Premature Coronary Disease in Systemic Lupus
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Roman et al.1 and Asanuma et al.2 (Dec. 18 issue) document accelerated development of atherosclerosis in patients with systemic lupus erythematosus (SLE), the implication being that atherosclerosis causes ischemic heart disease.3 Other causes of ischemic heart disease are possible, however. We recently observed two young women with corticosteroid-treated SLE who had intramyocardial vascular disease and myocardial infarction. The first patient was 20 years old and had a one-year history of SLE. Examination of the intramyocardial arteries showed extensive fibrinoid necrosis and thrombosis. There was no coronary-artery atherosclerosis. Extensive, biventricular acute myocardial infarction was the cause of death. The second patient was 25 years old and had a five-year history of SLE. Autopsy showed intramyocardial vasculitis with fibrinoid necrosis and thrombosis; mild-to-moderate coronary atherosclerosis without thrombosis; and scattered healed, healing, and acute myocardial infarctions in a nonvascular distribution. Bronchopneumonia was the cause of death. Although the prevalence of intramyocardial vasculitis in patients with SLE is uncertain — no examples were observed in 36 cases studied at autopsy4 — the possibility of its contribution to myocardial ischemia should not be discounted.
John Wurzel, M.D.
Bruce I. Goldman, M.D.
Temple University School of Medicine
Philadelphia, PA 19140
jwurzel@temple.edu
References
Roman MJ, Shanker B-A, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399-2406.
Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2407-2415.
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Med 1975;58:243-264.
To the Editor: Roman et al. suggest that patients with more severe SLE, leading to increased use of corticosteroids or immunosuppressants, have a lower likelihood of the development of carotid plaques than patients with less severe SLE. In our recent study1 involving a prospective cohort of patients with SLE, the cumulative dose of prednisone (from the time of the diagnosis of SLE) was an independent predictor of plaque formation. We assumed that manifestations of severe SLE (such as glomerulonephritis), which necessitate aggressive therapy, could contribute to accelerated atherosclerosis. Roman et al. retrospectively analyzed prednisone intake during the preceding five years, but not the cumulative dose from the time of diagnosis, which is presumably higher in patients with a longer duration of disease — that is, in those who have plaque.
Age is probably the single main determinant of atherosclerosis. In the series described by Roman et al., patients with plaque were much older and had milder SLE than those without plaque. Therefore, plaque in these patients may have been related not to their milder SLE, but rather to their older age — a factor not considered by the authors in the multivariate analysis of disease-related features.
Andrea Doria, M.D.
University of Padua Medical School
35128 Padua, Italy
adoria@unipd.it
Yehuda Shoenfeld, M.D.
Tel Aviv University
Tel Aviv 52621, Israel
Paolo Pauletto, M.D.
Hospital of Treviso
31100 Treviso, Italy
References
Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003;62:1071-1077.
To the Editor: Roman et al. and Asanuma et al. report that patients with SLE had a higher prevalence of carotid or coronary atherosclerosis than controls and that the atherosclerosis was not related to the classic risk factors for that disease — findings suggesting that SLE itself may increase the risk of cardiovascular disease. Even if inflammation and oxidative stress may be implicated,1 data in this regard are unclear. We have previously found higher values for isoprostanes, markers of oxidative stress, in patients with SLE than in controls.2 In a subsequent study that included 40 patients with SLE, a logistic-regression model demonstrated a significant association between urinary excretion of the isoprostane prostaglandin F2 type III and SLE (P<0.001); the association was independent of age, hypertension, diabetes, dyslipidemia, and corticosteroid treatment. To determine whether inflammation has a role in enhancing oxidative stress, we measured the plasma levels of tumor necrosis factor , which is a known pro-oxidant molecule,3 and found a significant correlation with the urinary excretion of prostaglandin F2 type III (Spearman's rho = 0.81, P<0.001). These findings showing a link between tumor necrosis factor and isoprostane lend support to the suggestion that inflammation and oxidative stress may be implicated in the accelerated atherosclerosis observed in patients with SLE.
