1 Introduction

The prevalence of various cardiovascular diseases (CVD) in the different rheumatologic disorders is a very important topic. Each disease has a number of unique manifestations despite the fact that an overlap is present due to shared common risk factors, which may be related to the longer life expectancy of the recent therapeutic advances. A growing understanding of the role of inflammation and immune system in the initiation and progression of atherosclerosis as well as the early detection of cardiovascular manifestations is due to the availability and use of sophisticated noninvasive cardiac and vascular diagnostic technology. Such discipline results in the detection of cardiac manifestation unique to each rheumatologic disorder. This was not possible previously due to short life expectancy, limited therapeutic interventions, vague understanding of pathological process for each disease, and the limited diagnostic resources.

Cardiovascular diseases (CVD), including coronary artery diseases (CAD), can be present at the time of or after the diagnosis of rheumatologic disease. Cardiovascular association can be the principal introduction of the rheumatologic diseases in case of late diagnosis. The manifestations of CVD in rheumatologic diseases vary from subclinical to severe manifestations [4, 5], and they involve different structures of the heart. They can lead to significant morbidity and mortality. Therefore, we need to draw attention to their symptoms, to the risk factors that contribute to CVD development, as well as adaption of preventive measures that may control them. We will also consider the coronary artery disease (CAD), which maybe a crucial contributor to morbidity and mortality in numerous rheumatological diseases [6,7,8,9].

The prevalence of atherosclerotic CAD is increased in patients with chronic inflammatory rheumatic diseases, particularly in those with systemic lupus erythematous (SLE) and rheumatoid arthritis (RA) [10, 11]. The increased risk of CAD results from both traditional risk factors and factors unique to these rheumatic diseases [12, 13]. For example, accelerated atherosclerosis is one of the important risk factors for the development of CAD, and it can be attributed to the prolonged inflammatory process in these diseases, vascular endothelial dysfunction, and a specific form of low-density lipoprotein (LDL). The importance of metabolic syndrome in various rheumatic diseases and its implications on morbidity and mortality will be discussed as metabolic syndrome, which is commonly diagnosed among those patients and also plays an important role in the CVD development [14,15,16].

Several medications are now used in the management of various rheumatologic diseases, which can affect the development of CAD—either by decreasing or increasing the CAD severity or by decreasing or increasing its risk factors. In fact, many discussions are held nowadays with focus on how and when to use them. For example, the use of aspirin and statins in rheumatology and their effect on CAD. We will discuss the latest guidelines for their use here.

In this chapter, we address the various cardiovascular events that patients are exposed to, with CAD as one of the major factors that increase their mortality [10]. We will also discuss the important areas in regard to the identification of high-risk groups that need interventions, how to decrease the risk of CAD in these groups, and the way to better understand the effects of common medications on the risk of CAD in these patients.

2 Cardiovascular Manifestations in the Rheumatic Diseases

In this section, we look at CVD involvements in the different rheumatologic diseases and address the important issues in regard to their development (Tables 16.1 and

Table 16.1 Type of CVD diseases
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16.2 give a summary of the points given below).

Table 16.2 Summarized types of CVD in rheumatologic diseases
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The coronary artery disease (CAD) contributes significantly to the morbidity and mortality in various rheumatic diseases, whereas the occurrence of atherosclerotic CAD is increased in patients with chronic inflammatory rheumatic diseases, particularly those with SLE and RA. This again is emphasizing the importance of those conditions to the development of CAD. This increased risk is mediated by the presence of both traditional risk factors and factors unique to those with systemic inflammatory disorders. It is a matter of higher risk as well as the presentation.

A larger proportion of patients with RA has a clinical silent CAD in comparison to demographically similar individuals in the general population. Patients with RA are also less likely to report chest pain during an acute coronary event than those without RA. It is still uncertain why this is happening, but acceptable explanations include the following: many patients with active disease and joint damage are less physically active; therefore, they are less likely to place sufficient demand on the heart to elicit angina, which may attribute to RA pain. Patients with CAD tend to use nonsteroidal anti-inflammatory drugs (NSAID), glucocorticoids, or disease-modifying antirheumatic drugs (DMARDs), which can change their pain perception. Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population. Cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA [8]. Epidemiologic studies have shown that this increased mortality is largely attributed to cardiovascular diseases, primarily CAD. Considerable evidence suggests that inflammation plays a role in the pathogenesis of atherosclerosis [10]. The prevalence of cardiovascular comorbidity is difficult to assess accurately since CAD has a tendency to remain silent in the rheumatoid patients, but deaths from CVD occur earlier than in the general population. It has also been suggested that the increased risk of CAD in RA precedes the onset of clinical rheumatoid disease [17].

The lowering of CAD morbidity and mortality by recognizing patients at risk, and revealing their nontraditionalFootnote 1 risk factors as well as their contribution in developing cardiovascular complications are important. Many rheumatic diseases have their share of these complications, e.g., RA, SLE, and vasculitis. The studies showed the importance of prevention strategies. Furthermore, many studies have been discussing various reasons of the increased in cardiac manifestations and the risk of mortality due to CAD. One could be the increase of traditional risk factors and its explanation. The second could be the special nontraditional risk factors, which are related to the pathophysiology of rheumatic diseases (See Tables 16.1 and 16.2).

Traditional risk factors include smoking,Footnote 2 hypertension, diabetes mellitus (DM), hyperlipidemia, and obesity [12].

The nontraditional risk factors are associated with elevation of CAD occurrences, which include severity of the disease, more extra-articular manifestation at presentation, corticosteroids, NSAIDs, and the low socioeconomic status. The presence of the accelerated atherosclerosis in those patients is associated with CAD development and subsequently the increased mortality from CAD in them (Tables 16.3 and

Table 16.3 Prevalence of traditional risk factors
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16.4).

