Takayasu arteritis …

Neuroimmunology

Updated 03.12.2024
Released 08.13.2001
Expires For CME 03.12.2027

Takayasu arteritis

Authors: José Hernández-Rodríguez MD PhD, Verónica Gómez-Caverzaschi MD

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Editor: Francesc Graus MD PhD

Takayasu arteritis

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Introduction

Overview

Takayasu arteritis is a primary systemic large-vessel vasculitis that affects the aorta and its major branches causing stenotic and occlusive lesions. Takayasu arteritis typically occurs in young women. Constitutional and musculoskeletal symptoms are frequent but nonspecific. Vascular manifestations include extremity claudication and cardiac failure. Up to 20% of patients develop cerebrovascular events, such as transient ischemic attack or stroke. This review provides an extensive overview of epidemiological, clinical, laboratory, vascular imaging, and therapeutic aspects of Takayasu arteritis. Methods of monitoring disease activity and vascular progression, as well as advances in pharmacological therapies and interventional procedures, have been updated.

Key points

	• Takayasu arteritis is a primary systemic large-vessel vasculitis affecting the aorta and its major branches.
	• Takayasu arteritis usually affects young females with a heterogeneous presentation, usually with constitutional and musculoskeletal symptoms besides ischemic manifestations and hypertension.
	• Although catheter-directed angiography is the gold standard for studying the arterial lumen more precisely, CT angiography and MR imaging and angiography (MRI and MRA) can be used for the initial Takayasu arteritis diagnosis. MRI and MRA are preferred for sequential vascular imaging during follow-up.
	• Disease activity is still assessed by the combination of clinical manifestations, elevated erythrocyte sedimentation rate (ESR), and changes in vascular imaging techniques.
	• Glucocorticoids are the treatment of choice to induce and maintain remission, but additional immunosuppressive agents, preferably methotrexate, are frequently needed. In patients with Takayasu arteritis refractory to these first-line agents, tocilizumab and anti-TNF agents have been demonstrated to be good therapeutic options.
	• Bypass with autologous vessel grafts have shown better long-term patency than other procedures. The use of angioplasty has also been reported to have better long-term results than artery stenting. Revascularization should be performed when the disease is in maintained remission.
	• Diagnosis and control of hypertension are crucial because hypertension is frequently unrecognized due to stenoses of large vessels.

Historical note and terminology

Definition, historical perspective, and classification criteria. Takayasu arteritis is a primary large-vessel vasculitis with a predilection for the aorta and its primary branches. Chronic inflammatory lesions often lead to stenotic or occlusive lesions and less frequently evolve to dilation and aneurysm formation (47).

The disease takes the name of Dr. Mikito Takayasu, an ophthalmologist who presented a young girl with retinal changes of chronic hypoperfusion at a Japanese ophthalmology meeting in 1905. At the same meeting, Dr. Onishi and Dr. Kagoshima presented a patient with similar retinal changes and the absence of radial pulses (92). Previously, the first description of Takayasu arteritis in the literature was by Rokushu Yamamoto in 1830 (92). A 45-year-old man presented with fever; a year later, he developed abnormal radial pulses in both arms and a subsequent absence of pulse in both carotid arteries. The patient died suddenly 11 years later.

Different classification criteria have been used for Takayasu arteritis in the last few decades. In the 1994 and 2013 (44) Chapel Hill Consensus Conference on the Nomenclature of Vasculitides, Takayasu arteritis was defined as a large-vessel arteritis, often granulomatous and predominantly affecting the aorta and its major branches. Disease onset usually occurs in patients younger than 50 years of age. The 1990 American College of Rheumatology criteria for the classification of Takayasu arteritis proposed the next criteria: (1) age at disease onset of 40 years or younger; (2) claudication of the extremities; (3) decreased brachial artery pulse; (4) blood pressure difference between both arms of more than 10 mmHg; (5) bruits over subclavian arteries or aorta; and (6) arteriographic abnormalities. A patient could be classified with Takayasu arteritis if three of the six criteria were fulfilled, with a sensitivity of 90.5% and a specificity of 97.8% (02).

The 2022 ACR/European League Against Rheumatism (EULAR) classification criteria for Takayasu arteritis include the identification of medium- or large-vessel vasculitis and the exclusion of other potential causes or mimickers (30). The final 12 criteria are described in Table 1.

Table 1. Diagnostic Criteria for Takayasu Arteritis

Absolute requirements
	• Age 60 or younger years at diagnosis
	• Evidence of vasculitis on imaging
Additional clinical criteria
	• Female sex		+1
	• Angina or ischemic cardiac pain		+2
	• Arm or leg claudication		+2
	• Vascular bruit		+2
	• Reduced pulse by physical examination in arms		+2
	• Reduced pulse or tenderness of carotid arteries		+2
	• Systolic blood pressure difference in arms ≥ 20 mm Hg		+1
Additional imaging criteria
	• Number of affected arterial territories (select one)
		One arterial territory	+1
		Two arterial territories	+2
		> Two arterial territories	+3
	• Symmetric involvement of paired arteries		+1
	• Abdominal aorta (renal or mesenteric) involvement		+3
5 or more points is needed for the diagnosis

The EULAR, the Paediatric Rheumatology European Society (PRES), and the Paediatric Rheumatology International Trials Organisation (PRINTO) updated consensus classification criteria for common childhood vasculitides in 2010 (96). The classification of children with Takayasu arteritis requires typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of the following five criteria: (1) decreased peripheral pulse or claudication; (2) blood pressure discrepancy higher than 10 mmHg in any limb; (3) bruits on the aorta or its major branches; (4) hypertension; and (5) elevated acute phase reactants.

The previous angiographic Takayasu arteritis classifications were updated by Hata and colleagues at the Takayasu Conference in 1994 (35). Vascular topographic extent was divided into four types (Table 2). In addition, the involvement of coronary or pulmonary arteries should be indicated as C (+) or P (+), respectively.

Table 2. Angiographic Takayasu Arteritis Classification

Type	Description
I	Involvement of primary branches of the aortic arch
IIa	Involvement of the ascending aorta, aortic arch, and its branches
IIb	Involvement of the ascending aorta, aortic arch and its branches, and thoracic descending aorta
III	Involvement of the thoracic descending aorta, abdominal aorta, and/or renal arteries
IV	Involvement of the abdominal aorta and/or renal arteries
V	A combination of features of both types lIb and IV

Clinical manifestations

Presentation and course

Takayasu arteritis usually affects young women, and the clinical presentation may be quite heterogeneous. Takayasu arteritis presents with nonspecific signs and symptoms of systemic inflammation in about 50% of patients (64). These systemic symptoms include fever, weight loss, malaise, and generalized myalgia and arthralgia. Clinical manifestations may differ slightly between different cohorts, such as American (47; 64), Italian (124), Mexican (62), Brazilian (13), Indian (43), French, and Spanish patients (15; 53). An initial clinical presentation with predominant constitutional symptoms often leads to delayed diagnosis as vessel occlusion may become evident later.

