ARTHRITIS & RHEUMATISMVol. 44, No. 10, October 2001, pp 2215–2217© 2001, American College of RheumatologyPublished by Wiley-Liss, Inc.

EDITORIAL

Atherosclerosis and Lupus: A Work in Progress

Michael D. Lockshin,1 Jane E. Salmon,1 and Mary J. Roman2

Among the clinical challenges of systemic lupuserythematosus (SLE), one of the most compelling is thehigh incidence of atherosclerosis in young women. Ini-tially noted in autopsy studies reported by Bulkley andRoberts in 1975 (1) and emphasized in a report onmyocardial infarction and sudden death by Urowitz et alin 1976 (2), atherosclerosis in SLE has generated aseparate science of its own. Rheumatology, cardiology,and general medical journals are now replete witharticles concerning autoimmune attack on endothelium(3), participation of inflammatory processes in athero-genesis (4,5), aberrant lipid metabolism in autoimmunity(6,7), and interplay of coagulation pathways and im-mune response (8). Special sessions at meetings of theAmerican College of Rheumatology, supplements tomedical journals (9), and even whole books (10) aredevoted to the interwoven cell and molecular biologiesof atherosclerosis and inflammation.

Despite these advances, in many respects thebasic clinical facts are unclear. What, for instance, is thetrue incidence of atherosclerosis in SLE patients abovethat of a comparison population? What risk factors, ifany, are specific to SLE? What are the possible points ofpreventive intervention?

Many studies have addressed these questions, butthey give conflicting answers (for review, see refs. 11 and

12). Prospective studies now in progress provide the bestpreliminary information. The Johns Hopkins group, ledby Petri, uses multiple regression analyses and compar-isons of affected and unaffected SLE patients. Theseinvestigators argue that hypertension, hypercholesterol-emia, hyperhomocysteinemia, and smoking are the pri-mary causes of cardiovascular morbidity in SLE (13,14).Manzi et al (15,16) and Selzer et al (17) in Pittsburgh,initially using Framingham and, more recently, contem-porary matched controls, report that “standard” riskfactors are less important predictors of cardiovascularevents than is the presence of active SLE. Our own teamat the Hospital for Special Surgery–Cornell, led byRoman and Salmon, has compared SLE patients with alarge, employment-based population matched for age,race, sex, hypertension, and other risk factors to deter-mine prevalence rates of underlying atherosclerosis, asopposed to clinical events. Our results agree with thoseof Manzi et al (18). Our group (11) and many others(12,19,20) have contributed their own opinions.

Reports in the clinical literature describe events(angina, myocardial infarction, and stroke) rather thanpreclinical disease. Reports in the extensive biologicliterature define mechanisms of atherogenesis (for re-view, see refs. 4, 9, and 10). These latter reports focusheavily on cytokine and other modulators of macro-phage and endothelial cell function, and on immuno-logic triggers of inflammation. Reports in the clinicalliterature have yet to define clearly many lupus-specificissues: the roles of coexistent cardiac valve disease,antiphospholipid antibody, or corticosteroids, to name afew. The Johns Hopkins, Pittsburgh, and Cornell studiesare ongoing. They incorporate contemporary biologicmeasures, such as levels of mediators and markers ofinflammation (particularly, of endothelial activation andadhesion), detailed lupus serology, lipid and homocys-teine measures, vascular imaging, and measures of vas-

Supported in part by National Institute of Arthritis andMusculoskeletal and Skin Diseases grant AR-45591 and by the BugherFoundation.

1Michael D. Lockshin, MD, Jane E. Salmon, MD: Hospitalfor Special Surgery, Weill Medical College, Cornell University, NewYork, New York; 2Mary J. Roman, MD, MPH: New York–Presbyterian Hospital, Weill Medical College, Cornell University, NewYork, New York.

Address correspondence and reprint requests to Michael D.Lockshin, MD, Barbara Volcker Center, Hospital for Special Surgery,535 East 70th Street, New York, NY 10021. E-mail:LockshinM@hss.edu.

Submitted for publication May 14, 2001; accepted in revisedform July 6, 2001.

Arthritis & RheumatismAn Official Journal of the American College of Rheumatologywww.arthritisrheum.org and www.interscience.wiley.com

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cular wall thickness, elasticity, and left ventricular mass.These studies will do much to elucidate the pathogenesisof atherosclerosis (the presumptive—preventable—precursor of cardiovascular events), but final results willnot be available for several years.

