Published: June 2014
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 less often may cause aneurysms.1 Several classification and nomenclature guidelines note that TA affects persons younger than 40 or 50 years, while the diagnosis of giant cell arteritis (GCA) has been said to be most appropriate for those who develop large-vessel vasculitis after the age of 50. These age-based definitions are felt by us and others to be arbitrary, and are not widely accepted by most authors. It has been suggested that these two entities may in fact represent extremes within the same spectrum of disease.
TA is a rare disorder that has been described in people of all races, in most parts of the world. While initially thought to be most prevalent in Asian countries, this data needs to be re-examined to be certain about possible ethnic skewing. The estimated annual incidence in North America is only 2.6 cases per million population.2 Women are affected up to 10 times more often than men, and the peak incidence is in the 3rd decade of life.1
Vascular injury is mediated by the actions of macrophages, cytotoxic T cells, gd T cells, and natural killer cells,3,4 which are the main cellular components of 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 elastic lamina can result in vascular dilatation or aneurysms. Such abnormalities most commonly occur in the aortic root and arch.
Cytokines (such as tumor necrosis factor-alpha [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 are roughly associated with disease activity in TA patients.6 In addition, 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 with normal controls, messenger RNA for TNF is increased in peripheral blood mononuclear cells of TA patients.5,8,9 Serum TNF-α5,8,9 is similarly increased in TA patients compared with healthy persons, and 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
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, or 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 (see Figure 1), followed by carotid, mesenteric, iliofemoral, and vertebral arteries.11
Symptomatic involvement of coronary and pulmonary arteries is less commonly detected.11 However, 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 (see Figure 2) 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 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 Hypertension has been noted in up to 80% of patients from India, Japan, Mexico, and Korea.11 Renal artery stenosis (Figure 3) 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
Neurologic symptoms are present in more than 50% of patients.11 These symptoms can result from stenosis of carotid or vertebral arteries (Figure 4a-b), which also causes dizziness, syncope, vertigo, and orthostatic symptoms. More severe manifestations such as transient ischemic attack (TIA) or stroke are seen in up to 5% to 10% of patients and are more often experienced by patients with carotid or vertebral disease. Severe or atypical headache occurs in 40% to 57% of patients.11
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. Because development of collateral vessels is the rule, symptoms usually do not occur unless at least two of the three main mesenteric vessels (celiac, superior mesenteric, and inferior mesenteric arteries) are compromised. 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
Because of the rarity of this disease, delays in diagnosis are common. In a recent U.S. cohort, the median delay to diagnosis was 17.5 months (range, 7-41.8 mos), and 44.8 months for those patients over the age of 40.22 The diagnosis of TA relies on clinical findings in the setting of compatible vascular imaging abnormalities.
No serologic tests have sufficient sensitivity and specificity to be considered a gold standard for diagnosis.23 Although acute-phase reactants may be helpful in assessing disease activity, they are elevated in only 60% to 70% of patients at diagnosis22 and, in many cases, do not correlate with systemic symptoms or progressive change on imaging studies. Normal acute-phase reactants do not ensure disease remission.23 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).11,24 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.1,22
Hitherto, the gold standard for supporting the diagnosis of TA has been contrast angiography imaging, which 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 magnetic resonance imaging (MRI) and magnetic resonance 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 ionizing radiation or 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.25
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.26,27 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, as well.27,28
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 vessel wall enhancement may suggest inflammation, this remains an assumption; it is suspected that vessel repair and remodeling may also produce similar findings. The accuracy of persistent enhancement in predicting later vessel anatomic change (stenoses or aneurysms) is uncertain.
Biopsies of large vessels are usually not practical in the absence of indications for bypass. In that setting, we strongly recommend that a specimen of an involved artery be obtained for histologic examination.29 Lesions can reveal granulomatous arteritis, with lymphoplasmacytic infiltrates, multinucleated giant cells, and cytotoxic and gd T lymphocytes,29–31 as well as patchy destruction of medial musculoelastic lamina and different degrees of adventitial fibrosis and myointimal proliferation (Figure 5a-b).31
TA can mimic other conditions. Diseases such as Marfan's syndrome, type IV Ehlers-Danlos syndrome, Loeys-Dietz, and other congenital disorders of connective tissue can manifest with aneurysmal disease and aortic valve insufficiency. However, these diseases are not associated with large-vessel stenoses, the hallmark of TA. In addition, signs and symptoms of systemic inflammation are absent in genetic vascular disorders of collagen and fibrillin synthesis, for which the histologic finding is cystic medial degeneration.