Francesco Violi, M.D.
Lorenzo Loffredo, M.D.
Domenico Ferro, M.D.
University La Sapienza
00161 Rome, Italy
francesco.violi@uniroma1.it
References
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Pratico D, Ferro D, Iuliano L, et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999;93:3401-3407.
Suematsu N, Tsutsui H, Wen J, et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003;107:1418-1423.
To the Editor: Roman et al. report that SLE is associated with an increased prevalence of atherosclerosis, which is most striking in premenopausal women, a population usually largely protected from coronary artery disease, even in the presence of a greatly unfavorable lipid profile, such as that related to heterozygous familial hypercholesterolemia.1 However, the authors do not mention increased iron stores, which are frequently associated with SLE, as one of the biologic factors that could have a role in the pathogenesis of atherosclerosis.2
Iron depletion does seem to be a possible protective factor against the development of ischemic heart disease in menstruating women.3 Furthermore, the serum ferritin level, a good indicator of the level of iron stored in the body, can be a useful marker of disease activity in patients with SLE.4 Thus, high levels of stored iron might be considered as an adjunctive risk factor for the development of atherosclerosis in young women with SLE.
Francesca Pezzetta, M.D.
Ospedale S. Michele
33013 Gemona del Friuli, Italy
Luca Mascitelli, M.D.
Casa di Cura Città di Udine
33100 Udine, Italy
lumasci@libero.it
References
Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb 1991;11:290-297.
Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc 2003;78:1274-1280.
Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003;145:190-194.
Lim MK, Lee CK, Ju YS, et al. Serum ferritin as a serologic marker of activity in systemic lupus erythematosus. Rheumatol Int 2001;20:89-93.
To the Editor: In a Perspective article accompanying the reports by Roman et al. and Asanuma et al., Hahn1 discusses the use of statins to prevent premature atherosclerosis in SLE. But are these lipid-lowering agents safe in patients with SLE? Some preliminary studies suggest that statins may trigger or aggravate SLE. An increasing number of cases of statin-induced SLE have been reported,2 and in one case the outcome was lethal.3 Symptoms, but not necessarily the serologic disease, generally improve after discontinuation of the drug. In many of the reported cases, tests for antinuclear antibodies were still positive many months or even years after interruption of the drug.
Cellular apoptosis, which plays a crucial role in SLE, may be exacerbated or triggered by statins.4 The release of nuclear antigens into the circulation may foster the production of pathogenic autoantibodies. Statins may also induce a shift from a type 1 to a type 2 helper T-cell immune response, leading to B-cell reactivity and the production of pathogenic autoantibodies.5,6 Some precautions must therefore be taken before the use of statins in patients with SLE is considered.
Bernard No?l, M.D.
Centre Hospitalier Universitaire Vaudois
1011 Lausanne, Switzerland
bernard.noel@chuv.hospvd.ch
References
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Rudski L, Rabinovitch MA, Danoff D. Systemic immune reactions to HMG-CoA reductase inhibitors: report of 4 cases and review of the literature. Medicine (Baltimore) 1998;77:378-383.
Sridhar MK, Abdulla A. Fatal lupus-like syndrome and ARDS induced by fluvastatin. Lancet 1998;352:114-114.
Blanco-Colio LM, Villa A, Ortego M, et al. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 2002;161:17-26.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-1402.
Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;420:78-84.
Dr. Roman and colleagues reply: The mechanisms by which myocardial infarction may occur in patients with SLE are manifold. Our detection of premature development and an excess prevalence of carotid atherosclerosis, which is strongly associated with coronary atherosclerosis, along with the autopsy data cited by Drs. Wurzel and Goldman, supports the important role of atherosclerosis as the leading cause of premature myocardial infarction in patients with SLE.
