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Rheumatic Diseases and the Cardiovascular System
Additional content is available online at Elsevier eBooks for Practicing Clinicians
The relationship between inflammatory rheumatic diseases and the cardiovascular system has long been recognized. As the treatment of these diseases has improved considerably over the last 30 years and increased survival, the importance and complexity of this interrelationship have achieved prominence. Indeed, we have entered an era in which established anti-rheumatic therapies are being trialed for the treatment of atherosclerosis. , Patients with multisystem rheumatic diseases may, on occasion, present initially to a cardiovascular physician or surgeon, and early recognition of the immune-mediated basis of the cardiovascular disease reduces morbidity and mortality. The vasculature may represent a primary target organ of the underlying rheumatic disease and can be affected at numerous sites and at micro- and macrovascular levels. Systemic sclerosis (SSc) impacts the microvessels and may be responsible for pulmonary arterial vasculopathy and pulmonary artery hypertension (PAH). Antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitides (AASVs) affect arterioles preferentially, while the large-vessel vasculitides affect the aorta and its major branches. Antiphospholipid syndrome (APS) causes both venous and arterial thromboses. Cardiac complications influence morbidity and mortality and in systemic lupus erythematosus (SLE) include coronary arteritis, pericarditis, myocarditis, and valvular heart disease. Renal artery stenosis leading to uncontrolled hypertension is a feature of Takayasu arteritis (TA), and occlusive lesions in the subclavian, axillary, or iliac arteries may lead to limb claudication in patients with TA and giant cell arteritis (GCA). Inflammatory rheumatic diseases have equally important secondary effects on the cardiovascular system. Chronic systemic inflammation predisposes to endothelial dysfunction and increased arterial stiffness, thereby escalating the risk of cardiovascular events. Cardiovascular specialists increasingly recognize the significantly increased prevalence of cardiac dysrhythmias, premature myocardial infarction and stroke in patients suffering from rheumatoid arthritis (RA) and SLE. Many outstanding clinical challenges remain; predominant among them are the development and rigorous evaluation of preventive strategies, early recognition, diagnosis and treatment of patients with rheumatic disease who have the highest risk for cardiovascular complications, alongside improved understanding of the underlying molecular mechanisms.
Atherosclerosis and the Rheumatic Diseases
Recognition of the role of inflammation in atherosclerosis has highlighted and stimulated study of the potential relationship between systemic inflammatory diseases and premature atherogenesis. This effort has substantially advanced our understanding of the epidemiology and underlying pathogenic mechanisms, revealing novel therapeutic targets. Current priorities include identification of patients most at risk and the development of preventive therapeutic strategies. , Evidence supporting an association between inflammatory diseases and premature cardiovascular events is best developed for RA and SLE. In addition, ankylosing spondylitis, psoriatic arthritis, AASV, TA, and APS may all associate with premature atherosclerosis. Cardiovascular specialists should consider an underlying inflammatory disease in young patients with otherwise unexplained angina, myocardial infarction, or stroke. Patients with a rheumatic disease who suffer a myocardial infarction have worse outcomes in terms of both heart failure and mortality than the age-matched general population.
Endothelial Dysfunction and Vascular Injury
Homeostatic mechanisms promote a quiescent, antithrombotic, antiadhesive vascular endothelium and control vasodilation and permeability (see Chapter 24, Chapter 36 ). Prolonged systemic inflammation such as that seen in RA and SLE may promote endothelial injury, increased endothelial apoptosis, and endothelial vasodilator dysfunction.
Traditional risk factors alone do not explain the increased burden of atherosclerosis, but inflammation may exacerbate the effects of classic risk factors. When compared with the general population, patients with systemic inflammatory diseases more commonly exhibit endothelial dysfunction and increased aortic stiffness. Although the results of individual studies vary, effective treatment of the underlying inflammation may not always reverse the endothelial dysfunction or improve the aortic stiffness. , , As plaque burden may not increase in rheumatologic diseases, systemic inflammatory environment may promote qualitative changes in plaques that predispose to plaque rupture, a conjecture supported by autopsy studies. Thus, both accelerated atherogenesis and higher-risk plaque may contribute to the observed increased incidence of premature cardiovascular events. ,
Various molecular mechanisms mediate the increased risk for atherosclerotic disease and cardiovascular events. In addition to traditional cardiovascular risk factors, disease-related factors may include effects of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interferon (IFN)-α, and IL-6 on endothelial activation, leukocyte adhesion, endothelial injury, and permeability. Chronic activation of toll-like receptor signaling, increased endothelial cell apoptosis and diminished capacity for repair may contribute. Autoantibodies (e.g., antiphospholipid antibodies), CD4 + CD28 − cytotoxic T cells, Th17/T REG imbalance, complement deficiency or excessive activation, genetic polymorphisms, and the deleterious effects of drugs, including corticosteroids and cyclosporine, are important. , , The potential role for clonal hematopoiesis caused by somatic mutations in bone marrow stem cells also merits further investigation in autoimmune rheumatic disease (see also Chapter 24 ).
Rheumatoid Arthritis
RA, an autoimmune, symmetric inflammatory polyarthritis with a female-to-male ratio of 3:1, affects up to 1% of the population in the Western world, with the onset of symptoms most commonly occurring between 30 and 50 years of age. Up to 80% of patients have a positive serum rheumatoid factor and/or anti–cyclic citrullinated peptide (CCP) antibodies. A systemic inflammatory response is evident, with low-grade fever, weight loss, raised erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), hypoalbuminemia, normochromic normocytic anemia, and thrombocytosis.