Fibromuscular dysplasia (FMD) is a non-inflammatory, non-atherosclerotic vascular disease, which results in arterial stenoses, aneurysms, and/or dissections of medium-sized arteries. There are several forms of FMD, of which multifocal FMD is the most common (>90%).32 Middle-aged females are preferentially affected, and although involvement of most arteries has been described, the renal and extracranial carotid and vertebral arteries are most frequently involved. Patients commonly present with hypertension (due to renal artery stenosis), headache, pulsatile tinnitus or TIA/stroke (due to involvement of carotid arteries), or bruits, potentially mimicking either TA or atherosclerotic disease. FMD may be distinguished from TA by the absence of signs of systemic inflammation, and the characteristic angiogram finding of "string of beads" changes in the mid-to-distal portion of arteries (Figure 6a-b).32
Infectious etiologies should be considered in all patients with large-vessel aneurysms. Agents known to cause aortic aneurysms include bacterial, syphilitic, mycobacterial, and mycotic pathogens. Stenotic disease in the setting of infection is uncommon.
Atherosclerotic vascular disease can manifest similarly to TA, but the setting in which these disorders occur differs. TA is more prevalent in young female patients and preferentially affects the large vessels of the upper extremities and the aortic root. Atherosclerosis more often occurs in older persons with vascular risk factors and is more common in the vessels of the lower extremities and abdominal aorta.
Rarely TA initially exhibits pulmonary perfusion scan abnormalities similar to those of chronic thromboembolic disease. TA needs to be ruled out when insidious progressive or episodic dyspnea occurs, in conjunction with multiple segmental pulmonary perfusion defects in a young patient.
Other vasculitides such as Cogan's syndrome, Behçet's syndrome, systemic lupus erythematosus (SLE), sarcoidosis, and the spondyloarthropathies may be associated with large-vessel vasculitis. Fortunately, in most cases their other disease manifestations help to distinguish them from TA.
The overlap between TA and GCA is generally underappreciated. For example, patients with TA might have musculoskeletal features that are similar to those of polymyalgia rheumatica, or they might experience amaurosis, blindness, jaw claudication, or headaches. Distinguishing between the two disorders may be merely a matter of semantics.
One of the greatest challenges in managing TA is determining disease activity. Kerr and colleagues1 defined active disease according to the existence of new or worsening of any two or more of the following parameters: signs or symptoms of vascular ischemia or inflammation, increase in sedimentation rate, new angiographic features in new territories, and systemic symptoms not attributable to another disease.
Although these features have been demonstrated to be helpful when present, their absence does not ensure disease remission; that is, they are not adequately sensitive. In addition to routine clinical assessment, it remains imperative that all patients have regular, serial imaging of the large vessels to monitor for new disease activity to guide treatment decision making. When using imaging to assess disease activity, it is important to remember that a lesion resulting from previous inflammation may continue to progress over time (i.e., a stenotic lesion may progress to occlusion, or an aneurysmal lesion may dilate over time) without ongoing inflammation being present. Currently, the best marker for unequivocally active disease remains the development of a new vascular lesion in a previously unaffected territory.
Glucocorticoids are the baseline for treatment of active disease. Initial therapy generally consists of prednisone in dosages of about 1 mg/kg/day. High doses of glucocorticoids result in clinical improvement in almost all patients and lead to remission in about 60%. However, when prednisone is tapered to less than 20 mg/day, most patients suffer relapse.11,24 Between 46% and 84% of patients will require a second agent to achieve and sustain remission.33 Frequently prescribed second-line agents include methotrexate, azathioprine and mycophenolate mofetil.34 Cyclophosphamide (1-2 mg/kg/day orally) may also help to achieve and maintain disease remission. However, because of the risk of severe toxicity with long-term therapy (>3-6 months), this drug is only recommended for patients with severe TA refractory to other immunosuppressive therapy.29,34 When remission has been induced with cyclophosphamide over 3 to 4 months, long-term maintenance of remission should be attempted with methotrexate or azathioprine.29
Minocycline, besides having antimicrobial activity, also suppresses production of metalloproteinases. Minocycline has been used in addition to glucocorticoids in a series of 11 patients with TA. Results were encouraging in regard to reducing levels of acute-phase reactants and improving control of disease activity. However, randomized studies must be done to establish the value of this agent in TA.35
Advances in our understanding of disease pathogenesis have led to the investigation and use of biologic agents in TA, in particular the anti-TNF agents, anti-IL6 receptor antibody tocilizumab, and B-cell targeted therapy rituximab. In a study performed at Cleveland Clinic, Hoffman and colleagues showed anti–TNF-α agents to be efficacious in sustaining glucocorticoid-free remissions in more than 60% of patients with previously refractory TA.10 In an extended study with up to 7 years follow up, the same authors have documented the sustainability of anti–TNF-α therapy in maintaining disease remission long term (median follow up 28 months).36 Since these initial reports, 19 additional case reports and case series have been published and reviewed, describing the use of anti-TNFs in a total of 128 TA patients.37,38 Taken together, these studies suggest that anti-TNF therapy may induce remission in 70% to 90% of TA patients who are unable to do so with prednisone and a non-biologic agent alone.37 Infliximab is the most commonly studied anti-TNF, and we would not recommend extrapolating these results to all agents of this class. In addition, it should be noted that the majority of patients who responded to infliximab did require an increase in dose or reduction in dosing interval over time to sustain remission, and relapses were common in those who discontinued the drug. In addition to the anti-TNF agents, tocilizumab, a recombinant humanized monoclonal antibody against the IL-6 receptor, is gaining popularity for the treatment of refractory TA. Thus far, 41 tocilizumab-treated patients have been described with impressive preliminary results.37–41 Clinical response was seen in 38 of 41 (92.6%), allowing for significant tapering or discontinuation of prednisone in most. Relapse occurred in only 8 of 38 responders (21%), and adverse events were infrequent and mild. It is interesting to note that 11 patients responded to tocilizumab after previously failing anti-TNF therapy, confirming that this drug works via novel pathways and may be of use in anti-TNF non-responders. Because of its anti–IL-6 activity, inflammatory markers may be unreliable for monitoring disease activity after treatment.37 Further study of this drug is warranted.