Serum ferritin is a measure of body iron stores, as indicated by Drs. Pezzetta and Mascitelli, but it also increases as an acute-phase reactant, independently of body iron stores (which remain unproven as a risk factor for coronary artery disease).1 Anemia is a feature of SLE, and the serum iron level is generally low in patients with SLE. Although we did not measure the serum ferritin level in our patients, the ability to distinguish an association between an elevation in the ferritin level and atherosclerosis due to increased iron stores, from generalized inflammation, would be difficult without a more direct measure of body iron stores.
Although the unpublished data of Dr. Violi et al. are of theoretical interest, their clinical relevance remains speculative, pending proof of an association between isoprostanes and atherosclerosis in patients with SLE. We appreciate Dr. No?l's call for caution in the use of statins because of the possibility that they might trigger autoimmune reactions similar to those encountered in SLE.
We disagree that atherosclerosis in SLE is primarily related to age, as suggested by Dr. Doria et al. A major strength of our case–control study is the ability to adjust for age as a determinant of atherosclerosis in SLE. The substantial increase in atherosclerosis, which was independent of age, is shown in Figure 1 of our article. The use of age as a single variable may obscure the effect of other variables on atherosclerosis in SLE. Therefore, we chose to divide age into two variables — age at the onset of disease and the duration of disease — to clarify the influence of these separate and additive components of age on atherosclerosis. Our findings — that an increased duration of disease and increased cumulative damage due to disease are independent correlates of atherosclerosis — suggest that chronic inflammation has an effect that is additive to that of aging in promoting atherosclerosis.
The difference between our study and that of Doria et al.2 with regard to the association between atherosclerosis and corticosteroid use is probably due to several factors. Doria et al. used thresholds for abnormal carotid-artery morphology based on data from persons significantly older than their patients with SLE, resulting in much lower prevalences of abnormalities (and less stability in multivariate analyses of data from small samples). Those authors emphasize the strong association between glomerulonephritis and corticosteroid use, but it is not clear that base-line renal disease was included in the multivariate analyses linking the dose of prednisone to plaque and intimal–medial thickening. We did not find an association between atherosclerosis and renal disease, but the use of cyclophosphamide, typically for glomerulonephritis, was negatively correlated with the presence of plaque. It is possible that treatment with cyclophosphamide prevents the chronic inflammation that promotes atherogenesis in SLE, whereas treatment with corticosteroids is less effective for this purpose.
Mary J. Roman, M.D.
Weill Medical College of Cornell University
New York, NY 10021
mroman@med.cornell.edu
Michael D. Lockshin, M.D.
Jane E. Salmon, M.D.
Hospital for Special Surgery
New York, NY 10021
References
Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;330:1119-1124.
Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003;62:1071-1077.
Dr. Stein replies: Drs. Wurzel and Goldman point out that ischemic heart disease in patients with SLE can occur through mechanisms other than atherosclerosis. Such mechanisms include arteritis, thrombosis, and spasm and may involve small vessels.1 However, the striking increase in the prevalence of atherosclerosis in SLE that both my colleagues and I and Roman et al. observed suggests that it is likely to contribute substantially to the increase in ischemic heart disease.
Dr. Violi and colleagues propose oxidative stress as a mechanism through which inflammation may accelerate atherosclerosis. There is evidence of increased oxidative stress in SLE and a wide range of rheumatic diseases,2 and thus, as they suggest, the relationship between markers of oxidative stress and atherosclerosis in SLE will be of interest.
Dr. No?l advocates caution in the use of statins to treat or prevent premature atherosclerosis in SLE. The efficacy and safety of statins have been evaluated extensively in large clinical trials performed in the general population and in patients with diseases that increase cardiovascular risk, but there is little information about the use of statins in patients with SLE; there is also little information about the potential beneficial or detrimental effects of statins on the clinical manifestations of lupus. Clinical studies are under way, and a preliminary report from one study indicates that patients with SLE may have an increased incidence of adverse effects from statins.3 In addition, the magnitude of the effect of statins on ischemic heart disease and the mechanisms mediating it may differ between patients with SLE and members of the general population. Thus, it will be valuable to have more information regarding the risks and benefits of statins in SLE. However, until such information is available, clinical decisions about the use of statins in patients with SLE will be based largely on safety and efficacy data from clinical trials involving patients without lupus and treatment guidelines derived from other populations of patients with an increased risk of atherosclerotic cardiovascular disease.