Atherosclerotic Disease in Rheumatoid Arthritis
A variety of studies have shown subclinical arterial disease with increased carotid intimal-media thickness (IMT) and early plaque development. Although RA independently raises the risk for atherosclerosis, the precise mechanistic relationship between RA and atherogenesis remains unknown. Similarly, the mechanisms and long-term outcomes of abnormalities in myocardial perfusion and coronary flow reserve in patients with RA and nonstenotic epicardial arteries remain to be established. The initial abnormalities in vascular function may occur at or before the onset of RA symptoms. The direct effect of chronic inflammation on vascular endothelium may itself promote atherogenesis, in addition to exacerbating the actions of traditional cardiovascular risk factors. , Moreover, the systemic inflammatory environment might contribute to the features of plaque and blood that promote cardiovascular events in patients with RA.
Patients with RA have increased classic risk factors for atherosclerosis. Tobacco smoking associates with both cardiovascular risk and the development of RA. Similarly, insulin resistance and the metabolic syndrome are more common in RA. Patients with RA may have a dyslipidemia characterized by high triglyceride levels and low levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. , The risk for myocardial infarction in patients with RA is considered similar to diabetes mellitus, and women with RA are twice as likely as age-matched controls in the general population to suffer myocardial infarction. Although death rates from both heart attack and stroke are comparable to that in the general population, events occur at an earlier age, with 50% of premature deaths in patients with RA being a direct consequence of cardiovascular disease. The excess mortality becomes apparent 7 to 10 years after diagnosis and associates with persistent disease activity and the presence of rheumatoid factor and anti-CCP antibodies. A recent review suggests that patients with RA who suffer a myocardial infarction have worse outcomes. However, this situation is changing, reflecting improved recognition of excess risk.
Treatment
Drug therapy for RA has evolved remarkably over the past 25 years, with the focus on biologic therapies and aggressive management of early disease. Clinical trials have demonstrated that this approach reduces symptoms and structural damage to joints. Increasing evidence suggests treatment to target to control synovitis also confers vascular protection. ,
Methotrexate has become the most widely used disease-modifying antirheumatic drug (DMARD), and since its introduction, mortality from myocardial infarction in patients with RA has improved. Sulfasalazine and hydroxychloroquine may confer similar benefit. Patients who do not respond adequately to DMARD therapy should switch to biologic therapies. These include those targeting TNF-α (infliximab, adalimumab, etanercept, certolizumab, and golimumab), the IL-6 receptor (tocilizumab, sarilumab), CTLA4Ig (abatacept), and the B cell–depleting monoclonal antibody rituximab, alongside oral small molecules targeting the Janus kinases (JAK) (baricitinib, tofacitinib, upadacitinib, ruxolitinib). , An aggressive disease-modifying approach minimizes the use of nonsteroidal antiinflammatory drugs (NSAIDs) and the requirement for corticosteroid therapy. Glucocorticoids may worsen traditional risk factors including insulin resistance, hypertension, and lipid profiles and may hasten carotid plaque formation in RA. Because NSAIDs and cyclooxygenase-2 (COX-2)-selective NSAIDs (coxibs), although effective, may elevate blood pressure and increase the frequency of thrombotic cardiovascular events, their use in patients with cardiovascular complications of inflammatory disease requires caution. However, evidence suggests that NSAID use in patients with RA does not confer an increased risk for cardiovascular events, thus indicating that their anti-inflammatory effects predominate.
Definitive demonstration of the potential cardiovascular benefits of the biologic therapies requires the results of long-term prospective studies (see later). TNF-α promotes vascular endothelial activation and dysfunction and may lead to plaque destabilization, and hence blockade would appear to be an attractive therapeutic option. Infliximab therapy may improve endothelial function as measured by flow-mediated dilation 4 to 12 weeks after infusion, whereas etanercept has been reported to reduce aortic stiffness. Analysis of carotid IMT suggests that TNF-α antagonists reduce systemic inflammation and retard progression of IMT. Tight therapeutic control of RA disease activity per se appears to have a beneficial effect on the risk for myocardial infarction. Treatment of the arthritis must be combined with a careful review of classic risk factors, with appropriate steps taken to modify them. Despite this, too few patients are routinely assessed for cardiovascular risk. Although we lack rigorous trials, most rheumatologists have a low threshold for addition of a statin. Meanwhile, debate continues concerning the pros and cons of disease-specific cardiovascular risk calculators. New guidelines have reviewed such issues.
Systemic Lupus Erythematosus
SLE, a systemic autoimmune disease, predominates in women at a ratio of 9:1 and affects all racial groups but more commonly those of Afro-Caribbean, Asian, and Chinese extraction. Initial constitutional symptoms include night sweats, lethargy, malaise, and weight loss. Mucocutaneous features including the classic butterfly facial rash, oral ulcers, and alopecia are frequent. Serositis, myalgia, arthralgia, and Jaccoud nonerosive arthropathy also occur. Potentially life-threatening complications include glomerulonephritis with renal failure, central nervous system (CNS) involvement with cerebral vasculitis, pneumonitis, shrinking lung syndrome, and PAH. Hematologic involvement includes lymphopenia in most and frequently hemolytic anemia, neutropenia, and thrombocytopenia. Cardiac manifestations of SLE include pericarditis, myocarditis, endocarditis, aortitis, and coronary arteritis. Understanding of the pathogenesis of SLE continues to improve. A defect in apoptotic cell clearance results in the exposure of nuclear antigens to an immune system with hyperreactive B cells. Loss of immune tolerance results in the generation of autoantibodies and immune complexes. Deposition of immune complexes in target organs leads to the activation of complement and tissue injury.
