Atherosclerotic vascular disease in the autoimmune rheumatologic woman

Abstract

Autoimmune rheumatologic conditions have increased cardiovascular morbidity and mortality compared to the general population. Many of these diseases occur more commonly in women, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, and Sjogren's. Most of the literature that has identified the link between autoimmune diseases and atherosclerotic cardiovascular disease (ASCVD) has been regarding patients with RA and SLE. The reason for the increased ASCVD is related to both traditional risk factors for atherosclerosis and nontraditional risk factors such as the burden of inflammation. Presently, our ability to adequately determinecardiovascular risk in the autoimmune patient is subpar, as scoring systems fail to take into account the role of inflammation. No present guidelines exist that take into account the increased burden of cardiovascular disease in this complex patient cohort.

1. INTRODUCTION

The likelihood of developing an autoimmune inflammatory condition is greater for women, with an overall lifetime risk of 8.4% (compared with 5.1% for men).1 Rheumatoid arthritis (RA) is by far the most common of the autoimmune inflammatory diseases, with an incidence of 40 per 100 000 individuals and women being 2 to 3 times more likely to develop RA compared to men. Systemic lupus erythematosus (SLE) has an even greater female preponderance, with a female to male ratio of 9 to 1. The majority of the literature discussing the relationship between atherosclerotic cardiovascular disease (ASCVD) and autoimmune disease relates to RA and SLE patients. Systemic sclerosis, Sjogren's, polymyalgia rheumatic, antiphospholipid antibody syndrome, and giant cell arteritis are other autoimmune inflammatory states with a greater prevalence in women but in whom there are less data discussing ASCVD risk.

These systemic autoimmune rheumatologic diseases encompass conditions in which there is a dysregulation of the immune system, whereby autoantibodies to self‐antigens develop, attacking various organs throughout the body. Inflammation is the hallmark in the majority of these conditions. Typically, it had been thought that the pathological effect of the inflammation was confined to the joints or organs where signs or symptoms were occurring clinically. Silently, however, the inflammatory milieu can be an initiator of atherosclerotic plaque development and progression.2

ASCVD is a multifactorial disease, and the role of inflammation in the development of atherosclerosis has only been embraced in the past decade.3 Macrophages and activated lymphocytes support the concept that atherosclerosis is an immune‐mediated, inflammatory condition.4, 5 Oxidized low‐density lipoprotein (LDL) appears to be one of the primary antigens in the process of adaptive immunity that is recognized in atherosclerotic plaques and their progression; however, many other antigens are also involved.6 Inflammation, in addition to initiating plaque formation, affects the coronary microvasculature as well as endothelial function.7

Systemic inflammation has become an established predictor for atherosclerosis,8 and attempts at suppressing inflammation a rationale to decrease cardiovascular (CV) events.9 In RA, patients with frequent inflammatory flares have a greater burden of ASCVD compared to those who stay in remission longer.10 Given the shared similarities in autoimmunity and inflammation between atherosclerosis and autoimmune disease, it is logical to discuss both entities under one pathobiology (Figure 1).

Figure 1.

Diagram depicting the inflammatory pathways by which mediators of synovitis may alter arterial biology and risk factors for atherosclerosis. PAI‐1 = plasminogen activator inhibitor‐1; TNF = tumor necrosis factor; CRP = C‐reactive protein; IFN = interferon; IL = interleukin (Reprinted with permission from The American Journal of Medicine)

This present review will focus on cardiovascular disease (CVD) in the setting of autoimmune inflammatory conditions. CVD for the purpose of this article will include ASCVD but also does indicate other aspects of heart disease.

2. EPIDEMIOLOGY OF ATHEROSCLEROSIS IN AUTOIMMUNE CONDITIONS

Heart disease remains the most likely cause of death for a woman, and until recently conferred a greater risk for women than for men.11 Despite these data, only 54% of women recognize that heart disease is their number 1 killer.12 As autoimmune rheumatologic conditions have increased CV events and mortality compared to the general population,13 and occur more commonly in women, discussion of the added burden of inflammatory conditions on CV risk is imperative.