C. Michael Stein, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232-6602
michael.stein@vanderbilt.edu
References
Moder KG, Miller TD, Tazelaar HD. Cardiac involvement in systemic lupus erythematosus. Mayo Clin Proc 1999;74:275-284.
Stein CM, Tanner SB, Awad JA, Roberts LJ II, Morrow JD. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum 1996;39:1146-1150.
Kiani AN, Petri M. Statin toxicity in the lupus atherosclerosis prevention study. Arthritis Rheum 2003;48:Suppl:S370-S370. abstract.
Dr. Hahn replies: I thank Dr. No?l for calling to our attention the report of hypersensitivity and lupus-like reactions that occur in some patients who are taking statins. He describes four such examples.1 One case in particular is convincing. In a 63-year-old man who had had two years of exposure to simvastatin (20 mg daily), polymyalgia rheumatica developed, but it abated over a period of a month after the simvastatin was discontinued. The patients in the three other cases had vasculitis or SLE, which did not respond completely to intensive immunosuppressive therapies, even though the statin was discontinued. Of other patients described in the literature, only one with a hypereosinophilic, hypersensitivity-type reaction had symptoms and laboratory abnormalities that resolved after the statin was discontinued and reappeared on rechallenge. Thus, as is usual in reports of drug-induced lupus, vasculitis, or hypersensitivity, most cases are post hoc ergo propter hoc arguments; a few are absolutely convincing. According to the Physicians' Desk Reference,2 of 10,259 persons treated with simvastatin, less than 1 percent had hypersensitivity reactions, including lupus-like diseases. Therefore, lupus-like and hypersensitivity syndromes are uncommon adverse effects of statins. Furthermore, there is no consistent evidence that exposure to "lupus-inducing" drugs worsens SLE in patients with spontaneous disease. In general, my colleagues and I do not withhold known "lupus-inducers" such as isoniazid or phenytoin from patients with SLE who need them.
I also thank Dr. Violi and colleagues for calling attention to their large body of work3,4 showing that in several chronic inflammatory or degenerative diseases (e.g., Alzheimer's disease, chronic inflammatory lung disease, and the antiphospholipid syndrome), markers of oxidative stress may indicate increased lipid peroxidation, which probably contributes to atherosclerosis by providing highly oxidized low-density lipoprotein that is deposited in arterial walls. They have reported increased lipid peroxidation, measured as urinary levels of the isoprostane prostaglandin F2 type III and similar products of oxidized prostaglandin-related molecules. Increased peroxidation is generally viewed as an adverse metabolic state that confers a predisposition to atherosclerosis.
In summary, we take the points made that exposing patients to statins may in a very small proportion increase their risk of SLE-like disease and that increased lipid oxidation is likely to play a role in accelerating atherosclerosis in patients with SLE and others with chronic inflammatory or degenerative diseases.
Bevra Hannahs Hahn, M.D.
University of California, Los Angeles
Los Angeles, CA 90095
References
Rudski L, Rabinovitch MA, Danoff D. Systemic immune reactions to HMG-CoA reductase inhibitors: report of 4 cases and review of the literature. Medicine (Baltimore) 1998;77:378-383.
Zocor tablets (simvastatin). In: Physicians' desk reference. 58th ed. Montvale, N.J.: Thomson PDR, 2004:2113-8.
Pratico D, Barry OP, Lawson JA, et al. IPF2alpha-I: an index of lipid peroxidation in humans. Proc Natl Acad Sci U S A 1998;95:3449-3454.
Pratico D, Ferro D, Iuliano L, et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999;93:3401-3407.
