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Relative risk of cardiovascular events in patients with rheumatoid arthritis
Relative Risk of Cardiovascular Events in Patients with Rheumatoid Arthritis Anthony N. DeMaria,
MD
Rheumatoid arthritis (RA) is associated with increased comorbidity and mortality resulting from cardiovascular disease. A review of past and recent studies suggests that inflammation and thrombosis may provide a link between both diseases. This association has significant clinical implications for therapy, because many of the drugs used in the symptomatic treatment of RA, such as nonsteroidal anti-inflammatory drugs and the new cyclooxygenase (COX)-2–specific inhibitors, affect mediators of both inflammation and thrombosis. Recent studies have elucidated the potential effects of COX-2–
specific inhibitors on thrombogenic events and their potential impact on cardiovascular disease. Although a causal effect of these drugs to increase the risk of cardiovascular disease has not been established, further investigation is needed on the effects of COX-2–specific inhibitors on cardiovascular risk. Such data would be of particular importance in determining appropriate therapeutic approaches to the treatment of patients with RA who are also at risk for cardiovascular events. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;89(suppl):33D–38D
s the world population ages, there is growing concern with the concomitant increase in the A prevalence of disorders that decrease the quality of life
such events and may provide insight into the cardiovascular findings of recent COX-2 trials.
and increase health resource utilization and costs among the elderly. Musculoskeletal disorders are high on the list of diseases that lead to disability, increased health care costs, and an overall increase in the burden of disease. According to available data from the Centers for Disease Control and Prevention, during the years 1991 to 1992, arthritis/rheumatism was ranked as the primary cause of disability in the United States among persons ⬎15 years of age.1 Osteoarthritis (OA) and rheumatoid arthritis (RA) are 2 of the most prevalent joint disorders. Although both have an age-related increase in prevalence,2– 4 data suggest that patients with RA have rates of comorbidity and mortality that are not only greater than those of the general population, but also greater than those of patients with OA.5 Most important, it has been suggested that the risk for cardiovascular comorbidity is increased in RA.6 This factor is especially relevant with respect to the presumed role of the cyclooxygenase (COX)-related products prostaglandin (PG)I2 (prostacyclin) and PGE2 in cardiovascular homeostasis7–9 and the recent introduction of the new COX-2–specific inhibitors that are being used for the symptomatic treatment of OA and RA. The purpose of this article is to review the comorbidity associated with RA, specifically focusing on the risk factors for cardiovascular events in these patients. A better, albeit incomplete understanding of the relation between RA and cardiovascular disease can provide a useful clinical perspective on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors in patients who may be at risk for
EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS
From the Department of Cardiology, University of California at San Diego Medical Center, San Diego, California, USA. Address for reprints: Anthony N. DeMaria, MD, Department of Cardiology, University of California at San Diego Medical Center, 200 West Arbor Drive, 8411, San Diego, California 92103. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved.
Prevalence, incidence, and risk factors: Although it is known that RA is chronic, multisystemic, and has characteristics suggesting an autoimmune component, no etiologic agent has yet been identified. The lack of an etiologic agent and the absence of unique clinical features have added to the complexity of determining epidemiologic parameters of the disease. However, the development of clinical criteria10 that can be applied for diagnosis has also provided standards that have been used in epidemiologic studies. Reviews of the epidemiology of RA suggest that the population prevalence is 0.5% to 1%, although the annual incidence is highly variable (12 to 1,200 per 100,000 population) and is dependent on a variety of factors, including sex, race or ethnicity, and age.11,12 Age and sex are strong predictors of RA; the estimated prevalence in those ⬎65 years of age in the United States is ⬎10%,2 with a ⬎2-fold prevalence in women compared with men.11 In addition to age and sex, genetic and environmental elements have also been implicated as predisposing factors. These proposed factors include major histocompatibility complex gene products,13 reproductive hormones,14,15 socioeconomic status,16 smoking,15 and education.15,17 Mortality and comorbidity: Increased mortality has long been associated with RA.18 Although a recent report showed similar rates of mortality in patients with RA and nonarthritic control subjects,19 most studies have determined that patients with RA (rheumatoid factor positive) have a higher rate of all-cause mortality compared with age- and sex-matched control subjects without RA. Studies that observed patients for ⱕ35 years suggest that the mortality rate is approximately twice as high in these patients compared with the general population, with calculated standardized mortality ratios that range from 0.87 to 0002-9149/02/$ – see front matter PII S0002-9149(02)02235-X
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3.0.20 –24 A number of studies also attempted to estimate the reduction in life span in patients with RA, and a review of these studies determined that RA is associated with a 5- to 10-year reduction in life expectancy.22 The increased mortality rate is not completely surprising considering that RA is associated with significant levels of comorbidity.5,25 In a cohort study, Gabriel et al5 showed that patients with RA had a higher likelihood of developing congestive heart failure, chronic pulmonary disease, dementia, and peptic ulcer disease than age- and sex-matched control subjects. Additionally, baseline comorbidity was a significant predictor of a further increase in comorbidity, and the presence of RA was shown to be highly predictive of a subsequent increase in comorbidity, even after controlling for the effects of age, sex, and baseline comorbidity.5 Although the contribution of specific determinants to excess mortality has not been fully investigated, studies suggest increased risk from a variety of causes including gastrointestinal, respiratory, cardiovascular, and infectious diseases.11,20 –24,26 –29 In nearly all studies, the most commonly reported cause of mortality was cardiovascular disease, accounting for ⬎50% of the mortality as shown in Table 1,20,21,26,28,30 and up to 30% to 40% of the excess mortality associated with RA.26,27,31 An observational cohort study using data obtained from a large general practice database with ⬎35 million patient-years of data, the General Practice Research Database (GRPD) not only confirmed that RA patients have a significantly increased risk of mortality (60%) and thromboembolic events (30% to 50%) compared with age- and sex-matched control subjects, but also that RA patients had similar significantly elevated risks (70% for death, 30% to 40% for thromboembolic events) compared with OA patients (Table 2).32 As discussed above, the cardiovascular comorbidity and increased mortality from cardiovascular events have been well documented in RA patients. However, the prevalence of cardiovascular disease among patients with RA has only recently been investigated. A study by McEntegart et al6 compared the prevalence of cardiovascular disease in RA patients with control subjects after adjusting for age, sex, smoking status, and number of cigarettes smoked per day. Except for diabetes, a higher prevalence of cardiovascular disease was observed in RA patients (Table 3), with statistically significant differences in the prevalence of angina (18% vs 8%, p ⫽ 0.03) and chest pain as determined by the Rose Angina Questionnaire (30% vs 15%, p ⫽ 0.007), and a nonsignificant 5-fold higher prevalence of stroke.
CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS The greater prevalence of cardiovascular disease among patients with RA compared with control subjects and the increased risk of cardiovascular events in these patients have suggested underlying factors that 34D THE AMERICAN JOURNAL OF CARDIOLOGY姞
TABLE 1 Deaths Attributed to Cardiovascular (CV) Disease in Patients with Rheumatoid Arthritis Total Deaths Standardized Deaths of CV Mortality (n) Disease (n) Ratio
Study (No. of Patients)
Prior et al.30 (409) 199 Ischemic heart disease Cerebrovascular disease Other CV disease Mutru et al.26 (1,000) 356 Ischemic heart disease Heart failure Cerebrovascular disease Other CV disease Wolfe et al.20 (3,501) 922 Cerebrovascular disease Other CV disease Myllykangas-Luosuja ¨ rvi et al.21 1,186 Ischemic heart disease Other CV disease Wållberg-Jonsson et al.28 (606) 265 Ischemic heart disease Cerebrovascular disease Total CV diseases
40 15 23
2.14 1.79 3.85
90 21 29 26
1.13 5.25 1.16 2.60
62 364
2.45 2.24
319 274
1.51 1.14
80 21 140
1.54 1.1 1.46
Adapted from Semin Arthritis Rheum.21
TABLE 2 Age- and Sex-Adjusted Rate Ratios for Cardiovascular Events in a Population of Rheumatoid Arthritis Patients Compared with Osteoarthritis Patients and Nonarthritic Control Subjects Rate Ratios (95% CI) Versus No Arthritis
Event All-cause mortality MI Sudden death Stroke Cardiovascular death (fatal MI, sudden death, fatal stroke) All thromboembolic events
1.60 1.55 1.30 1.37 1.45
Versus Osteoarthritis
(1.55–1.63) (1.46–1.65) (1.07–1.58) (1.29–1.45) (1.35–1.57)
1.72 1.32 1.33 1.26 1.41
(1.67–1.78) (1.24–1.41) (1.09–1.63) (1.18–1.34) (1.24–1.61)
1.47 (1.41–1.54) 1.31 (1.25–1.39)
CI ⫽ confidence interval; MI ⫽ myocardial infarction. Adapted from Arthritis Rheum.32
TABLE 3 Prevalence of Cardiovascular Disease in Patients with Rheumatoid Arthritis (RA) and Control Subjects Matched for Age, Sex, Smoking Status, and Number of Cigarettes per Day Prevalence (%)
Angina MI Stroke Diabetes Rose chest pain
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RA Patients (n ⫽ 76)
Control Subjects (n ⫽ 641)
p Value
18 7 5 1 30
8 5 1 3 15
0.03 0.65 0.08 0.7 0.007
MI ⫽ myocardial infarction. Adapted from Rheumatology (Oxford).6
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TABLE 4 Similarities Between Atherosclerosis and Rheumatoid Arthritis
Macrophage activation TNF-␣ Metalloproteinase expression IL-6 Mast cell activation T-cell activation Soluble IL-2 receptor CD3⫹DR⫹ CD4⫹CD28⫺ CD4⫹IFN-␥⫹ Th1/Th2 balance B-cell activation Autoantibodies (ox-LDL, HSP) Rheumatoid factor C-reactive protein Adhesion molecules (VCAM-1, ICAM-1, E-selectin, P-selectin) Endothelin Neoangiogenesis Possible antigens
Atherosclerosis
Rheumatoid Arthritis
⫹ ⫹ (UA) ⫹ ⫹
⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
(UA) (UA) (UA) (UA) (UA)
0 or ⫹ 0 ⫹ (UA) ⫹
0 or ⫹ ⫹ ⫹⫹ ⫹
⫹ ⫹ HSP, Ox-LDL, infectious agents
⫹ ⫹ Collagen II, cartilage antigens, HSP, infectious agents
⫹ ⫽ increased; ⫹⫹ ⫽ markedly increased; HSP ⫽ heat shock protein; ICAM ⫽ intercellular adhesion molecule; IFN ⫽ interferon; IL ⫽ interleukin; ox-LDL ⫽ oxidized low-density lipoprotein; TNF-␣ ⫽ tumor necrosis factor–␣; UA ⫽ systemic markers found increased in patients with unstable angina (other factors are expressed in atherosclerotic plaque); VCAM ⫽ vascular cell adhesion molecule. Reprinted with permission from Circulation.45
may be associated with the presence of RA. Data suggest that both the inflammatory response and thrombogenic factors are integral to the development and risk of cardiovascular disease in patients with RA. A retrospective cohort study designed to identify predictors of cardiovascular disease in patients with RA determined that, although there was an increased risk for cardiovascular events in men with RA and in people with a higher age at RA onset, inflammation was a major risk factor for both cardiovascular disease and mortality.33 In that study, the erythrocyte sedimentation rate, a marker of inflammatory activity, was demonstrated to be significantly associated with risk for cardiovascular disease and events. A follow-up study prospectively investigated the relation between hemostatic and inflammatory variables on progression of cardiovascular disease in RA.34 Again, there was a significant association between increased erythrocyte sedimentation rate levels and risk for cardiovascular events. Additionally, several hemostatic factors, including haptoglobin, von Willebrand factor, tissueplasminogen activator, and plasminogen activator inhibitor, were either associated with increased risk for cardiovascular events or were associated with cardiovascular disease progression. The recent study by McEntegart et al6 confirmed that 2 of the thrombotic variables that were associated with cardiovascular risk in the above study, von Willebrand factor and tissue plasminogen activator, are significantly elevated in patients with RA compared with control subjects. Other thrombotic variables, fibrinogen, D-dimer, and plasma viscosity, were also elevated. Recently, attention has focused on the role of in-
flammation in the production of vulnerable plaques that go on to fissure/rupture and superimposed thrombosis. RA itself is generally considered an inflammatory disease, unlike OA, which has inflammatory components but is not considered a disease characterized by inflammation. Both erythrocyte sedimentation rate and C-reactive protein have been used as indicators of inflammation and disease progression and outcome in RA; persistent elevation of C-reactive protein in the acute phase of RA is associated with functional deterioration,35 and elevated erythrocyte sedimentation rate is strongly correlated with radiographic progression of the disease.36,37 C-reactive protein has also been implicated as an independent but noncausal risk factor for cardiovascular disease in both men and women.38 – 41 Additional data have suggested not only that C-reactive protein potentially plays a direct role in promoting the inflammatory component of atherosclerosis by inducing expression of adhesion molecules in endothelial cells,42 but that high levels of this protein might result in a hyperresponsiveness to proinflammatory stimuli.43 Results of these and other studies have implied that the link between inflammation and both cardiovascular disease and RA is similar and extends to a variety of cellular and molecular mediators of the inflammatory response (Table 4).44,45 However, further studies are needed to characterize causal links between the 2 diseases. Although the specific role of thrombotic factors in cardiovascular disease in patients with RA has yet to be fully elucidated, it is important to consider thrombogenesis with respect to the important role of prostanoids in this process. Prostanoids play central roles not only in the inflammatory process that characterizes
