Introduction

Atherosclerosis is a multifactorial disease that can be considered an immune/inflammatory response of intima to tissue damage. In fact, the immune system plays a key role in mediating the development of atherosclerotic lesions, as demonstrated by the presence of macrophages and activated lymphocytes within atherosclerotic plaques and of a low-grade inflammatory component that parallels the development of the atherosclerotic process.¹

Systemic inflammatory diseases compose a heterogeneous group of disorders characterized by an excessive immune response against several self-antigens, due to the interaction between genetic predisposing factors, dysregulation of the immune system, and environmental factors. In many systemic inflammatory diseases, an increased risk of developing ischemic heart disease (IHD) has been reported.¹

The most studied systemic inflammatory diseases with increased risk of IHD follow:

• Rheumatoid arthritis. Primarily affects synovial joints but may involve other tissues, including heart and blood vessels.
• Psoriasis. A disorder of the skin that can also involve joints, causing a form of arthritis, in which morbidity and mortality are mainly due to cardiovascular (CV) diseases.
• Systemic lupus erythematosus (SLE). A disease with a heterogeneous presentation that can show a multi-organ involvement, such as heart.
• Systemic sclerosis. Characterized by skin fibrosis, microvascular abnormalities, and involvement of multiple organs.

Atherosclerotic Mechanisms

The development of atherosclerosis in systemic inflammatory diseases is likely accelerated by systemic chronic inflammation. However, occurrence of coronary lesions may also be attributable to coexistence of traditional CV risk factors. On the other hand, rheological characteristics such as whole blood viscosity, plasma viscosity, and erythrocyte deformability, aggregation, and nitric oxide production have been increasingly linked to CV risk in the general population and are independently associated with subclinical atherosclerosis in patients with systemic inflammatory diseases. Likewise, proinflammatory cytokines (Figure 1),² in addition to the expression of neoepitopes on endothelial cells, promote vulnerability and premature rupture of atherosclerotic plaques. Notably, increased mortality is also observed in patients with positive rheumatoid factors, and the extent of inflammation in rheumatoid arthritis has also been linked to increased CV mortality, suggesting the relevance of computing the inflammatory and specific rheumatoid arthritis biomarkers in the risk estimation.¹

Figure 1

Psoriasis is characterized by a strong T helper 1 and T helper 17 polarization of the adoptive immune response, with subsequent increased expression of cytokines such as gamma-interferon, interleukin-2, tumor necrosis factor-alpha (TNF-α), and interleukin-17. These mediators play a key role in the development of psoriatic plaques, stimulating angiogenesis and keratinocyte proliferation, and promote metabolic abnormalities and endothelial dysfunction, both of which contribute to atherosclerotic plaque formation and progression.²

Despite the high prevalence of CV risk factors, cohort studies have also suggested that disease-specific factors may contribute to the acceleration of the atherosclerotic process in patients with SLE. Consistently, increased C-reactive protein and proinflammatory cytokines levels involved in SLE, including interleukin-1, interleukin-6, interleukin-2, interleukin-18, monocyte chemotactic protein 1, gamma-interferon, and TNF-α, have been reported to be associated with the development of premature atherosclerosis in patients with SLE.¹

Although it has been proposed that ischemic myocardial injury in systemic sclerosis may result from an intermittent spasm of intramyocardial arteries (i.e., myocardial Raynaud's phenomenon), the pathogenesis of myocardial ischemia in systemic sclerosis remains unclear. In fact, accelerated atherosclerosis has been described in some patients with systemic sclerosis despite the absence of CV risk factors, suggesting that a viral trigger, immune reactions to viral or environmental factors, reperfusion injury, or anti-endothelial antibodies may be involved in the pathogenesis of IHD in these patients.¹

