Statin therapy in rheumatoid arthritis.

Abstract: Rheumatoid arthritis, a chronic inflammatory polyarthritis that destroys synovial joints, is associated with systemic as well as local inflammation and with an increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors. Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and high-risk populations. Not all of this protective benefit appears to be mediated by lowered cholesterol levels. Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis. Recent studies show that statins may provide mild anti-inflammatory benefit in rheumatoid arthritis, in addition to reducing cardiovascular risk.

Key Words: atherosclerosis, cholesterol, HMG-coA reductase inhibitor, rheumatoid arthritis, statin

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Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis that progressively destroys synovial joints. RA affects approximately 1% of the world's population, (1) has a prevalence 2 to 4 times higher in women than in men, (2,3) and has enormous personal, social, and economic impact. (4,5) At present, there is no known cure and, despite improved therapy, the long-term prognosis remains poor, with a reduced average life expectancy. (6,7) The reasons for decreased life expectancy are multifactorial, but cardiovascular disease is being increasingly recognized as a contributor to the increased morbidity and mortality in RA. (8-13) The direct costs for the treatment of patients with RA and the indirect costs of their disability and loss from the workplace are high. (14,15)

Rheumatoid Arthritis: Prototypic Inflammatory Disease

Rheumatoid arthritis is marked by extensive synovial hyperplasia and infiltration by lymphocytes, monocytes, macrophages, and fibroblasts. The immunologic phenomena associated with RA are consistent with dysregulation of T-helper 1 ([T.sub.H]1)-mediated immune responses. (16) Aberrant T-cell activation is one of the earliest events in the development of RA, with CD4+ T cells stimulating monocytes and macrophages to produce inflammatory cytokines, including interleukin-1 (IL-1), IL-6, and tumor necrosis factor-[alpha], and proteolytic enzymes, initiating destruction of the synovium, cartilage, and underlying bone. (17) Activated T cells also signal B cells to produce increased levels of immunoglobulins, including rheumatoid factor. In addition to local inflammation, therefore, these cytokines produce a significant amount of systemic inflammation in RA.

Cardiovascular Disease in Rheumatoid Arthritis

Rheumatoid arthritis is associated with an increased risk of cardiovascular disease (CVD) and death. (8-13) This excess in CVD frequently occurs at a younger age than in the normal population and cannot be fully explained by traditional cardiac risk factors such as family history, smoking, and diabetes. (9) The association of RA with increased CVD is particularly important, given the evolving understanding of atherosclerosis as an inflammatory disease. (18,19) Atherosclerosis and RA share many inflammatory mechanisms, including the production of cytokines, tumor necrosis factor-[alpha] and IL-6, activation of monocytes, macrophages, and lymphocytes, and expression of adhesion molecules. (20) C-reactive protein (CRP), an acute phase reactant and measure of systemic inflammation, long used as a measure of RA disease activity, is a strong predictor of cardiovascular events in the general population. (21,22) Moreover, the extent of inflammation associated with RA predicts both CVD and overall mortality rates in RA. (23) It has been suggested that the "high-grade" inflammation of RA itself accelerates atherosclerosis, (24) and Choi et al (25) reported that patients with RA treated with methotrexate, and thus presumably with better RA control, had lower CVD mortality rates when compared with non-methotrexate-treated patients.

Statins

Since the early 1990s, HMG-coA reductase inhibitors, or statins, have revolutionized the treatment of hyperlipidemia and the prevention of cardiovascular disease. By acting on the enzyme converting HMG-CoA to mevalonic acid, statins reduce cholesterol synthesis, increase low-density lipoprotein (LDL) uptake, and have smaller effects on decreasing triglyceride, apolipoprotein B, and very low-density lipoprotein levels. Large randomized controlled trials have demonstrated the benefits of these medications in the treatment of hypercholesterolemia, in the primary and secondary prevention of coronary artery disease (CAD), and in the prevention of non-hemorrhagic stroke. (26-35) Moreover, the magnitude of the protection and the rapidity in the drop in mortality rates afforded by statins in these trials cannot be explained entirely by cholesterol-lowering effects, and the most recent clinical trials have highlighted the benefit of statin therapy in individuals at high cardiovascular risk, even those with normal cholesterol levels. (30-32,34-36) Lowering of LDL cholesterol, down to LDL levels of 70 mg/dL or below, has been shown to confer cardiovascular protection in high-risk individuals. On the basis of these findings, the National Cholesterol Education Program and the American College of Physicians recently have altered their guidelines for high-risk and diabetic patients. (37-39)