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TABLE 5 Effects of Aspirin, Traditional Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), and Cyclooxygenase (COX)-2–Specific Inhibitors on the Biosynthesis of COX-1– Dependent Thromboxane (Tx)A2 and COX-2–Dependent Prostacyclin (PGI2)
Aspirin Traditional NSAIDs COX-2–specific inhibitors
PGI2
TxA2
Thrombotic Risk
⫽ 2 2
22 2 ⫽
2 Unclear Unclear
Reprinted with permission from Am J Med.46
RA but also in the regulation of thrombogenesis. The synthesis of 2 central mediators, prothrombotic thromboxane and antithrombotic prostacyclin, are dependent on COX, the enzyme that is the target of nonspecific NSAIDs and COX-2–specific inhibitors, the main pharmacologic agents used for the symptomatic treatment of RA. Although traditional NSAIDs and aspirin inhibit both COX-1 and COX-2, and thereby both thromboxane and prostacyclin, COX-2–specific inhibitors target COX-2, resulting primarily in inhibition of synthesis of prostacyclin.7 Prostacyclin may be especially important as a compensatory mediator of thrombogenesis, because it has been shown that prostacyclin biosynthesis is increased in unstable angina and other syndromes where there is platelet activation.8 The effect of NSAIDs and COX-2–specific inhibitors on prostacyclin and thromboxane biosynthesis are shown in Table 5.46 A potential for an imbalance between prostacyclin and thromboxane may have clinical implications for the treatment of RA patients at high risk for cardiovascular disease with NSAIDs.
CLINICAL IMPLICATIONS FOR TREATMENT OF RHEUMATOID ARTHRITIS Aspirin, nonspecific NSAIDs, and COX-2–specific inhibitors are all used for the symptomatic treatment of RA. Because the studies discussed above suggest an association between cardiovascular disease and RA and the possible similarity of mechanisms, it is important to consider the clinical implications of these drugs, because they affect the inflammatory and thrombogenic components linking cardiovascular disease and RA. The use of NSAIDs is associated with increased blood pressure, which may act to offset the effect of antihypertensive agents.47–50 These drugs have also been implicated in the development of heart failure in elderly patients.51 However, it is likely that, although this may increase the risk of a cardiovascular event in patients with RA, the causal mechanisms may already be present, and the recommendation is for careful monitoring of patients and prophylactic therapy for cardiovascular disease.47,48 Likewise, the new COX2–specific inhibitors have been shown to have a dosedependent effect on the incidence of hypertension,52,53 although the implications of this have not been determined because the extent of these effects has not been clinically studied. 36D THE AMERICAN JOURNAL OF CARDIOLOGY姞
However, recent emphasis on determining the relation between cardiovascular events and the use of NSAIDs and COX-2–specific inhibitors in RA patients has focused on the effects of these drugs on thrombogenesis. This focus has resulted from observations in a large-scale study with the COX-2–specific inhibitor rofecoxib (Vioxx Gastrointestinal Outcomes Research [VIGOR] trial)54 that RA patients taking rofecoxib had a greater incidence of cardiovascular events than patients taking the standard NSAID naproxen. In VIGOR, the incidence of myocardial infarction was 0.5%, 5-fold higher than the incidence for the comparator naproxen. These data differed from another large-scale study, the Celecoxib Long-term Arthritis Safety Study (CLASS) that used a different COX-2–specific inhibitor, celecoxib.52 However, in the CLASS study, the patient population consisted of those with OA or RA, and use of aspirin, a known inhibitor of platelet function, was permitted.55 In accounting for the results of VIGOR, it should be noted that although the results could potentially be caused by chance, considering the low number of events and that the study was not designed to show differences in this endpoint, there is also the possibility that rofecoxib increased the cardiovascular risk. However, unlike the CLASS study, patients were not permitted to use low-dose aspirin, although 4% of the patient population met US Food and Drug Administration (FDA) criteria for aspirin as secondary prophylaxis for cardiovascular/cerebrovascular events. Importantly, one third of the myocardial infarctions (33%) occurred in this group of patients. Another likely factor in the difference between rofecoxib and naproxen in the VIGOR trial is the putative cardioprotection of the latter drug because of an antiplatelet effect. Although no definitive studies have been reported on the platelet effect of naproxen, data exist that suggest that platelet aggregation is inhibited by naproxen over the entire dosing interval.53 Several reports from different countries (United Kingdom, Canada, and the United States) have confirmed the cardioprotective effect of naproxen. These studies determined that use of naproxen resulted in significant risk reductions for myocardial infarction in the general population by 26% (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.72 to 0.98),56 for thromboembolic events in RA patients by 42% (OR, 0.58; 95% CI, 0.37 to 0.92),57 and for myocardial infarction by 35% compared with other NSAIDs (OR, 0.65; 95% CI, 0.48 to 0.87).58 However, the cardio-