Table 16.4 Effects of traditional risk factors on RA
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2.1 Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic systemic inflammatory disease, which affects approximately 1% of the adult general population [18]. It has many extra-articular manifestations (e.g., heart and lung) in about 40% of patients with RA over their life time [19]. The mortality gap in comparison to the general population widened with the dramatic improvement in the overall mortality rate in the latter group [20]. For example, if we compare the general population to the patients with RA, there is an increased incidence of cardiovascular events, including myocardial infarction, stroke, and cardiac death among the patients with RA.

Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of mortality [18]. Patients with RA are at twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more [18]. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms, such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the constitutes of accelerated atherosclerosis observed in RA patients [18]. These patients are greatly susceptible to CAD (myocardial infarction and angina), heart failure, pericarditis, myocarditis, atrial fibrillation, valvular heart disease, and cardiac amyloidosis.

2.1.1 Pericarditis

Pericarditis is the most common cardiac manifestation in RA, which is usually an asymptomatic disease. Clinical pericarditis is observed in around 4% of the patients [21], which is lower than the autopsy proven one that occurs in around 30%–50% of patients with RA [22]. Patients with RA are more likely to develop pericardial effusion than the ones without RA by ten times [23]. Most of the patients develop the pericardial effusion after the onset of the arthritis; however, RA was diagnosed after pericardial effusion in a minority of patients [3]. The variables associated with the development of extra-articular manifestations including pericarditis are as follows: male gender, presence of increased serum concentrations of rheumatoid factor, joint erosions, subcutaneous nodules, number of disease-modifying antirheumatic drugs (DMARD), presence of nail fold lesions, and any other extra-articular feature 1 year before the time of the diagnosis, or treatment with corticosteroids at the time of the diagnosis [21].

Patients with findings of edema, shortness of breath, chest pain, raised jugular venous pressure, pericardial rub, and paradoxical pulse were found to have 100% mortality rate within 2 years [4]. In patients with pericardial effusion, the diagnosis of RA was mainly clinical without the need for invasive procedure [3]. Biologic agents are now considered one of the cornerstones of RA therapy associated with the development of pericardial effusion mostly within 4 months of the start of the infliximab and etanercept [24]. Purulent pericardial effusion was reported in patients receiving infliximab and etanercept [25, 26].

Treatment: Although most of the evidence came from patients with immune-mediated pericarditis, it can be extrapolated to the RA-associated pericarditis as follows:

  1. 1.

    Asymptomatic disease usually diagnosed accidently will resolve spontaneously.

  2. 2.

    Symptomatic disease therapy includes the following:

    • Nonsteroidal anti-inflammatory drug (NSAID) is the mainstay therapy for idiopathic pericarditis, and the two agents that proved their efficacy are ibuprofen and indomethacin [27].

      • Corticosteroids: low- to moderate-dosage prednisone (0.2–0.5 mg/kg per day) for 4 weeks and then slowly tapered, if the patient is intolerant to aspirin or NDSAID or with pericardial effusion [27].

      • Colchicine: in patients with acute and recurrent pericarditis in addition to aspirin or NSAID in the dose of 0.5 mg twice daily in patients >70 kg and 0.5 mg once daily in patients ≤70 kg [27].

      • If previous medical treatment fails, there is growing evidence for oral azathioprine, intravenous human immunoglobulins, and anakinra [27].

      • Tocilizumab was reported to be successful too [28, 29].

      • Surgical management includes pericardiocentesis, pericardiectomy, or pericardiotomy in the cases of hemodynamic compromise, cardiac tamponade, or constrictive pericarditis.

      • Biologic-agents-associated pericarditis should be stopped and treated accordingly [24].

      • Purulent pericarditis with biologic agents should be stopped and antibiotic therapy to be used accordingly [25, 26].

2.1.2 Myocardial Involvement

Myocarditis is less common than RA-associated pericarditis. It was found in 19% of patients with RA based on post-mortem study where the majority were females with active arthritis; however, most of the patients with myocarditis were clinically asymptomatic [30].

Cardiomyopathy with finding of left ventricle hypertrophy (LVH) was found in around 37% of asymptomatic RA patients by echocardiography [31]. The pathohistological finding was either diffuse or focal inflammation of the myocardium [32].

Diagnosis: The left ventricle function is usually evaluated with echocardiography, but it has a limited role in the evaluation of myocardium involvement. Cardiac magnetic resonance imaging (CMR) is helpful as noninvasive evaluation tool for myocarditis as it shows increased T2-weighted edema ratio (ER) score suggesting myocardial tissue edema. It has a role too in identifying the chronicity of myocarditis [33].

Treatment: Conventional therapy to support the left ventricle function is generally used. High-dose prednisolone (60 mg) daily for 2 months, tapered over 4 months followed by maintenance dose, normalizes the left ventricle ejection fraction and the gallium uptake [34].

2.1.2.1 Antimalarials-Induced Cardiotoxicity

Hydroxychloroquine and chloroquine are medications initially used as antimalarial treatment. They found to be effective as disease-modifying antirheumatic drugs. Hydroxychloroquine-induced cardiotoxicity has been reported in patients with RA [35].

Risk factors: Old age, female sex, long duration of therapy, high daily dose, preexisting cardiac disease, or renal impairment [35].

Presentation: Features of systolic dysfunction and prolonged QT interval were reported too [35].

Diagnosis:

  1. (a)

    Echocardiography shows diffuse thickening ventricular walls [35].

  2. (b)

    CMR: Shows areas of patchy gadolinium enhancement. It is important to differentiate it from other causes of cardiomyopathy [35].

  3. (c)

    Endomyocardial biopsy: Shows enlarged and vacuolated cells, and the presence of myeloid and curvilinear bodies within the cardiac myocytes [35].