Most patients have high-titer antinuclear antibodies and antibodies against double-stranded DNA (dsDNA). The latter are more specific for the diagnosis of SLE, which is reinforced by the presence of antibodies against one or more nuclear antigens, including Sm, Ro, La, and ribonucleoprotein (RNP). Complement activation and consumption of C3 and C4 leading to reduced plasma levels characterize active disease. The ESR also rises in active disease, while CRP levels typically remain normal except in those with serositis or secondary infection.
Atherosclerotic Disease in Systemic Lupus Erythematosus
The increased risk for myocardial infarction and stroke in patients with SLE is somewhere between 2-fold and 10-fold and up to 50-fold greater than that in the general population. The young age of patients with SLE and cardiovascular disease (67% of female patients with SLE and a first cardiac event are less than 55 years of age) suggests that SLE accelerates arterial disease. , A study of 1874 cases (9485 person-years follow-up) revealed a 2.66-fold increase in the risk of myocardial infarction, stroke and coronary intervention when compared with the general population. Although the pattern and extent of coronary artery disease in SLE does not appear to differ ( Fig. 97.1 ), the plaques may be more vulnerable to rupture. Patients with SLE have worse outcomes following myocardial infarction than the age-matched general population, with a higher risk for the development of cardiac failure and increased mortality. This difference may result from late diagnosis of ischemic heart disease and a reluctance to treat aggressively.
Hypertension is common in SLE because of renal disease and the widespread use of glucocorticoids. Similarly, patients with SLE commonly have metabolic syndrome, which associates with renal impairment, higher corticosteroid doses, and Korean or Hispanic ethnicity. Patients with SLE also have lipid abnormalities, including high levels of very low-density lipoprotein (VLDL) and triglycerides, elevated or normal LDL cholesterol, reduced HDL cholesterol and impaired cholesterol efflux.
Treatment
Mild SLE with rash and arthralgia can be treated with simple analgesics and NSAIDs, with hydroxychloroquine commonly added to minimize flares. Organ involvement, including mild renal impairment, hematologic abnormalities, myositis, arthritis, and cutaneous lesions, requires the addition of prednisone and typically an immunosuppressant such as mycophenolate mofetil (MMF), azathioprine, or methotrexate to aid in controlling the disease and to facilitate steroid sparing. Cyclophosphamide and corticosteroids remain the first-line treatment of life-threatening complications, including myocarditis, cerebritis, severe hematologic involvement, and glomerulonephritis. MMF often replaces cyclophosphamide for lupus nephritis because of its equivalent efficacy and concerns regarding the risk for permanent infertility seen in up to 50% of patients treated with cyclophosphamide. Most rheumatologists and nephrologists consider rituximab an effective treatment of severe SLE, although clinical trials to date have proved disappointing. A variety of regimens have been used, including combinations of rituximab, prednisone, and cyclophosphamide. Belimumab, a monoclonal antibody that binds to the soluble B lymphocyte stimulator and prevents its interaction with B cell surface receptors, has a modest disease-modifying effect in nonrenal SLE. Positive phase III trial data are emerging for belimumab in lupus nephritis, for IFN type 1 receptor antibody anifrolumab and calcineurin inhibitor voclosporin.
Defining effective strategies for prevention of cardiovascular disease in patients with SLE will require long-term prospective trials with adjudicated cardiovascular endpoints. Undertreated and/or persistently active disease associates with accelerated atherogenesis. Therefore, adequate individualized immunosuppressive therapy should minimize cardiovascular complications. Hydroxychloroquine reduces LDL cholesterol and lowers mortality from cardiovascular disease in patients with SLE. Aggressive management of traditional risk factors is also advocated, including regular diligent monitoring and tight blood pressure control. Statins are widely used, particularly in patients with renal impairment. Caution and careful monitoring should be exercised in patients with active myositis, as statin therapy can exacerbate this complication. The clinical data available do not support significant protection against atherosclerosis by statins 2 to 3 years after initiation, although longer-term analysis is awaited.
Atherosclerosis in Association With Other Rheumatic Diseases
The relationship between chronic inflammation and atherogenesis implies that many rheumatic diseases may be associated with premature and increased cardiovascular risk ( Table 97.1 ). Because data in support of this hypothesis derive from relatively small studies, important current clinical challenges include the need to determine (1) which rheumatic diseases pose the greatest cardiovascular threat, (2) a means of identifying subsets of patients most at risk, and (3) evidence-based strategies to minimize cardiovascular events.
TABLE 97.1
Coronary Artery Involvement and the Rheumatic Diseases
| Premature Atherosclerosis |
|
| Coronary Arteritis |
|
Ankylosing spondylitis, psoriatic arthritis, and gout all associate with atherosclerotic disease. Hyperuricemia independently predicts cardiovascular disease, and patients with gout often have hypertension, hyperlipidemia, obesity, and diabetes mellitus. Many drugs used for the treatment of cardiac disease, including diuretics, beta blockers, and low-dose aspirin, can increase serum uric acid levels. In contrast, losartan, angiotensin-converting enzyme (ACE) inhibitors, atorvastatin, and fenofibrate may reduce urate levels. Allopurinol may reduce the risk for congestive cardiac failure and cardiovascular-associated death, whereas an increased risk of cardiovascular death has been reported with febuxostat. In addition to achieving a serum uric acid level lower than 0.36 mmol/L (6 mg/dL), patients with gout should receive dietary advice and aggressive management of cardiovascular risk factors.
