Interplay of rheumatoid arthritis and cardiovascular disease: Insights and prospects

Abstract

Rheumatoid arthritis significantly increases the risk of cardiovascular disease due to chronic inflammation. This review’s purpose is to critically analyze the intricate relationship between rheumatoid arthritis and cardiovascular disease, highlighting the mechanisms by which systemic inflammation contributes to cardiovascular risk and the effectiveness of current treatment strategies. We systematically evaluate existing literature on conventional cardiovascular risk factors in rheumatoid arthritis patients, as well as inflammation-specific markers that influence cardiovascular outcomes. Our conclusions indicate that while several treatment modalities, including methotrexate and other disease-modifying agents, may mitigate cardiovascular risk, there is a prevalent underestimation of true risk by standard cardiovascular disease assessment protocols. This review provides unique contributions by emphasizing the importance of integrating novel risk factors into assessment protocols and advocating for personalized management strategies that cater to the specific needs of rheumatoid arthritis patients. By synthesizing these elements, we aim to enhance understanding and guide clinicians in improving outcomes for rheumatoid arthritis patients at heightened risk of cardiovascular complications.

Introduction

Patients with rheumatoid arthritis (RA) are at a higher risk of cardiovascular disease (CVD), a fact supported by decades of research. Subsequent studies have solidified the link between RA and CVD, showing that people with RA have a 1.5 to 2 times greater chance of developing coronary artery disease (CAD) compared to the general population. This increased risk of CVD in RA patients is largely due to the disease’s chronic inflammatory nature.^1,2 The incidence of myocardial infarction (MI) in RA patients is about double that of the general population. While rheumatoid cardiac nodules and valvular heart disease do occur in RA patients, they seldom lead to significant disease in those with concurrent cardiovascular (CV) conditions.^3,4 RA patients also tend to have compromised endothelial function, which can be worsened by a lack of physical activity. Yet, this does not fully explain the increased occurrence of CVD among this group. It is crucial to recognize that both genetic factors and exposure to various risk factors play a role in the development of RA. ⁵

Inflammation significantly contributes to the development of CVD, including the occurrence of synovitis in patients with RA. Individuals with RA are at a double risk of developing atherosclerosis and other heart-related issues compared to the general population. A decrease in high-density lipoprotein (HDL) cholesterol levels is linked to a higher risk of CVD and increased mortality rates. ⁶ Moreover, a flare-up of RA can lead to severe complications and even death in patients with CVD. Long-term use of corticosteroids in RA patients is associated with a heightened risk of developing CVD. On the other hand, disease-modifying antirheumatic drugs (DMARDs) have been shown to reduce CV risk. Despite the higher risk of CVD among RA patients, they frequently do not receive adequate prevention measures for both primary and secondary prevention. ⁷ The coexistence of CVD and RA is often overlooked, which can lead to an even greater risk. Thus, managing RA effectively and minimizing risk factors are crucial for those affected by RA. It is important to note that inflammation is a common factor behind various health issues, including CV complications in RA patients. As a result, the latest treatment guidelines from The European Alliance of Associations for Rheumatology (EULAR) highlight the importance of addressing CV risks in conjunction with RA management. ⁸

A detailed analysis involving 50 studies, 91,618 participants, and 33,250 fatalities revealed that heart disease accounted for 39.6% of the extra deaths linked to RA. ⁹ This review efficiently presents the most recent insights into the connection between RA and CVD, including risk prediction models, for easy understanding and reference.

Understanding RA and atherosclerosis

The causes of RA are not fully understood, but it is known that a combination of genetic and environmental factors plays a role in triggering the disease. Research has identified various genetic and epigenetic elements associated with RA, as well as environmental contributors such as exposure to cigarette smoke, dust, and the composition of our microbiome. ¹⁰ In addition, hormonal factors may be involved in the increased susceptibility among women. The disease often begins to progress years before symptoms appear, marked by the emergence of specific autoantibodies such as the rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Patients with ACPA-positive RA tend to experience more severe disease activity and have a higher risk of CV mortality. The presence of these antibodies may also play a role in the development of atherosclerosis. Interestingly, ACPA has been detected in individuals without RA who have CVD, where it is again linked to poorer CVD outcomes.^11,12