Treatment: Mainly withdrawal of the antimalarial agents and conventional heart failure treatment if needed [35].

2.1.3 Heart Failure

It is a clinical syndrome that is two times higher in RA patients than the general population [36].

Associations: Rheumatoid factor positivity was associated with higher risk of congestive heart failure [36].

Causes: Patients with RA develop heart failure mostly due to ischemic cardiomyopathy, drug-induced myopathy (e.g., antimalarial drugs), rheumatoid nodule, NSAID use, or amyloidosis.

Treatment: Treat the underlying cause and conventional heart failure treatment. Avoid the use of tumor necrosis factor-alpha (TNF alpha) inhibitors especially the high doses (10 mg/kg) in NYHA classes 3 and 4 heart failure [37]. In patients with congestive heart failure and RA, the combined use of synthetic DMARDs, non-TNF biologic, or tofacitinib over TNF inhibitors is recommended [38].

2.1.4 Coronary Artery Disease (CAD)

Patients with rheumatoid arthritis (RA) have a reduced life expectancy when compared with the general population, where cardiovascular death is considered the leading cause of mortality in patients with RA; it is responsible for approximately half the deaths observed in RA [8]. Epidemiologic studies have shown that this increased mortality is largely attributable to cardiovascular diseases, primarily CAD. Considerable evidence suggests that inflammation plays a role in the pathogenesis of atherosclerosis [10]. The prevalence of cardiovascular comorbidity is difficult to assess accurately because CAD has a tendency to remain silent in the rheumatoid patient, but deaths from CVD occur earlier than in the general population. It has also been suggested that the increased risk of CAD in RA precedes the onset of clinical rheumatoid disease [17].

Traditional risk factors for atherosclerosis, such as smoking, hypercholesterolemia, hypertension, DM, and sedentary lifestyle, may be more common in RA than in the population as a whole but do not account for all of the increase in the disease. Currently, there is a large body of evidence that a chronic inflammatory state can enhance the harmful effects of some traditional risk factors, such as the association between systemic inflammation and arterial wall stiffness in hypertension or the proatherogenic lipid profile (high LDL and lipoprotein (a) low HDL) seen with increasing rheumatoid disease activity. The burden of addressing CAD in RA is therefore divided between rigorous control of traditional risk factors and effective disease control through immunosuppression [39]. The more extended the span of the RA and the utilization of TNF alpha inhibitors are, there is a chance for improvement of atherosclerosis [40]. The two are a surrogate for the seriousness of the illness and a presence of coronary calcification [41]. Male gender and severe inflammatory state (high inflammatory markers and disease activity score) are usually associated with atherosclerosis [42].

Factors influencing cardiovascular disease in rheumatoid arthritis:

  • Oxidized LDL (oxLDL) and antibodies to oxidized LDL are both established as significant risk factors for CVD in RA. It has been consistently observed that the levels of oxLDL are higher in patients with active disease [39].

  • C-reactive protein: Higher levels of CRP are associated with CVD in non-RA patients [39]. Treatment of CAD with statins or angiotensin-converting enzyme (ACE) inhibitors has been demonstrated to lower CRP levels [39]. Attention was specifically focused on high-sensitivity CRP (hsCRP). Raised hsCRP is found in hypertension, smoking, and DM, as well as CAD.

    In RA baseline, CRP predicts cardiovascular mortality [43], and the molecule acts directly in a pro-inflammatory manner at a range of sites. For example, CRP activates vascular endothelial cells to express adhesion molecules in a dose-dependent manner, and CRP activates monocyte chemotactic protein-1 (MCP-1), which can be inhibited by statins and fenofibrates [39].

  • Homocysteine: Homocysteine is increasingly regarded as an epiphenomenon of CAD rather than a causative factor [39].

Elevated levels of homocysteine have been associated with CAD in the general population as well as in reduced levels of various vitamins including folate and B6 [39]. It has also been shown that homocysteine is present in higher concentrations in the joints of RA patients, where it may enhance production of pro-inflammatory cytokines such as IL-1 and thus act as a driver for joint damage; it may also accelerate atherosclerosis in a similar manner [44].

  • Physical disability due to rheumatoid arthritis : Poor functional status, especially in the lower limbs, is a powerful predictor of mortality in RA, while regular exercise is known to have beneficial effects on the cardiovascular system. Exercise capacity is also inversely related to the presence of metabolic syndrome [45]. Patients with chronic RA have physical disabilities, which prevent them from taking regular exercise. This influences CAD in several ways; the presence of CAD usually causes delay in the individual’s presentation to clinician since reduced physical activity may not exacerbate symptoms. The delay in presentation would also prevent treatment at an earlier stage of CAD, even with the lack of CVD, physical disability would still stop adequate exercise.

  • Leptin and the adipocytokines : Leptin is an adipokine that functions both as a hormone and a cytokine. It is produced by the adipose tissue, and its main role appears to be to reduce food intake and to stimulate the sympathetic nervous system. It is known to stimulate inflammatory cytokine production, and to have direct deleterious effects on articular cartilage. It is also known to cause endothelial dysfunction, oxidative stress, and platelet aggregation and to be elevated in RA; while fasting has been implicated as a means of reducing leptin levels and improving RA disease activity [39]. Leptin has the potential to play a key role linking obesity, inflammation, and cardiovascular damage.

Prevention of CAD in RA.

Since it is generally similar to prevention in patients without RA [46], here are some important points to prevent CAD in RA patients.

One needs to:

  • Stop smoking.

  • Measure fasting blood glucose annually or in the event of significant weight gain especially in patients taking steroids. In already diabetic patients, the steroids should be kept in the lowest dose.