RA patients have lower survival rates compared to the general population14, 15 (Figure 2), and this lower survival has been attributed to CVD.16 CV events in the RA population occur independently of the duration of the RA and may in fact occur even before the official diagnosis of RA.16, 17 The increased CVD mortality in RA has been linked to higher degrees of systemic inflammation (after controlling for traditional risk factors).16 More recently, a study revealed that RA patients who experience more flares of their disease have an increased risk of CVD compared to those who spend more time in remission.10 In addition, patients with RA have been shown to have higher rates of hospitalizations for myocardial infarction (MI), higher rates of silent MIs, and lower rates of angina pectoris compared to non‐RA subjects.17 In the Nurse's Health Study, women who developed RA had a twofold increased risk of an MI compared to those who did not develop RA.18 The risk for MI may be greater for women with RA compared to men with RA.19 The Trans‐Atlantic Cardiovascular Consortium for Rheumatoid Arthritis recently reported that there were sex differences in CVD events rates in RA patients above the age of 40 years, where the cumulative incidence of CVD was higher for men compared to women, independent of risk factors.20 Despite these dismal reports, recent data at a single institution suggest that CV mortality, specifically from coronary artery disease, is improving and approaching rates similar to the non‐RA population.21

Figure 2.

Survival among Rochester, Minnesota residents first diagnosed with rheumatoid arthritis (RA) between January 1, 1955 and December 31, 1994 (n = 609), compared with expected survival (Reprinted with permission from Arthritis & Rheumatism)

SLE is a rarer autoimmune condition compared to RA. Similarly, however, these patients are affected by CVD.22 Younger women with SLE have substantially higher rates of CVD compared to age‐matched controls.23 Those beyond the age of 45 years have a lower relative risk of MI compared to those under the age of 45 years.23 Subclinical atherosclerosis, identified on carotid ultrasound and coronary artery computed tomography, occurs more commonly in patients with SLE and does not appear to be related to traditional risk factors.24, 25

As inflammation has been linked to the occurrence of ASCVD, it is not unreasonable to assume that other autoimmune inflammatory conditions also exhibit increased CVD morbidity and mortality. Studies have suggested this relationship in systemic sclerosis, Sjogren's, and antiphospholipid antibody syndrome.13, 22

3. ROLE OF TRADITIONAL AND NONTRADITIONAL RISK FACTORS IN ASCVD IN AUTOIMMUNE CONDITIONS

Advancing age, hyperlipidemia, hypertension (HTN), diabetes mellitus (DM), tobacco use, and gender are all considered traditional risk factors for CVD, particularly for ASCVD. These entities are the backbone for risk scoring tools used to assess an individual's risk of CV events. However, the interplay between some of these factors with ongoing systemic inflammation is complex. The distribution of traditional CV risks, other than smoking, which is more common in RA, is similar between RA and non‐RA subjects.26 Most of these risk factors actually impart a lower risk for CV events in RA cohorts compared to the general population.26 High inflammatory states have been associated with lower cholesterol levels.27 Total cholesterol (TC) and LDL levels are suppressed during periods of inflammation, and high‐density lipoproteins (HDL) may become proinflammatory.28 Assessment of lipid levels may thus be very dependent on the inflammatory state of the individual. Higher rates of inflammation, assessed by erythrocyte sedimentation rates and C‐reactive protein, have been associated with lower TC/HDL ratios but with higher CV risk (the lipid paradox).29

Another risk factor that exhibits a paradoxical association in RA is obesity. Obesity is a complex risk factor, as it is associated with the development of other comorbidities, such as HTN, DM, and dyslipidemia. Obesity, particularly increased abdominal adiposity, is a key feature in metabolic syndrome, which increases the risk of CV events as well as an individual's risk of developing DM. In RA, however, a lower body mass index (BMI), which we can consider a nontraditional risk factor, is associated with greater CV risk.26 The lowest quartiles of BMI incur the lowest survival in RA, and this is after adjustment for traditional risk factors30, 31 (Figure 3). RA patients are at risk to have lower muscle mass with their low BMI, which may result from uncontrolled inflammation, in addition to limitations of physical activity.32 When comparing women versus men with RA, there are differences in the prevalence of risk factors, where men carry a higher burden of the traditional risk factors of HTN, smoking, and hyperlipidemia.20 In women, factors related to the RA itself, such as rheumatoid factor positivity or disease activity scores, appear to have a greater impact on CVD compared to men. The consortium's conclusions regarding CV risk factors in RA were that 30% of CV events could be accounted for by RA‐specific risk characteristics.20

Figure 3.