Pleiotropic Effects of Statins

In addition to combating hyperlipidemia, statins could potentially confer benefit to patients with RA in many other ways. Statins have pleiotropic effects independent of LDL lowering that probably contribute to their rapidity and efficacy in decreasing mortality rates. Statins influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide (NO) bioavailability, generation of free radicals, and angiogenesis. The study of these effects is an exploding field (40-42) (Table 1 (98-123)).

The product of the HMG-coA reductase enzyme mevalonate is an important precursor of farnesyl pyrophosphate and geranylgeranylpyrophosphate, both intracellular signaling molecules. (43) Many statin effects take place through these second messengers, independent of cholesterol lowering. For example, simvastatin-induced inhibition of matrix metalloproteinase-9 secretion from monocytes is mediated by a decrease in geranylgeranylpyrophosphate. (44)

In vitro studies have demonstrated statin inhibition of leukocyte-endothelial adhesion (45,46) and T-cell stimulation. (47,48) Statins bind to an allosteric site within leukocyte function antigen-1 (LFA-1), selectively blocking mediated costimulation of lymphocytes and LFA-1-mediated adhesion, unrelated to their inhibition of HMG-coA reductase. (47) Statins also have potent effects on endothelial cells, which play a crucial role in vascular homeostasis. Endothelial cells synthesize NO and endothelin-1, which regulate vascular tone, modulate blood cell-vessel wall interactions, prevent thrombosis, and influence smooth muscle cell growth. NO is a potent antiatherogenic compound, whereas endothelin-1 causes intense vasoconstriction and the inhibition of endothelial apoptosis and release of NO and prostacyclins (49-51) (Figure). Endothelial dysfunction, wherein vasoconstrictive effects outweigh vasodilatory effects, results from decreased bioavailability of NO, produced by endothelial NO synthase. Endothelial dysfunction is a strong and early predictor of CVD (52) and is observed in those at risk for CVD as the result of hyperlipidemia, hypertension, diabetes/insulin resistance, and cigarette smoking, even in the absence of detectable atherosclerosis. (53,54) Statins rapidly ameliorate endothelial dysfunction, (55-59) potentially by upregulating decay-accelerating factor, protecting the endothelium from complement-mediated damage. (60)

Not surprisingly, patients with RA have been found to have endothelial dysfunction and decreased arterial elasticity. (61-65) Recently, simvastatin was reported to improve endothelial function as measured by flow-mediated dilation of the brachial artery in a double-blinded, crossover trial in patients with RA. (66)

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Animal models have also led to important insights into the pleiotropic properties of statins. Lovastatin decreased experimental allergic encephalitis in a Lewis rat model, (67) and atorvastatin inhibited the development of chronic experimental autoimmune encephalomyelitis in mice. (68,69) Prophylactic treatment with statins augmented cerebral blood flow, reduced cerebral infarct size, and improved neurologic function after ischemic stroke in normocholesterolemic mice, presumably through the upregulation of endothelial NO synthase. (70) Simvastatin was found to promote atherosclerotic plaque stability in apolipoprotein E-deficient mice, independent of cholesterol lowering. (71) Simvastatin also had potent anti-inflammatory effects, on a scale comparable to those of indomethacin, on carrageenan-induced foot pad edema in a mouse model (72) and reduced inflammatory activity in a Th-1-driven mouse model of inflammatory arthritis. (73)

Clinically, pravastatin has been shown to significantly reduce CRP in men and women in the general population both with and without a history of CAD. (70) These changes were largely independent of reductions in LDL cholesterol. Other prospective studies have shown that CRP levels are a strong independent predictor of risk of future myocardial infarction and stroke; it is speculated that part of the protective effect of statins is in decreasing ongoing low-grade systemic inflammation, perhaps located in atherosclerotic plaques throughout the body. (71-74)

As an added benefit for patients with RA, statins may stimulate osteoblast function and new bone formation, as they do in vitro and in rodent models. (74) Statins augment the production of bone morphogenic protein-2, an important regulator of osteoblast differentiation and activity, and increase production of osteocalcin and vascular endothelial growth factor, suggesting an anabolic effect on bone. (75,76) Potentially, this could increase bone density and decrease fracture risk, although the epidemiologic evidence is conflicting, (77-81) and it is possible that individual statins affect osteoblast function differently. Randomized trials are needed to further clarify whether statins have a significant effect on bone density and fracture prevention.