Because Takayasu arteritis is predominantly a vascular stenosing disease, clinical manifestations derived from artery stenoses or occlusions are common and depend on the location and severity of the vascular lesions (47). Diminishing or absence of pulse or blood pressure; asymmetry of blood pressure in upper or lower extremities; bruits in vascular territories (most often found over the carotid, subclavian, abdominal, and femoral arteries); and extremity claudication, fatigue, and headache are present at the time of disease onset in about half of patients (64). The most commonly involved arterial territories in American cohorts include the aorta and subclavian arteries, followed by carotid, mesenteric, iliofemoral, and vertebral arteries. Symptomatic involvement of coronary and pulmonary arteries is infrequent. However, in asymptomatic patients, imaging studies reveal pulmonary vasculature lesions in over 50% of cases (67). Although most vascular lesions (> 90%) are stenoses, dilation or aneurysm formation have been detected in 17% to 25% of patients (124; 64). Aneurysmal disease most commonly affects the aortic root and may lead to clinically apparent valve regurgitation in up to 25% of patients (64). Aortic arch aneurysm rupture and congestive cardiac failure due to aortic insufficiency (also favored by uncontrolled hypertension) are two of the main causes of death in patients with Takayasu arteritis (47; 84; 124; 64).

Neurologic symptoms are present in more than 50% of patients and are usually caused by stenoses of carotid or vertebral arteries, which lead to dizziness, lightheadedness, syncope, vertigo, and orthostatic symptoms in most cases (91; 64). Headache also occurs in about half of patients. Severe neurologic manifestations, such as transient ischemic attack or stroke, are observed in 5% to 20% of patients (10% at diagnosis). Cardiovascular events are more frequently associated with carotid or vertebral stenotic lesions (64; 77). Stroke accounted for 9.5% of deaths in a series of patients with Takayasu arteritis (84).

Visual abnormalities, such as amaurosis fugax and permanent blindness, have been reported in 12% to 30% of patients with Takayasu arteritis (47; 09; 64). However, permanent visual loss is quite uncommon in North American patients (47; 64). Hypoperfusion of retinal and choroidal vessels caused by the stenosis of carotid arteries is responsible for Takayasu arteritis retinopathy (the ophthalmologic presentation described by Dr. Takayasu in 1905) and is characterized by formation of small vessel dilation, microaneurysms, arteriovenous anastomoses, and neovascularization of the retina. It has been reported to occur in 14% to 33% of Asian patients (09). Hypertensive retinopathy and glucocorticoid adverse events affecting the eyes (eg, glaucoma, cataracts) are also common in Takayasu arteritis, and they need to be included within the differential diagnosis of visual disturbances in patients with Takayasu arteritis.

Lung involvement in Takayasu arteritis is characterized by inflammation of large or medium-sized pulmonary arteries. Although most patients do not present with overt respiratory symptoms, pulmonary artery lesions (occlusion, stenosis, and post-stenotic dilation) can be detected in more than half of patients on imaging studies (34; 129; 67). Indeed, manifestations of pulmonary arteritis may become clinically apparent years after the systemic disease occurs. Hemoptysis, dyspnea, cough, or chest pain are experienced by up to 25% of patients (46). Interstitial pneumonitis, pleural effusion, massive hemoptysis, and thrombosis of pulmonary arteries have been scarcely reported (66; 67). In patients with pulmonary involvement, perfusion lung studies mimicking chronic thromboembolic disease can be found in 76% of cases (122). Therefore, in patients with chronic thromboembolic disease, Takayasu arteritis with pulmonary artery involvement must be part of the differential diagnosis (66).

Involvement of intestinal arteries is reported in 20% to 40% of patients (64). Although lesions of the celiac trunk or mesenteric arteries may result in intestinal or other intra-abdominal organ ischemia, clinical manifestations are infrequent, and many lesions do not cause symptoms.

Dermatologic lesions have been noted in about 28% of patients. Erythema nodosum, erythema induratum, and pyoderma gangrenosum are cutaneous lesions frequently associated with Takayasu arteritis (94). Cutaneous necrotizing and granulomatous vasculitis have also seldom been described (126).

Hypertension is present in at least 40% of American and European patients and is the major cause of disease-related morbidity (124; 64). The proportion of patients with hypertension has been reported to be even higher (up to 80%) in patients from India, Japan, Mexico, and Korea (64). Renal artery stenosis develops in 25% to 80% of patients (64). Although hypertension is more frequently caused by renal artery stenosis, it may also result from suprarenal aortic stenosis or decreased aortic compliance (46).

In two large U.S. cohorts of patients with Takayasu arteritis, the average age at disease onset was 25 years (range 7 to 64 years) (47; 64). The mean time between the start of symptoms and disease diagnosis was 10 months. Common manifestations at disease onset included claudication of the upper extremities (62%); loss or asymmetry of pulses (53% to 57%), mainly affecting the upper extremities; limb blood pressure discrepancy (53%); bruits (53%), usually over the carotid arteries; and hypertension (33%). Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries. Other manifestations included general and musculoskeletal symptoms (43% and 57%), central nervous system involvement (57%), and cardiac complaints (38%), usually due to aortic regurgitation (47; 64).

Pediatric onset of Takayasu arteritis has been described in 71 South American patients (72% female), with a mean age of 9.2 years at disease diagnosis (13). The average duration from the onset of symptoms to diagnosis was 1.2 years. Constitutional symptoms were the most common presentation (77.5%), followed by neurologic symptoms (70%). Six months following disease onset, musculoskeletal and neurologic manifestations were the most frequently presented (42% and 35.9%, respectively); over time, neurologic symptoms remained persistent in 22.7% of patients (13).

Prognosis and complications

Satisfactory outcomes in Takayasu arteritis include achieving control of disease activity and progression of vascular lesions as well as controlling blood pressure and minimizing treatment toxicity.

Induction of remission is achieved by most patients after initiation of glucocorticoids, with or without other immunosuppressive agents. However, relapses still occur in one third to one half of patients, and nearly 25% of patients continue to have active disease despite therapy, without reaching clear remission (47; 64; 16; 15; 13). In a North American series, 2 of 75 patients (7%) had a casual diagnosis in a spontaneous remission phase and did not require any treatment (64).

Morbidity and mortality in patients with Takayasu arteritis are directly associated with vascular territories involved and disease extent. Additional morbidity is due to the use of glucocorticoids and other immunosuppressive therapies that are often responsible for secondary effects, such as infections, hypertension, diabetes, osteoporosis, or cataracts. An unrecognized or inadequately treated hypertension, the presence of aortic aneurysms, aortic valve insufficiency, congestive heart failure, and coronary artery disease are clearly associated with an increased risk of premature death (46; 58). Sudden death may result from myocardial infarction, stroke, or rupture or dissection of an aortic aneurysm. Among these causes of death, several prognostic factors have been associated with higher mortality, such as hypoperfusion retinopathy, hypertension, aortic regurgitation, aneurysm, a continuous progressive active disease, and age over 35 years at diagnosis (41). However, a higher erythrocyte sedimentation rate at disease diagnosis was associated with a better outcome (41). Postoperative mortality, defined as death occurring during hospitalization, has been observed in up to 11% of patients (80). Most deaths tend to occur within the first 5 to 15 years after disease onset (41). However, despite these potential life-threatening complications, 5- to 10-year survival rates have been reported to be around 74% to 90% in reference centers (41; 46; 58; 98; 64; 109; 77).