Effect of body mass index (BMI), categorized as low (< 20 kg.m²⁰), normal (20‐30 kg/m²), and high (> 30 kg/m²) on cardiovascular mortality in rheumatoid arthritis (RA) and non‐RA cohorts. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated from a Cox regression model adjusted for a personal history of cardiac disease, smoking status, and presence of diabetes mellitus, hypertension, and malignancies (Reprinted with permission from Arthritis & Rheumatism)

In SLE, cholesterol abnormalities do not appear to occur any more frequently than in the general population33; however, when hypercholesterolemia coexists in an SLE patient, the risk of an adverse cardiac event is substantially greater than in the general population.19 HTN is much more commonly identified in SLE patients and is associated with33 increased ASCVD events and CV mortality.34

Traditional and nontraditional risk factors must be evaluated and addressed in women with an autoimmune inflammatory process. Proper identification of the role of each traditional risk factor must be incorporated into the background of acute and chronic degrees of inflammation. Thus, a multidisciplinary approach to address both aspects of the risk profile should be facilitated to fully benefit the patient's overall CV risk.

4. ROLE OF PHARMACOLOGIC TREATMENTS ON THE RISK OF ASCVD IN AUTOIMMUNE CONDITIONS

The medication regimen in women with autoimmune inflammatory conditions plays a role in both the risk to and potentially the benefit of ASCVD. The pharmacotherapy utilized in RA or SLE is directed at reducing inflammation. Nonsteroidal anti‐inflammatory drugs (NSAIDs) have long been a part of the armamentarium utilized in the treatment program for RA, SLE, and other rheumatologic conditions. Their risk in regard to CVD came into focus with data from the use of rofecoxib, a selective cyclo‐oxygenase‐2(COX‐2) inhibitor.35 The increased CV risk related to rofecoxib, compared to nonselective NSAIDs, led to its removal from the market. However, all NSAIDs include a warning on their drug information labeling indicating an increased risk of serious CV events. More recently, the PRECISION trial (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen), which investigated the sole COX‐2 inhibitor in the US market (celecoxib), showed noninferiority in regard to CV safety when compared to naproxen and ibuprofen.36 Additionally, one must take into account the link between NSAIDs and the development or worsening of HTN. This may be of particular concern in the SLE patient. Thus, the approach to the patient with a chronic inflammatory disease would be one of cautious use of NSAIDs; intermittent, low‐dose treatment for acute flares would be preferred over higher‐dosage chronic use.

Corticosteroids are also used frequently in patients with chronic inflammatory conditions. The majority of the time steroids are used intermittently to address acute inflammatory flares; however, in some refractory patients, steroids may become a chronic medication. Due to their profound anti‐inflammatory properties, these agents are beneficial in the short term. However, steroids have numerous adverse effects, such as the development of HTN, insulin resistance, weight gain, and increased cholesterol levels, all of which contribute to an increased risk of ASCVD. Higher doses (greater than 7.5 mg daily) of prednisone appear to carry the greatest risk.37 It is important to point out, however, that the steroid issue is not so clear‐cut. By reducing inflammation so significantly, steroids may confer some CV benefit. As has already been discussed, inflammation is a large component of risk for a patient with a chronic inflammatory state. The good versus bad of steroid use is likely multifactorial; dosage, timing, accumulative dose, and degree of inflammation suppression all play a role.37

Methotrexate (MTX) is a commonly used agent in RA and has been shown to reduce CV risk.38 The benefit seen in the RA population has led to the ongoing CIRT (Cardiovascular Inflammation Reduction Trial), which is specifically designed to address whether MTX can reduce major vascular events in a post‐MI population without inflammatory diseases.39

Tumor necrosis factor inhibitors are typically utilized after inadequate treatment response to MTX or other disease‐modifying antirheumatic drugs. This class of drugs has been associated with reduced CV events and may even improve endothelial function.40, 41 Interestingly, they have been shown to increase TC and LDL levels by almost 30%42; this further supports the concept that inflammation suppresses cholesterol levels, and treatment of inflammation increases the cholesterol values without increasing CV risk.

