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This article includes discussion of Takayasu arteritis, pulseless disease, Takayasu disease, and Takayasu syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Takayasu arteritis, sometimes called “pulseless disease,” is a rare form of vasculitis affecting the aorta and its major branches, resulting in large-vessel occlusions. It typically occurs in young Asian women, but can be found in any ethnic group and in men. The disease is heterogeneous in presentation. Early symptoms are often constitutional, making diagnosis difficult. Subsequently, arterial occlusions occur, producing more specific ischemic symptoms such as claudication, stroke, or death. In this article, the author highlights the potential for vascular wall imaging methods to detect and monitor vascular inflammation before occlusion occurs and reviews the evidence for effective therapy with biological agents in the treatment of this uncommon disease.
• Takayasu arteritis is a serious vasculitis of the young, preferentially affecting women of Asian descent.
• In Takayasu arteritis, a granulomatous panarteritis can lead to stenosis or occlusion of the aorta and its major branches, producing life-threatening ischemia of the arms or brain.
• Early symptoms of Takayasu arteritis can be constitutional, potentially delaying diagnosis.
• Neurologic complications of Takayasu arteritis include cerebral and spinal ischemia, typically secondary to hypoperfusion rather than embolic phenomena, but most commonly, patients report symptoms of presyncope/syncope, lightheadedness, dizziness, and headache during the course of the disease.
• International diagnostic criteria are based on features of occlusive arterial disease, characteristic of Takayasu arteritis, but detection of early-stage disease when only nonspecific symptoms are present requires newer vessel wall imaging approaches, such as high resolution MRI or FDG-PET scanning.
• Takayasu arteritis responds variably to traditional treatment with steroids and immunosuppressive agents; targeted therapies using monoclonal antibodies blocking actions of TNF-alpha and interleukin-6 have shown effectiveness producing improved relapse-free survival.
In 1830 Rokushu Yamamoto published the first description of Takayasu disease in a case report from his private practice (64). In it, Yamamoto, who practiced Japanese oriental medicine, described a 45-year-old man who initially had a high fever and who presented a year later with no pulse in 1 arm, and a weak pulse in the other. Later, both carotid arteries became nonpalpable, and he suddenly died in the 11th year of follow-up.
Mikito Takayasu gave the first scientific presentation of this disease (64) in 1905 at the 12th Annual Meeting of the Japanese Ophthalmology Society. He presented a case of a 21-year-old woman with vision loss whose optic fundi exhibited a peculiar wreath-like anastomosis around the optic disc (88). At the same meeting in 1905, Onishi and Kagosha each contributed cases of their own, in which the same characteristic ocular findings were noted; in addition, both pointed out that no radial pulses could be palpated in their patients. In 1920, in the first necropsy case (of a 25-year-old woman), Otha confirmed that Takayasu disease is a panarteritis involving intima, media, and adventitia, and that the characteristic optic fundus finding resulted from ischemia due to obstruction of the carotid artery. In 1951 Shimizu and Sano summarized the clinical features of Takayasu disease in an English journal under the name of "pulseless disease." The 1992 Chapel Hill Consensus Conference defined Takayasu disease as granulomatous inflammation of the aorta and its main branches that usually occurs in female patients younger than 40 years old (33). According to the criteria of classification of the 1990 American College of Rheumatology, a case of vasculitis can be classified as Takayasu disease if 3 out of the following 6 criteria are fulfilled (sensitivity: 90.5%, specificity: 97.8%): (1) age at disease onset 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 mm Hg, (5) bruits over subclavian arteries or aorta, and (6) arteriographic abnormalities (03). It is important to note that these criteria were validated by comparison of Takayasu arteritis patients with control patients having other vasculitic disorders; it is evident that these criteria presume exclusion of those with identifiable alternative causes of vascular occlusion such as atherosclerosis.
There are challenges for detecting Takayasu arteritis in young children because the American College of Rheumatology criteria for diagnosis is designed for adults. A consensus to define realistic classification criteria for common childhood vasculitides was updated in 2010. According to the European League Against Rheumatism, Paediatric Rheumatology European Society, and the Paediatric Rheumatology International Trials Organisation consensus criteria, the diagnosis of Takayasu arteritis requires angiographic abnormalities (conventional CT, or MRI/A) of the aorta or 1 of its major branches and pulmonary arteries plus 1 or more of the following: (1) claudication or decreased peripheral artery pulses, (2) blood pressure difference greater than 10 mm Hg in any limb, (3) bruits of the aorta or its major branches, (4) hypertension, and (5) elevated acute phase reactant (68).
Takayasu arteritis typically begins between 15 and 30 years of age, most often in individuals of Asian and Hispanic origin; however, it may also begin in childhood or after 40 years of age and is increasingly recognized in Caucasians (81). The early symptoms are protean and nonspecific, with hypertension in most patients and many with headaches, fever, dyspnea, weight loss, or arthralgias (08). In a series of North American adults with Takayasu arteritis, the most common symptoms at diagnosis included generalized symptoms of fatigue, weight loss, arthralgias, light-headedness, and headaches, as well as the potentially ischemic symptoms of chest pain and limb claudication (81). Similarly, a case series in South America found fever, asthenia, and weight loss followed by headache, syncope, arthralgias, and arthritis to be the most common presenting symptoms in children (11). The presentation with constitutional symptoms often leads to delayed diagnosis in the early phase of the disease before major vessel occlusion becomes evident.
The clinical hallmarks are vascular, including bruits, claudication, carotodynia, and diminished or absent pulses. However, arterial hypertension is a common clinical presentation in children (01; 08). The clinical manifestations range from asymptomatic involvement to a catastrophic course with central nervous system or cardiac ischemia, cardiac or renal failure, and aneurysmal rupture or dissection. Stenotic changes occur nearly 4 times more frequently than aneurysms (36). Constitutional symptoms such as fever, weight loss, malaise, arthralgia, and myalgia have been reported in up to 60% of adult patients and up to 77% in children. The rate of progression varies from years to decades.