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protective effect of naproxen in these studies was shown to be dependent on current use of the drug, suggesting that the antiplatelet effect of naproxen is short term, and long-term use is required for a full cardioprotective effect. Interestingly, the cardioprotective effect of aspirin has been thought to be related to its anti-inflammatory effect as well as its antiplatelet effect, because it was observed that the magnitude of myocardial infarction risk reduction during aspirin therapy was related to the baseline level of C-reactive protein.59 However, a subsequent study determined that short-term use of aspirin had no effect on C-reactive protein levels as an inflammatory marker,60 suggesting that aspirin’s cardioprotective effect may not be related to its antiinflammatory effect. Nevertheless, it cannot be ruled out that naproxen, as well as other NSAIDs, may have a cardioprotective effect as a result of their antiinflammatory activity. The overall importance of these data is that patients with RA have an increased cardiovascular risk, and therefore these patients should be carefully evaluated before and carefully monitored while on anti-inflammatory therapy. An important clinical question is what is the best anti-inflammatory agent to use. Aspirin, alone or in combination with other agents, is indicated for secondary prevention in patients with evidence of cardiovascular disease. The use of other NSAIDs is currently not recommended as prophylaxis and has not been adequately investigated. However, RA would not qualify for secondary cardiovascular prophylaxis at the present time. Although data are available suggesting that aspirin but not other NSAIDs may be useful in the primary prophylaxis for myocardial infarction in premenopausal women,61 the general usefulness of aspirin for primary prophylaxis of cardiovascular/cerebrovascular disease is not established. Secondary prophylaxis for cardiovascular/cerebrovascular events using aspirin is currently recommended based on its antiplatelet effect.62,63 The gastrointestinal-sparing effect of COX-2–specific inhibitors is the basis for their extensive use, but it is accompanied by the potential for an imbalance of thromboxane and prostacyclin. The addition of lowdose aspirin could mitigate a thrombotic state, but few data have accumulated on the gastrointestinal effects of these drugs in combination with aspirin or nonaspirin NSAIDs. Therefore, patient evaluation and monitoring becomes critical in determining the best therapeutic strategy for patients at risk for both gastrointestinal and cardiovascular events. Although cardiovascular prophylaxis should be of primary concern, further studies are needed (1) to characterize both the cardiovascular effects and risks of NSAIDs and COX-2 inhibitors alone or in combination with such prophylaxis and the gastrointestinal effects of COX-2 inhibitors and low-dose aspirin, and (2) to obtain consensus on appropriate therapeutic regimens for the treatment of patients with RA who are also indicated for risk of cardiovascular events.
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50. Ruoff GE. The impact of nonsteroidal anti-inflammatory drugs on hyperten-
sion: alternative analgesics for patients at risk. Clin Ther 1998;20:376 –387. 51. Page J, Henry D. Consumption of NSAIDs and the development of conges-
tive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777–784. 52. Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, MD: February 8, 2001. 53. Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, MD: February 8, 2001. 54. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343: 1520 –1528. 55. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, Makuch R, Eisen G, Agrawal NM, Stenson WF, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247–1255. 56. Solomon DH, Glynn RJ, Levin R, Avorn J. The relationship between NSAIDs and myocardial infarction. Arthritis Rheum 2001;44(suppl 9):S230. Abstract 1655. 57. Watson DJ, Rhodes T, Holmes RH, Guess HA. Reduced risk of acute thromboembolic events with naproxen in rheumatoid arthritis patients in the UK General Practice Research Database (GPRD). Arthritis Rheum 2001;44(suppl 9):S372. Abstract 1918. 58. Rahme E, Pilote L, Lelorier J. Association of conventional non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) with hospitalizations for myocardial infarction. Arthritis Rheum 2001;44(suppl 9):S266. Abstract 1278. 59. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979. 60. Feng D, Tracy RP, Lipinska I, Murillo J, McKenna C, Tofler GH. Effect of short-term aspirin use on C-reactive protein. J Thromb Thrombolysis 2000;9:37– 41. 61. Garcı´a Rodriguez LA, Varas C, Patrono C. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000;11:382– 387. 62. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. AHA Scientific Statement. Supplement to the guidelines for the management of transient ischemic attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association. Stroke 1999;30:2502–2511. 63. Smith SC Jr, Blair SN, Bonow RO, Brass LM, Cerqueira MD, Dracup K, Fuster V, Gotto A, Grundy SM, Miller NH, et al. AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: a statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 2001;104:1577–1579.
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MD
Rheumatoid arthritis (RA) is associated with increased comorbidity and mortality resulting from cardiovascular disease. A review of past and recent studies suggests that inflammation and thrombosis may provide a link between both diseases. This association has significant clinical implications for therapy, because many of the drugs used in the symptomatic treatment of RA, such as nonsteroidal anti-inflammatory drugs and the new cyclooxygenase (COX)-2–specific inhibitors, affect mediators of both inflammation and thrombosis. Recent studies have elucidated the potential effects of COX-2–
specific inhibitors on thrombogenic events and their potential impact on cardiovascular disease. Although a causal effect of these drugs to increase the risk of cardiovascular disease has not been established, further investigation is needed on the effects of COX-2–specific inhibitors on cardiovascular risk. Such data would be of particular importance in determining appropriate therapeutic approaches to the treatment of patients with RA who are also at risk for cardiovascular events. 䊚2002 by Excerpta Medica, Inc. Am J Cardiol 2002;89(suppl):33D–38D
s the world population ages, there is growing concern with the concomitant increase in the A prevalence of disorders that decrease the quality of life
such events and may provide insight into the cardiovascular findings of recent COX-2 trials.