Diagnosis of hypertension is often delayed because of the high frequency of stenoses of the aortic arch branches, which may result in misleading low peripheral blood pressure readings (when compared to pressure in the aortic root). For that reason, blood pressure should be assessed in the four extremities at the onset of disease and during follow-up visits when discrepancies in blood pressure between extremities or dismissed pulses in more than one extremity are detected. In these situations, vascular imaging studies can provide useful information about which extremities have unimpeded flow. When peripheral blood pressure recordings are questionable, an invasive angiogram with central aortic pressure measurements will determine whether any extremity provides an accurate reflection of central aortic pressure. In cases with hypertension secondary to renal artery stenoses, such lesions should be corrected by vascular interventional or surgical procedures.

Clinical vignette

A 37-year-old Caucasian woman without a significant past medical history was referred to our reference center for vasculitis with progressive claudication of the right arm after exertion over the last 2 months. Around 4 to 5 months before referral, she developed daily fever (37.5ºC to 38ºC) and fatigue and had lost 3 to 4 kg in weight in the last 6 to 8 weeks. From that time, only fatigue and mild headache persisted. During the last 2 weeks, she presented with occipital headache worsening, lightheadedness, and presyncope episodes, mainly with neck movements. In the previous 3 to 4 days, she also suffered repeated episodes of visual disturbances of the left eye, mainly as blurry vision, lasting 20 to 40 seconds each episode. Physical examination was remarkable for diminished blood pressure of the right arm exceeding 15 mmHg as compared with the left arm, which was normal. Right radial and cubital pulses were clearly diminished and asymmetric compared with left arm pulses. The patient’s weight was 65 Kg.

During this period, her primary care physician interpreted her initial symptoms as part of a viral process. A laboratory test performed a week before referral revealed an ESR of 60 mm/1st hour, CRP of 3 mg/dL, and hemoglobin of 118 g/L. The patient was finally referred to our center because of the occurrence of neuro-ophthalmological symptoms.

A diagnosis of Takayasu arteritis was initially suspected. QuantiFERON-TB Gold; luetic, hepatitis B and C virus, and HIV serologies; and autoimmunity markers were all negative. MRI and MRA of the aorta and supra-aortic trunks depicted a critical arterial stenosis in the right subclavian humeral artery, a distal stenotic segment in the right internal carotid artery, and an occluded lesion of the left vertebral artery. Vessel wall thickening was observed in all supra-aortic vessels, which showed intense FDG uptake on the PET-CT scan. A cerebral MRI did not disclose brain ischemic lesions. Ophthalmologic examination was normal as no vascular retinal lesions were observed at fundoscopy.

Arterial lesions in a 37-year-old woman with Takayasu arteritis

(A) MR angiography of the aorta and supra-aortic trunks depicted a critical arterial stenosis in the right subclavian humeral artery (orange dashed arrow), a distal stenotic segment in the right internal carotid artery (orange ...

Because total occlusion of the left vertebral artery was already established, and the contralateral vertebral artery and both internal carotid arteries supplied good intracranial circulation, no endovascular or surgery procedures were performed. The patient was diagnosed with Takayasu arteritis, and high-dose glucocorticoids were started: intravenous methylprednisolone 250 mg/day for 3 days followed by prednisone 60 mg/day for 1 month, together with subcutaneous methotrexate 15 mg weekly and aspirin100 mg/day. Prednisone was subsequently tapered.

Although MRI and MRA did not reveal luminal changes at 6 months, a slight reduction in T2-weighted hyperintense signal was noticed without a reduction in vessel wall thickening. During the first year, at months 7 and 11, the patient experienced two disease relapses consisting of worsening of right arm claudication, low-grade fever, and intense asthenia while taking prednisone doses of 15 and 10 mg/day. ESR was increased over 50 mm/1st hour in both determinations. Monthly intravenous tocilizumab at 520 mg was subsequently started. After 5 years of follow-up, the patient reduced prednisone doses from 15 to 20 to 2.5 mg/day and did not experience any new relapses. Vascular stenotic lesions and artery wall thickening remained stable during the sequential MR studies.

Biological basis

Etiology and pathogenesis

Takayasu arteritis is a primary vasculitis of unknown origin. Several factors are involved in disease predisposition. Therefore, Takayasu arteritis is considered of multifactorial etiology. The predominance of young women suggests a hormonal involvement in this condition.

Differences in ethnic and geographic distribution and familial clustering indicate the important role of genetic factors (128). Specific human leukocyte antigen (HLA) and other non-HLA susceptibility loci have been demonstrated as robust susceptibility loci shared across ancestries (08; 95).

Vascular injury is mediated by macrophages, cytotoxic T cells, gamma delta T cells, and natural killer cells, which are the main constituents within the inflammatory infiltrates (110; 03; 103). As with giant cell arteritis (another large-vessel granulomatous vasculitis), mononuclear cells are recruited at the vasa vasorum and cross through the vessel wall, switching to activated macrophages and forming giant cells (103). In Takayasu arteritis, initial vessel inflammation also occurs in the vasa vasorum. Enhanced expression of HLA class I and II antigens and intercellular adhesion molecule I (ICAM-1) has been detected within inflammatory infiltrates, particularly in the vasa vasorum (110). Perforin-secreting cells in the inflammatory infiltrates and depositions of perforin on vascular cells suggest the potential role of cytotoxic cells in tissue destruction (110). Expression of the 65-kDa heat-shock protein (HSP65), HLA I and II, and ICAM-1 within the inflammatory infiltrates might facilitate the recognition, adhesion, and cytotoxicity of the infiltrating lymphocytes (110). Natural killer (NK) and gamma-delta T lymphocytes recognize the surface antigen release perforin and promote inflammation and macrophages activation (103).

Activated macrophages produce proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and IL-17; a wide variety of chemokines and growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF); and other proteins, including perforin and matrix metalloproteinases (MMP), which are all involved in the induction and amplification of the inflammatory response and tissue injury (110; 03; 120). Macrophages also stimulate CD4+ T cells in T helper type 1 (TH-1) response, which, in turn, produce interferon gamma, which is also produced by CD8 cytotoxic T cells, gamma-delta T cells, and NK cells.

As previously described in giant cell arteritis, activated macrophages also release VEGF, promoting neovascularization, as well as PDGF, producing smooth muscle cell migration and intimal proliferation, leading to myointimal hyperplasia and subsequent vessel wall thickening and luminal stenosis or occlusion, the final lesion of Takayasu arteritis (103). Lesions predominantly causing destruction of the muscular and elastic layers may result in vascular dilation or aneurysms. Such abnormalities most commonly occur in the aortic root and arch.