With arterial stenosis or occlusion, the particular symptoms that are seen depend on the location and severity of the disease and the amount of collateral circulation. The clinical features usually reflect limb or organ ischemia resulting from gradual stenosis of involved arteries, most frequently the thoracic and abdominal aorta and its major branches. Other vessels, such as the pulmonary and coronary arteries, can also be affected.
Neurologic complications associated with Takayasu arteritis are secondary to cerebral and spinal cord ischemia due to involvement of aortic arch and branching vessels. However, symptoms are more frequently attributed to global hypoperfusion from stenosis and occlusion of the cervical vessels, rather than embolic phenomenon. Patients report symptoms of presyncope/syncope, lightheadedness, dizziness, and headache during the course of the disease much more commonly than stroke or transient ischemic attack. Cerebral ischemia has been observed in 5% to 20% of patients—10% of patients at diagnosis (53), but 1 study observed that stroke accounted for 9.5% of deaths in patients with Takayasu arteritis (36; 57).
Unusual initial presentations of Takayasu arteritis include Horner syndrome (10), subclavian steal syndrome (76), malignant hypertension (97), pulmonary renal syndrome (79), retinal artery branch occlusion (62), and sensorineural hearing loss (45).
One classification of Takayasu arteritis is based on the angiographic findings and the pattern of symptoms. According to Nasu and associates (60), there are 4 types: (1) limited to the aortic arch and its branches; (2) involving the thoracic and abdominal aorta and its proximal branches, sparing the aortic arch; (3) widespread involvement with a combination 1 and 2, diffuse arteritis involving the aortic arch; and (4) involvement of the pulmonary arteries and any of the features of 1, 2, or 3. This classification was broadened at the Takayasu Conference in 1994 depending on coronary (C+/C-) and pulmonary (P+/P-) involvement (25).
Takayasu arteritis is associated with substantial morbidity and may be life-threatening. Reported mortality rates in children range from 8% to 40% by 5 years. In order to prevent complications, it is important to be highly suspicious of the possibility of Takayasu arteritis in any young patient with unexplained arterial hypertension or an unexplained inflammatory syndrome without a clear localization. Its course usually proceeds over many years, with various degrees of activity. Remission at some time during the disease course is usual in treated patients (81), but relapses are also common. About 20% of patients have a monophasic and self-limiting illness. The disease more often progresses silently. Nearly a quarter of patients continue to have active disease despite therapy and 45% relapse after reaching remission (36). Unusual vascular complications can occur, such as fistulas from coronary artery to lung parenchyma (18), and aorta-esophageal fistulas (72).
An early investigation of long-term outcome came from Japan (30). A group of 120 Japanese Takayasu disease patients was recruited between 1957 and 1990 at the Kyoto University hospital and followed for a median of 13 years. The overall survival rate was 82.9%. Sixteen patients died, with their death being directly related to the Takayasu disease. All deaths occurred within 15 years after disease onset; two thirds of the deaths were within the first 5 years, and the other one third was between the 10th and 15th year of disease. The main cause of death was heart failure in 5 patients, whereas 4 patients succumbed to cerebrovascular events. The mean age at death was 48 years. Four factors were prognostically unfavorable according to the univariate Cox analysis: (1) the presence of 1 of the following complications: Takayasu retinopathy, hypertension, aortic regurgitation, and aneurysm; (2) a continuously progressive course of disease; (3) age at diagnosis greater than 35 years; and (4) the particular calendar year of diagnosis (greater mortality in patients recruited between 1957 and 1975, as compared to those recruited between 1976 and 1990). In the multivariate Cox regression analysis, only the presence of complication (1) and progressive course of disease (2) were significantly associated with outcome. A higher erythrocyte sedimentation rate at diagnosis was associated with a better outcome, indicating that disease that is still active can better respond to therapy.
Some series have shown better long-term survival rates. Mirouse and colleagues analyzed 318 patients with Takayasu arteritis and found a mortality rate of 1.9% at 5 years and 3.9% at 10 years (53). Mesenteric ischemia and aortic rupture accounted for half of the deaths. Relapses were frequent in this cohort, with 50% of patients experiencing a vascular complication within 10 years of diagnosis (12).
A longitudinal series of 126 American patients treated at the Mayo Clinic found a subset of 25% diagnosed at an older age of 40 years or more, with a greater delay in diagnosis in this group. Overall survival was high, with 97% alive at 10 years from diagnosis (81). In contrast, in a retrospective series of 272 South Africa patients, 57 of 106 patients died who were followed for a minimum of 5 years. Twenty-nine patients died of cardiac failure (46%), 7 from renal failure, 6 from stroke, and 7 from a ruptured aortic aneurysm. Other causes of death included postoperative complications, myocardial infarction, aortic thrombosis, suicide, and unknown cause (57).
In a retrospective analysis of 71 pediatric cases in Brazil between 1998 and 2011, 5 patients had died, with heat failure, kidney failure, and surgical complications being the causes of death (11). At the end of the study period, 61% of patients were in remission, and 31% had active disease.
We present a fictitious case to highlight the neurologic complications that can be associated with the disorder.
A 26-year-old Asian woman without significant past medical history presented to her primary doctor with a chief complaint of recurrent episodes of transient left eye vision loss lasting 10 to 30 seconds over the past 2 weeks. She had some mild generalized headaches, lightheadedness, fatigue, and 5 lb weight loss over the past month. Additionally, she described mild burning pain of the left arm with exertion. Vital signs revealed a blood pressure of 185 over 100 in the right arm, but could not be recorded in the left arm. Physical examination was unrevealing except for the presence of decreased pulses in the left upper extremity.