John Wurzel, M.D.
Bruce I. Goldman, M.D.
Temple University School of Medicine
Philadelphia, PA 19140
jwurzel@temple.edu
References
Roman MJ, Shanker B-A, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2399-2406.
Asanuma Y, Oeser A, Shintani AK, et al. Premature coronary-artery atherosclerosis in systemic lupus erythematosus. N Engl J Med 2003;349:2407-2415.
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Bulkley BH, Roberts WC. The heart in systemic lupus erythematosus and the changes induced in it by corticosteroid therapy: a study of 36 necropsy patients. Am J Med 1975;58:243-264.
To the Editor: Roman et al. suggest that patients with more severe SLE, leading to increased use of corticosteroids or immunosuppressants, have a lower likelihood of the development of carotid plaques than patients with less severe SLE. In our recent study1 involving a prospective cohort of patients with SLE, the cumulative dose of prednisone (from the time of the diagnosis of SLE) was an independent predictor of plaque formation. We assumed that manifestations of severe SLE (such as glomerulonephritis), which necessitate aggressive therapy, could contribute to accelerated atherosclerosis. Roman et al. retrospectively analyzed prednisone intake during the preceding five years, but not the cumulative dose from the time of diagnosis, which is presumably higher in patients with a longer duration of disease — that is, in those who have plaque.
Age is probably the single main determinant of atherosclerosis. In the series described by Roman et al., patients with plaque were much older and had milder SLE than those without plaque. Therefore, plaque in these patients may have been related not to their milder SLE, but rather to their older age — a factor not considered by the authors in the multivariate analysis of disease-related features.
Andrea Doria, M.D.
University of Padua Medical School
35128 Padua, Italy
adoria@unipd.it
Yehuda Shoenfeld, M.D.
Tel Aviv University
Tel Aviv 52621, Israel
Paolo Pauletto, M.D.
Hospital of Treviso
31100 Treviso, Italy
References
Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003;62:1071-1077.
To the Editor: Roman et al. and Asanuma et al. report that patients with SLE had a higher prevalence of carotid or coronary atherosclerosis than controls and that the atherosclerosis was not related to the classic risk factors for that disease — findings suggesting that SLE itself may increase the risk of cardiovascular disease. Even if inflammation and oxidative stress may be implicated,1 data in this regard are unclear. We have previously found higher values for isoprostanes, markers of oxidative stress, in patients with SLE than in controls.2 In a subsequent study that included 40 patients with SLE, a logistic-regression model demonstrated a significant association between urinary excretion of the isoprostane prostaglandin F2 type III and SLE (P<0.001); the association was independent of age, hypertension, diabetes, dyslipidemia, and corticosteroid treatment. To determine whether inflammation has a role in enhancing oxidative stress, we measured the plasma levels of tumor necrosis factor , which is a known pro-oxidant molecule,3 and found a significant correlation with the urinary excretion of prostaglandin F2 type III (Spearman's rho = 0.81, P<0.001). These findings showing a link between tumor necrosis factor and isoprostane lend support to the suggestion that inflammation and oxidative stress may be implicated in the accelerated atherosclerosis observed in patients with SLE.
Francesco Violi, M.D.
Lorenzo Loffredo, M.D.
Domenico Ferro, M.D.
University La Sapienza
00161 Rome, Italy
francesco.violi@uniroma1.it
References
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Pratico D, Ferro D, Iuliano L, et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999;93:3401-3407.
Suematsu N, Tsutsui H, Wen J, et al. Oxidative stress mediates tumor necrosis factor-alpha-induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation 2003;107:1418-1423.