IL-6 and RANTES serum levels correlate with disease activity in patients with Takayasu arteritis (90). TNF-alpha also plays an important role in granuloma formation and is known to be produced within the vessel wall in giant cell arteritis, the other large-vessel vasculitis (36). Compared to normal controls, mRNA for TNF is increased in peripheral blood mononuclear cells of patients with Takayasu arteritis (119; 120; 99). Serum TNF-alpha is similarly increased in patients with Takayasu arteritis compared to healthy individuals (119; 120; 99). The potential role of TNF-alpha and IL-6 in the pathogenesis of Takayasu arteritis is supported by the efficacy of anti-TNF-alpha and anti-IL-6 therapies in patients with refractory Takayasu arteritis (37; 81; 89; 16; 73; 75; 76; 71; 72; 85; 86).

Ectopic follicles containing follicular dendritic cells (CD21+) and adventitial B-cell aggregates or tertiary lymphoid organs have been observed in aorta specimens from patients with Takayasu arteritis. In addition, adventitial germinal center memory B cells have been detected by flow cytometry, with the concomitant presence of antigen-experienced T follicular helper cells (12). Another study found higher circulating CD19+ B-cell counts and IgG levels in patients with Takayasu arteritis than in healthy controls. Serum IgG and IgG1 levels were higher in active Takayasu arteritis than in nonactive Takayasu arteritis. In addition, positive correlations of serum IgG levels were observed with ESR and CRP levels as well as with disease activity (by NIH score) in treatment-naive patients with Takayasu arteritis and those on treatment during follow-up. Immunohistochemical staining has confirmed CD19+ B-cell and IgG infiltration in the aortic wall in patients with Takayasu arteritis (10). Although circulating germinal center memory B cells and aortic wall B-cell clusters (ectopic lymphoid formation) have been found in patients with Takayasu arteritis, the role of B cells in its pathogenesis remains to be elucidated. In this sense, several patients with Takayasu arteritis have been successfully treated with rituximab, a B-cell depleting agent (24; 38; 07; 93; 102; 82; 74).

Differential diagnosis

Confusing conditions

A definite diagnosis of Takayasu arteritis is usually challenging and is even more difficult in patients presenting with nonspecific features. The main differential diagnoses must be considered in systemic vasculitides in which large vessels are involved. Giant cell arteritis, isolated aortitis, and immunoglobulin G4 (IgG4)–related disease are the main systemic vasculitides that also classically affect the aorta or its major branches (14). Aortic inflammation has also been described to be associated with other systemic vasculitides, such as granulomatosis with polyangiitis (GPA), Behcet disease, and Cogan syndrome, as well as other systemic autoimmune diseases, such as rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, Sjogren syndrome, and sarcoidosis (14).

Giant cell arteritis merits special attention in the differential diagnosis of Takayasu arteritis as both systemic vasculitides predominantly affect large vessels by granulomatous infiltrates and giant cell formation. Giant cell arteritis mainly affects Caucasian patients who are usually older than 50 years of age, with a female predominance (2:1). Typical clinical features of giant cell arteritis include headache; jaw claudication; scalp tenderness; visual and neurologic ischemic events, mostly amaurosis (established or fugax); painful and pulseless thickening of temporal arteries; and polymyalgia rheumatica (104). In a study prospectively assessing the prevalence and topography of large-vessel involvement by CTA in 40 patients with newly diagnosed, biopsy-proven giant cell arteritis and in whom glucocorticoids were not used or given for more than 3 days, aorta and other large vessels were involved in up to two thirds of patients (104). In addition, the distribution of artery lesions was similar to those described in Takayasu arteritis (aorta 65%, brachiocephalic trunk 47.5%, carotid arteries 35%, subclavian arteries 42.5%, axillary arteries 17.5%, splanchnic arteries 22.5%, renal arteries 7.5%, iliac arteries 15%, and femoral arteries 30%). However, a prospective CTA study following a cohort of 35 patients with biopsy-proven giant cell arteritis for 1 year showed 3% and 6% of patients with stenotic lesions at diagnosis onset and at the last follow-up, respectively (106). Therefore, giant cell arteritis must be suspected in patients older than 40 to 50 years without overt stenotic artery lesions. Of note, juvenile forms of giant cell arteritis with temporal artery inflammation have scarcely been reported (60; 01).

Other diseases tributary in the differential diagnosis of Takayasu arteritis are infectious diseases, such as syphilis, tuberculosis, and fungal infections as well as hereditary vasculopathies or vascular collagenopathies, including the vascular form of Ehlers-Danlos syndrome, Loeys-Dietz syndrome, or Marfan syndrome (06). Arterial dilation, aneurisms, and tortuosity are vascular features of both groups of diseases (vascular infectious and collagenopathies) in which no stenotic lesions are usually observed.

Associated or underlying disorders

Takayasu arteritis has frequently been associated with Crohn disease (65; 31) and sarcoidosis (47; 108), two systemic diseases in which granulomatous lesions are characteristic. Other systemic diseases reported in association with Takayasu arteritis include ulcerative colitis (114), granulomatosis with polyangiitis (18; 70; 123), systemic lupus erythematosus (100; 04), and primary biliary cirrhosis following treatment for Takayasu arteritis (42; 25). The presence of the HLA-B52 allele has been reported to be associated with Takayasu arteritis (130).

Diagnostic workup

Diagnostic workup. Because biopsy of the aorta or a main artery is usually impractical, and there are no specific serologic tests for Takayasu arteritis, its diagnosis is based on clinical findings in the setting of vascular imaging abnormalities suggestive of arterial inflammation. However, histologic examination of arteries is recommended when a patient undergoes surgery for a vascular complication (58). Interestingly, an endovascular aortic biopsy has been performed during an angioplasty procedure in a patient with Takayasu arteritis (112). Histopathologic patterns have been described at different stages in arteries from patients with Takayasu arteritis. Active lesions usually reveal granulomatous arteritis, with transmural inflammation and patchy destruction of the internal elastic lamina. Lymphoplasmacytic cells, multinucleated giant cells, and cytotoxic and gamma delta T lymphocytes predominate within the infiltrates and are more prominent in the media (61; 11; 58). Healing lesions include variable degrees of intimal and adventitial fibrosis as well as extensive scarring of the media (61). This inflammatory reaction leads to a myointimal hyperplasia with a subsequent vessel wall thickening and luminal stenosis, resulting in reduction or suppression of blood supply and tissue ischemia (11). Lesions predominantly destroying the muscular layer and elastic lamina may result in artery dilation or aneurysms, which occur more commonly in the aortic root and arch (66).

The gold standard for the diagnosis of Takayasu arteritis is an appropriate clinical setting combined with catheter-directed angiography. Apart from providing information on the vessel shape and luminal caliber, this invasive study also records intravascular blood pressure measurements. In critical or severe vascular lesions, angiography also provides opportunities for intervention when the disease is quiescent (eg, angioplasty) (47). Limitations of catheter-directed angiography include the inability to provide information about the vessel wall or to differentiate between acute/active and chronic/inactive lesions. Inherent risks of the procedure include arterial invasiveness and exposure to ionizing radiation and contrast agents, with the potential for kidney toxicity.

