DEFINITION AND ETIOLOGY

Takayasu’s arteritis (TA) is a large-vessel vasculitis of unknown etiology that has a predilection for the aorta and its primary branches. Sustained inflammation of involved vessels leads most often to stenotic or occlusive lesions and can also result in development of aneurysms.¹

EPIDEMIOLOGY

TA is a rare disorder that has been described in patients of all races, but it occurs most often in Asian countries. The estimated annual incidence in North America is only 2.6 cases per million population.² Female patients are affected up to 10 times more often than male patients, and the peak incidence is in the third decade of life.¹

PATHOPHYSIOLOGY

Vascular injury is mediated by the actions of macrophages, cytotoxic T cells, γδ T cells, and natural killer cells,^3,⁴ which are the main constituents within the inflammatory infiltrates. The inflammatory process leads to myointimal proliferation, with subsequent vessel wall thickening and luminal stenosis, the most common lesion of TA. Lesions that predominantly cause destruction of the muscularis and the elastica can result in vascular dilatation or aneurysms. Such abnormalities most commonly occur in the aortic root and arch.

Cytokines (such as tumor necrosis factor-α [TNF-α], interleukin-6 ([IL-6], and interferon gamma [IFN-γ]), a variety of chemokines, and other proteins (including perforin and matrix metalloproteinases) are involved in induction and amplification of the inflammatory response and tissue injury.³^–⁵ IL-6 and chemokine (C-C motif) ligand 5 (CCL5 or RANTES) serum levels correlate with disease activity in TA patients.⁶ On the other hand, it is well known that TNF-α plays an important role in granuloma formation and TNF-α can be demonstrated within the vessel wall in large vessel vasculitis.⁷ Compared to normal controls, messenger RNA (mRNA) for TNF is increased in peripheral blood mononuclear cells of TA patients.^5,^8,⁹ Serum TNF-α^5,^8,⁹ is similarly increased in TA patients compared to healthy persons. A potential role for TNF-α in the pathogenesis of TA is suggested by the efficacy of anti–TNF-α therapies in patients with refractory TA.¹⁰

SIGNS AND SYMPTOMS

One of the difficulties in making a diagnosis of TA lies in the heterogeneity of presentations. TA manifests with clinically nonspecific signs and symptoms of systemic inflammation in about 50% of patients.¹¹ These include fever, weight loss, malaise, and generalized arthralgias and myalgias. The most common symptoms and signs of TA in different cohorts of patients (Americans,^1,¹¹ Italians,¹² Mexicans,¹³ and Indians¹⁴) have been reviewed.¹¹ Diminishing or absence of pulse or blood pressure, asymmetry of blood pressure in upper or lower extremities, bruits (most often found over the carotid, subclavian, abdominal, and femoral arteries), claudication of extremities, fatigue, and headache are present at the time of disease onset in about half of patients.¹¹ The most commonly involved arterial territories in American cohorts are the aorta and subclavian arteries, followed by carotid, mesenteric, iliofemoral, and vertebral arteries.¹¹

Symptomatic involvement of coronary and pulmonary arteries is less commonly detected.¹¹ However, in asymptomatic TA patients, imaging of pulmonary vasculature has shown evidence of involvement in more than 50% of cases.^15,¹⁶ Stenotic vascular lesions are found in more than 90% of patients; dilatation or aneurysm formation makes up 17% to 25% of lesions.^11,¹² The aortic root is the most common location for aneurysmal disease and can lead to clinically apparent valvular regurgitation, which occurs in a quarter of patients.¹¹ Rupture of an aortic arch aneurysm and congestive cardiac failure due to aortic insufficiency or hypertension are two of main causes of death in TA patients.^1,^11,¹²

Hypertension is a major source of disease-related morbidity and is present in at least 40% of U.S. and European patients.^11,¹² It has been noted in up to 80% of patients from India, Japan, Mexico, and Korea.¹¹ Renal artery stenosis (Fig. 1) is present in 25% to 80% of patients and is the most common cause of hypertension,¹¹ which can also result from suprarenal aortic stenosis or decreased aortic compliance.¹⁷

Figure 1 Stenosis of the right renal artery.

Neurologic symptoms are present in more than 50% of patients.¹¹ These can result from stenosis of carotid or vertebral arteries (Fig. 2), which leads to dizziness, syncope, vertigo, and orthostatic symptoms. More-severe manifestations, such as transient ischemic attack or stroke, are seen in up to 5% to 10% of patients and are more often experienced by patients with carotid or vertebral disease. Headache occurs in 40% to 57% of patients.¹¹

Figure 2 Stenotic lesions of the left subclavian (LSC) and bilateral common carotid (CC) arteries.