Given her ethnicity, subacute course, and absent pulses in the left upper extremity, a diagnosis of Takayasu arteritis was suspected. She underwent a computerized topography angiography (CTA) chest that demonstrated multifocal high-grade stenosis of her right subclavian artery and occlusion of the left subclavian artery. Serologic testing revealed elevated inflammatory markers, but otherwise negative for known rheumatologic and vasculitic diseases.
Due to the episodes of transient vision loss, she also underwent neuroimaging including magnetic resonance (MRI) brain and CTA of the head and neck. MRI brain revealed small watershed infarcts in the left parietal region at the borderzone between the middle cerebral artery and posterior cerebral artery territories. CTA demonstrated occlusion of the common carotid artery at its origin and high-grade stenosis of the left vertebral artery origin.
The patient’s episodes of vision loss were consistent with amaurosis fugax in the setting of left common carotid stenosis and hypoperfusion to the left eye. The patient was diagnosed with Takayasu arteritis and was initiated on high-dose steroids with 5 days of intravenous methylprednisolone; she then transitioned to prednisone 60 mg daily. After 3 months, repeat imaging revealed moderate improvement of her multifocal stenotic disease and improvement in her symptoms. Over the next 6 months, her steroids were tapered, and she was initiated on methotrexate for chronic immunosuppression.
This case highlighted a common presentation of an uncommon disease. Takayasu arteritis should be considered in anyone with multifocal steno-occlusive disease of the aorta and its branches, particularly in young Asian women and patients with subacute inflammatory prodrome. Diagnosis required clinical, serologic, and radiographic evidence of a large artery vasculitis, and treatment should be initiated promptly with high-dose steroids and gradual transition to steroid-sparing agents such as methotrexate or mycophenolate mofetil.
The etiology of Takayasu arteritis is unknown and presumed to be multifactorial. Differences in ethnic and geographic distribution and familial clustering suggest the important role of genetic factors (31; 17; 98). The evidence for linkage to specific human leukocyte antigen (HLA) or interleukin receptor genotypes is reviewed below. There is clearly an important role for cell-mediated immune abnormalities in genetically susceptible persons. Studies have shown an association between the HLA-B52 allele and susceptibility to Takayasu arteritis (77). A link with mycobacterium tuberculosis was assumed initially, supported by observations of children, in 38% of whom a lymphadenopathy with histological evidence of caseating necrosis was found (55). The suspected association with tuberculosis, however, could not be confirmed (36). An association with systemic lupus erythematosus and other autoimmune diseases has also been reported. Occurrence of hypergammaglobulinemia suggests an autoimmune mechanism; however, specific autoantibodies have not been found.
The occurrence of the disease predominantly in women of childbearing age, suggests that hormonal factors also may be important.
Takayasu arteritis is a cell-mediated, autoimmune, chronic panarteritis (82). Early and active-stage pathology consists of continuous or patchy granulomatous inflammation, which progresses at variable rates to fibrosis of the intima, media, and adventitia (96). Cellular infiltrates composed predominantly of lymphocytes and plasma cells are localized to the adventitia and outer part of the media, with variable numbers of Langerhans and foreign-body type giant cells (this picture contrasts with giant cell arteritis, in which giant cells tend to lie close to the internal elastic lamina). Multiple sites of focal or segmental stenosis or occlusion, poststenotic dilatation, and, infrequently, aneurysm formation may result.
Vascular inflammation initially occurs in the vasa vasorum (82). Enhanced expression of HLA-class I and II antigens and intercellular adhesion molecule I (ICAM I) was found at the sites of inflammation, mainly in the vasa vasorum (82). In their histopathologic study, Seko and associates shed light on the effector mechanism in vascular damage. The authors demonstrated perforin-secreting cells in the inflammatory infiltrate and depositions of perforin on vascular cells, and they suggested that cytotoxic cells are responsible for tissue destruction. The disease may begin with expression of the 65 kDa heat-shock protein in the vascular wall, inducing the expression of major histocompatibility class I chain-related A on vascular smooth muscle cells (04). Natural killer (NK) and gamma-delta T-lymphocytes recognizing this surface antigen release perforin, promoting inflammation and the release of inflammatory cytokines, including interferon gamma, tumor necrosis factor-alpha, interleukin-6, and interleukin-17, and stimulating a response by T helper type (TH-1) CD4+ T cells. Dendritic cell activation occurs by vessel-specific toll-like receptor expression patterns, likely determining the topography of vascular involvement (71). Mononuclear cells are recruited to the vascular wall and form activated macrophages and giant cells. Activated macrophages release VEGF, leading to neovascularization, and PDGF, producing smooth muscle cell migration and intimal proliferation. Ultimately, this myointimal proliferation leads to vascular stenosis and occlusion.
The activation of cellular-mediated immunity is reflected in the peripheral blood in Takayasu arteritis. An increase in total peripheral blood T cells, CD4+ T cell subset, and CD4+/CD8+ ratio has been detected (83). A CD4+ T-cell expansion correlated with disease activity. An increase in activated CD4+ T cells was found in patients with or without clinically active disease. In contrast, the role of B-cell activation and humoral immunity in Takayasu arteritis is controversial (04).
A genome-wide association study following 2 cohorts of patients in North America and Turkey identified both IL6 and RPS9/LILRB3 as genetic susceptibility loci (74). IL6 is a regulator of multiple aspects of the immune response, including moderating T cell differentiation into Th17 and Treg cells, further supporting the importance of cell-mediated immunity in Takayasu arteritis. RPS9/LILRB3 is part of the leukocyte immunoglubin-like receptor gene family that encodes cell-surface receptor proteins possessing immunoglobulin domains. LILRB3 is thought to bind to HLA class I antigens to provide an inhibitory signal limiting the immune response. A reduction in LILRB3 expression is hypothesized to increase the risk of autoreactivity by failure to limit immune response on MHC class I antigen presentation.
