CORRESPONDENCE: RESEARCH CORRESPONDENCE
Simvastatin improves endothelial function in patients with rheumatoid arthritis
Frank Hermann, MD,
Adrian Forster, MD,
Rémy Chenevard, MD,
Frank Enseleit, MD,
David Hürlimann, MD,
Roberto Corti, MD,
Lukas E. Spieker, MD,
Diana Frey, MD,
Matthias Hermann, MD,
Walter Riesen, PhD, MD hc,
Michel Neidhart, PhD,
Beat A. Michel, MD,
Jens P. Hellermann, MD, MSc,
Renate E. Gay, MD,
Thomas F. Lüscher, MD,
Steffen Gay, MD,
Georg Noll, MD and
Frank Ruschitzka, MD*
* Cardiovascular Center Cardiology, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland (Email: frankruschitzka{at}yahoo.com).
To the Editor: Rheumatoid arthritis (RA) is the most common systemic connective tissue disease and affects 2.1 million people in the U.S., 1.5 million of whom are women (1). Patients with RA are at increased risk of developing premature cardiovascular disease, which shortens life expectancy by 3 to 18 years (1). These data provide the rationale for preventive measures at an early stage before overt cardiovascular disease becomes evident. Interestingly, endothelial dysfunction, the key event in early atherogenesis, just recently has been described in patients with RA both with high and low disease activity (2).
Statins have demonstrated beneficial effects in primary and secondary prevention trials in a wide range of cardiovascular risk categories (3). In addition to their potent lipid-lowering effects, statins recently have been ascribed anti-inflammatory, antithrombotic, antioxidative, and immunomodulatory properties (4,5). Hence, the aim of the present study was to evaluate the effects of statin therapy on vascular function, plasma lipids, and oxidative stress in patients with RA who have normal cholesterol levels.
The present study was a randomized, crossover, double-blind and placebo-controlled interventional trial. Twenty patients were assigned randomly to receive either simvastatin 40 mg/day for four weeks followed by four weeks of matching placebo or vice versa. Endothelial function and laboratory and clinical parameters were assessed at baseline and the end of each treatment phase as described previously (2). Inclusion criteria were diagnosis of RA according to the revised American College of Rheumatology diagnostic criteria (6), age 18 to 65 years, and active disease, defined as Disease Activity Score in 28 joints of >2.6 (Table 1). Exclusion criteria were previous myocardial infarction, coronary intervention or coronary surgery, previous treatment with statins in the last six months, uncontrolled hypertension (>160/90 mm Hg), dyslipidemia (low-density lipoprotein [LDL] cholesterol >4.9 mmol), smoking, and kidney (creatinine >150 µmol/l) or liver disease. Disease-modifying antirheumatic drug therapy was unchanged for three months before inclusion to the study and remained stable throughout. Of the 20 patients studied, 13 received methotrexate, with an average dose of 16 mg/week, that was administered subcutaneously once a week. Concomitant medication, including corticosteroids (average oral dose of 3.4 mg/day) or nonsteroidal anti-inflammatory drugs and folic acid (average dose 7 mg/week), remained unchanged throughout the study course. Each patient gave written informed consent before entry into the study. The study protocol was approved by the local ethics committee of the University Hospital of Zürich.
This study is the first to show that statin therapy reduces plasma cholesterol and oxidative stress in the context of ongoing inflammation, thus resulting in an improvement of vascular function in normocholesterolemic patients with RA. Flow-mediated dilatation as a measurement of endothelial function improved after four weeks of treatment with simvastatin compared with placebo (5.5 ± 0.7% vs. 3.8 ± 0.4%; p = 0.02) (Fig. 1A). Stratified by median split, patients with higher markers of inflammation (n = 10; C-reactive protein >10 mg/l) showed a significantly higher improvement in flow-mediated dilation than patients with low markers of inflammation (n = 10; C-reactive protein <10 mg/l; p = 0.04) (Fig. 1B). There was no difference concerning the treatment sequence. Total cholesterol, LDL cholesterol, and apolipoprotein B (apoB) were lowered by simvastatin therapy by 21%, 34%, and 33%, respectively (p < 0.0001) (Table 2). Oxidized low-density lipoproteins (oxLDLs), as well as the ratio oxLDL to LDL (p < 0.001 and p = 0.03, respectively), were reduced by simvastatin treatment (Table 2), indicating attenuated oxidative stress.