To the Editor: Roman et al. report that SLE is associated with an increased prevalence of atherosclerosis, which is most striking in premenopausal women, a population usually largely protected from coronary artery disease, even in the presence of a greatly unfavorable lipid profile, such as that related to heterozygous familial hypercholesterolemia.1 However, the authors do not mention increased iron stores, which are frequently associated with SLE, as one of the biologic factors that could have a role in the pathogenesis of atherosclerosis.2
Iron depletion does seem to be a possible protective factor against the development of ischemic heart disease in menstruating women.3 Furthermore, the serum ferritin level, a good indicator of the level of iron stored in the body, can be a useful marker of disease activity in patients with SLE.4 Thus, high levels of stored iron might be considered as an adjunctive risk factor for the development of atherosclerosis in young women with SLE.
Francesca Pezzetta, M.D.
Ospedale S. Michele
33013 Gemona del Friuli, Italy
Luca Mascitelli, M.D.
Casa di Cura Città di Udine
33100 Udine, Italy
lumasci@libero.it
References
Hill JS, Hayden MR, Frohlich J, Pritchard PH. Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb 1991;11:290-297.
Tefferi A. Anemia in adults: a contemporary approach to diagnosis. Mayo Clin Proc 2003;78:1274-1280.
Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003;145:190-194.
Lim MK, Lee CK, Ju YS, et al. Serum ferritin as a serologic marker of activity in systemic lupus erythematosus. Rheumatol Int 2001;20:89-93.
To the Editor: In a Perspective article accompanying the reports by Roman et al. and Asanuma et al., Hahn1 discusses the use of statins to prevent premature atherosclerosis in SLE. But are these lipid-lowering agents safe in patients with SLE? Some preliminary studies suggest that statins may trigger or aggravate SLE. An increasing number of cases of statin-induced SLE have been reported,2 and in one case the outcome was lethal.3 Symptoms, but not necessarily the serologic disease, generally improve after discontinuation of the drug. In many of the reported cases, tests for antinuclear antibodies were still positive many months or even years after interruption of the drug.
Cellular apoptosis, which plays a crucial role in SLE, may be exacerbated or triggered by statins.4 The release of nuclear antigens into the circulation may foster the production of pathogenic autoantibodies. Statins may also induce a shift from a type 1 to a type 2 helper T-cell immune response, leading to B-cell reactivity and the production of pathogenic autoantibodies.5,6 Some precautions must therefore be taken before the use of statins in patients with SLE is considered.
Bernard No?l, M.D.
Centre Hospitalier Universitaire Vaudois
1011 Lausanne, Switzerland
bernard.noel@chuv.hospvd.ch
References
Hahn BH. Systemic lupus erythematosus and accelerated atherosclerosis. N Engl J Med 2003;349:2379-2380.
Rudski L, Rabinovitch MA, Danoff D. Systemic immune reactions to HMG-CoA reductase inhibitors: report of 4 cases and review of the literature. Medicine (Baltimore) 1998;77:378-383.
Sridhar MK, Abdulla A. Fatal lupus-like syndrome and ARDS induced by fluvastatin. Lancet 1998;352:114-114.
Blanco-Colio LM, Villa A, Ortego M, et al. 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 2002;161:17-26.
Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-1402.
Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 2002;420:78-84.
Dr. Roman and colleagues reply: The mechanisms by which myocardial infarction may occur in patients with SLE are manifold. Our detection of premature development and an excess prevalence of carotid atherosclerosis, which is strongly associated with coronary atherosclerosis, along with the autopsy data cited by Drs. Wurzel and Goldman, supports the important role of atherosclerosis as the leading cause of premature myocardial infarction in patients with SLE.
Serum ferritin is a measure of body iron stores, as indicated by Drs. Pezzetta and Mascitelli, but it also increases as an acute-phase reactant, independently of body iron stores (which remain unproven as a risk factor for coronary artery disease).1 Anemia is a feature of SLE, and the serum iron level is generally low in patients with SLE. Although we did not measure the serum ferritin level in our patients, the ability to distinguish an association between an elevation in the ferritin level and atherosclerosis due to increased iron stores, from generalized inflammation, would be difficult without a more direct measure of body iron stores.