Systematic review of articles on cardiovascular disease in psoriatic arthritis has revealed increased traditional risk factors, endothelial dysfunction, aortic stiffness, and subclinical atherosclerosis. The limited data available suggest that adequate suppression of inflammatory disease activity, which leads to improvement in endothelial dysfunction and carotid IMT, should be combined with regular assessment and control of traditional risk factors. , Patients with ankylosing spondylitis have also demonstrated impaired endothelial function, increased carotid IMT and pulse wave velocity, all of which indicate an increased risk for atherosclerosis. The long-term impact of anti-TNF-α, and the pros and cons associated with increasing use of anti-IL-17 and anti-IL-12/23 therapies on the incidence of cardiovascular events in spondyloarthritides will emerge from international biologic registries.
Vasculitides (See Chapter 42 , Chapter 43 )
The vasculitides, a heterogeneous group of diseases, represent a significant clinical challenge, both diagnostically and therapeutically. The primary systemic vasculitides are classified into large-, medium-, and small-vessel disease. This leaves a small group of unclassified conditions, including Behçet disease, relapsing polychondritis, primary CNS vasculitis, and Cogan syndrome.
The histologic features of vasculitis include perivascular inflammatory infiltrates that may invade the arterial wall, fibrinoid necrosis, thrombosis, fibrosis, and scar formation. Fibrinoid necrosis, a specific feature of the medium- and small-vessel vasculitides, typically affects the tunica media. Complications include stenosis and occlusions resulting in organ ischemia, thrombosis, aneurysm formation, and hemorrhage. Although biopsy is optimal for making the diagnosis, suitable tissue may not always be accessible, or arterial biopsy may present unacceptable hazards, such as in patients with TA. Thus, diagnosis often depends on clinical findings, laboratory indices, and imaging.
The vasculitides have a complex, multifactorial, and poorly understood immunopathogenesis. The endothelium may be subject to complement-mediated injury as a consequence of immune complex deposition in polyarteritis nodosa (PAN) or rheumatoid vasculitis. In the medium- and small-vessel vasculitides, ANCAs may stimulate formation of neutrophil extracellular traps (NETs), which damage the endothelium. The proinflammatory cytokines TNF-α, IL-1, IL-6, and IFN-γ may activate the endothelium and induce the expression of adhesion molecules, including E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1), thereby facilitating leukocyte adhesion and recruitment into the vessel wall and surrounding tissue.
Cardiovascular disease in patients with vasculitis, although relatively rare, can be life-threatening. Aortitis, hypertension, coronary arteritis, valvular heart disease, pericarditis, myocarditis, conduction abnormalities, accelerated atherosclerosis, and cardiac failure can all occur. This section focuses on the vasculitides most likely to be encountered by cardiovascular disease specialists.
Large-Vessel Vasculitis
Giant Cell Arteritis
GCA affects large and medium-sized arteries. The disease affects those older than 50 years, with incidence increasing with age. GCA occurs most commonly in northern Europe, Scandinavia, and the United States in people of northern European ancestry. GCA typically affects extracranial branches of the aorta and, in addition to the temporal arteries, may involve the subclavian and axillary arteries, the thoracic aorta, and, on occasion, the vertebrobasilar circulation, and femoral and iliac arteries. Clinical features include fever, weight loss, malaise, headache, temporal artery thickening with loss of pulsation, scalp tenderness, and jaw claudication. The most feared complication, anterior ischemic optic neuropathy (AION), may be manifested as amaurosis fugax or sudden permanent visual loss. Up to 25% of patients present with systemic features without the classic sign of tenderness and temporal artery involvement. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) has shown widespread FDG avidity throughout the aorta and subclavian and iliac arteries consistent with inflammation in more than 50% of patients.
Pathogenesis
Histopathologic examination reveals localized fragmentation of the internal elastic lamina closely associated with an inflammatory infiltrate consisting predominantly of IFN-γ-producing CD4+ T lymphocytes, monocytes/macrophages, and occasional characteristic multinucleated giant cells. Activated CD83+ dendritic cells initiate the arterial wall inflammation and colocalize with activated T cells. Local synthesis of mediators such as platelet-derived growth factor leads to proliferation of smooth muscle cells and concentric stenosis of the arterial lumen ( Fig. 97.2 ). Release of matrix metalloproteinases and generation of reactive oxygen species can result in arterial wall injury and aneurysm formation, typically involving the thoracic aorta.
Diagnosis
Biopsy is the definitive means of diagnosis and should be considered for all patients. However, the need for biopsy should not delay treatment. Temporal artery biopsy is positive in up to 80% of patients. Temporal artery ultrasound can reveal a characteristic halo sign with concentric homogeneous thickening of the arterial wall and evidence of flow disturbance and stenosis ( see Fig. 97.2 ).