Once this initial, unusual immune reaction is set in motion, which could span several years, plasma cells begin to produce large amounts of RF and ACPA. These autoantibodies then trigger macrophage activation via complement and Fc receptor engagement, predominantly affecting the joints. This process, intensified by the involvement of activated T cells, leads to inflammation in the synovium, resulting in joint pain, swelling, and stiffness. ¹³ However, the inflammatory response extends beyond the synovium, becoming systemic and spreading through the bloodstream. This triggers the release of various pro-inflammatory cytokines and chemokines, including tumor necrosis factor-alpha (TNF-α) and interleukins 1 and 6 (IL-1/IL-6), which in turn draw in more activated B and T cells, monocytes, and macrophages.^14,15

Recent findings have shown that the JAK/STAT signaling pathway, responsible for controlling cytokine signaling, is involved in the development of RA. This pathway, triggered by IL-6 and other cytokines, boosts the creation of pro-inflammatory cytokines. Consequently, this escalates systemic inflammation and contributes to the development of comorbidities outside of the joints, like atherosclerosis. ¹⁶

The development of CVD in patients with RA primarily occurs through the formation of atherosclerotic plaques, a process driven by various factors including vascular, metabolic, and inflammatory components. Risk factors such as dyslipidemia, hypertension, smoking, and inflammation contribute to the development of these plaques by damaging the arterial endothelium. This damage increases the permeability of endothelial cells, allowing low-density lipoprotein cholesterol (LDL-C) to penetrate and accumulate within the arterial wall’s inner layer, where it undergoes oxidation. ¹⁷ This leads to an increase in adhesion molecules on the endothelial surface, drawing monocytes into the area. These monocytes transform into macrophages, which consume the oxidized lipids, becoming “foam cells” that form visible “fatty streaks” within the arteries. Foam cells and injured endothelial cells release cytokines such as TNF-α and IL-6, further recruiting and activating leukocytes, endothelial, and smooth muscle cells. Some foam cells eventually undergo apoptosis, contributing to a necrotic core within the plaque. The plaque is further structured by smooth muscle cells, macrophages, and T lymphocytes, which create a fibrous cap. These atherosclerotic plaques can either slowly expand, leading to chronic ischemia or suddenly rupture, triggering acute CV incidents.^18,19

There is a consensus that chronic inflammation, such as that found in RA, can augment the development of atherosclerosis. This systemic inflammation leads to dysfunction of the endothelium, accelerating the formation and growth of atherosclerotic plaques. RA and atherosclerosis share several key mechanisms.^20,21 For instance, TNF-α, a critical pro-inflammatory cytokine in RA, is also produced by foam cells within plaques and contributes to the impairment of endothelial function. Furthermore, it increases the expression of adhesion molecules, which attracts more immune cells to the plaques. In addition, IL-6 is involved in the initiation of fatty streaks, while IL-1 is significant in the management of macrophages and T helper 17 cells. ²²

Systemic inflammation not only plays a direct role in the formation of atherosclerotic plaques but also amplifies CV risk factors. It does so by causing endothelial dysfunction and elevating oxidative stress, which in turn leads to an increase in systemic vascular resistance and hypertension.^23,24 In RA, inflammation also accelerates the breakdown of lipoproteins, often leading to reduced levels of HDL and LDL, a phenomenon known as the “lipid paradox,” which is still linked to an elevated future risk of CVD. In addition, inflammation transforms HDL levels into a pro-atherogenic state by diminishing its capacity for cholesterol efflux, or the ability to remove cholesterol from macrophages, which stands as an independent risk factor for CVD.^25,26 Elevated levels of lipoprotein(a), a modified LDL particle that is both pro-inflammatory and pro-atherogenic, are found in association with RA and pose an independent risk for CVD. The use of anti-inflammatory medications can significantly mitigate these effects, leading to a reduction in CVD risk among RA patients. ²⁷

Evaluating CV risk in RA patients

The 2015 update to the American College of Rheumatology guidelines for treating RA does not cover the topic of heightened CV risk, altered lipid profiles, or the responsibility of rheumatologists in evaluating CV risk among these patients. ²⁸ Similarly, the 2013 update of the ACC/AHA Task Force guidelines for CV risk assessment, intended for the broader population, also fails to address the elevated CV risk specific to individuals with RA. ²⁹ Generally, these guidelines suggest the use of race- and sex-specific equations to estimate the 10-year likelihood of experiencing a first event related to atherosclerotic cardiovascular disease (ASCVD) for adults between the ages of 40 and 79. The factors deemed statistically significant for inclusion in these risk assessment equations include age, total cholesterol (TC), HDL cholesterol (HDL-C), systolic blood pressure (both treated and untreated), diabetes mellitus (DM), and smoking status.^30,31 In cases where making a treatment decision based on risk is unclear, evaluating C-reactive protein (CRP) levels (⩾2 mg/L) might be considered to aid in treatment decisions and could justify a higher risk assessment. The importance of apolipoprotein B (apo-B) in this context remains unclear.^32,33