Recent Studies

Many studies have described the relationship between systemic inflammatory diseases and atherosclerosis. Mantel et al.³ compared the clinical presentation of incident acute coronary syndrome (ACS) between 2007 and 2010 and their short-term mortality in a cohort of 1,135 subjects with prevalent rheumatoid arthritis and in a cohort of 3,184 matched general population comparators. Mortality rates, in all cases with a hospitalization of incident ACS, were higher among the rheumatoid arthritis cases compared with population cases. Within the first week following the ACS event, 10.4% of the rheumatoid arthritis cases versus 6.7% of the population cases died. The proportion of deaths within the first month following ACS was 15.7% among rheumatoid arthritis cases versus 10.7% of population cases. The majority of all death (90% among rheumatoid arthritis cases and 91% among population cases during the first month of follow-up) was related to cardiac mortality.

Similarly, Ogdie et al.⁴ studied a longitudinal cohort with psoriatic arthritis (8,706 patients), rheumatoid arthritis (41,752 patients), psoriasis (138,424), and unexposed controls (81,573 patients). After adjustment for traditional risk factors, the risk of major adverse cardiac events (composite outcome) was elevated in patients with psoriatic arthritis without a disease-modifying antirheumatic drug, rheumatoid arthritis, and severe psoriasis (defined as patients prescribed a disease-modifying antirheumatic drug). Patients with psoriatic arthritis had an elevated risk for incident myocardial infarction (MI). The risk for MI was similarly elevated in patients with rheumatoid arthritis without a disease-modifying antirheumatic drug prescription and patients with severe psoriasis but was substantially higher in patients with rheumatoid arthritis who had been prescribed a disease-modifying antirheumatic drug. The risk of incident stroke was also significantly elevated in patients with psoriatic arthritis without a disease-modifying antirheumatic drug prescription, which was similar to patients with rheumatoid arthritis and severe psoriasis. Finally, CV death was significantly elevated only in patients with rheumatoid arthritis and severe psoriasis.

Another study by Osto et al.⁵ investigated the effects of psoriasis on coronary microvascular function, assessed by coronary flow reserve, in 56 young psoriatic patients without CV disease compared with 56 matched controls, showing that coronary flow reserve was significantly impaired in patients compared with controls (3.2 ± 0.9 vs. 3.7 ± 0.7; p = 0.02) and correlated with the severity and extent of psoriasis.

Finally, in a retrospective study, Frerix et al.⁶ evaluated 90 patients with systemic sclerosis and 100 patients with SLE. Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pathological intima-media thickness >0.9 mm was present in only 17 of 59 (28.9%) patients with systemic sclerosis and 13 of 49 (26.5%) patients with SLE with already-present atherosclerotic plaques. Age and nicotine pack-years were independently associated with atherosclerotic plaques in patients with SLE and patients with systemic sclerosis.

Impact of Treatment

The impact of treatments on the relationship between systemic inflammatory diseases and CV events is still debated because commonly used drugs have divergent effects on the atherosclerotic process (Table 1).¹ Pharmacological treatment of systemic inflammatory diseases involves analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) to reduce pain. Use of analgesics and their potential CV effects have been little investigated because of their predominantly symptomatic use, whereas the use of NSAIDs is more consolidated. Yet NSAIDs are currently less used as a first-line treatment because of their inability to control disease progression and several side effects, particularly gastrointestinal and cardiac.¹

Table 1

A prominent therapeutic role in the treatment of systemic inflammatory diseases is currently played by disease-modifying antirheumatic drugs, a heterogeneous group of molecules formally lumped in this family that represents the mainstay of systemic inflammatory disease treatment. Although their mechanism of action is not currently fully understood, these drugs are listed among immunosuppressants because they reduce the inflammatory process with favorable effects on symptoms and quality of life. This class of drugs includes methotrexate, azathioprine, cyclophosphamide, sulfasalazine, cyclosporine, and mycophenolate mofetil; chloroquine and hydroxychloroquine are antimalarial drugs also included in this group.¹