In this issue of Arthritis & Rheumatism, Esdaileand coworkers present an important new contribution(21). Using 2 prospective Canadian SLE cohorts, theseinvestigators have conducted a retrospective analysis oftraditional (Framingham) risk factors. The measuredoutcomes are clinical events, and the study does not godeeply into lupus-specific phenomena. In this account,risks for cardiovascular events are magnified 7–17-foldin SLE patients compared with the Framingham norm.These investigators’ results support those of Manzi et al(15) and Roman et al (18), in that coronary heart diseaseand stroke cannot be explained by Framingham riskfactors alone.

Weaknesses of Esdaile et al’s study include itsretrospective design, with the potential for incompleteand inaccurate reporting, and its use, like the first studyby Manzi and coworkers (15), of the Framingham pop-ulation database rather than a contemporaneous com-parison population matched for standard risk factors.Thus, the possibility remains that an unidentifiedFramingham–Montreal difference in genetics or lifestyleinfluences the data. In addition, the lack of complete,clearly defined electrocardiogram (EKG) data may haveresulted in an underestimation of attributable risk inSLE patients. (Left ventricular hypertrophy [LVH], de-termined by EKG and/or echocardiogram, is one of thestrongest risk factors for adverse cardiovascular out-come. In our own studies, women with SLE have asubstantial increase in echocardiographic LVH [18].)

One strength of the study by Esdaile et al is thatit makes relatively conservative assumptions. Another isthat it presents many thoughtful, original analyses toexclude potential bias. A likely reason for differencesamong the conclusions of the various studies on thissubject (in addition to study design) may be differencesin the socioeconomic and racial distributions of thestudied populations. Although the Johns Hopkins grouptried to exclude this bias in its calculations, lowersmoking rates, less obesity, and less comorbid diseasecharacterized the generally wealthier and more-educated (and more representative of the majority)patient populations of the 3 studies that report a highlupus-specific risk (13,15,18).

Where do these partially conflicting data leavepatients, clinicians, and investigators today? Some an-swers are already reasonably clear. We have consensus

that the relative risk for atherosclerotic cardiovascularevents in SLE patients is high, but we have less agree-ment on the cause. While the need to control traditionalrisk factors aggressively is unquestionable, the weight ofcurrent evidence is that increased risk is caused by morethan hypertension, hypercholesterolemia, and smoking.We are not yet able to predict which individual patient ismost at risk. Does the presence of antiphospholipidantibody, in fact, increase the risk of atherosclerosis?Does Libman-Sacks endocarditis or lupus activity ordamage measures increase this risk? Does treatment ofSLE increase or decrease this risk?

Success at predicting cardiovascular events willprobably require prospective studies (now being done)or better surrogate indicators than have traditionallybeen used in other populations. These surrogates willlikely include biologic markers, such as lipoprotein(a),oxidized low-density lipoprotein, homocysteine, heat-shock protein, circulating adhesion molecules, �2-glycoprotein I, and new autoantibodies, all of which arenow being tested. Surrogates may also include patient-specific imaging and functional studies, such as carotidultrasound for atheromata and intimal–medial thick-ness, echocardiographic measurements of left ventricu-lar wall mass and function, tests of vascular stiffness, orcomputed tomography of vascular walls to detect calci-fication (11,12), all of which are now being done. Which,if any, of these measures will be sufficiently specific,sensitive, affordable, and convenient for screening allSLE patients remains to be seen.

The ongoing prospective studies will (presum-ably) confirm the magnitude of atherosclerosis risk,prioritize surrogate markers, and suggest general ther-apy or prevention measures. Refinement of hypothesesof pathogenesis will follow, and these refinements willsuggest lupus-specific interventions. Then we, as physi-cians, will be able to explore the next great frontier oflupus: prevention of long-term atherosclerosis-associated disability. Meanwhile, we must aggressivelyapply what we already know—treat hyperlipidemia, hy-perglycemia, hyperhomocysteinemia, and hypertensionvigorously and assist patients with smoking cessation(11)—and, according to the data reported in this issue ofArthritis & Rheumatism (21), treat lupus activity vigor-ously as well.