The 2018 ACC Guideline for Managing Blood Cholesterol identifies several factors that enhance the risk of ASCVD. These include having an inflammatory disease like RA, a high-sensitivity CRP level of 2 mg/L or higher, Lp(a) levels above 50 mg/dL, apo-B levels of 130 mg/dL or more, and triglycerides that are consistently 175 mg/mL or higher. ³⁴ For individuals aged 40–75 with LDL levels of 70 mg/dL or higher, who do not have DM and whose 10-year ASCVD risk calculation is between 5% and less than 7.5% (considered “borderline risk”), the presence of these risk enhancers suggests that starting moderate-intensity statin therapy may be appropriate. This is particularly relevant for patients with RA, as the condition itself is an independent risk factor, and the associated systemic inflammation often means these patients are likely to exhibit multiple risk enhancers. ³³ For instance, while a high-sensitivity CRP level of 2 mg/L indicates increased CV risk in the general population, the average CRP level in a group of patients with treated RA was found to be significantly higher, at 9.7 mg/L. It is also critical to note that the consideration of risk enhancers is currently recommended only for patients with a minimum 5% 10-year risk of ASCVD. In addition, the guidelines outline high-risk conditions such as DM, being over 65, having hypertension, and smoking, but RA is not yet classified as a high-risk condition. ³⁵ For patients aged 40–75 with DM and an LDL level over 70 mg/dL, starting moderate-intensity statin therapy is advised without needing to calculate the 10-year ASCVD risk. Given that CV risk in RA patients can be comparable to those with DM, this presents a significant question: Should RA patients be considered at similar risk to those with DM and be managed according to these guidelines? Currently, the use of statins for primary prevention in RA patients should align with the guidelines set for the general population. ³⁶

In 2016, the task force from the European League Against Rheumatism (EULAR) released an updated guideline featuring 10 recommendations focused on the screening, identification, and management of CVD risk factors in patients with inflammatory joint conditions, including RA. ³⁷ It is important to acknowledge that RA serves as an independent risk factor for developing CVD, and it is widely speculated that a multiplication factor of 1.5 should be applied to patients with RA to account for this increased risk. Furthermore, the EULAR task force has designated rheumatologists as the primary care providers responsible for overseeing the management of CVD risk in individuals with RA and other inflammatory joint diseases. ³⁸

Lipids can be classified in various ways based on their potential to cause atherosclerosis, but most traditional methods for estimating an individual’s risk of CVD over 10 years focus on TC, LDL-C, and HDL-C. However, these conventional risk assessment models have proven to be ineffective at accurately predicting CVD risk in patients with RA.^39,40 A retrospective study based on population data found that widely used risk calculators, such as the Framingham risk score and Reynold’s risk score, significantly underestimated the risk of CVD in RA patients. Moreover, applying a multiplier of up to 1.8 did not improve the accuracy of risk stratification for RA patients from low to high risk. Another study corroborated these results, showing that the Systematic Coronary Risk Evaluation (SCORE), Framingham risk score, and Reynold’s risk score typically underestimated CVD risk in RA patients, especially in the lower two-thirds of the predicted CV risk spectrum. ⁴¹ These findings prompt a critical question: Are we adequately evaluating and managing CVD risk in patients with RA? The underestimation of CVD risk could lead to inadequate preventive measures and treatment of traditional CV risk factors. ³¹

There is a proposal to incorporate additional, novel risk factors in assessing CVD risk among RA patients. This is because traditional markers such as TC and LDL-C may not accurately reflect the true risk in this group. The inclusion of systemic inflammation markers (CRP, IL-6, and TNF-α), carotid intima-media thickness via ultrasound, N-terminal pro-brain natriuretic peptide, and cardiac troponin T is recommended for a more precise prediction of CVD risk in RA patients. ⁴² Furthermore, the development of an RA-specific CV risk model is proposed to enhance the prediction of CVD risk in these patients. Given the chronic systemic inflammation experienced by RA patients, which likely contributes to their accelerated atherosclerosis, there is a clear need for a more unified strategy in evaluating and managing CVD risk in this population. ³¹ We summarized the risk factors and related management strategies in Table 1.