Currently, noninvasive CTA (48) and vascular MRI with its two components, contrast-enhanced MRI and MRA (conventional or 3-dimensional reconstruction), are considered to have good diagnostic accuracy. They can effectively complement or replace intra-arterial angiography because both CTA and MRI imaging techniques evaluate the vascular lumen and vessel wall (121; 23; 115). In addition, the progressively improved and increased high-resolution images offered by these noninvasive imaging techniques can potentially detect active vasculitic lesions prior to the development of artery stenosis. CTA offers high-resolution images of the vessel lumen and arterial wall details, such as thickening, appearance (density, calcifications), or degree of contrast enhancement (48). During a delayed venous phase of contrast, a low-attenuation ring between the enhancing outer aortic wall and the lumen corresponds with the thickened intimal layer and may serve as a marker of activity in Takayasu arteritis. A decrease in mural thickness during follow-up CT is associated with good vascular progression (48). These CTA changes have also been reported in patients with giant cell arteritis, another large-vessel vasculitis (104; 106).

MRA with 3-dimensional reconstruction and MRI with contrast enhancement provide information about the artery lumen and vessel wall, respectively. Mural thickness and assessment of artery wall enhancement may help identify inflammation or edema as post-contrast T1-weighted imaging with mural enhancement reflects an increase in vascularity or excessive leakage of contrast out of the vasa vasorum, which is probably associated with vessel wall inflammation and disease activity. T2-weighted hyperintense signal correlates with mural edema related to acute inflammatory changes (121; 23). Although MRI can provide additional information regarding the appearance of the vessel wall, predicted vascular anatomic change may be uncertain because the presumed inflammatory changes may correspond with vascular remodeling in an inactive phase or diffuse atherosclerosis (121). A study comparing the accuracy of intra-arterial angiography with MRI and MRA showed 100% sensitivity and specificity for the diagnosis of Takayasu arteritis but failed in 2% of lesions in which MRA overestimated them as vascular occlusions (129).

PET-CT combined with 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) is widely applied in the diagnostic process of large-vessel vasculitis, mostly Takayasu arteritis, giant cell arteritis, and other forms of aortitis (28; 105; 118). PET-CT has been demonstrated to improve diagnostic precision, mainly in those patients with vasculitis presenting with constitutional symptoms and no clear vascular manifestations. Given the cumulative radiation exposure of repeated procedures during follow-up, PET-CT is reserved for cases in which a disease relapse is not really evident by clinical, laboratory, and conventional imaging (CT or MR) data and in which other potential causes need to be ruled out. However, the accuracy of PET-CT for the detection of low-grade relapsing or partially treated arteritis is limited as it can also reflect vascular remodeling, active fibrosis, or atherosclerotic processes. This was demonstrated by studies in which no correlation was found between arterial wall FDG uptake and either systemic inflammation or disease activity (by the NIH score) (39; 118). However, the thickness of arterial lesions with FDG uptake correlated with the maximum standardized uptake values (SUVmax) (39; 118). Therefore, PET-CT may be useful for the identification of active local arterial wall inflammation or vascular remodeling in Takayasu arteritis patients with clinically evident active disease or in those with uncertain active disease. However, further studies analyzing the role of arterial wall thickness and FDG uptake in predicting vascular outcomes are still needed.

The 2018 EULAR recommendations include CTA, MRI/MRA, and PET-CT as noninvasive imaging modalities for the diagnosis of Takayasu arteritis in suspected individuals; CTA and MRI/MRA are recommended for monitoring patients who have already been diagnosed (22). However, MRI/MRA has clearly become the first choice for monitoring vascular progression in patients with Takayasu arteritis (usually young women) on a regular basis. Compared to conventional angiography and CT angiography, MRI/MRA also warrants a better safety profile as radiation, risk of contrast toxicity, and vessel trauma are not associated with this imaging technique (121; 115; 118).

Ultrasound is a noninvasive imaging technique used to visualize vessel wall thickening (usually circumferential) of the main arteries in Takayasu arteritis. Although ultrasound is of limited value in assessing the thoracic aorta and requires appropriate technology and experienced radiologists to interpret the results, it has been shown to be useful in evaluating Takayasu arteritis (56; 113). Contrast-enhanced ultrasonography has excellent sensitivity (100%) and specificity (80%) in detecting disease activity of the carotid arteries when compared to FDG-PET (57). The 2018 EULAR guidelines recommend ultrasound as an alternative imaging modality in patients with suspected Takayasu arteritis (22). Ultrasound can also be used for long-term monitoring of structural damage, particularly for detecting stenosis, occlusion, dilation, and aneurysms, mainly in carotid, axillary, and subclavian arteries and in arteries of the lower limbs. Therefore, ultrasound might be particularly useful in patients with claudication of the upper or lower extremities (22).

Fundoscopy and fundus fluorescein angiography have been helpful in identifying retinal lesions in hypertensive retinopathy or hypoperfusion (Takayasu) retinopathy (09).

Disease activity assessment. No specific laboratory markers have been found to be helpful for the diagnosis of Takayasu arteritis. However, increased acute phase reactants, particularly ESR, may be helpful in assessing disease activity in Takayasu arteritis. In a remarkable proportion of patients, ESR values do not correlate with disease activity according to systemic symptoms or progression on imaging studies, mainly because normal ESR values do not confirm disease remission in all Takayasu arteritis cases (64). However, new biomarkers for disease activity in Takayasu arteritis have been investigated. In this regard, circulating levels of MMP, specifically MMP3 and MMP9, have been associated with disease activity (68; 40). Two studies of 57 Italian and 45 Japanese patients with Takayasu arteritis found a better correlation of serum levels of pentraxin-3 (produced within inflammatory infiltrates) with disease activity than ESR or the CRP levels (19; 40). The routine use of these potential biomarkers for the assessment of disease activity in Takayasu arteritis is still pending validation.

Sequential imaging studies in Takayasu arteritis have revealed disease progression (determined by the presence of new vascular lesions) in about half of patients presenting with asymptomatic disease and normal ESR values (64). The presence of subclinical disease activity may be underestimated at clinical evaluation as almost 50% of patients with Takayasu arteritis with apparent clinical remission have been noted to have histopathologic evidence of vascular inflammation when undergoing vascular surgery (47).

In 1994, Dr. Hoffman’s team at the National Institutes of Health (Bethesda, Maryland) defined active disease in Takayasu arteritis according to the existence of new symptoms or the worsening of any two or more of the following parameters: (1) signs or symptoms of vascular ischemia or inflammation; (2) increase in sedimentation rate; (3) angiographic features; and (4) systemic symptoms not attributable to another disease. These criteria for disease activity assessment are known as NIH criteria or Kerr criteria (47) and have been demonstrated to be specific and helpful when present. However, their absence does not assure disease remission. These criteria have been used in other studies of patients with Takayasu arteritis (98; 124; 39; 75; 118) and seem to be similarly useful for monitoring Takayasu arteritis activity and guiding treatment decision-making when used in conjunction with serial imaging modalities, preferably MRI/MRA followed by CTA or PET-CT (when needed), instead of repeated catheter-directed angiography.