Finally, biological agents are now widely used for treatment of patients with systemic inflammatory diseases, especially anti-TNF-α drugs conventionally associated with methotrexate. The effects of these drugs on CV diseases are complex, particularly because these molecules may promote the development of heart failure despite a favorable anti-inflammatory and antiatherosclerotic effect.¹

Summary

The awareness of the association between systemic inflammatory diseases and CV risk prompted the European Society of Cardiology to focus on prevention of CV diseases in systemic inflammatory conditions in the recent guidelines for CV prevention.⁷ Guidelines underline the increased risk of MI in patients with systemic inflammatory diseases, emphasizing that these conditions are characterized by accelerated atherosclerosis and higher CV morbidity and mortality compared with the general population. However, some relevant aspects remain uncovered in the current guidelines due to lack of sufficient evidence. In addition, mechanistic studies are needed to clarify the pathogenesis of IHD in patients with systemic inflammatory diseases and the interplay between CV risk factors and disease-related proatherosclerotic mechanisms. Finally, the impact of therapies, including recent disease-modifying agents on the course of cardiac involvement in patients with systemic inflammatory diseases, remains to be elucidated. Reciprocal awareness and cross-talking between cardiologists and other specialists involved in the management of these diseases are needed to reduce the burden of CV disease in patients with systemic inflammatory diseases.

References

1. Gargiulo P, Marsico F, Parente A, et al. Ischemic heart disease in systemic inflammatory diseases. An appraisal. Int J Cardiol 2014;170:286-90.
2. Mosca S, Gargiulo P, Balato N, et al. Ischemic cardiovascular involvement in psoriasis: a systematic review. Int J Cardiol 2015;178:191-9.
3. Mantel Ä, Holmqvist M, Jernberg T, Wållberg-Jonsson S, Askling J. Rheumatoid arthritis is associated with a more severe presentation of acute coronary syndrome and worse short-term outcome. Eur Heart J 2015;36:3413-22.
4. Ogdie A, Yu Y, Haynes K, et al. Risk of major cardiovascular events in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a population-based cohort study. Ann Rheum Dis 2015;74:326-32.
5. Osto E, Piaserico S, Maddalozzo A, et al. Impaired coronary flow reserve in young patients affected by severe psoriasis. Atherosclerosis 2012;221:113-7.
6. Frerix M, Stegbauer J, Kreuter A, Weiner SM. Atherosclerotic plaques occur in absence of intima-media thickening in both systemic sclerosis and systemic lupus erythematosus: a duplexsonography study of carotid and femoral arteries and follow-up for cardiovascular events. Arthritis Res Ther 2014;16:R54.
7. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-81.

Keywords: Acute Coronary Syndrome, Analgesics, Anti-Inflammatory Agents, Non-Steroidal, Antimalarials, Antirheumatic Agents, Arteries, Arthritis, Psoriatic, Arthritis, Rheumatoid, Atherosclerosis, Azathioprine, Biological Factors, Biomarkers, Blood Viscosity, C-Reactive Protein, Chemokine CCL2, Chloroquine, Cyclophosphamide, Cyclosporine, Cytokines, Disease Progression, Endothelial Cells, Erythrocyte Deformability, Heart Failure, Hydroxychloroquine, Immunosuppressive Agents, Interferon-gamma, Interleukin-18, Interleukin-1, Interleukin-6 Receptor alpha Subunit, Interleukin-2, Interleukin-17, Keratinocytes, Lupus Erythematosus, Systemic, Lymphocytes, Macrophages, Methotrexate, Mycophenolic Acid, Myocardial Infarction, Nicotine, Nitric Oxide, Plaque, Atherosclerotic, Quality of Life, Reperfusion Injury, Rheumatoid Factor, Risk Factors, Scleroderma, Systemic, Stroke, Sulfasalazine, Tumor Necrosis Factor-alpha, Viscosity, Angina, Stable

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