Much of the literature describing Takayasu arteritis has originated from Japan, Southeast-Asian countries, and Africa. Thus, the disease was once thought to be restricted to these regions. During the past few decades, however, patients with the disease have been increasingly recognized in Europe, North America, and South America. Takayasu arteritis is now known to have a worldwide distribution with greatest prevalence in the Far East. Annual incidences per million of 2.6, 1.2, and nearly 5 were reported in Olmsted County, United States (23), Sweden (94), and Germany (73), respectively. By contrast, the prevalence in Japan, based on an autopsy study, was 30 per million (60).
A few variants in clinical manifestations have been recognized in different ethnic groups (63), suggesting a genetic disposition. It appears that in Japan the ascending aorta and the aortic arch are more often affected (63). Ophthalmic disturbances occur in 20% of Japanese patients (63) and 70% of Indians, whereas this manifestation is rarely seen in other groups. More than half of Japanese patients have cardiac symptoms, and about 50% have hypertension. In contrast, more patients in India, Thailand, South America, and Mexico have involvement of the thoracic and abdominal aorta. Chinese patients have higher frequencies of secondary hypertension but few cardiac symptoms. More than half of the Chinese patients have bruits in the upper abdomen, suggesting a high frequency of abdominal aorta involvement. Although women are mainly affected, female predominance is not as apparent in all ethnic populations. For example, in Japan the female-to-male ratio is 8:1, whereas in Central and South America the ratio is 3:1 to 7:1, in China 2.8:1, and in India 1.6:1 (63).
The largest studied cohort of Takayasu arteritis in the United States consists of 60 patients (58 women, 2 men; 75% Caucasian origin) observed on the average for over 5 years (36). The average age at disease onset was 25 years (range: 7 to 64). An average of 10 months passed between occurrence of the first symptoms and the diagnosis. During the complete study period, apart from vascular symptoms, 57% had involvement of the central nervous system, 53% had rheumatic complaints, 43% had general symptoms, and 38% had cardiac involvement, usually aortic regurgitation. The most common vascular finding was a bruit, usually over the carotid arteries. Intermittent claudication of the upper extremities occurred in 62% of patients, nonpalpable or weak pulses in 53% (more in the upper extremities), and arterial hypertension in 33%.
In a report of 272 South African patients (75% female), the average age of onset was 25 years with hypertension being the most common presentation (77%) (57). Of 44 Mexican patients (38 women) with the disease (75), the average age at diagnosis was 35 years (range: 15 to 64 years). Arterial hypertension was present in 35 patients, and 4 patients had ophthalmic manifestations.
The classification of Nasu and colleagues (60) is based on angiographic findings and the pattern of symptoms in 27 Italian patients: 33% had type 1, 11% type 2, and 56% type 3 disease (92). In the South African cohort, 70% of patients had type 3 disease, with involvement of the entire aorta. In 26 children younger than 16 years of age at the time of diagnosis (mean age at diagnosis 11.7 years, 80% females), 14 out of 26 had type 3 Takayasu arteritis (55). Arterial hypertension was present in 22 out of 26 patients. General symptoms were noted in 65%, rheumatic symptoms in 65%, gastrointestinal symptoms in half, and nodular skin changes in 19%. No patients had retinal abnormalities.
In 71 cases of juvenile onset Takayasu patients in South America, the mean age of onset was 9.2 years, with 72% being females (11). Average duration from onset of symptoms to diagnosis was 1.2 years, with constitutional symptoms being most common on presentation (77.5%) and neurologic symptoms being second (70%). At the 6-month follow-up, musculoskeletal complaints were most frequent (42%) and were followed by neurologic symptoms (35.9%). Over time, neurologic complaints became most persistent and frequent (22.7%).
Cerebrovascular symptoms occur in 40% to 60% of affected patients (63). A report of 142 South African patients seen between 1981 and 1997 indicates that 29 patients (20%) had cerebrovascular manifestations as the first symptom (28).
Pulmonary artery involvement was first described by Oata in 1940, who reported an incidence of 56% in 210 patients (65). Others have reported pulmonary artery involvement in 14% to 86% of patients, the prevalence being higher in autopsy series (24). Angiographic studies also suggest a prevalence of about 50% (60). Cough, dyspnea, and hemoptysis were the most frequent clinical symptoms related to pulmonary artery disease.
Cardiac disease and hypertension are common features in patients with Takayasu arteritis. In 272 South African patients, 210 had hypertension and 122 had cardiac disease. The major cardiac manifestations included cardiac failure (90 patients), valvular heart disease (61 patients), ischemic heart disease (14 patients), and 20 patients with pulmonary hypertension (57). Heart failure may not entirely be secondary to hypertension and aortic regurgitation. Left ventricular systolic dysfunction was assessed in 78 patients with angiographically confirmed Takayasu arteritis (70). This echocardiographic study showed that left ventricular systolic dysfunction was associated with involvement of the aortic arch. Patients with more extensive involvement of the aorta had an increased risk for left ventricular systolic dysfunction. Aortic regurgitation and systemic hypertension were not associated with left ventricular systolic dysfunction. This suggests that cardiac inflammation plays a role in left ventricular systolic dysfunction in Takayasu arteritis.