  • Monitor blood pressure for RA patients before beginning medications and then at regular intervals for patients using NSAID, cyclosporine, and corticosteroids. NSAIDs reduce the antihypertensive effects of diuretics, β-blockers, and angiotensin-converting enzyme inhibitors, but it is less likely to interfere with calcium channel blockers [47]. In those group of patients either to increase the dose of the antihypertensive medications or to use a calcium channel blocker.

  • Manage hypercholesterolaemia according to recommendation for the general population.

  • Manage obesity as well as weight loss.

  • Supplement the diet with fish oil that is rich in omega-3 fats, because this has demonstrated efficacy in the treatment of RA, facilitated reduction of NSAIDs use and reduced cardiovascular mortality risk [48].

  • Diagnose and treat RA early:

    • Methotrexate: shown to decrease cardiovascular mortality among RA patients [49].

    • TNF inhibitors: shown to decrease the risk of MI among patients who have controlled synovitis within 6 months of treatment [50].

2.1.5 Rheumatoid Nodule

Valvular nodule is 10 times higher in RA patients than the general population [23].

Incidence: Echocardiographic evidence of aortic valve nodule was observed less than mitral valve nodule in the rate 0.3% vs. 0.6% among RA patients [31], respectively.

Presentation: Differs according to the site of the nodule, as it causes functional impairment, such as arrhythmias and valve disease [51]. It was associated with complete atrioventricular (AV) block necessitating pacemaker as it involves the AV node [52, 53].

Treatment: According to the presentation.

2.2 SLE

It is a multisystem autoimmune disease with a strong female predilection.

Cardiovascular morbidity and mortality is a frequent complication, particularly in females aged 35–44 years, where the risk of myocardial infarction is raised 50-fold [54]. The cardiac morbidity is the most common cause of death in SLE patients, which is around 25% of deaths in SLE [55].

The heart is one of the most frequently affected organs in systemic lupus erythematosus (SLE), where any part can be affected, including the pericardium, myocardium, coronary arteries, valves, and the conduction system. In addition to pericarditis and myocarditis, high incidence of CAD has become increasingly recognized as cause of mortality, especially in older adult patients and those with long-standing SLE [56].

Pericarditis is the most common cardiac abnormality in SLE patients, but lesions of the valves, as well as myocardium and coronary vessels, may all occur. In the past, cardiac manifestations were severe and life threatening, often leading to death. Therefore, they were frequently found in postmortem examinations. Nowadays, cardiac manifestations are often mild and asymptomatic. However, they can be frequently recognized by echocardiography and other noninvasive tests (Echocardiography is a sensitive and specific technique in detecting cardiac abnormalities, particularly mild pericarditis, valvular lesions, and myocardial dysfunction). Therefore, echocardiography should be performed periodically on SLE patients [57].

2.2.1 Pericarditis

The most common clinical cardiovascular manifestation of SLE.

Prevalence: Echocardiographic evidence of pericardial effusion was detected in 27% of SLE patients, where most of them had asymptomatic disease [58]. Lupus pericarditis occurs predominantly in females in around 92% [59] which is mostly due to main predominance of SLE in females.

Associations: Mostly associated with active SLE in 93% and involvement of other organs with SLE in 72% [59]. In the absence of renal failure, constrictive pericarditis or pericardial effusion is rarely reported [60]. Patients with tamponade had lower serum level of C4 in comparison to the ones who did not develop tamponade [61].

Clinical presentation: Ranges from asymptomatic to pericardial effusion [58] to cardiac tamponade in 16% [59].

Diagnosis: Either by the presence of pericardial effusion by echocardiography only or the presence of 2 out of 4 of the following (Retrosternal pain, pericardial friction rub, widespread ST-segment elevation, and new/worsening pericardial effusion) among SLE patients [59].

Treatment: The treatment of lupus pericarditis is mainly derived from immune-mediated pericarditis, as previously mentioned in the RA section, where it responded well to NSAID and corticosteroids [59]. High-dose corticosteroids, complete drainage, and pericardial window were used for treating patients with large pericardial effusion/tamponade [61, 62].

2.2.2 Myocarditis

Effects: SLE is associated with the increase in the left ventricle mass, and this would be even more if SLE was associated with hypertension (HTN) [63].

Associations: The association is strong between lupus myocarditis with the presence of myositis but weak with the presence of the antibodies to nuclear ribonucleoprotein (RNP) [64]. High SLE Disease Activity Index is an independent risk factor in the development of lupus myocarditis [5], where anticardiolipin IgG and lupus anticoagulant were positive in patients with severe symptoms [65].

Clinical features: It ranges from asymptomatic disease discovered accidently to symptomatic heart failure and sudden death [5].

Diagnosis: Echocardiography: Most patients suffered from wall motion abnormalities (WMA), whereas less than 50% of lupus myocarditis patients showed decrease in the left ventricle ejection fraction after the exclusion of other causes of myocarditis [5].

Treatment: Conventional treatment of heart failure [5]. Immunosuppressive therapy (high-dose systemic corticosteroids with subsequent dose tapering, intravenous immunoglobulin, plasmapheresis, or cyclophosphamide) showed improvement in heart failure symptoms, EF, and the WMA of the heart [5]. After corticosteroids therapy, the EF improved up to a mean of 49.5% after around 7 months of follow-up from a mean of 33.8% [66]; one article reported normal EF after follow-up [67]. Refractory lupus myocarditis can be treated with rituximab [68]. Intravenous “pulse” cyclophosphamide was used in patient with lupus myocarditis refractory to corticosteroids, and it showed improvement in heart failure symptoms and EF from 19% to 63% [69]. Mycophenolate mofetil was effective in a case series [70]. Intravenous immunoglobulin was effective in the treatment of patients with severe lupus myocarditis in conjunction with corticosteroids and cyclophosphamide [65]. One rare case report showed that plasmapheresis and extracorporeal membrane oxygenation (ECMO) were effective in lupus myocarditis [71].

