb;23(1):13-7
12373076
Inflamm Res. 2002 Feb;51(2):58-62
11926313
Circulation. 2002 Mar 5;105(9):1135-43
11877368
Cardiovasc Res. 2004 Apr 1;62(1):105-11
15023557
Lancet. 2002 Jul 6;360(9326):7-22
12114036
Nat Med. 2000 Dec;6(12):1399-402
11100127
Arthritis Rheum. 2001 Jun;44(6):1234-6
11407680
Br J Pharmacol. 2002 Jan;135(1):284-92
11786505
Arthritis Res. 2000;2(5):374-8
11094451
Circ Res. 2002 Oct 18;91(8):696-703
12386146
J Clin Endocrinol Metab. 2002 Feb;87(2):563-8
11836286
Am J Cardiol. 1994 May 26;73(14):3D-11D
8198021
Circ Res. 2003 Nov 14;93(10):948-56
14563711
J Clin Invest. 1997 Dec 1;100(11):2671-9
9389730
Atherosclerosis. 2000 Oct;152(2):359-66
10998463
Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1784-9
12426205
Arterioscler Thromb Vasc Biol. 2000 Feb;20(2):556-62
10669656
Kidney Int. 2001 Nov;60(5):1990-7
11703619
Circulation. 1999 Nov 23;100(21):2124-6
10571968
Drug Metab Dispos. 2001 Mar;29(3):282-8
11181496
Lancet. 1994 Nov 19;344(8934):1383-9
7968073
N Engl J Med. 1995 Sep 7;333(10):621-7
7637722
Atherosclerosis. 2002 Jan;160(1):49-58
11755922
Am J Cardiol. 1998 Aug 27;82(4B):3J-10J
9737640
Am J Cardiol. 2001 Sep 1;88(5):504-8
11524058
Circulation. 1997 Sep 2;96(5):1398-402
9315523
Int J Cardiol. 2001 Feb;77(2-3):247-53
11182189
JAMA. 2001 Apr 4;285(13):1711-8
11277825