and increase health resource utilization and costs among the elderly. Musculoskeletal disorders are high on the list of diseases that lead to disability, increased health care costs, and an overall increase in the burden of disease. According to available data from the Centers for Disease Control and Prevention, during the years 1991 to 1992, arthritis/rheumatism was ranked as the primary cause of disability in the United States among persons ⬎15 years of age.1 Osteoarthritis (OA) and rheumatoid arthritis (RA) are 2 of the most prevalent joint disorders. Although both have an age-related increase in prevalence,2– 4 data suggest that patients with RA have rates of comorbidity and mortality that are not only greater than those of the general population, but also greater than those of patients with OA.5 Most important, it has been suggested that the risk for cardiovascular comorbidity is increased in RA.6 This factor is especially relevant with respect to the presumed role of the cyclooxygenase (COX)-related products prostaglandin (PG)I2 (prostacyclin) and PGE2 in cardiovascular homeostasis7–9 and the recent introduction of the new COX-2–specific inhibitors that are being used for the symptomatic treatment of OA and RA. The purpose of this article is to review the comorbidity associated with RA, specifically focusing on the risk factors for cardiovascular events in these patients. A better, albeit incomplete understanding of the relation between RA and cardiovascular disease can provide a useful clinical perspective on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors in patients who may be at risk for
EPIDEMIOLOGY OF RHEUMATOID ARTHRITIS
From the Department of Cardiology, University of California at San Diego Medical Center, San Diego, California, USA. Address for reprints: Anthony N. DeMaria, MD, Department of Cardiology, University of California at San Diego Medical Center, 200 West Arbor Drive, 8411, San Diego, California 92103. E-mail: [email protected]. ©2002 by Excerpta Medica, Inc. All rights reserved.
Prevalence, incidence, and risk factors: Although it is known that RA is chronic, multisystemic, and has characteristics suggesting an autoimmune component, no etiologic agent has yet been identified. The lack of an etiologic agent and the absence of unique clinical features have added to the complexity of determining epidemiologic parameters of the disease. However, the development of clinical criteria10 that can be applied for diagnosis has also provided standards that have been used in epidemiologic studies. Reviews of the epidemiology of RA suggest that the population prevalence is 0.5% to 1%, although the annual incidence is highly variable (12 to 1,200 per 100,000 population) and is dependent on a variety of factors, including sex, race or ethnicity, and age.11,12 Age and sex are strong predictors of RA; the estimated prevalence in those ⬎65 years of age in the United States is ⬎10%,2 with a ⬎2-fold prevalence in women compared with men.11 In addition to age and sex, genetic and environmental elements have also been implicated as predisposing factors. These proposed factors include major histocompatibility complex gene products,13 reproductive hormones,14,15 socioeconomic status,16 smoking,15 and education.15,17 Mortality and comorbidity: Increased mortality has long been associated with RA.18 Although a recent report showed similar rates of mortality in patients with RA and nonarthritic control subjects,19 most studies have determined that patients with RA (rheumatoid factor positive) have a higher rate of all-cause mortality compared with age- and sex-matched control subjects without RA. Studies that observed patients for ⱕ35 years suggest that the mortality rate is approximately twice as high in these patients compared with the general population, with calculated standardized mortality ratios that range from 0.87 to 0002-9149/02/$ – see front matter PII S0002-9149(02)02235-X
33D
3.0.20 –24 A number of studies also attempted to estimate the reduction in life span in patients with RA, and a review of these studies determined that RA is associated with a 5- to 10-year reduction in life expectancy.22 The increased mortality rate is not completely surprising considering that RA is associated with significant levels of comorbidity.5,25 In a cohort study, Gabriel et al5 showed that patients with RA had a higher likelihood of developing congestive heart failure, chronic pulmonary disease, dementia, and peptic ulcer disease than age- and sex-matched control subjects. Additionally, baseline comorbidity was a significant predictor of a further increase in comorbidity, and the presence of RA was shown to be highly predictive of a subsequent increase in comorbidity, even after controlling for the effects of age, sex, and baseline comorbidity.5 Although the contribution of specific determinants to excess mortality has not been fully investigated, studies suggest increased risk from a variety of causes including gastrointestinal, respiratory, cardiovascular, and infectious diseases.11,20 –24,26 –29 In nearly all studies, the most commonly reported cause of mortality was cardiovascular disease, accounting for ⬎50% of the mortality as shown in Table 1,20,21,26,28,30 and up to 30% to 40% of the excess mortality associated with RA.26,27,31 An observational cohort study using data obtained from a large general practice database with ⬎35 million patient-years of data, the General Practice Research Database (GRPD) not only confirmed that RA patients have a significantly increased risk of mortality (60%) and thromboembolic events (30% to 50%) compared with age- and sex-matched control subjects, but also that RA patients had similar significantly elevated risks (70% for death, 30% to 40% for thromboembolic events) compared with OA patients (Table 2).32 As discussed above, the cardiovascular comorbidity and increased mortality from cardiovascular events have been well documented in RA patients. However, the prevalence of cardiovascular disease among patients with RA has only recently been investigated. A study by McEntegart et al6 compared the prevalence of cardiovascular disease in RA patients with control subjects after adjusting for age, sex, smoking status, and number of cigarettes smoked per day. Except for diabetes, a higher prevalence of cardiovascular disease was observed in RA patients (Table 3), with statistically significant differences in the prevalence of angina (18% vs 8%, p ⫽ 0.03) and chest pain as determined by the Rose Angina Questionnaire (30% vs 15%, p ⫽ 0.007), and a nonsignificant 5-fold higher prevalence of stroke.
CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS The greater prevalence of cardiovascular disease among patients with RA compared with control subjects and the increased risk of cardiovascular events in these patients have suggested underlying factors that 34D THE AMERICAN JOURNAL OF CARDIOLOGY姞
TABLE 1 Deaths Attributed to Cardiovascular (CV) Disease in Patients with Rheumatoid Arthritis Total Deaths Standardized Deaths of CV Mortality (n) Disease (n) Ratio
Study (No. of Patients)
Prior et al.30 (409) 199 Ischemic heart disease Cerebrovascular disease Other CV disease Mutru et al.26 (1,000) 356 Ischemic heart disease Heart failure Cerebrovascular disease Other CV disease Wolfe et al.20 (3,501) 922 Cerebrovascular disease Other CV disease Myllykangas-Luosuja ¨ rvi et al.21 1,186 Ischemic heart disease Other CV disease Wållberg-Jonsson et al.28 (606) 265 Ischemic heart disease Cerebrovascular disease Total CV diseases
40 15 23
2.14 1.79 3.85
90 21 29 26
1.13 5.25 1.16 2.60
62 364
2.45 2.24
319 274
1.51 1.14
80 21 140
1.54 1.1 1.46
Adapted from Semin Arthritis Rheum.21
TABLE 2 Age- and Sex-Adjusted Rate Ratios for Cardiovascular Events in a Population of Rheumatoid Arthritis Patients Compared with Osteoarthritis Patients and Nonarthritic Control Subjects Rate Ratios (95% CI) Versus No Arthritis
Event All-cause mortality MI Sudden death Stroke Cardiovascular death (fatal MI, sudden death, fatal stroke) All thromboembolic events
1.60 1.55 1.30 1.37 1.45
Versus Osteoarthritis
(1.55–1.63) (1.46–1.65) (1.07–1.58) (1.29–1.45) (1.35–1.57)
1.72 1.32 1.33 1.26 1.41
(1.67–1.78) (1.24–1.41) (1.09–1.63) (1.18–1.34) (1.24–1.61)
1.47 (1.41–1.54) 1.31 (1.25–1.39)
CI ⫽ confidence interval; MI ⫽ myocardial infarction. Adapted from Arthritis Rheum.32
TABLE 3 Prevalence of Cardiovascular Disease in Patients with Rheumatoid Arthritis (RA) and Control Subjects Matched for Age, Sex, Smoking Status, and Number of Cigarettes per Day Prevalence (%)
Angina MI Stroke Diabetes Rose chest pain
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RA Patients (n ⫽ 76)
Control Subjects (n ⫽ 641)
p Value
18 7 5 1 30
8 5 1 3 15
0.03 0.65 0.08 0.7 0.007
MI ⫽ myocardial infarction. Adapted from Rheumatology (Oxford).6
MARCH 21, 2002
TABLE 4 Similarities Between Atherosclerosis and Rheumatoid Arthritis
Macrophage activation TNF-␣ Metalloproteinase expression IL-6 Mast cell activation T-cell activation Soluble IL-2 receptor CD3⫹DR⫹ CD4⫹CD28⫺ CD4⫹IFN-␥⫹ Th1/Th2 balance B-cell activation Autoantibodies (ox-LDL, HSP) Rheumatoid factor C-reactive protein Adhesion molecules (VCAM-1, ICAM-1, E-selectin, P-selectin) Endothelin Neoangiogenesis Possible antigens
Atherosclerosis
Rheumatoid Arthritis
⫹ ⫹ (UA) ⫹ ⫹
⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
⫹ ⫹ ⫹ ⫹ ⫹
(UA) (UA) (UA) (UA) (UA)
0 or ⫹ 0 ⫹ (UA) ⫹
0 or ⫹ ⫹ ⫹⫹ ⫹
⫹ ⫹ HSP, Ox-LDL, infectious agents
⫹ ⫹ Collagen II, cartilage antigens, HSP, infectious agents
⫹ ⫽ increased; ⫹⫹ ⫽ markedly increased; HSP ⫽ heat shock protein; ICAM ⫽ intercellular adhesion molecule; IFN ⫽ interferon; IL ⫽ interleukin; ox-LDL ⫽ oxidized low-density lipoprotein; TNF-␣ ⫽ tumor necrosis factor–␣; UA ⫽ systemic markers found increased in patients with unstable angina (other factors are expressed in atherosclerotic plaque); VCAM ⫽ vascular cell adhesion molecule. Reprinted with permission from Circulation.45
may be associated with the presence of RA. Data suggest that both the inflammatory response and thrombogenic factors are integral to the development and risk of cardiovascular disease in patients with RA. A retrospective cohort study designed to identify predictors of cardiovascular disease in patients with RA determined that, although there was an increased risk for cardiovascular events in men with RA and in people with a higher age at RA onset, inflammation was a major risk factor for both cardiovascular disease and mortality.33 In that study, the erythrocyte sedimentation rate, a marker of inflammatory activity, was demonstrated to be significantly associated with risk for cardiovascular disease and events. A follow-up study prospectively investigated the relation between hemostatic and inflammatory variables on progression of cardiovascular disease in RA.34 Again, there was a significant association between increased erythrocyte sedimentation rate levels and risk for cardiovascular events. Additionally, several hemostatic factors, including haptoglobin, von Willebrand factor, tissueplasminogen activator, and plasminogen activator inhibitor, were either associated with increased risk for cardiovascular events or were associated with cardiovascular disease progression. The recent study by McEntegart et al6 confirmed that 2 of the thrombotic variables that were associated with cardiovascular risk in the above study, von Willebrand factor and tissue plasminogen activator, are significantly elevated in patients with RA compared with control subjects. Other thrombotic variables, fibrinogen, D-dimer, and plasma viscosity, were also elevated. Recently, attention has focused on the role of in-
flammation in the production of vulnerable plaques that go on to fissure/rupture and superimposed thrombosis. RA itself is generally considered an inflammatory disease, unlike OA, which has inflammatory components but is not considered a disease characterized by inflammation. Both erythrocyte sedimentation rate and C-reactive protein have been used as indicators of inflammation and disease progression and outcome in RA; persistent elevation of C-reactive protein in the acute phase of RA is associated with functional deterioration,35 and elevated erythrocyte sedimentation rate is strongly correlated with radiographic progression of the disease.36,37 C-reactive protein has also been implicated as an independent but noncausal risk factor for cardiovascular disease in both men and women.38 – 41 Additional data have suggested not only that C-reactive protein potentially plays a direct role in promoting the inflammatory component of atherosclerosis by inducing expression of adhesion molecules in endothelial cells,42 but that high levels of this protein might result in a hyperresponsiveness to proinflammatory stimuli.43 Results of these and other studies have implied that the link between inflammation and both cardiovascular disease and RA is similar and extends to a variety of cellular and molecular mediators of the inflammatory response (Table 4).44,45 However, further studies are needed to characterize causal links between the 2 diseases. Although the specific role of thrombotic factors in cardiovascular disease in patients with RA has yet to be fully elucidated, it is important to consider thrombogenesis with respect to the important role of prostanoids in this process. Prostanoids play central roles not only in the inflammatory process that characterizes
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TABLE 5 Effects of Aspirin, Traditional Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), and Cyclooxygenase (COX)-2–Specific Inhibitors on the Biosynthesis of COX-1– Dependent Thromboxane (Tx)A2 and COX-2–Dependent Prostacyclin (PGI2)
Aspirin Traditional NSAIDs COX-2–specific inhibitors
PGI2
TxA2
Thrombotic Risk
⫽ 2 2
22 2 ⫽
2 Unclear Unclear
Reprinted with permission from Am J Med.46
RA but also in the regulation of thrombogenesis. The synthesis of 2 central mediators, prothrombotic thromboxane and antithrombotic prostacyclin, are dependent on COX, the enzyme that is the target of nonspecific NSAIDs and COX-2–specific inhibitors, the main pharmacologic agents used for the symptomatic treatment of RA. Although traditional NSAIDs and aspirin inhibit both COX-1 and COX-2, and thereby both thromboxane and prostacyclin, COX-2–specific inhibitors target COX-2, resulting primarily in inhibition of synthesis of prostacyclin.7 Prostacyclin may be especially important as a compensatory mediator of thrombogenesis, because it has been shown that prostacyclin biosynthesis is increased in unstable angina and other syndromes where there is platelet activation.8 The effect of NSAIDs and COX-2–specific inhibitors on prostacyclin and thromboxane biosynthesis are shown in Table 5.46 A potential for an imbalance between prostacyclin and thromboxane may have clinical implications for the treatment of RA patients at high risk for cardiovascular disease with NSAIDs.