Although visual disturbances, including amaurosis fugax and permanent blindness, have been described in 12% to 30% of some TA series,^1,^11,¹⁸ permanent loss of vision is quite uncommon in North American patients.^1,¹¹ Hypoperfusion of retinal and choroidal vessels due to stenosis of carotid arteries is responsible for TA retinopathy, which is characterized by dilation of small vessels, formation of microaneurysms and arteriovenous anastomoses, and neovascularization of the retina. Its reported incidence is 14% to 33% in Asian patients.¹⁸ Hypertensive retinopathy and glucocorticoid adverse events affecting eyes (e.g., glaucoma, cataracts) are common in TA and also need to be considered in these patients.

Pulmonary involvement in TA is characterized by vasculitis affecting the large or medium-sized pulmonary arteries. These abnormalities (occlusion, stenosis, and post-stenotic dilatation) are detected in more than 55% of TA patients on imaging studies,^15,¹⁶ but most are asymptomatic. Manifestations of pulmonary vascular involvement can become apparent years before the systemic arterial disease has been suspected. Clinical symptoms such as hemoptysis, dyspnea, cough, or chest pain occur in about 25% of patients. Shortness of breath, not clinically attributable to cardiac or pulmonary disease, affects almost 20% of patients.¹⁷ Rare cases of TA with interstitial pneumonitis, pleural effusion, massive hemoptysis, and thrombosis of pulmonary arteries have been reported.^16,¹⁹ Perfusion lung scans can be abnormal in 76% of patients²⁰ and mimic chronic thromboembolic disease. In these cases, the differential diagnosis of both entities needs to be considered.¹⁹

Visceral artery involvement is described in 20 to 40% of cases.¹¹ Lesions of the celiac trunk or mesenteric arteries can result in ischemia of the abdominal viscera. However, clinical symptoms are infrequent and many lesions do not cause gastrointestinal ischemic symptoms.

Dermatologic manifestations are noted in up to 28% of patients. Although rare cases of cutaneous necrotizing and granulomatous vasculitis have been described, more common associations are erythema nodosum, erythema induratum, and pyoderma gangrenosum.²¹

DIAGNOSIS

The diagnosis of TA relies on clinical findings in the setting of compatible vascular imaging abnormalities.

Laboratory Tests

No serologic tests have sufficient sensitivity and specificity to be considered a gold standard for diagnosis.²² Although acute-phase reactants may be helpful in assessing disease activity, in many patients they may not correlate with systemic symptoms or progressive change on imaging studies. Normal acute-phase reactants also do not ensure disease remission.²² Sequential imaging evaluations have revealed disease progression (as determined by the presence of new vascular lesions in new territories) in more than 50% of patients with clinically stable profiles and normal erythrocyte sedimentation rate (ESR).^11,²³ Clinical evaluation also underestimates the presence of subclinical disease activity; 44% of patients with TA with apparent clinically quiescent disease undergoing bypass have histopathologic evidence of vascular inflammation.¹

Vascular Imaging Techniques

Hitherto, the gold standard for supporting the diagnosis of TA has been contrast angiography imaging. It provides information about vessel lumen caliber, permits recording of intravascular pressure measurements, and, when necessary, provides opportunities for intervention (e.g. angioplasty).¹ Catheter-directed angiography, however, has limitations, including its inability to provide information about vessel wall thickness. It also carries risks related to arterial invasiveness and rarely injury, intravascular contrast reactions, and renal toxicity. Cardiovascular magnetic resonance (C-MR) with its two components, contrast-enhanced MRI and MR angiography (MRA, conventional or three-dimensional), is now considered by some to have diagnostic accuracy almost as good as conventional catheter-directed angiography for large-vessel vasculitis. Although measurements of intravascular pressure or intravascular interventions are not possible with C-MR, images can be provided with a good safety profile and without the use of nephrotoxic contrast agents. For these reasons, C-MR overall is advantageous for initial diagnosis and for routine sequential follow-up for vasculitis involving large vessels.²⁴

Although MRI can provide additional information on the inflammatory status of the vessel wall, the value of the data regarding prediction of vascular anatomic change is uncertain.^25,²⁶ Positron emission tomography (PET) imaging using labeled fluorodeoxyglucose has been demonstrated to be useful in identifying the presence or absence of inflammation within large vessels.^26,²⁷

Combinations of some of these techniques, such as MRI/MRA or computed tomography–angiography with PET, are being used with promising results. However, additional studies are needed to more clearly define the performance characteristics of each technique, especially in regard to imaging enhancement, and how imaging findings correlate with disease progression when studied longitudinally. Although enhancement usually suggests inflammation, this remains an assumption and it is uncertain whether vessel repair and remodeling also produce similar findings. The accuracy of persistent enhancement in predicting later vessel anatomic change (stenoses or aneurysms) is also uncertain.