2.2.3 Coronary Artery Disease (CAD)

Prevalence: The prevalence of the angina, myocardial infarction, and sudden cardiac death was found to be 8.3% as per a Johns Hopkins SLE cohort study [9]. Another study found more than 50-fold risks of MI in young women 35–44 years old when compared to the control group [11].

Risk Factors

  1. (a)

    Traditional risk factors for atherosclerosis.

    It has an increased prevalence in patients with SLE as hypertension, DM, premature menopause, sedentary lifestyle, and high homocysteine level [12].

  2. (b)

    Inflammation-related risk factors.

    • High disease activity and elevated level of CRP [13].

    • In lupus nephritis, it was found that patients with long-term lupus nephritis had frequent episodes of cardiac lesions, mainly cardiac infarctions [72].

    • Low serum levels of C3, antiphospholipid antibodies (APL), and elevated levels of antibodies to anti-ds DNA were found to be independent predictors of thrombosis. Hydroxychloroquine is protective against future thrombosis in those patients [73].

    • Several autoantibodies such as anti-DNA, APL, anti-SSA (Ro antibodies), and anti-endothelial cell antibodies present in patients with SLE can mediate cardiac damage [74].

    • Old age at diagnosis of SLE [9, 11].

    • Longer duration of SLE [9, 11].

    • Longer duration of steroid therapy [9].

    • High levels of oxidized low-density lipoprotein cholesterol and homocysteine [9].

Preventions of CAD in SLE.

To prevent CAD, one has to:

  • Control the traditional risk factors, to use the statins according to the guidelines for the general population, and to control blood pressure aggressively.

  • Improve the lipid profile by using hydroxychloroquine as it lowers the level of the cholesterol in the blood, especially in patients taking steroids [75], and it is associated with a reduced risk of DM [76].

  • Minimize the use of steroids.

2.2.4 Endocarditis (Libman–Sacks Endocarditis)

It was first described by Libman and Sacks in 1942 after they discovered valvular lesions in four patients with SLE.

Prevalence: Echocardiographic evidence was detected in around 11% of patients with SLE [77].

Associations: It was found to be associated with longer SLE duration and activity, thrombosis, stroke, thrombocytopenia, and antiphospholipid syndrome [77]. Its coexistence with antiphospholipid antibodies (APLs) increases the risk of thromboembolic complications, especially stroke [78].

Pathology: Since the main involved valve is the mitral followed by the aortic [78], the left side is mainly more involved than the right. Therefore, the main dysfunction is regurgitation; stenosis is rarely found [78].

Diagnosis: Echocardiography: It is manifested as valve vegetations, thickening, and/or regurgitation [79]. Transesophageal echocardiography (TEE) was found to be more sensitive than transthoracic echocardiography (TTE) for the detection of echocardiographic findings [79]; for example, valvular thickening was found higher with TEE at 70% vs. 52% with TTE [79].

How to differentiate it from infective endocarditis? Infective endocarditis is an uncommon complication of SLE, yet at the same time, it should be in the differential diagnosis as both diseases can be presented with fever and valvular vegetation. Three laboratory tests can help differentiate between them to a degree, and these are the white blood cell count (WBC), the CRP level, and the antiphospholipid antibody (APL) level [80]. The test results show that the WBC is expected to be low during lupus flare and high during infection, CRP is high with infection and suppressed during lupus flare, and the aPL is high in SLE and unlikely to be positive in infection [80].

Treatment

The control of the SLE disease activity is important with the use of the corticosteroids. Although the use of corticosteroid is not beneficial for the valve lesion, it is important to control underlying diseases [78]. The corticosteroids, on the other hand, were noted to be associated with fibrosis and severe dysfunction (e.g., mitral valve insufficiency) after high doses of corticosteroid are used [81, 82]. Patients with Libman–Sacks Endocarditis, who suffered from a thromboembolic event, are recommended to be on life-long anticoagulation to prevent further episodes [78]. Accordingly, conventional treatment of heart failure and valvular lesion as needed is crucial.

2.3 Systemic Sclerosis (SSc)

Widespread vascular lesions, fibrosis of the skin, and internal organs characterize a connective tissue disease. More than half of the patients with SSc, who underwent autopsy, were found to have significant cardiac abnormalities [37]. Cardiac involvement is recognized as a poor prognostic factor when clinically evident, with a 5-year mortality rate is around 75% [83]. Primary myocardial involvement is common in SSc; increasingly, evidence strongly suggests that myocardial involvement is related to repeated focal ischemia leading to myocardial fibrosis with irreversible lesions. Reproducible data have shown that this relates to microcirculation impairment with abnormal vasoreactivity, with or without associated structural vascular abnormalities. Consistently, atherosclerosis and macrovascular coronary lesions do not seem to be increased in SSc. Myocardial involvement leads to abnormal systolic, diastolic left ventricular dysfunction, and right ventricular dysfunction. Sensitive and quantitative methods have demonstrated the ability of vasodilators—including calcium channel blockers and angiotensin-converting enzyme inhibitors—to improve both perfusion and function abnormalities. By that, they emphasize the critical role of microcirculation impairment [84].

Asymmetric hypertrophy of the interventricular septum with signs of sub-aortic obstruction consistent with hypertrophic obstructive cardiomyopathy was evident in echocardiogram in patients with diffuse SSc. Hypertrophic cardiomyopathy is associated with the human lymphocyte antigen HLA DR3 [85], and this may provide a possible link with SSc as this HLA phenotype is common in the latter condition [85].

2.3.1 Myocardial Fibrosis

Prevalence: Around 66% of patients with SSc based on MRI [86]. The presence of the left ventricle (LV) dysfunction (ejection fraction (EF) <55%) was reported in around 5.4% among SSC patients [1].

