Atherothrombotic comorbidity in the rheumatic diseases. The evidence becomes clearer. What should clinicians do?
It has been known for more than 30 years that patients with systemic lupus erythematosus (SLE) display a bimodal mortality pattern (1). Patients who die soon after the onset of the disease tend to have high levels of SLE disease activity and often have infections. In contrast, patients who survive and live for years with the disease are more likely to die of myocardial infarction (MI) and other atherothrombotic complications (1). More recent studies have found a higher than expected incidence of cardiovascular (CV) events in SLE (2), with some age strata experiencing an extremely high CV risk compared with healthy patients of the same age (3). In addition, SLE patients may be more likely to die following an MI than are persons without SLE (4).
Many of the studies that have reported a high CV risk in SLE and other rheumatic diseases have studied patients from specialty clinics, comparing them with controls from the general population (2). Those studies have the advantage of representing the patient population that is actually seen in specialty clinics, but these studies may be susceptible to bias that overestimates the CV risk attributable to SLE. Patients who are seen in specialty clinics may have characteristics in addition to their SLE that predispose them to CV disease.
The study by Hak et al, which is published in this issue of Arthritis Care & Research, avoids this potential bias (5). Hak and colleagues studied the Nurses' Health Study cohort, which has a sample size large enough to include a substantial number of nurses who were without connective tissue disease at the time of recruitment into the cohort but developed SLE during observation. The authors compared the incidence of MI between the nurses with SLE and the nurses who did not have the disease. Because both cases and controls stem from the same population, the comparison is less susceptible to biases that could amplify the CV event-rate difference. This makes it less likely that the high rate of MI observed in the nurses with SLE is a consequence of unmeasured variables related to illness and receipt of medical care. The nurses with SLE had approximately double the incidence of MI than did the nurses without SLE, a rate ratio that is not as high as that reported in studies of SLE patients from specialty clinics. Because of the characteristics of the population studied, this finding is likely to represent a conservative estimate of CV risk in lupus. Nevertheless, a doubling in the rate of MI is still a dramatically increased risk. Moreover, the study adds specificity to the association between CV disease and lupus, reducing the possibility that it is due to confounding by socioeconomic status, comorbidity, or proximity to the health care system.
Now that the increased CV risk in SLE seems unlikely to be an artifact of study design, the question is what the clinician, when faced with an SLE patient, can do to minimize the risk of the patient experiencing a CV event. We are hampered by a lack of controlled trials directly addressing the question of primary CV prevention in SLE and other rheumatic diseases. However, sufficient information is available from studies in people without rheumatic diseases, and with rheumatic diseases other than SLE, to develop reasonable strategies applicable to most patients. The following suggestions to prevent CV disease can be implemented safely with most patients. A definitive measure of their efficacy in the rheumatic diseases will have to await well-designed, randomized controlled trials in patients with these conditions.
Promote healthy lifestyle, ideal weight, and exercise
CV disease prevention guidelines include lifestyle recommendations (6, 7). All patients, including those with SLE and other systemic rheumatic diseases, should be encouraged to follow a healthy lifestyle that includes a diet designed to achieve and maintain an ideal body weight. Whenever possible, during periods when SLE displays less disease activity, patients should exercise regularly. Cigarette smoking should be discouraged in the strongest possible terms with all patients.
Follow existing guidelines for CV risk factor reduction (6)
CV morbidity and mortality are important and are frequent components of the clinical picture of SLE and other rheumatic diseases. Rheumatologists should address these problems with the same level of interest and commitment that they dedicate to nephritis, pulmonary disease, arthritis, or any other SLE manifestation. Depending on the clinical setting, it may be appropriate for rheumatologists to delegate the implementation of smoking cessation and the management of hypertension, diabetes mellitus, and hypercholesterolemia to generalists or to other specialists (8). However, rheumatologists should pay attention to the CV risk factors of their patients and ensure that they are managed correctly.
Follow existing guidelines if the patient is status post prior CV event
For patients who have already experienced a CV event, guidelines are available for the secondary prevention of further CV events (7). These should be followed in patients with rheumatic diseases as in patients with any other conditions. Rheumatologists should ensure that this is done correctly.
Follow existing guidelines if diabetes mellitus is present
Studies suggest that the presence of diabetes mellitus increases the risk of CV events to a level comparable with that observed among patients who have already had a CV event (9). Therefore, rheumatic disease patients with diabetes mellitus should be managed using the strategies for secondary prevention of CV events.