Statin Use in Rheumatoid Arthritis and Inflammatory Diseases

Exciting recent studies conducted by groups in Scotland and Japan have tested oral statins for the treatment of RA itself. In a study by McCarey et al (82) in Glasgow, 116 patients with RA were randomly assigned to atorvastatin or placebo in addition to existing disease modifying antirheumatic drug (DMARDs) for 6 months. Clinical measures, including disease activity scores and swollen joint counts improved modestly but significantly, on a scale comparable to the improvement seen with minocycline for RA. (83) Markers of systemic inflammation, including erythrocyte sedimentation rate, CRP, fibrinogen, and IL-6, also fell, reflecting better disease control and potentially lowering cardiac risk. Importantly, no adverse events were reported, although there were multiple exclusion criteria, including diabetes, hepatic, renal, and muscle test abnormalities.

Kanda et al (84,85) in Japan tested the disease-modifying effects of 10 mg per day of simvastatin in 24 patients with RA in an open-label 12-week study and reported improvement in multiple clinical measures, including swollen and tender joint counts, and patient's and physician's assessments of pain and disease activity, as well as CRP, erythrocyte sedimentation rate, and rheumatoid factor levels. Simvastatin has also been investigated as a treatment for relapsing, remitting multiple sclerosis in an open-label study involving 30 patients. It showed very promising results with a significant decrease in the number of gadolinium plaques in the central nervous system at 4, 5, and 6 months of treatment. (86)

Developing Targeted Therapies

That statins, developed to inhibit the key enzyme in cholesterol biosynthesis, happened to have pleiotropic effects on the inflammatory process, endothelial function, and plaque stabilization, has been serendipitous, and has led to incredible new insights into the mechanisms of inflammation and atherosclerosis. Furthering our understanding of these mechanisms and of the actions of stains will allow for specifically targeted therapies for atherosclerosis and for other inflammatory diseases. For example, the [beta]2 integrin LFA-1, bound by statins, is important in the activation and trafficking of T cells. Efalizumab, a new humanized monoclonal antibody, targets CD11a, one of the subunits of LFA-1, and is being used to treat psoriasis. (87) The prospect of an oral statin analog targeting LFA-1 for the treatment of RA and other inflammatory diseases is enticing.

A Note of Caution

Statins have been touted as having the potential to hit "two birds with one stone" in RA. (88) However, we should prescribe statins, as all medications, with caution for our patients with RA. Some of the multiple effects of statins could potentially exacerbate RA activity, although this has not been clinically observed and in those few studies mentioned there was a modest clinical response compared with placebo. For example, increased angiogenesis is a requisite for synovial proliferation in RA, and the effects of statins on angiogenesis are unclear. (89,90) Opposing effects on thrombosis and fibrinolysis have been reported with different statins, making it appear that these may be individual medication, not class effect. (91)

Statin therapy for patients with RA may carry elevated risks of adverse effects and interactions as well. The risk of statin hepatotoxicity is compounded by the use of methotrexate or leflunomide, and the risk of muscular toxicity is elevated with concomitant use of cyclosporine in women and in the elderly. (92) Long-term safety data for patients on immunosuppressive agents, in particular biologic agents, are still lacking. Statins are teratogenic and should not be prescribed in young women of childbearing age without ensuring reliable contraception. Likewise, statins are contraindicated in breast feeding and should not be prescribed for those with hepatic or renal insufficiency. They may increase the international normalized ratio in those patients taking long-term warfarin therapy. In addition, not all statins are created equal in terms of their efficacy in lipid-lowering and anti-inflammatory effects, nor in their side effect profiles. For example, cerivastatin was withdrawn from the market due high rates of severe myotoxicity. Simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, and the newly marketed rosuvastatin have important differences in their lipophilicity, metabolism, and potential for side effects. (93-95)