Although traditionally considered a disease of T cells, some evidence points to a role for B-cell involvement in TA pathogenesis.42–44 Accordingly, use of rituximab has now been reported in six refractory TA patients, with promising results.44–46
Surgical interventions for revascularization in TA patients are indicated for symptomatic coronary artery disease or cervicocranial artery stenosis, uncontrolled hypertension secondary to renal artery stenosis, severe extremity claudication, moderate to severe aortic valve regurgitation, and aortic aneurysm at risk of rupture or dissection.29 Procedures to re-establish flow in stenotic or occluded vessels include surgical use of synthetic grafts or autologous vessel bypass, endarterectomy, and percutaneous transluminal angioplasty (PTA), with or without stenting. Aortic root replacement or repair is employed for aortic insufficiency, which is usually associated with aortic valve replacement for regurgitant flow.29 Although often initially successful, vascular interventions in TA patients are prone to failure due to the ongoing inflammatory process, degree of vessel fibrosis, and length of lesions. Selecting the best intervention for the lesion in question remains a very difficult area and requires the evaluation of an experienced cardiac or vascular surgeon.
In two American longitudinal cohorts, intervention for either vessel stenosis or aortic regurgitation was required in one-half to two-thirds of TA patients over mean periods of 3 to 5 years.1,11 PTA and stenting used alone or as a combined treatment in TA have been reviewed in a study that included 11 series of TA patients and 224 vascular lesions. Patency rate was variable among series.11 In our experience at Cleveland Clinic, a cohort of 30 TA patients was followed for a mean of 3 years and re-evaluated with sequential imaging studies (mean interval between studies, 4.8 months). A total of 64 revascularization procedures were carried out for stenotic vascular lesions. Angioplasty and vascular bypass and reconstruction procedures were performed in 20 and 44 instances, respectively. Overall, bypass grafts had better sustained patency than angioplasty or stent-treated vessels. Restenosis or occlusion after intervention occurred in 78% of angioplasty and 36% of bypass procedures. Bypass was especially successful when it was feasible to use autologous donor vessels.1,47
Since this study, several large TA cohorts have confirmed superior patency rates following bypass grafting as compared to stenting for TA lesions,48–50 with follow up extending out to 6.5 years. In the future, however, advances in surgical techniques such as the use of stent grafts may eventually lead to improved outcomes for endovascular procedures in these patients.51 Although some cases of aortic branch vessel and coronary artery stenosis have been treated with endarterectomy, this procedure is technically difficult or impossible to perform effectively, and it can even be dangerous in TA because arterial lesions can be rigid and often involve the entire thickness of the vessel wall.29
Revascularization should ideally be performed during periods of disease remission. In a retrospective review of 79 TA patients undergoing revascularization, inflammation at the time of intervention was independently associated with arterial complication (odds ratio 7.48, P = 0.04).48 There appears to be a clear benefit to achieving good control of disease activity with the use of immunosuppression both pre- and postoperatively. In a UK cohort of 97 patients with 6 years follow up, outcomes after vascular intervention were significantly better in those who received preoperative immunosuppression. This was particularly true for the group undergoing endovascular repair.49 No patients developed severe complications from the use of perioperative immunosuppression, and no adverse effects on surgical recovery were noted. A second, unrelated study demonstrated that postoperative immunosuppression, with both glucocorticoid and a second agent, independently reduced the risk of re-stenosis after surgery (hazard ratio [HR] 0.41, P = 0.044).52 Whenever possible, we recommend that tissue should be obtained at the time of surgery to help determine disease activity and guide medical therapy.