Table 1.

Risk factors for cardiovascular disease in RA patients and management strategies.

Risk factor	Description	Management strategies
Chronic inflammation	Persistent inflammation increases atherosclerosis risk	Utilize DMARDs and biologics to control inflammation
Traditional cardiovascular risk factors	Includes hypertension, diabetes, dyslipidemia, and smoking	Regular screening and management of blood pressure, cholesterol, and diabetes. Encourage smoking cessation
Elevated CRP	Higher CRP levels indicate increased cardiovascular risk	Monitor CRP levels regularly; adjust treatment based on results
Lipid abnormalities	Changes in HDL and LDL cholesterol levels in RA patients	Evaluate lipid profiles and consider statin therapy as needed
Corticosteroid use	Long-term use associated with increased CVD risk due to metabolic effects	Minimize dosage; monitor cardiovascular health; explore alternative therapies
Lack of physical activity	Sedentary lifestyle contributes to CVD risk	Encourage regular physical activity tailored to patient capabilities
Obesity	Increased body weight linked to elevated cardiovascular risk	Implement weight management strategies through diet and exercise
Genetic factors	Genetic predisposition may increase CVD and RA risk	Genetic counseling and personalized treatment plans may be beneficial
Age and gender	Older age and female gender are risk factors	Tailored screening and management plans for older adults and female patients

CRP: C-reactive protein; RA: rheumatoid arthritis; CVD: cardiovascular disease; HDL: high-density lipoprotein; DMARD: disease-modifying antirheumatic drug; LDL: low-density lipoprotein.

Antirheumatic strategy

Medications for treating RA can paradoxically impact the CV system, even though they reduce disease activity and the risk of adverse CVD outcomes. Nonetheless, certain medications, such as glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs), heighten CVD risk.^43,44 Below, we discuss these effects in more detail.

There is growing evidence of the CV dangers associated with long-term use of NSAIDs, which work by blocking cyclooxygenase (COX) enzymes. A comparative analysis of seven NSAIDs found naproxen to have the lowest CV risk, while the other six presented similar CVD risks. ⁴⁴ Recent theories highlight that inflammation mainly targets the inducible COX-2 enzyme, leading to the prevalent prescription of COX-2 inhibitor NSAIDs. ⁴⁵ These inhibitors, such as meloxicam and celecoxib, are favored for their reduced gastrointestinal side effects compared to traditional NSAIDs. However, NSAID treatment is tied to a notably increased mortality risk from the start and throughout the treatment duration. COX-2 inhibition diminishes the vascular and antiplatelet benefits of prostacyclin, curbing its production, which can elevate blood pressure and hasten the rupture of atherosclerotic plaques and thrombosis.^46,47 Several factors might amplify the CV risk associated with COX-2 inhibitors, though the exact mechanisms are yet to be fully understood. The variety of NSAIDs, the balance between COX-1/2 inhibition, the extent of inhibition, dosage, and treatment duration for patients with CV and gastrointestinal risks must be carefully weighed due to the potential adverse effects on CV outcomes. Elderly patients, who are particularly susceptible to NSAIDs, exhibit a high incidence of CVD. NSAID use should be tailored to the individual, employing the lowest effective dose for the shortest possible duration. ⁴⁸

Glucocorticoids are commonly used to manage RA, mainly for short-term reduction of disease activity. However, these medications can lead to complications such as heightened blood pressure, altered blood lipid profiles, impaired glucose tolerance, insulin resistance, and central obesity, all of which contribute to the risk and progression of CVD. Existing guidelines for using glucocorticoids in RA treatment are not optimal, necessitating a more careful evaluation of the dosage, treatment length, and overall duration of therapy. ⁴³ Despite the consensus that glucocorticoids can be an effective treatment for RA when used in low doses for brief periods, the lack of concrete and detailed evidence has led to somewhat ambiguous recommendations. It is advised that patients undergo regular monitoring of blood pressure and glucose levels before and throughout the course of treatment. Moreover, early and comprehensive management of RA, incorporating a combination of medications, is recommended.^49,50 Consequently, glucocorticoids are recognized as a risk factor for heart failure (HF).