REFERENCES

1. Bulkley BH, Roberts WC. The heart in SLE and the changesinduced in it by corticosteroid therapy: a study of 36 necropsycases. Am J Med 1975;53:243–64.

2. Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe

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HA, Ogryzlo MA. The bimodal mortality pattern of SLE. Am JMed 1976;60:221–5.

3. Bordron A, Revelen R, Dueymes M, Youinou P. Pathogenicity ofantiendothelial cell autoantibodies. In: Shoenfeld Y, Harats D,Wick G, editors. Atherosclerosis and autoimmunity. Amsterdam:Elsevier; 2001. p. 203–10.

4. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med1999;340:115–26.

5. Gordon PA, George J, Khamashta MA, Harats D, Hughes G,Shoenfeld Y. Atherosclerosis and autoimmunity. Lupus 2001;10:249–52.

6. Borba EF, Bonfa E, Vinagre CGC, Ramires JAF, Maranhao RC.Chylomicron metabolism is markedly altered in systemic lupuserythematosus. Arthritis Rheum 2000;43:1033–40.

7. Romero FI, Atsumi T, Tinahones FJ, Gomez-Zumaquero JM,Amengual O, Khamashta MA, et al. Autoantibodies againstmalondialdehyde-modified lipoprotein(a) in antiphospholipid syn-drome. Arthritis Rheum 1999;42:2606–11.

8. Matsuura E, Koike T. Accelerated atheroma and anti-beta2-glycoprotein I antibodies. Lupus 2000;9:210–6.

9. Khamashta M, Hughes G, editors. Special issue: Acceleratedatheroma—leads from lupus. Lupus 2000;9:159–231.

10. Shoenfeld Y, Harats D, Wick G, editors. Atherosclerosis andautoimmunity. Amsterdam: Elsevier; 2001.

11. Salmon JE, Roman MJ. Accelerated atherosclerosis in SLE:implications for patient management. Curr Opin Rheumatol 2001;13:341–4.

12. Jimenez S, Ramos-Casals M, Cervera R, Font J, Ingelmo M.Atherosclerosis in systemic lupus erythematosus: clinical rele-vance. In: Shoenfeld Y, Harats D, Wick G, editors. Atherosclerosisand autoimmunity. Amsterdam: Elsevier; 2001. p. 255–65.

13. Petri M, Perez-Gutthann S, Spence D, Hochberg MC. Risk factorsfor coronary artery disease in patients with SLE. Am J Med1992;93:513–9.

14. Petri M. Cardiovascular morbidity in the Hopkins lupus cohort. In:Shoenfeld Y, Harats D, Wick G, editors. Atherosclerosis andautoimmunity. Amsterdam: Elsevier; 2001. p. 249–54.

15. Manzi S, Selzer F, Sutton-Tyrrell K, Fitzgerald SG, Rairie JE,Tracy RP, et al. Prevalence and risk factors of carotid plaque inwomen with systemic lupus erythematosus. Arthritis Rheum 1999;42:51–60.

16. Manzi S, Kuller LH, Edmundowicz D, Sutton-Tyrrell K. Vascularimaging: changing the face of cardiovascular research. Lupus2000;9:176–82.

17. Selzer F, Sutton-Tyrrell K, Fitzgerald S, Tracy R, Kuller L, ManziS. Vascular stiffness in women with systemic lupus erythematosus.Hypertension 2001;37:1075–82.

18. Roman MJ, Salmon JE, Sobel R, Lockshin MD, Sammaritano L,Schwartz JE, et al. Prevalence and relation to risk factors ofcarotid atherosclerosis and left ventricular hypertrophy in systemiclupus erythematosus and antiphospholipid antibody syndrome.Am J Cardiol 2001;87:663–6.

19. Ward MM. Premature morbidity from cardiovascular and cere-brovascular diseases in women with systemic lupus erythematosus.Arthritis Rheum 1999;42:338–46.

20. Aranow C, Ginzler EM. Epidemiology of cardiovascular disease insystemic lupus erythematosus. Lupus 2000;9:166–9.

21. Esdaile JM, Abrahamowicz M, Grodzicky T, Li Y, Panaritis C, duBerger R, et al. Traditional Framingham risk factors fail to fullyaccount for accelerated atherosclerosis in systemic lupus erythem-atosus. Arthritis Rheum 2001;44:2331–7.

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