CLINICAL IMPLICATIONS FOR TREATMENT OF RHEUMATOID ARTHRITIS Aspirin, nonspecific NSAIDs, and COX-2–specific inhibitors are all used for the symptomatic treatment of RA. Because the studies discussed above suggest an association between cardiovascular disease and RA and the possible similarity of mechanisms, it is important to consider the clinical implications of these drugs, because they affect the inflammatory and thrombogenic components linking cardiovascular disease and RA. The use of NSAIDs is associated with increased blood pressure, which may act to offset the effect of antihypertensive agents.47–50 These drugs have also been implicated in the development of heart failure in elderly patients.51 However, it is likely that, although this may increase the risk of a cardiovascular event in patients with RA, the causal mechanisms may already be present, and the recommendation is for careful monitoring of patients and prophylactic therapy for cardiovascular disease.47,48 Likewise, the new COX2–specific inhibitors have been shown to have a dosedependent effect on the incidence of hypertension,52,53 although the implications of this have not been determined because the extent of these effects has not been clinically studied. 36D THE AMERICAN JOURNAL OF CARDIOLOGY姞
However, recent emphasis on determining the relation between cardiovascular events and the use of NSAIDs and COX-2–specific inhibitors in RA patients has focused on the effects of these drugs on thrombogenesis. This focus has resulted from observations in a large-scale study with the COX-2–specific inhibitor rofecoxib (Vioxx Gastrointestinal Outcomes Research [VIGOR] trial)54 that RA patients taking rofecoxib had a greater incidence of cardiovascular events than patients taking the standard NSAID naproxen. In VIGOR, the incidence of myocardial infarction was 0.5%, 5-fold higher than the incidence for the comparator naproxen. These data differed from another large-scale study, the Celecoxib Long-term Arthritis Safety Study (CLASS) that used a different COX-2–specific inhibitor, celecoxib.52 However, in the CLASS study, the patient population consisted of those with OA or RA, and use of aspirin, a known inhibitor of platelet function, was permitted.55 In accounting for the results of VIGOR, it should be noted that although the results could potentially be caused by chance, considering the low number of events and that the study was not designed to show differences in this endpoint, there is also the possibility that rofecoxib increased the cardiovascular risk. However, unlike the CLASS study, patients were not permitted to use low-dose aspirin, although 4% of the patient population met US Food and Drug Administration (FDA) criteria for aspirin as secondary prophylaxis for cardiovascular/cerebrovascular events. Importantly, one third of the myocardial infarctions (33%) occurred in this group of patients. Another likely factor in the difference between rofecoxib and naproxen in the VIGOR trial is the putative cardioprotection of the latter drug because of an antiplatelet effect. Although no definitive studies have been reported on the platelet effect of naproxen, data exist that suggest that platelet aggregation is inhibited by naproxen over the entire dosing interval.53 Several reports from different countries (United Kingdom, Canada, and the United States) have confirmed the cardioprotective effect of naproxen. These studies determined that use of naproxen resulted in significant risk reductions for myocardial infarction in the general population by 26% (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.72 to 0.98),56 for thromboembolic events in RA patients by 42% (OR, 0.58; 95% CI, 0.37 to 0.92),57 and for myocardial infarction by 35% compared with other NSAIDs (OR, 0.65; 95% CI, 0.48 to 0.87).58 However, the cardio-
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protective effect of naproxen in these studies was shown to be dependent on current use of the drug, suggesting that the antiplatelet effect of naproxen is short term, and long-term use is required for a full cardioprotective effect. Interestingly, the cardioprotective effect of aspirin has been thought to be related to its anti-inflammatory effect as well as its antiplatelet effect, because it was observed that the magnitude of myocardial infarction risk reduction during aspirin therapy was related to the baseline level of C-reactive protein.59 However, a subsequent study determined that short-term use of aspirin had no effect on C-reactive protein levels as an inflammatory marker,60 suggesting that aspirin’s cardioprotective effect may not be related to its antiinflammatory effect. Nevertheless, it cannot be ruled out that naproxen, as well as other NSAIDs, may have a cardioprotective effect as a result of their antiinflammatory activity. The overall importance of these data is that patients with RA have an increased cardiovascular risk, and therefore these patients should be carefully evaluated before and carefully monitored while on anti-inflammatory therapy. An important clinical question is what is the best anti-inflammatory agent to use. Aspirin, alone or in combination with other agents, is indicated for secondary prevention in patients with evidence of cardiovascular disease. The use of other NSAIDs is currently not recommended as prophylaxis and has not been adequately investigated. However, RA would not qualify for secondary cardiovascular prophylaxis at the present time. Although data are available suggesting that aspirin but not other NSAIDs may be useful in the primary prophylaxis for myocardial infarction in premenopausal women,61 the general usefulness of aspirin for primary prophylaxis of cardiovascular/cerebrovascular disease is not established. Secondary prophylaxis for cardiovascular/cerebrovascular events using aspirin is currently recommended based on its antiplatelet effect.62,63 The gastrointestinal-sparing effect of COX-2–specific inhibitors is the basis for their extensive use, but it is accompanied by the potential for an imbalance of thromboxane and prostacyclin. The addition of lowdose aspirin could mitigate a thrombotic state, but few data have accumulated on the gastrointestinal effects of these drugs in combination with aspirin or nonaspirin NSAIDs. Therefore, patient evaluation and monitoring becomes critical in determining the best therapeutic strategy for patients at risk for both gastrointestinal and cardiovascular events. Although cardiovascular prophylaxis should be of primary concern, further studies are needed (1) to characterize both the cardiovascular effects and risks of NSAIDs and COX-2 inhibitors alone or in combination with such prophylaxis and the gastrointestinal effects of COX-2 inhibitors and low-dose aspirin, and (2) to obtain consensus on appropriate therapeutic regimens for the treatment of patients with RA who are also indicated for risk of cardiovascular events.