Differences in ethnic and geographic distribution and familial clustering suggest a genetic influence on susceptibility to Takayasu arteritis. Initial HLA analysis of the disease in 82 Japanese patients showed a high prevalence of the HLA B52 antigen, present in 44% of patients, compared to a prevalence of 13% in 128 healthy controls (31). A subsequent independent study of 47 unrelated Japanese Takayasu arteritis patients confirmed an elevated prevalence of HLA-B52 at 64% and found no other significant associations among 21 HLA-A and HLA-B loci surveyed (56). Furthermore, a retrospective analysis of Takayasu arteritis patients found HLA-B52 allele positive patients had significantly greater C-reactive protein levels (CRP) (9.0 vs. 3.2) and initial prednisolone dosages (37.7 mg/day vs. 23.1 mg/day) compared to HLA-B52 negative counterparts, showing an association between genotype and disease severity (67). Subsequent analyses in Japanese patients have extended the association with Takayasu arteritis to the markers HLA-DRB1*1502 (46% in patients vs. 24% in controls), DRB5*0102, DQA1*0103, DQB1*0601, and DPB1*0901 (17). HLA B67 has also been described as a risk allele in Japanese patients (87). No HLA associations with Takayasu arteritis could be confirmed in smaller studies of Caucasian patients (36). However, studies in 26 Mestizo Mexican patients and in 330 Turkish patients with Takayasu arteritis confirmed a consistent association with the HLA-B52 allele, though at lower prevalences than in the Japanese patients (93; 77).
Altered prevalences of certain alleles in the genes for interleukin (IL)-12, IL-2, and IL-6 have also been found in Turkish patients with Takayasu arteritis (78). HLA-Bw52 positive Japanese patients have a significantly higher rate of aortic regurgitation and, in general, a poor prognosis (98). A genome-wide association study analysis identified IL6, RPS9/LILRB3, and an intergenic locus on chromosome 21q22 as genetic susceptibility loci (74). In sum, clear evidence points to the role of genetic determinants of cellular immunity and Takayasu arteritis.
There are several reports on the association between Takayasu arteritis and other inflammatory diseases. One paper found that up to 30% of Takayasu patients had some type of other inflammatory disease in addition to Takayasu arteritis (66). In particular, there are several reports of Takayasu arteritis with sarcoidosis (36). Generally, sarcoidosis precedes the Takayasu arteritis by many years. Associations have also been reported between Takayasu arteritis and Crohn disease (19), ulcerative colitis (06), Wegener granulomatosis (100), uveitis (35), and systemic lupus erythematosus (80). Associations with hyperthyroidism or skin diseases, such as erythema nodosum and pyoderma gangrenosum, have been reported (66). Finally, there is a case report of a patient who developed primary biliary cirrhosis after treatment for Takayasu arteritis (32). At times, there are changes in the aortic wall in addition to those of Takayasu arteritis that have also been related to various infectious processes (eg, syphilis, tuberculosis), antiphospholipid antibody syndrome, Ehlers-Danlos syndrome, Marfan syndrome, neurofibromatosis, vascular changes due to radiation, and Behçet disease. These observations have prompted introduction of the term “Takayasu syndrome.” It remains unclear whether Takayasu syndrome is a separate disease entity or merely a set of complications that can arise in various disease processes.
Given that this is an immune mediated disease with genetic risk factors, there is no known effective preventative strategy.
The diagnosis of Takayasu can be challenging given its nonspecific presentation. Numerous vasculitides can present with symptoms related to inflammation of the aorta and its branches and are best differentiated based on other systemic involvement. Alternative etiologies to consider include giant cell arteritis, rheumatoid arteritis, systemic lupus erythematosus, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, Behcet disease, and sarcoidosis. Giant cell arteritis is perhaps the most common mimicker due to multiple overlapping features, as both vasculitides predominantly affecting larger vessels. Panarteritis and giant cell formation are characteristic features of both giant cell arteritis and Takayasu disease. Ten percent to 15% of the patients with giant cell arteritis develop inflammatory changes of the aorta and its larger branches, most commonly affecting the ascending aorta and the aortic arch, with or without aneurysms or dissection, aortic regurgitation, and cardiac insufficiency (43). These changes are nearly always seen in an advanced stage. In the majority of patients with giant cell arteritis patients, these changes develop years after the first diagnosis, sometimes resulting in fatality due to acute aortic dissection. Serological studies may not show abnormalities related to inflammation at this time.
Differences between Takayasu arteritis and giant cell arteritis include the following: Takayasu arteritis usually presents prior to the age of 40 years, often involves vascular changes in the upper extremities, with blood pressure differences in the 2 arms, and is commonly associated with bruits over the aorta and subclavian arteries. Giant cell arteritis presents at older ages, is often accompanied by a high sedimentation rate, affects mostly Caucasians, and is often associated with jaw claudication, proximal myalgia, and tenderness along the course of the temporal arteries.
In addition, Takayasu arteritis targets the large elastic arteries, whereas giant cell arteritis primarily affects the medium-sized muscular arteries with internal and external elastic laminae (43). Intracranial arteries are seldom involved in giant cell arteritis but represent a major target of the inflammatory response in Takayasu arteritis (38). With these considerations, Takayasu arteritis can be correctly diagnosed in 90% of cases (51).
Early diagnosis of Takayasu arteritis is challenging. Diagnostic workup should include serological and immunological testing to rule out the possibility of another vasculitis as well as vascular imaging to assess the anatomy and degree of arterial occlusive disease. Unfortunately, a histological diagnosis is usually possible only when surgery is undertaken (eg, vascular reconstruction, aortic valve replacement), due to the risks associated with endovascular biopsy. However, it can be considered when performed during angioplasty procedure to detect active inflammation of the aortic wall (84).