Pathology: Patchy distribution of myocardial fibrosis is pathognomonic [87]; Foci of contraction band necrosis (mostly due to the recurrent vasospasm of the small vessels of the heart) is found in all parts of the myocardium mainly in the subendocardial area [88]. Asymptomatic patients with impaired coronary flow reserve did not show stenotic lesions of the major epicardial coronary arteries [89]. Contrarily, symptomatic patients (e.g., angina) with SSc had evidence of CAD in similar rate to the symptomatic ones without SSc [90].

Associations: There is association between the high volume of fibrosis and Raynaud’s phenomenon duration of 15 years or more and abnormal Holter study results [86]. Male sex, old age, presence of digital ulcerations, and myositis were associated with higher prevalence of LV dysfunction [1].

Diagnosis

  1. (a)

    Echocardiography: Most patients had LV hypertrophy in around 22.6%, followed by LV diastolic dysfunction in around 17.7%, and a rare percent of LV systolic dysfunction in around 1.4%, in the absence of the pulmonary arterial hypertension [91].

  2. (b)

    Heart MRI: Delay enhancement MRI can identify areas of fibrosis in a significant number of patients [86].

Treatment

Vasodilators (e.g., calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors) showed improvement of the myocardial perfusion and halting of the disease progression [92]. Patients showed radiological improvement in myocardial perfusion and function after the administration of nifedipine (60 mg daily) for 14 days [93]. Among SSc patients, it was found that the ones treated with calcium channel blockers (CCB) have less reduced LVEF [1]; the cardiac protective effect of CCB still needs to be established.

2.3.2 Myocardial Ischemia

SSc is an independent risk factor for acute myocardial infarction with no protective effect was noted with the immunosuppressive therapy [6].

2.3.3 Pericarditis

Prevalence: Symptomatic pericardial disease is observed in around (5–16%) of the patients, which is lower than the autopsy proven one and was demonstrated in around (33–72%) of SSc patients [94]. Symptomatic pericarditis in patients with limited scleroderma is more than the patients with diffuse scleroderma, which was observed at the rate of 30% vs. 16%, respectively [2].

Associations: Symptomatic pericarditis is associated with pulmonary hypertension [95], while cardiac tamponade and heart failure are associated with poor prognosis [87].

Presentation: It is usually asymptomatic [2], yet it can rarely be present with large symptomatic pericardial effusion [2]. The large pericardial effusion usually occurs after the clinical and laboratory manifestations of the scleroderma [2], but still it can happen before, so it is part of the differential diagnosis of pericardial effusion [96]. Renal failure can be presented in the setting of large pericardial effusion and constrictive pericarditis [87].

Laboratory: exudative pericardial effusion pattern with predominance of mononuclear cells [97].

Treatment: In the setting of pericarditis, NSAID and corticosteroids were effective [94], and with the presence of active inflammation, immunosuppressive therapy may have a role [94].

Conventional heart failure treatment is helpful [94]. Cardiac tamponade is to be treated accordingly, e.g., pericardiocentesis [87]. Constrictive pericarditis is to be treated accordingly, e.g., diuretics, sodium and fluid restriction, and/or pericardial stripping [87].

2.4 Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a systemic autoimmune disease associated with arterial and venous thrombotic events and recurrent fetal loss. The heart is a target organ in APS.

Endocardial disease, intracardiac thrombosis, myocardial involvement including CAD and microvascular thrombosis, as well as pulmonary hypertension, have all been described in APS patients. Valvular involvement is the most common manifestation with a prevalence of 82% detected by transesophageal echocardiography. Symmetrical—nodular thickening of the mitral and/or aortic valves—is characteristic. Anticoagulant/antiplatelet treatment is ineffective in terms of valvular lesion regression [98]. Some patients require cardiac valve replacement. However, patients with APS have shown an increased perioperative morbidity and mortality. Intracardiac thrombosis, although a rare complication, can cause pulmonary and systemic emboli [98].

2.4.1 Aspirin and APS

The primary prophylaxis of thrombosis with low dose aspirin (81 mg) in asymptomatic, persistently antiphospholipid antibody (APL)-positive individuals was not beneficial when compared to placebo [99]. SLE patients with persistent positive lupus anticoagulant (LA) antibody are at high risk of thrombosis, and primary prophylaxis with low-dose aspirin and hydroxychloroquine is recommended [100].

2.5 Ankylosing Spondylitis (AS)

It is a chronic inflammatory condition that usually affects young men, mainly affecting the spine and the sacroiliac joints and, to lesser extent, the peripheral joints. Cardiac dysfunction and pulmonary disease are well known and commonly reported extra-articular manifestation associated with ankylosing spondylitis (AS). The cardiac manifestations were reported in around 2–10% [101], and it may reach up to 30% [102] of patients with AS—mostly conduction defects and aortic insufficiency [101]. The cardiac manifestation is mostly observed in patients with long-term AS and peripheral joint involvement [103]. AS has also been reported to be specifically associated with aortitis, aortic valve diseases, conduction disturbances, cardiomyopathy, and CAD. There is no difference between the type of rheumatic therapy and its use among patients with AS, who have myocardial infarction versus who does not [101].

2.5.1 Aortic Involvement

It was first described in 1973 AD by Bulkley and Roberts during autopsy examination of patients with AS that had congestive heart failure due to severe aortic regurgitation [104]. It is an important topic, because if patients with AS developed chest pain, you should rule out aortic dissection.

Prevalence: Echocardiographic evidence of aortic regurgitation was mostly mild and was observed in around 3–13% of patients with AS [60]. Positive HLA-B27 patients with aortic regurgitation around half of them do not have clinical features of rheumatic disease [105].