Although the unpublished data of Dr. Violi et al. are of theoretical interest, their clinical relevance remains speculative, pending proof of an association between isoprostanes and atherosclerosis in patients with SLE. We appreciate Dr. No?l's call for caution in the use of statins because of the possibility that they might trigger autoimmune reactions similar to those encountered in SLE.
We disagree that atherosclerosis in SLE is primarily related to age, as suggested by Dr. Doria et al. A major strength of our case–control study is the ability to adjust for age as a determinant of atherosclerosis in SLE. The substantial increase in atherosclerosis, which was independent of age, is shown in Figure 1 of our article. The use of age as a single variable may obscure the effect of other variables on atherosclerosis in SLE. Therefore, we chose to divide age into two variables — age at the onset of disease and the duration of disease — to clarify the influence of these separate and additive components of age on atherosclerosis. Our findings — that an increased duration of disease and increased cumulative damage due to disease are independent correlates of atherosclerosis — suggest that chronic inflammation has an effect that is additive to that of aging in promoting atherosclerosis.
The difference between our study and that of Doria et al.2 with regard to the association between atherosclerosis and corticosteroid use is probably due to several factors. Doria et al. used thresholds for abnormal carotid-artery morphology based on data from persons significantly older than their patients with SLE, resulting in much lower prevalences of abnormalities (and less stability in multivariate analyses of data from small samples). Those authors emphasize the strong association between glomerulonephritis and corticosteroid use, but it is not clear that base-line renal disease was included in the multivariate analyses linking the dose of prednisone to plaque and intimal–medial thickening. We did not find an association between atherosclerosis and renal disease, but the use of cyclophosphamide, typically for glomerulonephritis, was negatively correlated with the presence of plaque. It is possible that treatment with cyclophosphamide prevents the chronic inflammation that promotes atherogenesis in SLE, whereas treatment with corticosteroids is less effective for this purpose.
Mary J. Roman, M.D.
Weill Medical College of Cornell University
New York, NY 10021
mroman@med.cornell.edu
Michael D. Lockshin, M.D.
Jane E. Salmon, M.D.
Hospital for Special Surgery
New York, NY 10021
References
Sempos CT, Looker AC, Gillum RF, Makuc DM. Body iron stores and the risk of coronary heart disease. N Engl J Med 1994;330:1119-1124.
Doria A, Shoenfeld Y, Wu R, et al. Risk factors for subclinical atherosclerosis in a prospective cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2003;62:1071-1077.
Dr. Stein replies: Drs. Wurzel and Goldman point out that ischemic heart disease in patients with SLE can occur through mechanisms other than atherosclerosis. Such mechanisms include arteritis, thrombosis, and spasm and may involve small vessels.1 However, the striking increase in the prevalence of atherosclerosis in SLE that both my colleagues and I and Roman et al. observed suggests that it is likely to contribute substantially to the increase in ischemic heart disease.
Dr. Violi and colleagues propose oxidative stress as a mechanism through which inflammation may accelerate atherosclerosis. There is evidence of increased oxidative stress in SLE and a wide range of rheumatic diseases,2 and thus, as they suggest, the relationship between markers of oxidative stress and atherosclerosis in SLE will be of interest.
Dr. No?l advocates caution in the use of statins to treat or prevent premature atherosclerosis in SLE. The efficacy and safety of statins have been evaluated extensively in large clinical trials performed in the general population and in patients with diseases that increase cardiovascular risk, but there is little information about the use of statins in patients with SLE; there is also little information about the potential beneficial or detrimental effects of statins on the clinical manifestations of lupus. Clinical studies are under way, and a preliminary report from one study indicates that patients with SLE may have an increased incidence of adverse effects from statins.3 In addition, the magnitude of the effect of statins on ischemic heart disease and the mechanisms mediating it may differ between patients with SLE and members of the general population. Thus, it will be valuable to have more information regarding the risks and benefits of statins in SLE. However, until such information is available, clinical decisions about the use of statins in patients with SLE will be based largely on safety and efficacy data from clinical trials involving patients without lupus and treatment guidelines derived from other populations of patients with an increased risk of atherosclerotic cardiovascular disease.