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Figure 1 (A) Flow-mediated dilation was increased after four weeks of simvastatin therapy (p = 0.02 vs. placebo). Endothelium-independent function assessed by glycerol trinitrate (GTN)-induced vasodilation remained unchanged (p = 0.58 vs. placebo). (B) Flow-mediated dilation in 10 patients with high and in 10 patients with low inflammation markers. Patients with elevated markers of systemic inflammation (n = 10; C-reactive protein [CRP] >10 mg/l) showed pronounced improvement in flow-mediated dilation (vs. patients with CRP <10 mg/l, n = 10; p = 0.04). Open bars = placebo; closed bars = simvastatin.
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Although modest but clinically apparent anti-inflammatory effects of atorvastatin were reported just recently by McCarey et al. (7), the effects of statins on vascular function in systemic connective tissue disease, particularly in patients with RA who had low serum cholesterol levels without overt cardiovascular disease, were unclear before this study. The improvement of endothelial function in the present study may be explained partly by the reduction of LDL cholesterol and apoB. The sum of apoB concentrations in all atherogenic particles provides better risk prediction than LDL cholesterol alone, particularly in individuals with normal and low LDL cholesterol concentrations (8).
Inflammation is a hallmark both of atherosclerosis and RA (4,9), and striking similarities exist between the pathogenesis of atherosclerotic vascular disease and RA (9). Thus, mechanisms that are responsible for synovial inflammation and subsequent joint destruction may not only be confined to the joints but also evident in the vessel wall, explaining the excess of cardiovascular disease in RA. Interestingly, the improvement of endothelial function in the present study was more pronounced in patients with elevated markers of inflammation, thus extending findings of a recent study demonstrating modest but clinically apparent anti-inflammatory effects of atorvastatin in patients with RA (7).
Endothelial dysfunction is characterized by impaired bioavailability of nitric oxide due to decreased production or accelerated degradation of nitric oxide by reactive oxygen species (10). Indeed, in the present study, simvastatin reduced formation of reactive oxygen species, as indicated by a reduction of oxLDL. Importantly, the reduction of the oxLDL/LDL ratio exceeded that of LDL alone, clearly indicating attenuation of oxidative stress. Oxidized LDL is not only an index of lipid peroxidation, but it also causes endothelial dysfunction itself through the impairment of signal transduction from endothelial cell surface receptors, inhibition of nitric oxide synthase activity, and inactivation of nitric oxide released from endothelial cells (10).
In conclusion, the reduction of proatherogenic lipids and markers of oxidative stress result in an improvement of vascular function, indicating that statins may hold the potential as a novel add-on therapy in the treatment of RA. Yet, the potential hepatotoxicity of statins, especially in combination with other disease-modifying antirheumatic drug therapies, is of clinical concern and needs to be addressed in future clinical studies. The definitive answer as to the net effect of statins on cardiovascular events in patients with RA, can only be provided by well-designed, large-scale clinical trials.
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Acknowledgments
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The authors thank the contributing staff of the Departments of Cardiology and Rheumatology of the University Hospital of Zurich as well as the Swiss Polyarthritis Association.
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Footnotes
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Please note: this study was supported by the Swiss National Research Foundation.
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References
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1. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis Circulation 2003;107:1303-1307.[Abstract/Free Full Text]
2. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis Circulation 2002;106:2184-2187.[Abstract/Free Full Text]
3. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial Lancet 2002;360:7-22.[CrossRef][Web of Science][Medline]
4. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis Circulation 2002;105:1135-1143.[Abstract/Free Full Text]
5. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator Nat Med 2000;6:1399-1402.[CrossRef][Web of Science][Medline]
6. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum 1988;31:315-324.[Web of Science][Medline]
7. McCarey DW, McInnes IB, Madhok R, et al. Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial Lancet 2004;363:2015-2021.[CrossRef][Web of Science][Medline]
8. Sniderman AD, Furberg CD, Keech A, et al. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment Lancet 2003;361:777-780.[CrossRef][Web of Science][Medline]
9. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis Circulation 1999;100:2124-2126.[Free Full Text]
10. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress Circ Res 2000;87:840-844.[Abstract/Free Full Text]
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