Treatment with statins does not exhibit a clinically relevant corticosteroid-sparing effect in patients with giant cell arteritis

Autor: Maria C. Cid, José Hernández-Rodríguez, Josep M. Grau, Ana García-Martínez
Rok vydání: 2004
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Zdroj: Arthritis Care & Research. 51:674-678
ISSN: 0004-3591
DOI: 10.1002/art.20541
Popis: Introduction Giant cell arteritis (GCA) is a chronic granulomatous vasculitis preferentially targeting largeand medium-sized vessels in aged people. The inflammatory lesions eventually lead to vessel occlusion and 15% of patients develop cranial ischemic complications, particularly visual loss (1,2). The granulomatous nature of GCA lesions, with the frequent presence of multinucleated giant cells, has classically suggested a delayed-type hypersensitivity reaction but the potential triggering agents remain unknown (1–3). CD4 T cells infiltrating the vessel wall display a T helper type 1 functional differentiation with copious production of interferon (IFN ), a major cytokine in macrophage activation (3). Activated macrophages produce angiogenic factors and proinflammatory cytokines, such as interleukin-1 , tumor necrosis factor , and interleukin-6 (IL-6) (2,3). These mediators amplify the inflammatory response by inducing endothelial cell adhesion molecules for leukocytes and chemokines, and by generating new vessels through which additional leukocytes may subsequently invade the vessel wall (2,4–7). Macrophages also participate in tissue destruction by producing oxidative damage and secreting metalloproteases, and in tissue repair by secreting fibrogenic cytokines that eventually may lead to vessel occlusion with its ensuing ischemic complications (3). Corticosteroids are, at present, the treatment of choice for patients with GCA (1–3). Although their ability to modify the course of the disease or to cure it is questionable, corticosteroids induce dramatic functional changes in GCA lesions both in humans and in human arteritis– severe combined immunodeficient mouse chimeras (4,8,9). These functional changes result in a rapid relief of symptoms and prevention of ischemic complications. However, therapeutic requirements are highly variable among patients. Some patients achieve persistent remission of the disease within a few months, whereas others present recurrent relapses and need maintenance doses of corticosteroids for long periods of time. Sustained corticosteroid therapy has been associated with the development of dyslipidemia by inducing insulin resistance, increasing the hepatic synthesis of very lowdensity lipoproteins and triglyceride, enhancing the activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, and inhibiting lipoprotein lipase. Moreover, studies in vitro have demonstrated that corticosteroids inhibit the activity of the low-density lipoprotein (LDL) receptor leading to an increase in LDL levels in patients (10–13). For that reason, some patients diagnosed with GCA receiving corticosteroid therapy may require lipidlowering agents during their followup. HMG-CoA reductase inhibitors, statins, are widely and effectively used as hypolipidemic agents. They competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. Treatment with statins results in a reduction of the cholesterol levels through a decrease in cholesterol synthesis and by increasing the expression of hepatic LDL receptors, which clear LDL and LDL precursors from the bloodstream (14). Numerous clinical trials have demonstrated that statins reduce coronary heart disease mortality and the incidence of cardiovascular events (14–16). Recently, it has been demonstrated that statins also have antiinflammatory properties, through various mechanisms (14). The effect of statins on the inflammatory component of atherosclerosis is considered to be an important mechanism through which statins reduce cardiovascular events and death (14,17,18). Furthermore, statins have demonstrated to be of therapeutic benefit in animal models of chronic inflammatory conditions (19– 21) and have been shown to reduce graft rejection in heart Supported by Ministerio de Ciencia y Tecnologia and Fondo Europeo de Desarrollo Regional (FEDER; SAF 0203307) and Generalitat de Catalunya (2001/SGR/00379). Dr. Garcia-Martinez was supported by a research award from Hospital Clinic. Dr. Cid was supported by a research award from IDIBAPS. Ana Garcia-Martinez, MD, Jose Hernandez-Rodriguez, MD, Josep M. Grau, MD, Maria C. Cid, MD: Hospital Clinic, University of Barcelona, Barcelona, Spain. Address correspondence to Maria C. Cid, MD, Department of Internal Medicine, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. E-mail: mccid@clinic.ub.es. Submitted for publication June 18, 2003; accepted in revised form December 16, 2003. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 51, No. 4, August 15, 2004, pp 674–678 DOI 10.1002/art.20541 © 2004, American College of Rheumatology
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