TNF-α is a cytokine that plays a pivotal role in the inflammatory cascade, influencing both cellular and humoral immune responses. Elevated levels of TNF-α have been observed in the synovial fluid and membranes of patients with RA. Its interaction with various cells within the synovial membrane leads to local inflammation and the formation of vascular polyarteritis nodosa, which in turn causes damage to cartilage and bone. This underscores the importance of researching TNF inhibitors.^51,52 These inhibitors have become a key treatment option for RA patients who do not respond well to standard therapies. Specifically, they have shown effectiveness in treating RA patients with conditions such as hormone-related issues, homocysteine blood disorders, pulmonary interstitial diseases, secondary pulmonary hypertension, and increased blood coagulation.^53,54 However, TNF inhibitors may elevate CV risk factors, including insulin resistance, decreasing HDL levels, and disrupting endothelial function. Studies in animal models have demonstrated that TNF-α can induce insulin resistance, though such effects have not been conclusively observed in clinical settings. Research indicates that reducing TNF inhibitors does not offer superior benefits over decreasing the use of DMARDs. ⁵⁵

Hindering TNF-α activity not only enhances the metabolic index and cholesterol profiles in patients with RA but also has been linked to a decrease in CV events risk in these patients. Meta-analyses typically show that treatment with TNF-α inhibitors leads to increases in levels of TC, LDL, HDL, and triglycerides.^56,57 Despite these benefits, using infliximab, a TNF-α blocker, in patients with HF has been shown to adversely affect their prognosis. Recent findings indicate that RA patients undergoing treatment with anti-TNF-α medications experience lower mortality rates compared to those receiving conventional antirheumatic drugs. However, it remains unclear if this reduction in mortality is directly attributable to a decrease in CVD.^58,59

IL-6, a cytokine produced by T lymphocytes, macrophages, and adipocytes, plays a significant role in stimulating the liver to produce CRP and fibrinogen. It is implicated in causing RA and accelerating ankylosing spondylitis (AS) through its interaction with either its membrane-bound or soluble receptors. ⁶⁰ Research indicates that signaling via the IL-6 receptor (IL-6R) is directly involved in the onset of CAD. Tocilizumab, a monoclonal antibody targeting the IL-6R, has been used to treat RA due to its effectiveness in reducing disease severity and its generally good patient tolerance. ⁶¹ However, while tocilizumab is effective, it may significantly disrupt lipid and cholesterol balance, potentially increasing LDL and TC levels, which leads to ambiguous CV outcomes.^62,63

The introduction of DMARDs has led to a decline in both the incidence and mortality rates associated with CVD. However, there has been no observed biological protection against CVD with the use of DMARDs. This finding aligns with other research indicating that the employment of biologic DMARDs does not correlate with a decreased risk of MI.^64,65 A limitation in these studies is the inability to evaluate the CVD risk for specific biologic DMARDs, as the majority of patients receive treatment with TNF inhibitors based on reimbursement policies. Interestingly, treatment with methotrexate (MTX) has been shown to lower the risk of HF, especially in those patients who struggle with maintaining a good ejection fraction. Additionally, lower levels of CRP have been associated with a reduced risk of HF in RA patients. MTX stands out as the most frequently prescribed DMARD noted for its association with reduced CV risk. A recent meta-analysis highlighted that MTX can lower CV events by 21%.^66,67 Furthermore, MTX has been shown to diminish the risk of heart disease in RA patients. As a folic acid analog, MTX offers considerable immunosuppressive and anti-inflammatory benefits in RA and other autoimmune conditions. It achieves this by inhibiting the function of crucial enzymes like dihydrofolate reductase, thymidine synthase, and aminoimidazole ribonucleotide converting enzyme, thereby suppressing cell growth and turnover. ⁶⁸ This inhibition leads to decreased synthesis of purines, pyrimidines, and DNA, which are beneficial in treating the disease. Another critical action of MTX involves the accumulation of adenosine through the inhibition of angiotensin, contributing to its major immunomodulatory and anti-inflammatory effects in RA through the reduced synthesis of purine and pyrimidine and increased adenosine levels.^69,70 In addition, research has explored whether low doses of MTX could lower the risk of heart disease in individuals with metabolic syndrome or DM. Over recent years, MTX has been proposed as a key medication in managing RA and other autoimmune diseases, with potential reapplication for managing CV risk. ⁷¹