Pathology: Arteritis around the aortic root and valve due to inflammatory process with platelets aggregation lead to tissue thickening [104]. There is fibrous growth of the intimal layer that leads to aortic root dilatation [104]. Increase in stiffness of the aorta and decreased global myocardial performance are features of AS and correlate with the disease activity and its duration [106].

Diagnosis: Echocardiography: TEE showed aortic root thickening, increased stiffness, dilatation, and nodularities of the aortic cusps. The first two were the most common findings [107]. Valve regurgitation was seen in around half of the patients [107].

2.5.2 Myocardial Involvement

Prevalence: Diastolic dysfunction was found at the rate of 20% [108] ranging to 50% [109], while systolic dysfunction was affected less than that in around 18% of AS patients [110].

Pathology: It was found to have an increase in myocardial inflammation and the connective tissue/myocyte rate, which will give the picture of the increase in diffuse interstitial connective tissue [110].

Presentation: Diastolic dysfunction in AS is usually not severe enough to cause diastolic heart failure [111]. Rarely, were LV systolic dysfunction and hypertrophy reported in the absence of significant aortic regurgitation [48].

2.5.3 Conduction Abnormalities

It is the most common finding in AS patients, and it usually precedes the other cardiac findings [102].

Prevalence: Conduction abnormalities were observed in around 2–20% of AS patients [60]. Around half of the positive HLA-B27 patients with conduction abnormalities do not have clinical features of rheumatic disease [105].

Pathology: Inflammatory process leads to damage of the interventricular septum wall, and AV node dysfunction is secondary to the compromise of the arterial supply to the AV node [112]. Another factor is the autonomic nervous system abnormalities that can lead to conduction defects and arrhythmias at the end [113].

Associations: Disease duration is associated with the prolongation of the PR and the QRS intervals [112]. Conduction abnormalities occur more frequently in patients with positive HLA-B27 [105].

Types:

  1. 1.

    Supraventricular extrasystoles and ventricular extrasystoles are very common findings among AS patients [102].

  2. 2.

    Prolonged QRS interval in about 29.2% of AS patients [112].

  3. 3.

    First-degree atrioventricular (AV) block in around 4.6% of AS patients [112].

  4. 4.

    Complete right bundle branch block (RBBB) in around 0.8% of AS patients [112].

  5. 5.

    Left anterior hemiblock 0.8% of AS patients [112].

2.6 Psoriatic Arthritis

The increased risk of clinical and subclinical CVD is mostly due to accelerating atherosclerosis, and the incidence of mortality in CAD was similar to that of RA [114]. Patients with psoriatic arthritis have higher occurrences of CVD risk factors and CAD, peripheral vascular disease, and congestive heart failure [115].

2.6.1 Arrhythmias

Incidence: Patients with psoriasis were found to have higher risk of developing arrhythmia than the normal population at the rate of 15.41 per 1000 person-years, and this was even higher among patients with psoriatic arthritis [116].

2.6.2 CAD:

Incidence: The incidences of myocardial infarction is 5.13 per 1000 person-years, while it is 5.13 for severe psoriasis, which is higher than the general population [7]. The new events of heart failure were higher among psoriasis patients, especially among the severe psoriasis group than the general population [117].

Associations: Severe psoriasis is associated rationally with a higher risk of death, specifically cardiovascular being the most common cause [118]. CAD is associated with young patients [7, 119], psoriatic arthritis [119], and/or severe psoriasis [7, 119]. Severe psoriasis has higher risk of CAD and stroke [119].

Pathology: Metabolic diseases, such as obesity and diabetes mellitus, are more among psoriasis patients, which may play a role in the development of atherosclerosis in addition to the inflammatory process [120].

Prevention: Treatment with methotrexate and TNF alpha inhibitors therapy appears to lower the rates of CAD among patients with psoriasis [120].

2.7 Systemic Vasculitis

CVD is significantly involved in different types of systemic vasculitis, ranging from large to small vessel vasculitis (see Chap. 20 on “Vasculitis and Rheumatology”).

3 The Accelerated Atherosclerosis Effects on CAD in Rheumatologic Diseases

This can be called an immune system-mediated inflammatory process as the immune cells can be found within atherosclerotic plaques, and inflammation activates this process.

(Table 16.5 shows the major contributing factors for atherosclerosis in different rheumatologic diseases).

Table 16.5 : Atherosclerosis in rheumatologic diseases
Full size table

4 Metabolic Syndrome and Rheumatological Diseases

The concept of metabolic syndrome was first recognized by Raven when he discussed that insulin resistance has a central role in type 2 DM, hypertension, and CAD [121]. Later, it became known as metabolic syndrome. The major components of metabolic syndrome include dyslipidemia, central obesity, insulin resistance, and hypertension [122]. The major components are not occurring concurrently; as it was found that insulin sensitivity will predict the increase in waist circumference (obesity), and the latter will predict the remaining components, e.g., dyslipidemia and hypertension [123]. The adipose tissue is acting as endocrine organ by the secretion of the pro-inflammatory factors called adipokines. Insulin resistance has a role in the development of CVD (probably due to the adipokines from the adipose tissue) [124] as it has a role in the enhancement of vascular inflammation and endothelial dysfunction [125]. Different adipokines have been recognized in metabolic syndrome with rheumatic diseases, and their effects were emphasized (see Table 16.6).

Table 16.6 The effects of different adipokines on rheumatologic diseases [154]
Full size table

Patients with rheumatic diseases are under the pressure of chronic inflammation mainly with RA and SLE. Many patients with rheumatic diseases—mainly RA, SLE, and AS—have been diagnosed with metabolic syndrome [14,15,16].

Here, we will discuss the rheumatic diseases and its relationship with metabolic syndrome.