Cardiovascular Complications
Although relatively rare, severe cardiovascular complications can occur and include aortic dissection and thoracic aortic aneurysms ( Table 97.2 ). , Imaging and autopsy studies suggest that aortitis and aortic wall thickening are frequent in GCA, although their relationship with the development of aortic aneurysm remains unclear. Those with conventional cardiovascular risk factors including cigarette smoking, poorly controlled disease, and aortic regurgitation have a higher risk. Increased FDG uptake in the thoracic aorta can associate with an increased risk for aortic dilation. In the absence of guidelines, we recommend annual thoracic aortic screening for those with FDG-PET–positive thoracic aortic uptake or magnetic resonance angiography (MRA) or computed tomography angiography (CTA) evidence of aortic wall thickening and every 2 to 3 years in the remainder of patients. CTA and MRA are the optimal imaging techniques. Pericarditis, coronary arteritis, limb ischemia, accelerated atherosclerosis, myocardial infarction, and cerebrovascular accidents all associate with GCA. Yet most outcome studies do not report increased mortality, so the impact of severe cardiovascular disease seems to be small.
TABLE 97.2
Cardiovascular Disease in the Systemic Vasculitides
| Vasculitides | Cardiovascular Complications |
|---|---|
| Large-Vessel Vasculitis | |
| Giant cell arteritis | Thoracic/abdominal artery aneurysm, limb ischemia, pericarditis, coronary arteritis, IHD, MI |
| Takayasu arteritis | Aortic regurgitation, limb ischemia, aortic stenosis, aortic aneurysm, stroke, hypertension, coronary arteritis and aneurysm, IHD, MI, myocarditis, cardiac failure |
| Kawasaki disease | Coronary artery aneurysm, MI, myocarditis, pericarditis, valvular dysfunction, cardiac failure |
| Medium-Vessel Vasculitis | |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) | Myocarditis, pericarditis, coronary arteritis, cardiomyopathy, cardiac fibrosis, valvular dysfunction, MI |
| Polyarteritis nodosa | Myocarditis, pericarditis, coronary arteritis, coronary aneurysm, hypertension, cardiac failure |
| Wegener granulomatosis (granulomatous polyangiitis) | Myocarditis, pericarditis, coronary arteritis, valvular heart disease, cardiac failure |
| Microscopic polyangiitis | Pericarditis, coronary microaneurysm, MI |
IHD , Ischemic heart disease; MI, myocardial infarction.
Takayasu Arteritis
TA, a granulomatous panarteritis, affects the aorta and its major branches, typically before the age of 40 years. The disease predominates in women, with a female-to-male ratio of up to 10:1. Because the diagnosis is often delayed, substantial arterial injury accrues.
Presentation is typically nonspecific and associated with fever, night sweats, arthralgia, malaise, profound tiredness, and lethargy. TA may be accompanied by symptoms of upper limb claudication, and carotidynia occurs in up to 25% of patients. The aorta may be involved throughout its length, and even though any branches can be diseased, the most commonly affected are the subclavian and common carotid arteries. More than 90% of patients have stenotic/occlusive arterial lesions, whereas approximately 25% have aneurysms. The pulmonary arteries are involved in up to 50% of patients, and aortic valve regurgitation and coronary arteritis may occur ( Fig. 97.3 ).
TA has severe consequences, with 74% reporting compromised daily activities and 23% unable to work. In our cohort, survival at 15 years is higher than 95%; similarly, in the United States, 94% to 96% survival rates are reported, whereas in Korea the survival rate was 87% at 10 years. In Japan, 15-year survival rates have improved to 96.5%. However, the survival rate fell to 67% in a subset of patients with serious complications and/or a progressive disease course.
Pathogenesis
Arteritic lesions demonstrate adventitial thickening and focal leukocytic accumulation in the media with intimal hyperplasia. The leukocytes include activated dendritic cells, T and B lymphocytes, macrophages, and multinucleated giant cells (see Fig. 97.3 ). Growth factor–driven mesenchymal cell proliferation leads to intimal hyperplasia and fibrosis and subsequent arterial stenosis or occlusion. Local matrix metalloproteinase synthesis may predispose to aneurysmal dilation.
Diagnosis
Diagnosis of TA depends principally on the physician including the disease in the differential diagnosis. The variable nature of the features of TA and the lack of constitutional symptoms in 30% to 50% of patients initially present a challenge to prompt diagnosis. In addition to improved physician awareness, a list of “red flags” that raise the possibility of TA is helpful ( Table 97.3 ). One’s index of suspicion must be high in young patients with an unexplained acute-phase response or hypertension. Similarly, common initial signs, including diminished or absent pulsation or arterial bruits, can suggest the diagnosis.
TABLE 97.3
“Red Flags” for Takayasu Arteritis
In patients younger than 40 years the following may indicative of TA:
|
CRP, C-reactive protein; ESR , erythrocyte sedimentation rate.
Laboratory abnormalities during active disease include raised ESR and CRP (in 75% of patients), often accompanied by normochromic normocytic anemia, thrombocytosis, hypergammaglobulinemia, and hypoalbuminemia. No specific autoantibodies or other serologic abnormalities exist. Noninvasive imaging is now the optimal means of diagnosis because tissue biopsy is rarely available. High-resolution ultrasound, cardiac magnetic resonance (CMR), MRA, CTA, and PET have all been studied. , Although the potential of these techniques is not in doubt, their specificity and sensitivity in the management of TA remain undetermined. 18 F-FDG-PET-CT may reveal evidence of active arteritis and lead to early detection of prestenotic disease. Demonstration of arterial wall enhancement, edema, or thickening on MRA and CTA may also facilitate the diagnosis of prestenotic disease, and stenoses and aneurysms can be readily identified and monitored (see Fig. 97.3 ). Color duplex ultrasound has particular use in assessing the common carotid and proximal subclavian arteries in TA. Homogeneous, bright concentric arterial wall thickening is a typical finding in affected common carotid arteries.