C. Michael Stein, M.D.
Vanderbilt University School of Medicine
Nashville, TN 37232-6602
michael.stein@vanderbilt.edu
References
Moder KG, Miller TD, Tazelaar HD. Cardiac involvement in systemic lupus erythematosus. Mayo Clin Proc 1999;74:275-284.
Stein CM, Tanner SB, Awad JA, Roberts LJ II, Morrow JD. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum 1996;39:1146-1150.
Kiani AN, Petri M. Statin toxicity in the lupus atherosclerosis prevention study. Arthritis Rheum 2003;48:Suppl:S370-S370. abstract.
Dr. Hahn replies: I thank Dr. No?l for calling to our attention the report of hypersensitivity and lupus-like reactions that occur in some patients who are taking statins. He describes four such examples.1 One case in particular is convincing. In a 63-year-old man who had had two years of exposure to simvastatin (20 mg daily), polymyalgia rheumatica developed, but it abated over a period of a month after the simvastatin was discontinued. The patients in the three other cases had vasculitis or SLE, which did not respond completely to intensive immunosuppressive therapies, even though the statin was discontinued. Of other patients described in the literature, only one with a hypereosinophilic, hypersensitivity-type reaction had symptoms and laboratory abnormalities that resolved after the statin was discontinued and reappeared on rechallenge. Thus, as is usual in reports of drug-induced lupus, vasculitis, or hypersensitivity, most cases are post hoc ergo propter hoc arguments; a few are absolutely convincing. According to the Physicians' Desk Reference,2 of 10,259 persons treated with simvastatin, less than 1 percent had hypersensitivity reactions, including lupus-like diseases. Therefore, lupus-like and hypersensitivity syndromes are uncommon adverse effects of statins. Furthermore, there is no consistent evidence that exposure to "lupus-inducing" drugs worsens SLE in patients with spontaneous disease. In general, my colleagues and I do not withhold known "lupus-inducers" such as isoniazid or phenytoin from patients with SLE who need them.
I also thank Dr. Violi and colleagues for calling attention to their large body of work3,4 showing that in several chronic inflammatory or degenerative diseases (e.g., Alzheimer's disease, chronic inflammatory lung disease, and the antiphospholipid syndrome), markers of oxidative stress may indicate increased lipid peroxidation, which probably contributes to atherosclerosis by providing highly oxidized low-density lipoprotein that is deposited in arterial walls. They have reported increased lipid peroxidation, measured as urinary levels of the isoprostane prostaglandin F2 type III and similar products of oxidized prostaglandin-related molecules. Increased peroxidation is generally viewed as an adverse metabolic state that confers a predisposition to atherosclerosis.
In summary, we take the points made that exposing patients to statins may in a very small proportion increase their risk of SLE-like disease and that increased lipid oxidation is likely to play a role in accelerating atherosclerosis in patients with SLE and others with chronic inflammatory or degenerative diseases.
Bevra Hannahs Hahn, M.D.
University of California, Los Angeles
Los Angeles, CA 90095
References
Rudski L, Rabinovitch MA, Danoff D. Systemic immune reactions to HMG-CoA reductase inhibitors: report of 4 cases and review of the literature. Medicine (Baltimore) 1998;77:378-383.
Zocor tablets (simvastatin). In: Physicians' desk reference. 58th ed. Montvale, N.J.: Thomson PDR, 2004:2113-8.
Pratico D, Barry OP, Lawson JA, et al. IPF2alpha-I: an index of lipid peroxidation in humans. Proc Natl Acad Sci U S A 1998;95:3449-3454.
Pratico D, Ferro D, Iuliano L, et al. Ongoing prothrombotic state in patients with antiphospholipid antibodies: a role for increased lipid peroxidation. Blood 1999;93:3401-3407.