It is also difficult to assess disease activity in Takayasu arteritis. Just as the absence of systemic clinical features does not exclude ongoing vascular inflammation, the presence of ischemia does not prove that there is activity. Vascular collaterals may develop slowly. The erythrocyte sedimentation rate is elevated in nearly 80% of cases. A normal erythrocyte sedimentation rate, however, does not exclude the disease in an active phase. Inactivity of the disease is assumed when there are no systemic complaints, erythrocyte sedimentation rate is normal, and angiography results are stable. However, 42% of patients classified clinically as inactive proved to be active on histological examination after having had surgery on the blood vessels (39).
Better biomarkers of disease activity in Takayasu arteritis have been sought. Matsuyama and colleagues have suggested using matrix metalloproteinases (47). Specifically, an association was found between levels of MMP3 and MMP9 and disease activity scores. A report described serum levels of pentraxin-3, a protein produced at sites of vascular inflammation, as better distinguishing active from inactive disease than did the erythrocyte sedimentation rate or the C-reactive protein in 57 Italian patients (15), with subsequent confirmation in a group of 45 Japanese patients (29). As these markers become more widely available, they may effectively complement clinical assessment of disease activity in Takayasu arteritis.
Imaging procedures. Imaging procedures play a central role in the evaluation of Takayasu arteritis. Intra-arterial angiography has been considered the “gold standard” and has served as the basis for the classification of disease types (see above). Angiography demonstrates the major arterial occlusions that are the hallmark of the disease in its advanced stages.
In a study reviewing the angiograms of 26 children with Takayasu arteritis, the most consistent findings were stenosis of the aorta and a high incidence of both fusiform and saccular aneurysms (48).
Although angiography has been valuable with respect to diagnosis, it has several shortcomings. In addition to the risks of the procedure and exposure to radiation, it can neither differentiate between disease activity and inactivity nor between disease stage (acute vs. chronic). Angiography is ineffective at identifying the disease in the early inflammatory phase as it only delineates fixed changes in vessel lumen diameter, a serious limitation when attempting to reduce morbidity. Methods that go beyond imaging of the lumen, to study the arterial wall itself, offer more promise for detecting and monitoring early disease activity (46). Noninvasive MR and CT angiography methods have been recognized as approaches that can be effectively used to complement or replace conventional angiography, providing both an assessment of the vascular lumen and an image of the vessel wall (05; 37). MR angiography, using contrast enhancement and 3-dimensional reconstruction techniques, provides detailed anatomic information about lumen configuration, and parallel MR imaging can provide information about the vascular wall thickness, assessment of wall enhancement, and the presence of edema (05). Post-contrast, T1-weighted imaging detects mural enhancement reflecting increased vascularity or excessive leakage of contrast out of the vasa vasorum, indicating probable disease activity. T2-weighted imaging, which is sensitive to mural edema and is seen in more acute disease, will produce a hyperintense signal.
CT angiography can, likewise, show both high-resolution imaging of the vessel lumen and detection of arterial wall thickening or enhancement, providing evidence for arterial inflammation (37). In 18 patients with active Takayasu arteritis studied with serial CT examinations of the thoracic aorta, frequent findings included high density, calcifications, and thickening of the aortic wall and contrast enhancement of the wall. Mural thickness decreased significantly on follow-up CT examinations. During the venous phase of contrast, a low-attenuation ring, lying between the enhancing outer aortic wall and the contrast-filled lumen, was identified with the thickened intimal layer and served as a marker of active Takayasu arteritis.
Both MR and CT angiography are clearly useful in the evaluation of the anatomy of luminal changes in Takayasu, potentially supplanting the need for intra-arterial angiography. In a published, blinded study using 3-dimensional-MRA, a 100% sensitivity and specificity for the diagnosis of Takayasu arteritis was reported in 20 patients out of 30 suspected of having Takayasu arteritis (99). Compared with the gold standard of conventional intra-arterial angiography, 2% of stenotic arteries were overestimated as occluded. In the study of Yamada and colleagues, 50% of the patients had pulmonary artery involvement, which is more easily detected by MR methods (99). The European League Against Rheumatism (EULAR) has endorsed noninvasive imaging with MR or CT as the first choice in suspected Takayasu arteritis (16).
Whether these emerging MR and CT-based methods for vessel wall imaging can also achieve the goal of reliable detection of vascular inflammation prior to significant stenosis is less well established, as the identification of mural thickening or mural edema with active inflammation can be questioned. A metaanalysis of reported studies of MR and CT imaging modalities in Takayasu arteritis concluded that the utility of these modalities for assessing disease activity remains unclear. Evaluation of vessel wall imaging techniques as part of a prospective trial has been called for (46). Nevertheless, the increasingly high resolution images of vessel walls produced by these noninvasive techniques offer great potential for directly detecting vasculitic activity prior to development of luminal stenosis.
Fluorodeoxyglucose-PET (FDG-PET) imaging may assist in early disease detection and shows the most promise for specifically detecting disease activity. This test shows differences in tissue glucose metabolism as uptake of deoxyglucose. During the early phase of the disease, an increased accumulation of fluorodeoxyglucose in the inflamed vessel wall exists, including those of the pulmonary arteries. Several articles have suggested that this imaging technique may be used to assess disease activity and that imaging abnormalities may resolve with treatment (02). A study of FDG-PET uptake in 26 patients with Takayasu arteritis or giant cell arteritis versus age matched controls demonstrated a specificity of 99.8% (95% CI 89.1-100%), sensitivity of 60% (95% CI 40.6-77.3%), a positive predictive value of 99.7% (95% CI 77-100%), and a negative predictive value of 67.9% (95% CI 49.8 -80.9%) (95). One study on 39 patients found FDG-PET to be superior to using ESR and CRP as a marker for disease activity, with a sensitivity of 92.6%, specificity of 91.7%, positive predictive value of 96.2%, and negative predictive value of 84.6% (89). To specifically evaluate the utility of FDG-PET for identifying disease activity in patients with large vessel vasculitis (LVV), Grayson and colleagues prospectively followed 115 participants with serial FDG-PET imaging at 6 month intervals (21). The participants included 26 with Takayasu arteritis, 30 with giant cell arteritis, and 59 without large vessel vasculitis. Clinically active disease was identified with good sensitivity (85%) and specificity (83%). Moreover, FDG-PET signal was predictive of future clinical relapse. These studies support FDG-PET as a promising tool for the assessment of disease activity and follow-up in Takayasu arteritis.