Management

Pharmacological therapy. Glucocorticoids are the drug of choice for patients with Takayasu arteritis and active disease. An initial prednisone dose of 0.5 to 1 mg/kg/day is recommended as high-dose glucocorticoids result in clinical improvement in almost all patients and induce remission in about 60%. When prednisone is tapered to less than 20 mg/day, most patients experience relapses (64). Due to the high rate of relapse and the development of new artery lesions while receiving glucocorticoids, concomitant use of an additional immunosuppressive agent, such as methotrexate, is recommended for better control of disease remission, reduction of disease, and glucocorticoid-associated morbidity (64; 83). Methotrexate should be given at a mean effective dose of 0.3 mg/kg/week (or 15–25 mg/week), preferably subcutaneously for higher or total bioavailability compared to the erratic absorption by oral intake (58).

Among the other conventional immunosuppressive agents used with glucocorticoids, mycophenolate mofetil is of uncertain efficacy; azathioprine (at 150 mg/day), leflunomide (at 20 mg/day), and oral cyclophosphamide (at 1–2 mg/kg/day) have been effective in controlling systemic symptoms and disease progression (49; 127). Cyclophosphamide is only recommended for patients with severe Takayasu arteritis refractory to other immunosuppressive drugs due to the risk of severe toxicity after long-term therapy (> 6 months) (58; 49). Nevertheless, a meta-analysis identified an inferior clinical response and adverse effect profile with cyclophosphamide compared to tocilizumab (79). When glucocorticoid discontinuation is attempted, relapses still occur in a remarkable proportion of patients with Takayasu arteritis, despite concomitant use of any of these additional immunosuppressive agents (58).

Besides having antimicrobial activity, minocycline also suppresses production of MMP. It has been used, in addition to glucocorticoids, in a series of 11 patients with Takayasu arteritis. Results for the reduction of levels of acute phase reactants and improvement in the control of disease activity were encouraging. However, more robust studies must be done to establish the real efficacy of minocycline in Takayasu arteritis (69).

The use of biological immunosuppressive agents targeting different key inflammatory molecules in Takayasu arteritis, such as TNF and IL-6, have brought dramatic progress in the management of patients with Takayasu arteritis. Those with refractory or relapsing forms of the disease had higher effectiveness in controlling disease activity, with fewer side effects as compared to glucocorticoids and other conventional immunosuppressive agents (37; 32; 75; 71).

An initial study of anti-TNF therapy by Hoffman and colleagues showed anti-TNF-alpha agents to be efficacious in sustaining glucocorticoid-free remissions in over 60% of patients with previously refractory Takayasu arteritis (37). In an extended study, the same authors documented the sustainability of anti-TNF-alpha therapy in maintaining disease remission for a longer follow-up period in most patients (mean follow-up of over 2 years) (81). In the last two decades, the increased number of patients with Takayasu arteritis treated with TNF blockers has confirmed their efficacy. In 2011, a review of 84 patients with refractory Takayasu arteritis treated with infliximab or etanercept showed complete and partial response in 37% and 54%, respectively, with 40% of patients achieving glucocorticoid discontinuation (16). Only 10% of patients did not respond. Similar results were found in a French multicenter retrospective study of 35 patients with refractory Takayasu arteritis (73). An international multicenter study of 132 refractory patients treated with TNF blockers similarly showed a complete response in 66% of patients; conventional immunosuppressive treatment was ceased in 40% of patients (71). However, about 50% of patients experienced relapses during anti-TNF treatment.

Anti-IL-6 therapy with tocilizumab was first used effectively in Takayasu arteritis in 2018 in a 20-year-old woman with a concomitant ulcerative colitis (89). Since then, tocilizumab has increasingly been used with success in patients with refractory Takayasu arteritis. In a 2018 retrospective, multicenter French study of 46 patients with Takayasu arteritis treated with tocilizumab, 81% reported good disease control 1 year from initiation, with a significant reduction in daily prednisone doses and disease activity by NIH scores. Just as with anti-TNF agents, disease relapses occurred in about half of patients during a follow-up of 2 years (75). An international retrospective study of 109 patients with refractory Takayasu arteritis treated with intravenous and subcutaneous tocilizumab showed that both administration modalities were similarly effective in achieving complete remission in 70% of patients (72). However, patients treated with monthly intravenous doses achieved better results with regards to risk and incidence of disease relapse than patients receiving subcutaneous tocilizumab.

Tocilizumab use in Takayasu arteritis has been evaluated in two clinical trials. A double-blind clinical trial compared weekly doses of subcutaneous tocilizumab with placebo in 36 patients with relapsing Takayasu arteritis (85). Time to relapse, as the primary endpoint, favored tocilizumab without achieving statistical significance. However, differences in the per-protocol sensitivity analysis significantly favored the tocilizumab-treated group. In addition, a trend towards delaying the time to relapse favored tocilizumab in all the secondary endpoints. Although the primary endpoint was not met, tocilizumab tended to have better results for increasing the time to relapse without safety concerns than placebo. In a 96-week, extended open-label study of the previous trial, 28 patients were treated with subcutaneous tocilizumab (86). About half of them reduced prednisone to 50% of the initial dose, and 86% of patients had improved or stable vascular imaging studies; only 14% showed vascular progression. Therefore, tocilizumab demonstrated steroid-sparing effects and clinical and imaging improvement during a long-term treatment period, without adverse effects.

Another clinical trial on Takayasu arteritis (TOCITAKA) analyzed the efficacy and tolerance of monthly intravenous tocilizumab as a first-line treatment for 6 months in 13 patients with treatment-naive Takayasu arteritis (76). The primary endpoint was the number of patients discontinuing glucocorticoids after tocilizumab treatment, and secondary endpoints included the assessment of disease activity and the number of relapses during an 18-month follow-up. Fifty-four percent of patients discontinued prednisone, and disease activity decreased in all patients after the first 6 months of tocilizumab therapy. However, relapse occurred in 45% of patients who had achieved remission after tocilizumab discontinuation during a 12-month follow-up. This study corroborates the effectiveness of tocilizumab as an effective steroid-sparing agent in Takayasu arteritis, but maintenance therapy is still necessary.

A French study and an international multicenter retrospective study have evaluated the differences between TNF-blockers and tocilizumab in 49 and 209 patients with refractory Takayasu arteritis, respectively (73; 71). Both studies evidenced similar efﬁcacy, relapse, and drug retention rates for anti-TNF and anti-IL-6 therapies. The similar efficacy of both medication groups has also been corroborated by a systematic review and meta-analysis (79).

The possible role of B cells in the pathogenesis of Takayasu arteritis has been explored (12; 10). B-cell depletion therapy has been used with rituximab, a chimeric anti-CD20 monoclonal antibody, in refractory patients with Takayasu arteritis; rituximab was effective in most of them (24; 38; 07; 93; 102; 82). However, the real efficacy of rituximab needs further validation in controlled clinical trials (74).