Cardiovascular Complications
In addition to the sequelae associated with cerebral, internal organ, and limb ischemia, aneurysms, PAH, or aortic rupture may develop. Cardiac complications include aortic valve insufficiency, accelerated atherosclerosis, cardiac ischemia, myocarditis, myocardial infarction, and heart failure. Coronary disease is often asymptomatic, as illustrated by the identification of silent myocardial injury in 27% of a cohort that we studied. Thallium stress scintigraphy revealed myocardial perfusion defects in 53%, whereas intra-arterial angiography has shown that up to 30% have coronary artery lesions typically affecting the ostia and proximal segments, with the left main coronary artery being most commonly affected. Ostial vasculitic coronary lesions are typically uncalcified, while more distal calcified lesions reflect secondary accelerated atherosclerosis. Neither MRA nor 18 F-FDG-PET-CT reliably identifies coronary arteritis, which is best identified by coronary CTA. Inflammation of the ascending aorta predisposes to coronary artery involvement, as well as to dilation of the aortic root with subsequent aortic valve regurgitation and the need for aortic valve replacement. Left ventricular dysfunction may affect up to 20% and may reflect myocarditis, ischemic heart disease, and hypertension. High blood pressure occurs commonly with renal artery stenosis often in association in TA.
Kawasaki Disease
Kawasaki disease (KD) predominantly affects children younger than 5 years with a peak incidence at 6 to 24 months of age. The vasculitis affects medium and small arteries, notably the coronary arteries. All racial groups may be affected, with the highest incidence is recorded in Asia (20 to 100 per 100,000 children <5 years of age). KD is an acute self-limited illness that typically resolves within 1 to 2 months, although mortality still remains 1% to 2%. Characteristic initial features include fever of 5 days’ duration or longer, bilateral conjunctivitis, and mucocutaneous lesions, including red fissured lips and a strawberry tongue. Cervical lymphadenopathy may be prominent, with erythema affecting the palms and soles and a polymorphous exanthema.
Pathogenesis
The cause of KD is unknown, although occasional seasonal epidemics and increased incidence in siblings suggests infection may trigger the disease and lead to an uncontrolled immunologic response in a genetically susceptiblE host. Tissue specimens show endothelial injury, perhaps caused by proinflammatory cytokines and activated neutrophils. Infiltration of the arterial wall by neutrophils, T cells, and macrophages is associated with the development of arterial stenosis or, more commonly, aneurysms. Coronary artery aneurysms develop in up to 20% of patients during the first month of the illness, and 50% will regress in the following years. A variety of organisms have been implicated, including streptococci, staphylococci, and Propionibacterium acnes . Although no definitive evidence supports an infectious cause, the emergence of a Kawasaki-like syndrome in children affected by SARS-Cov-2 has reignited interest.
Diagnosis
Neutrophilia, thrombocytosis, and a raised acute-phase response occur acutely. Echocardiography can detect coronary involvement from the second week of illness and can be used to monitor progress. Coronary angiography is not performed acutely because of the risk of precipitating myocardial infarction, but it can be used after 6 months to establish the degree of coronary artery involvement. The electrocardiogram (ECG) demonstrates abnormalities in up to 50% of patients, including tachycardia, T wave inversion, ST depression, atrioventricular block, and rarely, ventricular arrhythmia.
Cardiovascular Complications
Coronary artery aneurysms develop in up to 25% of untreated patients with KD. Sudden death can occur as a consequence of myocardial infarction following acute coronary thrombosis or rupture of a coronary artery aneurysm. Pericarditis, pericardial effusion, myocarditis, valvular dysfunction, and cardiac failure may all occur, whereas peripheral arterial involvement is less common but may affect the limb, renal, and visceral arteries.
Treatment
Intravenous immunoglobulin (IVIG) 2 g/kg over 10 to 12 hours should be prescribed as soon as diagnosis is made and within 10 days of presentation. Aspirin (30 to 100 mg/kg/day) is given concurrently until the patient is afebrile and then reduced to 3 to 5 mg/kg/day. This treatment combination reduces development of coronary artery aneurysm to 5%, with a significant impact on mortality. Ten to twenty percent of cases are resistant to IVIG. In this event a repeat course is recommended, and this can be combined with prednisone (2 mg/kg/day in divided doses). Alternative therapies for refractory disease, anti-TNF-α monoclonal infliximab (5 mg/kg IV over 2 hours) and the IL-1 receptor antagonist anakinra (100 to 200 mg/day SC), are both the subject of ongoing clinical trials.
Most patients with KD have a good outcome. Yet in up to 20% of those with coronary artery aneurysms, coronary stenoses eventually develop, and these patients require long-term follow-up into adulthood by an experienced cardiologist. Although the risk for long-term complications, including myocardial infarction and sudden death, is greater in those with giant aneurysms, the risk for thrombosis and myocardial infarction still remains increased in those in whom aneurysms have regressed and throughout adult life.