Hydroxychloroquine (HCQ) showed lower rates of major adverse cardiovascular events (MACE) and cerebral infarctions in RA patients, except for those on biologics, where an increased risk of acute myocardial infarction (AMI) was noted. ⁷³ While overall, HCQ was linked to reduced AMI rates, this was not reflected in specific subgroups. ⁷² Mechanistically, HCQ benefits may stem from its impact on lipid profiles, glucose control, and inflammation modulation. In subgroup analyses, females experienced a lower risk of MACE and cerebral infarction with HCQ, but the results were less clear for males. ⁷³ Although HCQ may provide some cardiovascular benefits, its safety profile, particularly concerning potential side effects such as arrhythmias, remains uncertain, indicating a need for further research to confirm its efficacy in preventing cardiovascular complications in RA patients.^74,75

Sulfasalazine, an older antirheumatic drug being studied in the TARGET study, is a prodrug derived from the combination of the antibiotic sulfapyridine and the NSAID 5-aminosalicylic acid.^76,77 This oral sulfonamide exhibits antithrombotic properties by inhibiting platelet thromboxane synthetase, thereby reducing thromboxane production and preventing arachidonic acid-mediated platelet aggregation, similar to the effects of aspirin in CVD protection. ⁷⁸ In addition, sulfasalazine decreases lymphocyte proliferation and the adhesion of monocytes and leukocytes, while also reducing inflammatory cytokine production, likely through the inhibition of the NF-κB pathway, a key regulator of inflammation and atherogenesis. By preventing the degradation of IκB, sulfasalazine disrupts NF-κB activation, which is considered beneficial in preventing atherosclerosis development. ⁷⁹ It also improves lipid profiles by increasing HDL-C and lowering the atherogenic ratio. Observational data from the QUEST-RA study further suggest that prolonged use of sulfasalazine is associated with a reduced risk of cardiovascular events and MI. ⁸⁰

Leflunomide has shown efficacy comparable to MTX for the treatment of RA and was approved in the Netherlands in 2000, exhibiting benefits within 1–3 months.^81,82 However, it is associated with a higher overall incidence of hypertension (6%–10%) compared to placebo or other treatments such as sulfasalazine and MTX, with drug-related hypertension occurring in about 2%–4% of cases.^83,84 A retrospective study involving 99 outpatient leflunomide initiations indicated a discontinuation rate of over 60%, primarily due to inefficacy, and found hypertension in 8% of patients, which exceeds expected rates from prior literature. ⁸⁵

The B cell-activating factor (BAFF) is crucial for the survival, activation, and differentiation of B cells, influencing their maturation and function through specific pathways. There are two primary types of B cells, known as B1 and B2 cells, which play different roles in the development of atherosclerosis.^86,87 B1 cells are known to offer protection against atherosclerosis, whereas B2 cells can contribute to its development. Within the B2 category, there are further subdivisions, including MZ-B cells and Fol-B cells, both of which are involved in secreting immunoglobulins, activating inflammatory T cells, and exacerbating AS. The BAFF receptor pathway is a crucial mechanism in the survival of B2 cells and is significantly implicated in CAD.^88,89 Interestingly, treatments with anti-BAFF antibodies have been shown to worsen AS in mice, despite effectively reducing mature B2 cell populations, indicating a complex mode of action. Using anti-CD20 monoclonal antibodies to deplete B cells can hinder the progression of AS in Apoe/mice on a high-fat diet. This method has paved the way for biological therapies targeting B cells, which are now being explored in the clinical management of autoimmune diseases such as RA.^90,91

The likelihood of CVD is heightened in patients with RA, yet the impact of treatments for RA on CVD risk remains uncertain. Given the significant occurrence of CVD among individuals with RA, it is crucial to conduct thorough assessments for these patients. This situation highlights the significant influence of inflammation related to RA on the risk of developing CVD, indicating that effective RA treatments could potentially mitigate the harmful influence of inflammation on CVD risk. ⁹² It is well-established that inflammatory rheumatic diseases exacerbate atherosclerotic CVD and elevate the risk of mortality from CVDs. The way in which RA triggers early cardiac dysfunction through the extensive activation of inflammatory factors has been explored in prior studies. Normally, catecholamines are responsible for regulating cardiac contractions, with adrenaline interacting with G protein-coupled receptors that are essential for CV function. Consequently, the specific reasons behind early cardiac dysfunction in RA patients are yet to be fully understood.^93,94