Ustekinumab, a humanized monoclonal antibody targeting IL-12/IL-23 pathways, was used in four refractory patients with active Takayasu arteritis with good results; inflammatory markers were improved on follow-up in three of them (117; 116). To date, tofacitinib is the only Janus kinase (JAK) inhibitor reported to induce remission in a patient with Takayasu arteritis resistant to both anti-TNF and anti-IL-6 agents (50). Abatacept, a fusion protein that decreases T-cell activation by binding to CD80/86 and secondarily blocking its interaction with CD28, was used in a randomized trial of 26 patients with Takayasu arteritis (four newly diagnosed) and did not improve relapse-free survival compared to placebo (51). These results did not support the use of abatacept in Takayasu arteritis.

Although antiplatelet or anticoagulant therapy has been shown to reduce the risk of ischemic events in patients with giant cell arteritis without an increased risk of bleeding complications (55), treatment with aspirin does not seem to protect patients with Takayasu arteritis from the development of ischemic vascular complications (53). Aspirin treatment has been identified as a risk factor for developing neurologic ischemic events in a large series of patients with Takayasu arteritis (78). As with giant cell arteritis, in which the use of statins at doses recommended for hypercholesterolemia is not associated with a clinically relevant glucocorticoid-sparing effect (29), statins do not provide benefit in the progression of arterial lesions nor in the number of relapses in patients with Takayasu arteritis (53). In Takayasu arteritis, the development of ischemic events is associated with the presence of traditional cardiovascular risk factors, but treatment with antiplatelet drugs and statins do not act as useful preventive therapy. However, the role of antiplatelet or anticoagulant therapies or statins as primary or secondary vascular prophylaxis in patients with Takayasu arteritis is still pending validation in randomized clinical trials.

Autologous hematopoietic stem cell transplantation (AHSCT) is used in patients with severe vasculitis and other autoimmune diseases resistant to different therapy lines. AHSCT was also reported to be useful in a series of six patients with Takayasu arteritis refractory to a median of six (4–8) previous lines of therapy (52). At 6 months post-transplantation, remission was achieved by all patients and persisted at 12 months in five cases. Recurrence of active Takayasu arteritis occurred in four patients at a median (range) time of 27 (7–52) months after AHSCT; immunosuppressive drugs were restarted in three of the patients. At last follow-up, all of the patients were alive; four patients were in remission (two of them could stop previous treatment), and two patients had improved compared to baseline.

Endovascular and surgical treatment. Surgical interventions for revascularization in patients with Takayasu arteritis are indicated to limit severe ischemic symptoms associated with steno-occlusive disease of the supra-aortic arteries, coronary ischemia, renal artery stenosis causing renovascular hypertension, upper or lower limb claudication, moderate to severe aortic valve regurgitation, stenosis of the descending or abdominal aorta, and aortic aneurysm at risk of rupture or dissection (58). Procedures to re-establish flow in stenotic or occluded vessels include percutaneous transluminal angioplasty, endarterectomy, and surgical use of synthetic grafts or autologous vessel bypass. Aortic root replacement or repair is used for aortic insufficiency, usually in association with aortic valve replacement for valve regurgitation (58).

In two American longitudinal intervention Takayasu arteritis cohorts, one thirds to two thirds of patients underwent endovascular or surgical treatment for either vessel stenosis or aortic regurgitation over a mean of 3 to 5 years (47; 64). A study reviewing more than 600 patients with Takayasu arteritis from eight published series revealed that percutaneous transluminal angioplasty and stenting used alone or as a combined treatment provided a variable patency rate among the studies (64). In a cohort of 30 patients with Takayasu arteritis followed for a mean of 3 years and re-evaluated with sequential imaging studies at mean intervals of 4.8 months, a total of 64 revascularization procedures were performed (64). All patients had vascular stenoses. Twenty angioplasty and 44 vascular bypass and reconstruction procedures were carried out. Among all the revascularization techniques, bypass grafts showed better sustained patency than angioplasty or stent-treated vessels. Posterior restenosis or occlusion occurred in 78% of patients who underwent angioplasty and 36% of those with surgical procedures (64). The same trend favoring surgical revascularization over endovascular repair has been observed in a series of 235 patients with Takayasu arteritis (54). Of note, bypass was particularly successful when performed with autologous donor vessels (47; 59). Subsequent studies have confirmed that angioplasty provides a better patency rate than stent placement (92% vs. 56%) after 5 years of follow-up (97).

In a series of 42 patients with Takayasu arteritis undergoing surgical revascularization, five of five (100%) patients with quiescent disease who did not receive glucocorticoids at the time of surgery, and 20 of 24 (83%) patients with quiescent disease who received glucocorticoids at the time of surgery, did not require a new revascularization procedure after 10 years of follow-up (26). However, four of seven (57%) patients with active disease who received glucocorticoid therapy at the time of surgical repair required new interventions to maintain or re-establish vascular patency. Therefore, revascularization procedures in Takayasu arteritis should ideally be performed during disease remission.

At the time of vascular surgery, the surgeon should be advised to obtain an artery segment from the origin or insertion of grafts by the physician in charge of the patient. The histologic examination will be useful in determining the type of lesion and disease activity. Obtaining arterial tissue is particularly important because clinical symptoms and acute phase reactants may not accurately reflect disease activity (58; 64).

Although several patients with Takayasu arteritis and aortic branch vessel and coronary artery stenosis have been treated with endarterectomy, some authors recommend avoiding this procedure because it can be technically difficult or impossible to perform or may even carry a risk of vessel rupture as arterial lesions can be rigid and often involve the entire thickness of the vessel wall (58).

Surgery is associated with increased mortality in patients with Takayasu arteritis. A longitudinal series of 106 patients with Takayasu arteritis followed over a mean of 20 years reported early deaths (during hospitalization) in 11% of patients (80). In this setting, death mainly occurred as a result of cardiovascular complications, including congestive heart failure, aneurysm rupture, stroke, or hemorrhage.

Hypertension management. Recognition and treatment of hypertension in patients with Takayasu arteritis is crucial for achieving good long-term outcomes. Detection of hypertension is often delayed due to the high frequency of subclavian arteries and brachiocephalic trunk stenoses, which may result in falsely low peripheral blood pressure readings in the upper limbs. When stenoses are distributed by all extremities, peripheral blood pressure measurements will not reflect the real central aortic pressures. Therefore, it is important to have a complete vascular imaging map covering all the vascular territories (central and peripheral) supplying blood to the extremities. When stenoses make questionable the reliability of recordings of blood pressure in the extremities, an intra-arterial angiography with central aortic pressure measurements is critical in order to identify a target pressure range and the extremity that offers more accurate blood pressure values. Vascular repair of the stenotic artery lesions in extremities to better determine blood pressure and revascularization of renal artery stenoses causing hypertension do not have to be postponed.

Cerebrovascular ischemic complications in Takayasu arteritis: presentation, risk factors, and management

Neurologic manifestations of Takayasu arteritis derived from the involvement of supra-aortic arteries include headache; lightheadedness and dizziness; and transient or established visual disturbances, such as blurring, scotoma, amaurosis, or diplopia. Headache is the most frequent neurologic symptom, affecting 8% to 52% of cases, depending on the series (62; 47; 43; 124; 64).