Statins, as anti‐inflammatory and lipid‐lowering agents, have shown their effect in preventing CV events in the general population and have shown a reduction in mortality in RA patients.43 Speculation of statins preventing RA development is under research.44 Patients with autoimmune inflammatory rheumatologic conditions need careful evaluation of baseline lipid levels and follow‐up after initiation of statin therapy, as RA patients may be less likely to reach therapeutic lipid levels compared to non‐RA patients.45 Assessing lipid levels during periods of active inflammatory flares may give erroneous measurements; thus, reassessment during periods of remission would be important.27, 28, 29

Low‐dose aspirin may have a role in CVD prevention in RA; however, it does not appear to prevent the development of RA itself in women.46

Pharmacotherapy in patients with chronic autoimmune inflammatory conditions is complex. Its role in suppressing inflammation can be beneficial in terms of cardiovascular risk. However, these agents are frequently being changed and modified based on disease states and symptom improvement or deterioration, thus making it a confounding factor in the assessment of ASCVD risk.

5. EVALUATION OF THE WOMEN WITH AN AUTOIMMUNE RHEUMATOLOGIC CONDITION

As noted previously, women with autoimmune inflammatory conditions have an increased risk of CVD and particularly ASCVD. That increased risk, however, is not well defined by our present ASCVD scoring systems. The Framingham Risk Score (FRS) and Reynolds Risk Score underestimate 10‐year CVD risk significantly in the RA population.47 The newer ASCVD 10‐year pooled cohort does appear to reclassify low FRS RA subjects into a higher risk category, but it is unclear if it fully predicts CV event rates.48 The Systematic Coronary Risk Evaluation, used in Europe, likewise underestimates CV risk.49 Attempts have been made to include RA in some of these risk algorithms, using the presence of the inflammatory condition along with disease activity/duration to recalculate a risk score. However, these RA‐specific CV risk scores have not been shown to be better than the calculators used for the general population in predicting CV events.50

Thus, if the scoring tools available are not able to adequately determine ASCVD risk, the question is whether other tests or modalities can be utilized to determine that risk. Some small studies have suggested that assessing for subclinical atherosclerosis using carotid ultrasound or coronary computed tomography angiogram (CCTA) may identify higher‐risk individuals51; however, whether this predicts future CV events is again unknown. Compared to the general population, RA patients have a higher prevalence and greater extent of coronary artery calcification.52 In addition, this coronary artery calcification detected by CCTA correlates with higher grades of inflammation and RA disease severity,53 supporting the concept of the atherogenic effect of chronic systemic inflammation.

Presently, there are no guidelines to help determine the best approach to ASCVD risk stratification in patients with autoimmune inflammatory conditions. The hope is that with ongoing efforts, a new, validated scoring system will take into account the effects of systemic inflammation on ASCVD risk.

At the present time, women (or men) with an inflammatory condition should alert the provider that there is an increase in the ASCVD risk beyond what is reported from CV scoring algorithms. Having this heighted awareness will allow for thorough review and aggressive treatment of the traditional and nontraditional risk factors. A lower threshold for testing for heart disease may not be unreasonable given the burden of CV disease seen in this population.

6. CONCLUSION

A woman is at an increased risk of developing an autoimmune inflammatory condition during her lifetime, and with that development incurs a greater risk of ASCVD. There is a general lack of the recognition of this additional risk factor among both patients and their healthcare providers. Assessment of cardiovascular risk does not take into account the burden of systemic inflammation, and present ASCVD scoring algorithms underestimate the scope of risk in the patient with an autoimmune inflammatory disease. Traditional risk factors play a role in risk calculation but may have varying degrees of relevance in the patient with systemic inflammation. Nontraditional risk factors, which center on the presence of inflammation, play a substantial role in the development and progression of ASCVD. Aggressive control of inflammation along with identification and treatment of risk factors must be implemented to decrease CV morbidity and mortality in a high‐risk patient cohort.

Conflicts of interest

The authors declare no potential conflicts of interest.

Kurmann RD, Mankad R. Atherosclerotic vascular disease in the autoimmune rheumatologic woman. Clin Cardiol. 2018;41:259–264. 10.1002/clc.22916