To summarize, inflammation has been identified as the primary cause of HF. Research indicates that individuals with RA have a higher risk of developing HF, though it remains uncertain whether this is due to an increase in conditions like hypertension and ischemic heart disease or if it is the immune disorder itself causing myocardial dysfunction. The role of cytokines, chemokines, cell adhesion molecules, and pro-inflammatory cell surface receptors is crucial in starting and maintaining inflammatory responses. ⁹⁵ Inflammation involves mechanisms that are both cell and cytokine-mediated. The advancement of HF-related cytokines is linked to ongoing pro-inflammatory cytokine activity. These cytokines can trigger myocardial hypertrophy, apoptosis, and fibrosis, and lead to adverse myocardial remodeling. In instances of cardiac injury, inflammatory signaling molecules can prompt compensatory cardiac hypertrophy and fibrosis.^96,97 TNF-α, in particular, has been found to induce cardiomyocyte dysfunction, hypertrophy, and fibrosis, all of which can culminate in cardiomyopathy. High levels of TNF-α are also associated with cardiac fibrosis, ventricular dilation, and increased mortality rates.^98,99

Signaling from anti-inflammatory cytokines can mitigate the remodeling of the heart, which leads to hypertrophy. These mediators also promote the proliferation of T lymphocytes into Th2 cells. This raises the question of the role of inflammation in HF: Is it a direct cause, or just one of several contributing factors?^100,101 Most of the body’s inflammatory processes, which are geared toward protection and regeneration, share common signaling molecules. Interestingly, while traditional CV risk factors are more prevalent among patients with RA than in the general population, these factors alone do not fully explain the heightened CV morbidity and mortality seen in RA patients.^102,103 The extent of inflammation does not fully account for these clinical disparities, suggesting that inflammation acts more as a final common pathway rather than the primary initiator.^104,105

Several inflammatory mechanisms involved in the pathology of RA have been implicated in contributing to atherosclerosis. The primary approach to managing RA involves modulating the immune system, employing a range of both biological and non-biological pharmacological treatments. These therapies can be administered individually or in combination to manage inflammation both within the joints and systemically, aiming to halt the progression of joint damage.^106,107

Recent studies, including those by Fleischmann et al. ¹⁰⁸ and Charles-Schoeman et al., ¹⁰⁹ highlight the CV safety profiles of newer therapeutic agents like upadacitinib and tofacitinib in RA patients. Fleischmann et al. conducted a post hoc analysis of the SELECT program, noting that patients at risk for CV disease exhibited a favorable safety profile with upadacitinib, emphasizing the importance of monitoring CV outcomes in this patient population. ¹⁰⁸ Similarly, Charles-Schoeman et al. reported a comparative CV risk between tofacitinib and traditional TNF inhibitors, suggesting that while both therapies are effective for managing RA, their CV safety must be thoroughly evaluated, particularly for patients with a history of atherosclerotic CV disease. ¹⁰⁹

Solomon et al. ¹¹⁰ further elucidate the role of immunomodulators in reducing CV risk among RA patients. Their findings suggest that specific immunomodulatory treatments can significantly enhance CV outcomes, reinforcing the necessity for active CV risk management by rheumatologists. ¹¹⁰ This aligns with the review’s suggestion to utilize advanced imaging and inflammation markers in predicting CV risks more effectively, moving beyond traditional risk factors and highlighting the underestimation challenges presented by current guidelines.

In a systematic review by Singh et al., ¹¹¹ the authors emphasize a multi-faceted approach to CV risk management in RA patients, advocating for lifestyle modifications alongside pharmacological therapies. This review encapsulates the critical need for integrating dietary, physical activity, and psychological interventions to lower CV risk while managing RA effectively. Such an approach is particularly pertinent given that RA patients frequently experience compounded risks from traditional factors. ¹¹¹

Weber et al. ¹¹² provide insights into the shared inflammatory pathways linking RA to atherosclerotic CV disease. Their work underscores the role of pro-inflammatory cytokines such as TNF-α and IL-6, which are not only involved in the pathophysiology of RA but also exacerbate CV risk, reflecting the systemic nature of these diseases. ¹¹² Their findings support the review’s discussion of inflammation as a critical driver of both conditions, necessitating a coordinated therapeutic strategy that addresses systemic inflammation to improve CV outcomes.