Cerebrovascular events in Takayasu arteritis include transient ischemic attacks and stroke. Although transient ischemic attacks have been reported to occur in 1% to 3% of patients with Takayasu arteritis (43; 64), stroke occurs in 2% to 10% of patients (47; 43; 124; 64). However, in a series of 320 patients with Takayasu arteritis (86% women), with a median (IQR 25-75) age at diagnosis of 36 (25-47) years, 63 (20%) patients suffered a cerebrovascular ischemic event. Among patients developing these complications, 41 (65%) had strokes and 22 (35%) had transient ischemic attacks. Stroke accounted for 9.5% of deaths in a Takayasu arteritis series (84). The origin of the cerebral ischemia was localized in the carotid arteries in 55 (87%) patients and in the vertebral arteries in eight (13%) patients. A mean (range) of two (0–11) multiple stenotic lesions were observed in 33 (52%) patients. Aneurysms developed in 10 (16%) patients.

Several risk factors associated with cerebrovascular ischemic events have been identified and include the following: (1) a previous history of stroke or transient ischemic attack before Takayasu arteritis diagnosis; (2) smoking; (3) myocardial infarction history; (4) thoracic aorta involvement; (5) time from first symptoms to diagnosis of over 1 year; and (6) being on aspirin treatment. After a multivariate analysis, two factors independently associated with the development of cerebrovascular ischemic complications were identified: (1) diagnostic delay from symptom onset to Takayasu arteritis diagnosis of over 1 year; and (2) having previously experienced a stroke or transient ischemic attack (78).

In a retrospective multicenter cohort of 126 patients with Takayasu arteritis, 17 (13%) patients (one woman) had at least one stroke (15 patients) or transient ischemic attack (two patients) (17). Eight patients developed stroke after the diagnosis of Takayasu arteritis. In four patients, stroke occurred as a complication of carotid surgery. Overall outcomes were poor; at the end of follow-up, neurologic impairment and recurrences of stroke were observed in 59% and 24% of patients, respectively, and 24% of them suffered from epilepsy. Patients with Takayasu arteritis suffering from stroke had the same cardiovascular risk factors than those without stroke. Stroke may also occur while patients are on immunosuppressive therapy. This study confirmed that stroke is associated with poor prognosis and important disability in patients with Takayasu arteritis. Internal carotid surgery should be performed carefully due to the increased risk of stroke after the procedure (17).

Information on the therapeutic approach of acute cerebrovascular events in Takayasu arteritis is scarce. However, treatment of the acute stroke in Takayasu arteritis usually includes glucocorticoids at high doses and additional immunosuppressive drugs. Patients with active Takayasu arteritis have an increased risk of developing thrombosis or restenosis. Therefore, whenever possible, surgical interventions should be performed when the disease is in maintained remission, as with other vascular territories (17).

Although mechanical thrombectomy of a cerebral artery and carotid percutaneous transluminal balloon angioplasty and stent implantation have been successfully performed in isolated patients with Takayasu arteritis (17; 20), intrastent thromboses have been reported (17). Isolated cases of acute stroke with recovery after fibrinolytic therapy have been reported in patients with Takayasu arteritis (21).

Special considerations

Pregnancy

Pregnancy complications, including pregnancy loss and preterm birth, are higher among women with all forms of vasculitis, including Takayasu arteritis (05). Of these, special consideration should be given to women of reproductive age expressing pregnancy desire or patients with an unexpected pregnancy. Cyclophosphamide, methotrexate, and mycophenolate mofetil should be avoided in pregnant patients due to their teratogenic effects. Other drugs used for vasculitis and considered to be of low risk in pregnancy include glucocorticoids, colchicine, azathioprine, and TNF blockers (63).

Pregnancies in patients with Takayasu arteritis are at increased risk for adverse pregnancy outcomes compared to the general population. In a systematic review of 27 studies with 825 pregnancies, miscarriage occurred in 16%, hypertension in 37%, and preeclampsia in 14% of patients (101). Therefore, pregnant women with Takayasu arteritis should be closely monitored.

Anesthesia

Anesthetic management in patients with Takayasu arteritis is not well established due to the heterogeneity of disease presentation. An anesthetic approach must be decided once the severity and all the organs affected, usually by mild, severe, or critical ischemia, are well known. Therefore, preoperative assessment should prioritize cardiovascular baseline status for a guided cardiovascular monitoring during the intra- and postoperative period (27). Other aspects of Takayasu arteritis that must be foreseen prior to surgery and controlled for during anesthesia include uncontrolled hypertension (mostly in those caused by renal artery stenosis), difficulties in monitoring arterial blood pressure, and end organ dysfunction resulting from hypertension or stenosis of major blood vessels (45).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

José Hernández-Rodríguez MD PhD

Dr. Hernández-Rodríguez of Hospital Clínic de Barcelona (HCB)-IDIBAPS has no relevant financial relationships to disclose.
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Verónica Gómez-Caverzaschi MD

Dr. Gómez-Caverzaschi of Hospital Clínic de Barcelona has no relevant financial relationships to disclose.
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Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Former Authors

Eva Reinhold-Keller MD
Janelle Laughlin MD
Stephanie Booth MD
Linda Hushaw APN/CNP MSN
Nadera Sweiss MD
Ray Sawaqed MD
Changrui Xiao MD
James R Brorson MD
Stephen W English MD MBA
Samir R Belagaje MD FAAN

Patient Profile

Age range of presentation: 2 to 50 years
Sex preponderance: Female♂ >2:1 (up to 10:1)
Heredity: Unknown hereditary mechanism
Population groups selectively affected: Asians

Caucasians

Hispanics
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD 10: Aortic arch syndrome [Takayasu]: M31.4
ICD 11: Aortic arch syndrome: 4A44.1
OMIM: Takayasu arteritis: 207600

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Takayasu arteritis

Associated Disorders

Crohn disease
sarcoidosis
ulcerative colitis
granulomatosis with polyangiitis
systemic lupus erythematosus
- primary biliary cirrhosis

Differential Diagnosis

giant cell arteritis
isolated aortitis
immunoglobulin G4 (IgG4)–related diseases
granulomatosis with polyangiitis
Behcet disease
- Cogan syndrome
- rheumatoid arthritis
- spondyloarthropathies
- systemic lupus erythematosus
- Sjogren syndrome
- sarcoidosis
- juvenile giant cell arteritis
- syphilis
- tuberculosis
- fungal infections
- Ehlers-Danlos syndrome
- Loeys-Dietz syndrome
- Marfan syndrome

Also Relevant

Aortic diseases: neurologic complications
Carotid bruit
Cerebral arteriopathies
Cerebral vasculitis presenting with dementia
Pregnancy: CNS complications
- Stroke in young adults
- Systemic lupus erythematosus
- Systemic small-vessel vasculitis

Takayasu arteritis

Introduction

Overview

Key points

Historical note and terminology

Table 1. Diagnostic Criteria for Takayasu Arteritis

Table 2. Angiographic Takayasu Arteritis Classification

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Cerebrovascular ischemic complications in Takayasu arteritis: presentation, risk factors, and management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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