Idiopathic Aortitis
Aortitis can complicate SLE, Cogan syndrome, Behçet disease, human leukocyte antigen (HLA) B27-positive spondyloarthropathy, KD, and GCA. Aortitis may also be idiopathic, although a number of such cases are now recognized to fall within the IgG4-related disease spectrum. The clinical features are nonspecific and include malaise, lethargy, chest pain, fever, and weight loss, and the diagnosis is often missed, or made during incidental imaging or at the time of surgery. The ESR and CRP are typically raised, and the extent of the disease can be demonstrated by 18 F-FDG-CT-PET scanning and aortic MRA or CTA ( Fig. 97.4 ). Dilation of the aortic root may require aortic valve and root replacement, whenever possible preceded by immunosuppressive therapy to control aortic wall inflammation. Treatment involves corticosteroids and a steroid-sparing immunosuppressant drug such as azathioprine, methotrexate, or MMF. The B-cell depleting antibody rituximab has proven particularly effective for IgG4-related disease.
Treatment of Large-Vessel Vasculitis
The evidence base for the treatment of large-vessel vasculitis is remarkably small. Although GCA and TA typically respond to steroids, gaining remission requires high doses and a considerable side effect burden. In GCA, the dependence on prednisone and conflicting evidence concerning the efficacy of steroid-sparing drugs, combined with concerns about AION, often result in overtreatment and considerable side effects. Indeed, 86% of patients experience glucocorticoid-related adverse events at 10-year follow-up. Both of these diseases have a high relapse rate when the dose of corticosteroid is tapered, suggesting persistent vasculitis. Potential mechanistic insight comes from the identification of two pathogenic pathways in GCA. Raised plasma IL-17 and Th17 cells in the arterial wall are rapidly reduced by prednisone therapy and remained suppressed as the dose is reduced. In contrast, the Th1-promoting cytokine IL-12 and IFN-γ-producing Th1 cells typically demonstrate corticosteroid resistance, which may account for the reemergence of disease. , Corticosteroid treatment of GCA should be tapered carefully to maintain remission and minimize side effects. Although the literature is somewhat conflicting, methotrexate may offer corticosteroid-sparing efficacy for those unable to reduce the dose of prednisone sufficiently. Most patients with active TA require steroid-sparing immunosuppressive drugs. Methotrexate, MMF, and azathioprine are the most widely prescribed, and small open-label studies support their use. In patients failing to respond or in those with life-threatening disease such as coronary arteritis or myocarditis, treatment with intravenous pulsed cyclophosphamide is recommended.
GiACTA, a double-blind, placebo-controlled study of the efficacy and safety of anti–IL-6 receptor monoclonal antibody tocilizumab in GCA reported that at 52 weeks, tocilizumab plus either a 26-week or 52-week prednisone taper demonstrated superiority in achieving sustained remission in GCA compared to the prednisone taper control arms alone. While case reports also suggest that anti-TNF-α therapy can treat refractory GCA effectively, two small, randomized, placebo-controlled trials failed to demonstrate a significant clinically useful benefit. In patients with TA who fail to respond adequately to combination therapy with prednisone and steroid-sparing immunosuppressant drugs, including cyclophosphamide, current opinion is that both TNF-α and IL-6 blockade are effective, although clinical trial data is sparse. A review of all published cases of TA treated with TNF-α antagonists found complete remission in 37%, partial remission in 53.5%, and no response in 9.5%. An initial placebo-controlled trial of tocilizumab in TA suggested a beneficial effect. The suppression of both constitutional symptoms and CRP synthesis by tocilizumab complicates disease monitoring and may be falsely reassuring. Follow-up of patients with TA should therefore include angiographic monitoring, preferably with MRI because it avoids radiation exposure.
Critical analysis of the published results suggests that percutaneous angioplasty or bypass surgery requires caution in patients with TA or GCA. Indications for surgical intervention include aneurysmal enlargement with risk for rupture, severe aortic regurgitation or coarctation, stenotic or occlusive lesions resulting in severe symptomatic coronary artery or cerebrovascular disease, uncontrolled hypertension as a consequence of renal artery stenosis, and stenoses leading to critical limb ischemia. Whenever possible, surgery should be delayed until immunosuppression has achieved clinical remission.
Medium-Vessel Vasculitis
The medium-vessel vasculitides include Churg-Strauss syndrome (CSS, eosinophilic granulomatosis with polyangiitis, EGPA), granulomatosis with polyangiitis (GPA; Wegener granulomatosis), and microscopic polyangiitis (MPA). Although these diseases have overlapping features, they represent distinct clinical entities. GPA is most frequently associated with a cytoplasmic ANCA (cANCA) staining pattern that recognizes the antigen proteinase-3, whereas MPA most commonly associates with a perinuclear ANCA (pANCA) directed against myeloperoxidase.
Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss Syndrome)
EGPA, a systemic small-vessel necrotizing vasculitis with a prevalence of 10 to 14 per million population, encompasses three disease phases. An initial prodrome characterized by allergic rhinitis, sinusitis, and asthma precedes peripheral blood eosinophilia and eosinophilic infiltrative lesions in the lung and myocardium. Some years later, a systemic phase follows with necrotizing vasculitis affecting the skin, peripheral nerves, gastrointestinal tract, and kidney (in 30%). Up to 40% of patients with EGPA are ANCA positive, most typically pANCA. ANCA-negative patients are more likely to suffer cardiopulmonary complications, whereas pANCA-positive patients seem to be more at risk for renal and peripheral nerve involvement. The diagnosis depends on the clinical features, imaging studies, ANCA, and whenever possible, biopsy results. Patients have a markedly raised peripheral eosinophil count and evidence of necrotizing vasculitis, including eosinophilic infiltration ( Fig. 97.5 ).
