Fueling the Fire

“Attack to self” by the immune system constitutes the core fundamental feature of autoimmunity. Despite our increasing understanding of the immune system and new targeted treatments for many of these diseases, at the fundamental level autoimmunity still cannot be “cured.” Whether it is the immune system attacking a single organ or multiple organs, this can result in devastating and life-altering consequences to an individual. Yet, the immune system is essential to survival—our first-line central defense to threats serving as protection from infections and environmental invaders. This dysregulated homeostatic balance between regulatory and effector function that may lead to autoimmunity similarly requires important considerations for treatment—weighing the risks and benefits and off-target effects for various immunotherapies.^1,2

It is deeply appreciated that patients with autoimmune disease have excess cardiovascular risk; yet, the molecular mechanisms and contribution of autoimmunity in promoting chronic inflammation and atherosclerosis is less clear. The appreciation of this risk and the complexity of cardiovascular manifestations present across autoimmunity has now led to the emergence of the subspeciality area of cardio-rheumatology—a subspecialty that specifically focuses on patients with immune-mediated inflammatory diseases.^3,4 At the forefront is prevention and the well appreciated relationship between autoimmunity and atherosclerotic cardiovascular disease (ASCVD). Yet, the precise mechanisms by which each of these diseases associate with ASCVD is less clear, as is how and when to screen and implement therapies. The standard ASCVD risk scores that are used for the general population often do not adequately estimate risk among patients with autoimmunity—and this is particularly problematic in the young. Individual diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriatic disease, are now recognized in the American College of Cardiology/American Heart Association ASCVD guidelines as “risk enhancers” for intermediate-risk patients.⁵ Yet, cardiovascular disease remains one of the leading causes of mortality of patients with autoimmune diseases, and the cardiovascular manifestations of patients with autoimmune disease expand well beyond ASCVD. A recent study from the United Kingdom examined over 19 different autoimmune conditions for multiple different cardiovascular conditions beyond just ASCVD and demonstrated excess CV risk.⁶

In this issue of the Journal of the American College of Cardiology, Mortenson et al⁷ examined whether autoimmune disease independently correlates with greater coronary atherosclerosis and ASCVD events among 85,512 patients in the Western Danish Heart registry who were referred for coronary computed tomography angiography (CTA). Patients with autoimmune diseases—which included 18 different conditions—represented ~4.7% and were more likely to have any plaque or severe plaque (defined at CAC >90th percentiles). Over a median follow-up of 5.3 years, and after adjusting for baseline traditional cardiovascular risk factors, patients with autoimmune disease were 46% more likely to experience an ASCVD event. Interestingly, the excess relative risk was highest in young patients (age <50 years) and those with CAC = 0, consistent with the finding that among individuals with CAC = 0, event rates were higher among individuals who had autoimmune disease.

This study represents the largest coronary CTA investigation focusing on individuals with autoimmunity. A strength of this study is the large population, because the infrequent prevalence of these conditions often limits robust disease-specific analyses.

When evaluating the different types of autoimmune conditions, the most common connective tissue disease was rheumatoid arthritis representing 37% of the cohort, whereas systemic lupus erythematosus was only present in 3%. The authors grouped other diseases into organ-specific autoimmune diseases, of which type 1 diabetes (20%) was most common, although this is a disease that is pathophysiologically distinct from most standard rheumatologic conditions, and a subgroup analysis removing type 1 diabetes did demonstrate similar findings. Psoriasis—which could be argued to be a more systemic disease—was surprisingly rare and occurred in only 3% of the autoimmune disease cohort. This may be reflective of either referral biases for coronary CTA or undercoding of this condition.

Importantly, they examined multiple subgroups and found similar relationships among men and women and among different combinations of autoimmune diseases. As expected, traditional risk factors were strong determinants of risk, and this risk increased with number of risk factors. This underscores the important need for aggressive treatment of these modifiable risk factors among autoimmune diseases. Importantly, autoimmune disease patients with CAC = 0 had a higher relative risk—almost doubled—of ASCVD. This may suggest other mechanisms may be at play such as platelet mediated atherothrombosis.⁸ Given the increasing prevalence of CAC with age, younger patients with autoimmunity would be less likely to have calcified plaque. This finding has clinical implications because the warranty of a CAC = 0 may not be the same in a patient with autoimmunity, and other risk stratification tools, in addition to treatment of all underlying risk factors, should be considered. In particular, coronary CTA may be an attractive option because it can identify noncalcified plaque and provide a robust estimation of overall plaque burden. In addition, coronary CTA may be able to provide information on the presence of coronary inflammation by assessing the pericoronary adipose tissue.⁹ Given the increased rate of ASCVD events in this cohort, and the known underutilization of preventive treatments such as statins, it is important to treat underlying risk factors, including but not limited to low-density lipoprotein cholesterol, blood pressure, and inflammation.

It is important to also discuss the limitations of this study. Detailed characterization of individualized disease was not available, including important details such as disease activity. As the most common connective tissue disease, rheumatoid arthritis disease activity is known to be associated with cardiovascular risk, and biologic disease-modifying antirheumatic drugs such as anti-TNF use after coronary CTA was surprisingly low.¹⁰ Although the authors do provide details on some anti-inflammatories, for corticosteroids, details of dose and length of treatment was not available. The relationship between specific treatments and impact on ASCVD remains an important question in the field that can be examined with future coronary CTA studies. Furthermore, other cardiovascular risk factors such as high sensitivity C-reactive protein and lipoprotein(a), were not available because these are not routinely checked in clinical practice. However, such biomarkers may be even more important among individuals with autoimmune or inflammatory conditions, and it will be important for future studies to further characterize the relationship of these markers with coronary plaque burden and autoimmunity.

We commend the authors on this robust and large coronary CTA study in autoimmunity and hope these findings “fuel the fire” for the need not only for awareness of cardiovascular risk but also for better treatment of traditional modifiable risk factors, as well as better risk stratification tools. It is an exciting time because advances in coronary CTA and multimodality imaging will allow more options to identify earlier stages of various manifestations of cardiovascular disease.¹¹ Ultimately, advances in imaging, prevention, and targeted therapeutics will enable the field of cardiorheumatology to propel forward and enhance our ability to prevent and treat cardiovascular disease, both for individuals with and without autoimmune and inflammatory diseases.