4.1 RA

It was initial to associate insulin sensitivity to be lower in RA patients compared to osteoarthritis patients [126]. Later, it was found that the main factors of insulin resistance in RA are obesity and disease activity [127]. The prevalence of metabolic syndrome among RA patients ranges from 44% to 53% [15, 128]. Such patients were found to have higher disease activity than those without metabolic syndrome with low level of high-density lipoprotein cholesterol [15]. Its presence is associated with higher systemic inflammatory marker and glucocorticoids use [129]. Patients with RA, who were diagnosed with metabolic syndrome, were found to have higher risk of coronary artery calcification [128].

4.2 SLE

Non-diabetic patients with SLE were found to have significant decrease in sensitivity to insulin, and around 18% of them were diagnosed with metabolic syndrome [130]. The prevalence of metabolic syndrome among SLE patients ranges from 16% to 32.4% [14, 131, 132]. SLE patients have higher fasting insulin level, and cardiovascular risk factors were also elevated among the last group [133]. Metabolic syndrome was associated with higher level of C-reactive protein, homocysteine, lipoprotein, and cholesterol [14] . Metabolic syndrome and CVD among SLE patients were associated with prolonged SLE duration and increased cumulative organ damage [131]. Lupus nephritis, high corticosteroid doses, Korean and Hispanic ethnicity were associated with metabolic syndrome in SLE patients [132]. The use of hydroxychloroquine was associated with protective effect of CVD [131].

4.3 AS

The prevalence of metabolic syndrome among AS is around 45.8% [16], whereas low AS disease activity is not associated with accelerated atherosclerosis [134].

4.4 Psoriasis

Psoriasis is associated with DM. The prevalence of DM was higher with severe psoriasis than mild psoriasis in the rate of 7.1% vs. 4.4%, respectively [135]. The prevalence of metabolic syndrome among psoriatic patient ranges from 15% to 35.5% [136,137,138]. Psoriatic patients are prone to the development of the main components of metabolic syndrome (e.g., DM and hypertension) [139]. Treating psoriasis was found to be associated with improvement in the metabolic risk biomarkers, such as high-sensitivity CRP, adiponectin, and the oral glucose tolerance test [140].

4.5 Gout

The initial association of gout with metabolic syndrome was with the close association of hyperurecemia and the components of metabolic syndrome (e.g., hypertension, insulin resistance, and obesity) was noted [141]. Elevated uric acid levels among gout patients can be associated with insulin resistance since renal clearance is inversely related with insulin resistance [142]. The prevalence of metabolic syndrome among gout patients ranges from 44% to 88% [143,144,145].

5 The Various Medications that Are Being Used in the Management of Rheumatologic Disease that Have Variable Effects on CAD

It is important to mention these factors because managing clinicians may not pay attention to these effects as they focus mainly on the activity of the rheumatologic disease.

5.1 NSAIDs

  • The risks of major cardiovascular events—such as myocardial infarction, stroke, and death—appear to increase to a similar degree by the use of most nonselective NSAIDs at high doses. The exception is naproxen, which does not increase such risk [146].

  • All of the COX-2 selective inhibitors (coxibs) appear to increase the risk of ischemic cardiovascular disease in a dose-dependent fashion. Recent data showed that naproxen, celecoxib, and ibuprofen did not differ in the risk of the cardiovascular mortality, but naproxen was less than the last two for the risk of the gastrointestinal bleeding [147]. Certain COX-2 inhibitors are associated with twofold increase in CAD risk.

  • COX inhibition leads to CAD with two possible mechanisms:

    • It can interfere with normal platelet and endothelial vasodilator functions.

    • It can cause hypertension.

  • All (NSAIDs) can increase blood pressure in both normotensive and hypertensive individuals. Its use may reduce the effect of all antihypertensive drugs except calcium channel blockers.

    (Figure 16.1 summarizes the effects of NSAIDs on the cardiovascular system)

    Fig. 16.1
    figure 1

    NSAIDs and risk of CVD

    Full size image

5.2 Glucocorticoids (GC)

This medication is known to have serious noxious effects by increasing blood pressure, insulin resistance, body weight, and fat distribution. There is an excess risk of cardiovascular morbidity and mortality when the drug is used in high cumulative doses and for a long duration. There is 68% of increased risk of myocardial infarction among RA patients treated with GCs [148]. Cushing disease is associated with accelerated atherosclerotic vascular disease [149].

5.3 Methotrexate

Many studies have demonstrated that its use has been associated with a beneficial reduction in CVD events among patients with systemic inflammation diseases primarily from RA [49]. It is known to decrease homocysteine level. RA patients who used methotrexate have lower LDL levels, significant increase in mean HDL, and decrease in carotid artery intima-media thickness, compared with baseline values.

5.4 TNF Biologic DMARDs

  • A large study showed significant reduction in fatal and nonfatal CVD outcomes associated with TNF inhibitors, but this remains controversial.

  • The cardiovascular benefit of TNF inhibitors may be limited to patients with RA whose synovitis responds to these agents. Patients whose disease activity was reduced by TNF inhibitor therapy within the first 6 months of treatment had markedly decreased risk of myocardial infarction compared with those who continued to have active disease.

  • It was associated with a significant increase in both total cholesterol and HDL with no change in regard to the atherogenic index [150].

5.5 Non-TNF Biologic DMARDs

  • Rituximab has no significant effect on CVD, with no positive outcome on lipid profile or endothelial dysfunction.

  • Tocilizumab is associated with beneficial low CRP after early introduction, but it has unclear worse effect regarding elevation of total cholesterol, LDL [151, 152] when used for years, even though it does not increase CVD events. Tofacitinib is also associated with increased level of LDL [153].

In summary, for the prevention of CAD in rheumatologic diseases, we should do the following:

  • Traditional CAD risk factors control.

  • Early diagnosis and management of CAD.

  • Long follow-up for CAD complications.

  • Early diagnosis and management of rheumatologic disease with strict control of the disease activity.