The diagnosis of EGPA requires consideration of a number of alternatives, including GPA and MPA. A history of asthma, the presence of marked peripheral eosinophilia, and a dense eosinophilic infiltrate highly suggest EGPA. Viral infections, including cytomegalovirus and hepatitis B and C, must be excluded. In light of the eosinophilia, parasitic infestation, particularly by helminths, should be sought and excluded. Eosinophilia in the absence of demonstrable vasculitis may represent idiopathic hypereosinophilic syndrome or an underlying leukoproliferative disorder.
Cardiovascular Complications
Of all the vasculitides, EGPA most likely associates with severe and potentially fatal cardiac disease (see Table 97.2 ). Cardiac involvement complicates up to 60% of cases, and the disease spectrum includes pericarditis, myocarditis, coronary arteritis, myocardial infarction, cardiac fibrosis, arterial thrombosis, and valvular dysfunction. Cardiac disease is a prominent cause of death. Cardiomyopathy occurs as a result of ischemia secondary to arteritis affecting the intramyocardial arteries or, less frequently, the epicardial coronary arteries. Myocarditis associates with eosinophilic infiltration, fibrosis, and occasionally, granuloma formation. Release of major basic protein and eosinophil-derived neurotoxin by infiltrating eosinophils can lead to direct tissue injury. Myocarditis may result in the development of restrictive, congestive, or dilated cardiomyopathy, or death.
Investigation
Cardiac involvement in EGPA requires urgent investigation, aggressive treatment, and initially, a 12-lead ECG and transthoracic echocardiography (see Fig. 97.5 ). Common findings include evidence of left ventricular dilation in 30% of patients, reduced shortening fraction, and increased cardiac wall echogenicity. Contrast-enhanced CMR provides the most sensitive means of detecting myocardial involvement. If the diagnosis remains in doubt, endomyocardial biopsy may reveal eosinophilic infiltration with or without fibrosis, although vasculitis is rarely seen and the patchy nature of the disease renders diagnostic yield low.
Treatment
High-dose corticosteroid treatment typically results in a good response and associates with a 90% remission of disease. Relapses occur frequently on tapering steroid therapy, and prednisone-related side effects are common. In the presence of severe disease, including cardiac, gastrointestinal, CNS, and renal involvement, an immunosuppressant drug should be prescribed concomitantly. Although further clinical trials are required, the first choice of drug is pulsed intravenous cyclophosphamide. Once remission is achieved, generally by 3 to 6 months, cyclophosphamide can be replaced by azathioprine or methotrexate. In some patients with milder disease and evidence of steroid side effects, azathioprine or methotrexate should be added to aid in steroid tapering. In refractory disease, anecdotal case reports have suggested the effectiveness of IVIG or TNF-α blockade. The anti-IL-5 mAb mepolizumab has demonstrated efficacy in a randomized, placebo-controlled trial and further results from the study of B cell depletion are awaited.
Polyarteritis Nodosa
PAN is an increasingly rare disease characterized by a systemic necrotizing vasculitis of medium-sized arteries complicated by aneurysmal nodules. Viral infections, particularly with cytomegalovirus, human immunodeficiency virus, and hepatitis B and C virus, should be specifically sought and excluded. The classic type of PAN is an ANCA-negative vasculitis with the predominant clinical features including fever, malaise, arthralgia, weight loss, livedo reticularis, cutaneous nodules, and a vasculitic rash. Abdominal, cardiac, and testicular pain may occur, and some patients manifest mononeuritis multiplex. Hematuria, proteinuria, and/or hypertension indicates renal involvement.
The pathogenesis of PAN remains poorly understood. The initial vascular endothelial injury is followed by local release of IL-1 and TNF-α, which predispose to chronic inflammation and augmented leukocyte adhesion molecule expression. Recruitment of neutrophils is followed by monocyte infiltration, local endothelial disruption, thrombosis, and fibrinoid necrosis ( Fig. 97.6 ). The associated arterial wall injury predisposes to aneurysm formation. The diagnosis of PAN is not straightforward. Although a biopsy can be definitive, yield is variable and dependent on an accessible lesion. A deep skin biopsy specimen from an involved nodular site is optimal. Combined sural nerve and muscle biopsy may also be helpful. Occasionally, nodules are detected on a medium-sized peripheral artery that can safely undergo biopsy. Renal biopsy should be approached with caution because of the risk for hemorrhage from microaneurysms. Despite increasing use of noninvasive imaging with CTA or MRA, mesenteric arteriography remains the most accurate way of identifying renal or hepatic microaneurysms.
Cardiovascular Complications
Cardiac involvement in PAN is often subclinical and clinically apparent in only 10% of patients. Congestive cardiac failure is most commonly seen and may reflect myocarditis or coronary arteritis. Alternatively, the underlying cause may be PAN-related renal disease complicated by hypertension. Five percent of patients develop pericarditis, as well as supraventricular tachycardia and valvular disease. Coronary angiography may reveal coronary artery microaneurysms, coronary arteritis, or coronary spasm. Coronary CTA may demonstrate coronary artery aneurysms.
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