Reports of surgical risk vary, but risks appear to be increased in patients with TA. One series, following 106 patients over a mean period of 19.8 years, stratified postoperative mortality into early and late deaths. Early deaths, defined as death occurring during hospitalization, occurred in 11% of patients.53 Death occurred in most as a result of cardiovascular complications including congestive heart failure, aneurysm rupture, stroke, or hemorrhage. However, another series of 33 patients reported only one perioperative death (resulting from infection) over a mean follow-up period of 3 years.54 In general, perioperative mortality is influenced by a number of factors, and the experience of the surgical team and medical center in caring for TA patients is a crucial element of surgical success.29
Detection and treatment of hypertension in TA are critical in achieving good long-term outcomes. Recognition of hypertension is often delayed because of the high incidence of subclavian and innominate artery stenoses, which can cause falsely low peripheral blood pressure readings in reference to pressure in the aortic root. When stenoses affect all extremities, there might not be any peripheral extremity where blood pressure measurements reflect central aortic pressures. Thus, it is crucial for the clinician to have a map of the entire large-vessel anatomy to identify potential territories at risk and to provide proper care for patients with TA and central hypertension. The importance of complete vascular imaging at the time of diagnosis cannot be overemphasized. When stenoses make reliability of extremity blood pressure recordings questionable, invasive angiography with measurement of central aortic pressure and determination of gradients is critical. In these cases, even when the accuracy of peripheral measurements has been established, identifying a target pressure range that minimizes end-organ damage while allowing vital organ perfusion in the setting of arterial stenoses can be challenging. Close monitoring with avoidance of abrupt decreases in mean pressures is critically important.
Persistent inflammation appears to be a risk factor for premature atherosclerosis in a variety of chronic illnesses such as rheumatoid arthritis and SLE. Indeed, when compared with healthy controls, TA patients have increased carotid intima-medial thickness55 and increased arterial stiffness,56 which are surrogate markers for coronary atherosclerosis. Furthermore, intima-medial thickness is increased even in patients with angiographically normal carotid arteries in the setting of active disease.55 Additionally, stenotic and dilated lesions of large- and medium-sized arteries in TA become sites of unusually high turbulence and consequent vascular stress. Areas of turbulent flow have been recognized as foci for arterial atherosclerotic lesions in animal and human studies. These experiences emphasize the importance of identifying, treating, and monitoring all modifiable cardiovascular risk factors in these patients. In addition to vigilant monitoring and controlling hypertension, in the absence of contraindications, anti-platelet therapy should be used. Initially shown to reduce the risk of TIA and ischemic optic neuropathy in patients with GCA, aspirin has now proven protective against TIA, stroke, myocardial infarction, and unstable angina in TA patients as well (HR, 0.055, P = 0.011).57 Although other interventions have not been well-studied to date, a preventative cardiology consultation to address additional screening and manage other cardiovascular risk factors is recommended in all TA patients.
Chronic morbidity and disability are common in TA1,11 and are directly correlated with the vascular territories involved, frequency of disease relapse, and extent of disease. In addition, there is considerable morbidity associated with immunosuppressive therapies (e.g., infections, hypertension, diabetes, osteoporosis, or cataracts related to use of corticosteroids). Although estimated mean 5-, 10-, and 15-year survival rates are 97%, 97%, and 86% respectively, because it predominantly affects the young, mortality remains increased in TA when compared with the general population, with a standardized mortality ratio of 3.0.22 Fortunately, death from TA is uncommon. When it does occur, in most cases it is the result of cardiovascular complications including congestive heart failure, aneurysm rupture, stroke, or hemorrhage.29,54 Postoperative mortality, defined as death occurring during hospitalization, has been observed in up to 11% of patients52; however, other series have reported few postoperative mortalities.1,11,49
Systemic therapies with immunosuppressive and antiproliferative agents (e.g., sirolimus, everolimus) are currently in use in cardiac transplant protocols. These agents target the maladaptive response of intimal hyperplasia that leads to allograft vasculopathy. New stents, impregnated with slow-release forms of these agents, are being used to decrease intimal proliferation and restenosis. Sirolimus-eluting stents have demonstrated higher efficacy than conventional stents in patients with atherosclerotic coronary artery disease, and their mechanism of action has made them of interest in TA. Several case reports have described the use of such drug-eluting stents in TA; however, results have been variable thus far.58–62
Patients with TA require a multidisciplinary approach for optimal care. The team should include rheumatologic, imaging, cardiovascular, and surgical specialists.
TA is a rare, chronic inflammatory disease of the large arteries, leading to vessel stenosis or aneurysm. It is imperative to consider the diagnosis in a younger person presenting with symptoms of ischemia, asymmetrical blood pressures or pulses, or suggestive imaging. Immunosuppressive medications remain the cornerstone of therapy, with surgical interventions reserved for treatment of critical, symptomatic, or life-threatening lesions.