Ultrasonography has also been helpful for evaluating Takayasu arteritis. It is noninvasive; it can visualize stenosis, occlusion, and aneurysms (85); and it has the advantage of avoiding radiation or contrast dye exposures. In contrast to conventional angiography, vessel wall thickening (a major pathologic feature of the disease) can be detected. The most frequent lesion seen using ultrasound was a characteristic long and homogeneous circumferential thickening, which was detected in 98% of 43 patients (40). Contrast-enhanced ultrasonography demonstrated excellent sensitivity (100%) and specificity (80%) to detect disease activity of the carotid arteries when compared to FDG-PET imaging (41).
Fundus fluorescein angiography has been helpful in characterizing the retinopathy of Takayasu arteritis. Delayed arm-to-retina circulation time is seen in all cases, but a delayed arteriovenous filling time is usually found in moderate and severe cases of retinopathy.
Medical therapy. Steroids and immunosuppressants are usually prescribed empirically. The response rate to monotherapy with steroids is between 20% and 100% (26). Evidence suggests that insufficient use of corticosteroids without immunosuppression results in a higher relapse rate (58). Although glucocorticoids remain the mainstay of medical treatment, multiple corticosteroid-sparing agents have been utilized to reduce relapses during corticosteroid tapering and include methotrexate (36), mycophenolate mofetil, and leflunomide (91). Gudbrandsson and colleagues reviewed a population and referral-based cohort of Takayasu patients in Norway, with some diagnosed prior to 2000 and some after 2000, and they found evidence for lowered rates of new lesion development and higher sustained remission rates in the more recently diagnosed patients, corresponding with a much higher rate of initial treatment with disease-modifying antirheumatic drugs (22).
Biological agents offer the possibility of therapy specifically targeted to disease mechanism, potentially with reduced side effects as compared to broad immunosuppression. Because granulomas are dependent in part on tumor necrosis factor-alpha, a role for anti-tumor necrosis factor-alpha has been suggested, especially for patients who have failed to respond to corticosteroids and immunosuppressive agents. In an open-label trial of the tumor necrosis factor-alpha-binding monoclonal antibodies etanercept and infliximab, 10 of 15 patients (67%) went into sustained remission, as defined as no new vascular lesions and the ability to discontinue glucocorticoid therapy. Follow-up in these patients lasted 1 to 3.3 years. Four patients had a partial response defined by a decrease in corticosteroids by 50%. One patient failed to respond, developing new arterial lesions without significant reduction in steroids (27). Other reports of use of antitumor necrosis factor-alpha agents followed, and in a 2011 review, a total of 84 cases with refractory Takayasu arteritis, treated with infliximab or etanercept, were collected and described (13). Complete remission was achieved in 37%, and partial response was found in 54%, leaving only 10% as nonresponders. Forty percent of patients were able to discontinue glucocorticoid therapy entirely. Side effects included infectious complications and hypersensitivity reactions, but the therapy was well-tolerated in the majority of patients.
Interleukin-6 is a multifunctional cytokine that regulates immune responses and inflammatory reactions. Overproduction of interleukin-6 has been shown to occur in the aortic tissue and serum in patients with Takayasu arteritis, leading to consideration of therapy targeted at interleukin-6 activity. Nishimoto and colleagues treated a 20-year-old woman with refractory active Takayasu arteritis complicated by ulcerative colitis with the anti-interleukin-6 receptor antibody, tocilizumab (61). Within 3 weeks of the start of treatment, tocilizumab improved the inflammatory manifestations and laboratory findings of Takayasu arteritis. Also, tocilizumab suppressed the ulcerative colitis activity. Following that initial report, tocilizumab use has been frequently described in Takayasu arteritis, particularly in cases refractory to treatment with prednisone and other immunosuppressants (20; 90; 91). Initial response rates in these patients have been high. Many patients achieved initial control of their disease, with discontinuation or reduction in prednisone dosing and improvement in signs of vascular wall inflammation. In 46 French cases treated with tocilizumab that were reviewed retrospectively, a response rate of 81% at 1 year was found, with reduction in prednisone dosing and disease activity scores (50). However, relapses of disease still occurred in this group, with half of patients relapsing by 2 years.
Tocilizumab was compared prospectively to placebo in a double-blind trial in 36 Takayasu arteritis patients who had recently relapsed (59). The primary endpoint was the time to relapse, which was observed during a scheduled taper of glucocorticoids. In an intention-to-treat analysis, the hazard ratio for relapse with tocilizumab versus placebo was 0.41, with a confidence interval of 0.15 to 1.10, falling just short of the margin for statistical significance. A per-protocol analysis found a significantly lowered hazard ratio for relapse of 0.34 in those treated with tocilizumab. Serious adverse events were not increased in the tocilizumab group. Tocilizumab or TNF-α antagonists were compared retrospectively with disease-modifying antirheumatic drugs in a review of 49 Takayasu arteritis patients in France, with report of an overall 3 year relapse-free rate of 90.9% versus 58.7%, with no difference found between tocilizumab and anti-TNF-α agents (49).
Overall, both anti-TNF-α agents and tocilizumab show substantial promise for improved relapse-free survival in Takayasu arteritis.