In Table 2, we provided a brief overview of the range of medications and their key features.

Table 2.

Antirheumatic medications and their cardiovascular implications.

Medication class	Effect on RA	Cardiovascular implications	Management considerations
NSAIDs	Reduce pain and inflammation	Long-term use increases mortality risk; naproxen has the lowest risk	Use the lowest effective dose for the shortest duration; monitor closely for cardiovascular effects
Glucocorticoids	Effective for short-term control of disease activity	Associated with hypertension, insulin resistance, and dyslipidemia; recognized as a heart failure risk factor	Monitor blood pressure and glucose levels; use low doses for short periods
TNF inhibitors	Target TNF-alpha to reduce inflammation	Potentially elevate cardiovascular risk factors like insulin resistance and lipid levels	Regularly assess cardiovascular health; individualize treatment based on risk
IL-6 inhibitors (e.g., Tocilizumab)	Reduce disease severity and inflammation	May disrupt lipid balance, increasing LDL and total cholesterol	Evaluate lipid profiles regularly and manage accordingly
DMARDs	Lower disease activity and improve quality of life	No observed biological protection against CVD; MTX generally reduces cardiovascular events	Consider MTX as a first-line treatment and monitor cardiovascular outcomes
BAFF Inhibitors	Target B cells involved in inflammation	Complex effects on atherosclerosis; some treatments may worsen progression	Monitor for cardiovascular implications; consider risks versus benefits

NSAIDs: nonsteroidal anti-inflammatory drugs; DMARDs, disease-modifying antirheumatic drugs; BAFF: B cell-activating factor; RA: rheumatoid arthritis; CVD: cardiovascular disease; TNF: tumor necrosis factor; IL-6: interleukin 6; LDL: low-density lipoprotein; MTX: methotrexate.

Limitations

While this review aims to provide a comprehensive overview of the interrelationship between RA and CVD, several limitations must be acknowledged. First, much of the data cited is derived from observational studies, which can be limited by confounding factors and may not establish causality. Randomized controlled trials are necessary to better understand the impact of specific RA treatments on CV outcomes.

Second, the inclusion criteria for studies vary, with different populations studied that may not fully represent the diverse RA patient group. Variability in demographic factors, disease duration, and treatment regimens can influence results and their applicability to the broader population of RA patients.

Third, the evolving nature of treatment for RA, particularly the development of new biologics and targeted therapies, means that the CV implications of these newer treatments are still under evaluation. Future studies must continue to monitor the long-term CV effects of these newer medications.

Lastly, the focus on systemic inflammation as a common pathway, while supported by significant evidence, may not capture all contributory mechanisms of CVD in RA patients. Genetic, environmental, and lifestyle factors must also be studied in conjunction with inflammatory processes to fully understand CV risk in this population.

In conclusion, this review highlights the critical need for enhanced risk assessment and management strategies for RA patients, aiming to mitigate their elevated CV risk while effectively managing their rheumatologic disease. Continued research and collaboration among various specialties are essential for improving outcomes and quality of life for this patient population.

Conclusion

The relationship between RA and CVD highlights the crucial need to recognize and manage the increased CV risk faced by RA patients. Chronic inflammation is a key driver in both conditions, facilitating the development of atherosclerosis and associated CV complications. Effective RA management, particularly through DMARDs and biologic therapies, is essential not only for controlling disease activity but also for potentially reducing CV risk.

Current CV risk assessment guidelines often fail to adequately reflect the elevated risks in RA patients, necessitating the integration of additional novel risk factors, such as systemic inflammation markers and advanced imaging techniques. Furthermore, the diverse medications utilized in RA treatment—ranging from NSAIDs to glucocorticoids and TNF inhibitors—pose a dual challenge of controlling inflammation while mitigating CV risks.

Future research should focus on elucidating the mechanisms linking RA-induced inflammation and CV complications. A multidisciplinary approach involving rheumatologists, cardiologists, and healthcare providers is vital to ensure comprehensive management that addresses both the inflammatory aspects of RA and the associated CV implications. By enhancing our understanding of these interactions and refining risk assessment strategies, we aim to improve clinical outcomes and quality of life for patients with RA at heightened risk for CV events.