1. Centers for Disease Control. Prevalence of disability and associated health
conditions. MMWR Morb Mortal Wkly Rep 1994;43:730 –731,737–739. 2. Engel A, Roberts J, Burch TA. Rheumatoid arthritis in adults in the United
States 1960 –1962. Washington, DC: National Center for Health Statistics, 1966. 3. Felson DT, Naimark A, Anderson J, Kazis L, Castelli W, Meenan RF. The
prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1987;30:914 –918. 4. Davis MA, Ettinger WH, Neuhaus JM, Mallon KP. Knee osteoarthritis and physical functioning: evidence from the NHANES I Epidemiologic Followup Study. J Rheumatol 1991;18:591–598. 5. Gabriel SE, Crowson CS, O’Fallon WM. Comorbidity in arthritis. J Rheumatol 1999;26:2475–2479. 6. McEntegart A, Capell HA, Creran C, Rumley A, Woodward M, Lowe GD. Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis. Rheumatology (Oxford) 2001;40:640 – 644. 7. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A 1999;96:272–277. 8. FitzGerald GA, Smith B, Pedersen AK, Brash AR. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984;310:1065–1068. 9. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001;167:2831–2838. 10. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–324. 11. Gabriel SE. The epidemiology of rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:269 –281. 12. Sangha O. Epidemiology of rheumatic diseases. Rheumatology (Oxford) 2000;39(suppl 2):3–12. 13. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30:1205–1213. 14. Kanik KS, Wilder RL. Hormonal alterations in rheumatoid arthritis, including the effects of pregnancy. Rheum Dis Clin North Am 2000;26:805– 823. 15. Reckner Olsson AR, Skogh T, Wingren G. Comorbidity and lifestyle, reproductive factors, and environmental exposures associated with rheumatoid arthritis. Ann Rheum Dis 2001;60:934 –939. 16. Berkanovic E, Oster P, Wong WK, Bulpitt K, Clements P, Sterz M, Paulus H. The relationship between socioeconomic status and recently diagnosed rheumatoid arthritis. Arthritis Care Res 1996;9:257–262. 17. Callahan LF, Pincus T. Formal education level as a significant marker of clinical status in rheumatoid arthritis. Arthritis Rheum 1988;31:1346 –1357. 18. Spector TD, Scott DL. What happens to patients with rheumatoid arthritis? The long-term outcome of treatment. Clin Rheumatol 1988;7:315–330. 19. Kroot EJ, van Leeuwen MA, van Rijswijk MH, Prevoo ML, Van ’t Hof MA, van De Putte LB, van Riel PL. No increased mortality in patients with rheumatoid arthritis: up to 10 years of follow up from disease onset. Ann Rheum Dis 59:954 –958. 20. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, Spitz PW, Haga M, Kleinheksel SM, Cathey MA. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481– 494. 21. Myllykangas-Luosuja¨ rvi RA, Aho K, Isomaki HA. Mortality in rheumatoid arthritis. Semin Arthritis Rheum 1995;25:193–202. 22. Guedes C, Dumont-Fischer D, Leichter-Nakache S, Boissier MC. Mortality in rheumatoid arthritis. Rev Rhum Engl Ed 1999;66:492– 498. 23. Riise T, Jacobsen BK, Gran JT, Haga HJ, Arnesen E. Total mortality is increased in rheumatoid arthritis. A 17-year prospective study. Clin Rheumatol 2001;20:123–127. 24. Martinez MS, Garcia-Monforte A, Rivera J. Survival study of rheumatoid arthritis patients in Madrid (Spain). A 9-year prospective follow-up. Scand J Rheumatol 2001;30:195–198. 25. Mikuls TR, Saag KG. Comorbidity in rheumatoid arthritis. Rheum Dis Clin North Am 2001;27:283–303. 26. Mutru O, Laakso M, Isomaki H, Koota K. Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989;76:71–77. 27. Symmons DP, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25:1072–1077. 28. Wållberg-Jonsson S, Ohman M-L, Rantapaa-Dahlqvist S. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol 1997;24:445– 451. 29. Myllykangas-Luosuja¨ rvi R, Aho K, Kautiainen H, Isomaki H. Cardiovascular mortality in women with rheumatoid arthritis. J Rheumatol 1995;22:1065–1067. 30. Prior P, Symmons DP, Scott DL, Brown R, Hawkins CF. Cause of death in rheumatoid arthritis. Br J Rheumatol 1984;23:92–99. 31. Myllykangas-Luosuja¨ rvi R, Aho K, Kautiainen H, Isomaki H. Shortening of life span and causes of excess mortality in a population-based series of subjects with rheumatoid arthritis. Clin Exp Rheumatol 1995;13:149 –153. 32. Watson DJ, Rhodes T. Higher incidence of cardiovascular disease (CVD) with rheumatoid arthritis (RA) than osteoarthritis (OA) in the UK General
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