The possible role for B-cells and antiendothelial antibodies in the pathogenesis of Takayasu arteritis has led to attempts to use the chimeric anti-CD20 monoclonal antibody rituximab, which depletes circulating B cells, in the treatment of refractory disease. Unizony and colleagues reviewed reports of 5 patients with Takayasu treated with rituximab after failure of other therapies, with clinical responses in 4 of the 5 (91). Two additional cases successfully treated with rituximab have been reported (09). In summary, several biological agents targeted at specific mediator of the immune response in Takayasu arteritis offer substantial promise for improved treatment of this disease.
Surgical treatment. Surgery has an important auxiliary role in Takayasu arteritis; percutaneous transluminal coronary angioplasty (with or without stent implantation), aneurysm-surgery, aortic valve replacement, and vascular reconstructive surgery, eg, bypass surgery should be carried out when the diseases is inactive. Otherwise, the surgical success rate is considerably lower in active disease (36; 54). A retrospective study from 1979 to 2001 analyzed outcomes from 62 revascularization procedures performed in 20 patients. The authors found 11 of 31 bypass grafts restenosed or occluded between day 1 and 168 months. Three of 7 percutaneous angioplasties restenosed or occluded after 72 months, and 5 of 7 stents restenosed or became occluded between 2 and 45 months of follow up (42). These results suggest a relatively high failure rate with revascularization procedures. In contrast, in a study of 25 patients who had 58 angioplasty procedures, 52 procedures were successful; after 18.4 months of follow up, 9 (17%) restenosed, resulting in a clinical success rate of 82% (52). In this study longer-term follow up may be necessary to assess the long-term benefit of these procedures in Takayasu arteritis patients. In a US cohort study involving 75 patients, a high occurrence (78%) of restenosis, after an initially successful percutaneous transluminal angioplasty, was reported (44). The long-term efficacy of endovascular repair (stent grafting) for aortic aneurysm remains uncertain. Additional studies on updated endovascular therapies, including percutaneous transluminal angioplasty with stenting and endovascular aneurysmal repair with the use of a stent graft, are needed to assess outcomes.
Supportive therapy. Most patients have arterial hypertension. However, uncertainties in the determination of blood pressure due to stenotic arteries render the management of antihypertensive therapy difficult. If upper extremity blood pressure measures are unreliable, a wide cuff may be placed on an unaffected thigh or a direct measurement from the proximal aorta may provide an accurate measurement. It is always necessary to weigh the aggressiveness of the blood pressure reduction against the threat of reduced organ perfusion. Thrombotic events do not play a role in Takayasu arteritis. Therefore, anticoagulation is not recommended.
Acute stroke treatment. In an era of increasing acute stroke recognition and increased utilization of thrombolytic therapy and endovascular thrombectomy, more patients with Takayasu arteritis may be candidates for acute stroke treatment. However, there is sparse literature addressing the role of these interventions in patients with Takayasu arteritis. Acute stroke is a neurologic emergency, and treatment must include a careful yet urgent risk-benefit evaluation, including screening for other sequelae of large vessel vasculitis such as aortic dissection, which would be a contraindication of acute thrombolytic therapy. Despite limited experience, there are case reports and case series reviewing acute cerebrovascular events in Takayasu arteritis, highlighting the safe administration of intravenous alteplase (14). In the absence of clear contraindications, intravenous alteplase should be strongly considered in eligible patients. Furthermore, given the predilection for vasculitis of the internal carotid arteries, patients with Takayasu arteritis may present with acute ischemic stroke secondary to extracranial or intracranial steno-occlusive disease (07). Given the often devastating neurologic sequalae associated with large vessel occlusions, patients with Takayasu arteritis should be offered mechanical thrombectomy if eligible.
Women of childbearing age are the primary sufferers of Takayasu arteritis. Five of 5 pregnant patients in a National Institutes of Health study had a normal pregnancy (36). A larger series in women in northern India showed a high rate of hypertension, pre-eclampsia, or intrauterine growth retardation complicating 37 pregnancies in 15 women, with 1 maternal death (86). In an Italian cohort with 104 patients including 91 women, 24 pregnancies in 18 women occurred after the onset of disease (92). These results showed a decrease in the incidence of pregnancy, from 8.2 pregnancies for every 100 fertile women to 2.8 after the onset of the disease. There is a risk of exacerbation of associated arterial hypertension, aortic insufficiency, and cardiac failure. Pregnancies should be planned only during an inactive stage. Pregnant patients need to be supported carefully in an interdisciplinary setting for the complete duration of pregnancy to be able to recognize the most effective treatments for vascular, cardiac, and other complications (69). Favorable outcomes in pregnancy can be found, with rates of terminations, maternal complications, and preeclampsia/eclampsia no different at population levels, though with higher rates of cesarian section (22).
A detailed evaluation of the vascular, cardiac, and pulmonary disease is necessary before performing surgery. Because of focal stenotic involvement of blood vessels, Takayasu arteritis could be complicated by severe uncontrolled hypertension (eg, because of renovascular involvement), end-organ dysfunction, stenosis of major blood vessels affecting regional circulation, and difficulties encountered in (noninvasive) monitoring of the arterial blood pressure. Kathirvel and colleagues reported on their experience in 8 patients for various surgical procedures and various anesthetic techniques (34). Difficulties in maintaining normal blood pressure at the preoperative level was a common issue in these cases. Preoperatively, 3 of these 8 patients had severe uncontrolled (renovascular) hypertension and were referred for surgical treatment, ie, nephrectomy or arterioplasty with a saphenous venous graft. The choice of anesthetic technique (eg, general anesthesia, epidural anesthesia) must be tailored to the particular involvement of a patient. Patients with weak or absent pulses in the extremities require special monitoring devices, such as Doppler flow signals, pulse oximetry, etc.
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.See Profile
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