Although patients with RA are at increased risk of CAD when compared with the general population, not all patients with RA are facing the same risk. Certainly, a 32-year-old nonsmoking woman with newly diagnosed RA is not at the same 10-year cardiac risk as a 65-year-old hypertensive, hyperlipidemic male smoker with many years of active RA. It is advisable to assess an individual's 10-year risk of CAD on the basis of traditional risk factors (96) before prescribing long-term statin use. The increased risk of CAD conferred by RA alone, in particular severe and active disease, should be factored into this assessment, although CAD risk models specific for RA and inflammatory rheumatic disease (similar to those for diabetes mellitus (97)) do not yet exist. The risk-benefit ratio for long-term statin use should also be considered because it may be that those patients at highest risk of statin toxicity would stand to gain the most from its use. However, statins may offer a modest additive therapeutic option for patients with RA; potentially, they may be both therapeutic, damping inflammation in multiple ways, and preventive, diminishing longer-term cardiovascular morbidity and mortality, for these patients.

Table. Pleiotropic effects of statins (a)

1. Effects on endothelial function
   * Inhibition of endothelin-1 expression (98)
   * Stimulation of endothelial NO (b) synthase (98-100)
   * Improvement in endothelial function via increased endothelial
     NO (101-104)
   * Protection against ischemic stroke in mice, mediated by endothelial
     NO synthase (70,105)
   * Upregulation of decay-accelerating factor, protecting against
     complement-mediated endothelial injury (60)
2. Effects on macrophage and T-cell recruitment
   * Decrease in leukocyte-endothelial adhesion (45-47,106,107)
   * Inhibition of T-cell stimulation (47,48)
3. Effects on inflammation
   * Reduction of cytokine synthesis, including interleukin-6, (108-110)
     interleukin-1[beta], (108,109) and tumor necrosis
     factor-[alpha] (109)
4. Effects on arterial wall remodeling/plaque stabilization
   * Inhibition of proliferation and increase in apoptosis of vascular
     smooth muscle cells (111,112)
   * Variable effects on angiogenesis (89,90)
   * Inhibition of matrix metalloproteinase expression (44,113,114)
5. Effects on free radical generation
   * Decrease in production of reactive oxygen species (104,115,116)
6. Effects on thrombosis (may not be class effects)
   * Reduction in tissue factor expression (117,118)
   * Decrease in platelet activation (105)
   * Increased fibrinolysis (119)
   * Variable effects on plasminogen activator inhibitor-1 (120-123)
7. Effects on osteoblasts and bone density
   * Increase in osteoblast activity and enhancement of bone formation
     in vitro and in rodents (74)
   * Elevated production of bone morphogenic protein-2, osteocalcin and
     vascular endothelial growth factor (75,76)

(a) Adapted from Reference 41.
(b) NO, nitric oxide.

This research was funded by grants NIH AR47780, Kirkland Fellowship, Arthritis Foundation/American College of Rheumatology Physician Scientist Development Award, Harvard Medical School/Eli Lilly 50th Anniversary Scholars in Medicine Award.

Accepted February 14, 2005.

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RELATED ARTICLE: Key Points

* Rheumatoid arthritis is associated with systemic as well as local inflammation and with increased risk of cardiovascular disease and death not fully explained by traditional cardiac risk factors.

* Statins (HMG-coA reductase inhibitors), medications originally designed to lower cholesterol, have been shown to have powerful effects on decreasing cardiovascular mortality rates in the general and in high-risk populations.

* Statins also influence multiple steps in the inflammatory process, including leukocyte migration and adhesion, T-cell stimulation, nitric oxide bioavailability, generation of free radicals, and angiogenesis.

* Statins may be ideal drugs for rheumatoid arthritis, providing a mild anti-inflammatory effect and reducing cardiovascular risk.

Karen H. Costenbader, MD, MPH, and Jonathan S. Coblyn, MD

Both authors are on staff at the Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Dr. Costenbader has disclosed stock ownership in Bristol Myers Squibb. Dr. Coblyn is on the Speaker's Bureau of Merck, Abbott and Pfizer Pharmaceuticals.

Reprint requests to Dr. Karen H. Costenbader, Division of Rheumatology, Immunology, and Allergy, Section of Clinical Sciences, PBB-B3, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E-mail: [e-mail].