Minimize the use of glucocorticoids
Glucocorticoids have a central role in the management of SLE and other rheumatic diseases, and in many instances their effect can be lifesaving. However, glucocorticoids also have major adverse effects, including atherosclerosis and CV disease (10–12). Recognizing that the use of glucocorticoids in most instances is unavoidable, particularly in SLE, clinicians should aim to use the lowest possible dose, and to taper high doses as soon as it is safe to do so.
Consider the use of hydroxychloroquine
Hydroxychloroquine is effective for the long-term reduction of disease flares in SLE (13). Its use is associated with improved survival in SLE (14), and the drug is a proven disease-modifying antirheumatic drug in RA (15). Patients with SLE who take hydroxychloroquine are less likely to experience thrombotic events (16), a benefit that may include patients with antiphospholipid antibodies (17). In the early 1990s, observational data suggested lipid-lowering effects could be added to the benefits of hydroxychloroquine (18). More recent data suggest that, in addition to its now proven effect on lipids (19), hydroxychloroquine may be useful to prevent and treat diabetes mellitus (20). Combined with its disease-modifying effects in SLE and rheumatoid arthritis (RA), and its favorable side effect profile, the lipid-lowering and antidiabetic properties of hydroxychloroquine make it a useful component of the armamentarium to reduce CV risk in SLE and RA.
Consider the use of low-dose aspirin
The efficacy of low-dose aspirin (i.e., 81 mg daily) in the primary and secondary prevention of CV events is well proven (21). There is evidence that the protective effect of aspirin is strongest among individuals with elevated C-reactive protein (CRP) levels (22), further supporting its potential benefit in patients with rheumatic diseases, most of whom have high CRP blood concentrations. Aspirin should be used as indicated in patients with rheumatic diseases.
Consider the use of statins
Low-density lipoprotein (LDL) cholesterol plays a central role in atherogenesis. This makes LDL cholesterol a prime target of efforts to lower CV disease risk, a goal most often achieved with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, i.e., statins. LDL cholesterol levels that are considered normal in Western societies may be too high for optimal function of LDL receptors (23). Therefore, it is recommended that LDL cholesterol levels be maintained at <100 mg/dl in people at high risk of MI, and at <70 mg/dl for very high-risk patients. The latter category would include persons with established CV disease plus multiple CV risk factors, presence of the metabolic syndrome, or occurrence of an acute coronary syndrome (24).
Recently, the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) provided data on the effect of a statin drug in people whose only CV risk factor was an elevated CRP level (25). The study revealed that treatment with statins was accompanied by a significant reduction in both CRP level and LDL cholesterol, and a decrease in CV event incidence compared with placebo (25, 26). These results may justify the use of statins in patients with rheumatic diseases who have elevated CRP levels, even though their cholesterol level may be normal. In addition to their effects on lipids and CRP levels, statins have pleiotropic effects that appear to be independent of their effect on lipids (27). Some of these may be particularly beneficial to patients with rheumatic diseases. For example, in laboratory mice, statins suppressed collagen-induced arthritis and its associated cellular immune dysfunction (28). Similar effects may occur in humans, as suggested in a randomized controlled trial in which the patients who received atorvastatin experienced a modest but significant reduction in disease activity (29). A smaller randomized trial in patients with RA revealed that statins reduced disease activity and aortic stiffness, as well as improved endothelial function (30). The latter effect may be mediated by inhibition of adhesion molecule expression by endothelial cells (31). In a provocative case–control study using the UK's Research Practice Database, statin use for hyperlipidemia was associated with a reduction in the odds of having RA, suggesting the drugs may reduce susceptibility to the disease (32). Statins may also have beneficial effects in other organ systems, including the skeletal, central nervous, and immune systems (27, 33). Rheumatologists may be underutilizing statins. They should keep these drugs in mind as an option to prevent CV disease in their patients.
In summary, the study by Hak and colleagues provides a conservative estimate of the risk of CV disease in SLE (5). Atherothrombosis is sufficiently frequent in SLE, RA, and other rheumatic diseases, that it should be considered part of the clinical picture of these diseases. It therefore seems justified for rheumatologists and other subspecialists who provide care to patients with rheumatic diseases to assume an active role in CV disease prevention. Although controlled clinical trials of different CV preventive strategies have not been conducted in exclusive rheumatic disease populations, there is a plethora of evidence from nonrheumatic populations. This evidence can be used to guide CV disease prevention in most patients with SLE and other rheumatic conditions.