Takayasu Arteritis

Practice Essentials

Takayasu arteritis is a rare, systemic, inflammatory large-vessel vasculitis of unknown etiology that most commonly affects women of childbearing age.^[1] It is defined as "granulomatous inflammation of the aorta and its major branches" by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis.^[2] See the image below. (See Etiology and Epidemiology.)

View Image

Complete occlusion of the left common carotid artery in a 48-year-old woman with Takayasu disease. Also note narrowing of the origin of the right subc....

Takayasu arteritis commonly occurs in woman younger than age 50 years; however, it has been reported in patients as young as age 6 months (see Pediatric Takayasu Arteritis). Takayasu arteritis can manifest as isolated, atypical, and/or catastrophic disease. It can involve any or all of the major organ systems. The disease has been reported in all parts of the world, although it appears to be more prevalent in Asians. (See Epidemiology.)

Angiography-based categories

Takayasu arteritis can be divided into the following six types based on angiographic involvement (see Workup)^[3] :

• Type I - Branches of the aortic arch
• Type IIa - Ascending aorta, aortic arch, and its branches
• Type IIb - Type IIa region plus thoracic descending aorta
• Type III - Thoracic descending aorta, abdominal aorta, renal arteries, or a combination
• Type IV - Abdominal aorta, renal arteries, or both
• Type V - Entire aorta and its branches

Patient education

Patients need to understand the nature of the disease and the need to take medications to prevent complications. When in remission or when experiencing mild forms of Takayasu arteritis, patients are tempted to stop antihypertensive drugs, thus increasing their risk of serious neurologic and other systemic complications. (See Treatment and Medication.)

• References

Background

Takayasu arteritis is named in honor of Japanese ophthalmologist Mikito Takayasu, who first reported a case of the disease in 1905. His patient was a 21-year-old woman with retinal vessel changes and decreased pulses in branches of the aortic arch. Such ophthalmologic findings are rarely encountered and are not included in the American College of Rheumatology criteria for the disorder.^[4]

Shimizu and Sano reported six cases of Takayasu arteritis in an English-language publication in 1951, terming the disorder "pulseless disease because of an absence of radial pulse in their patients. This led to a misunderstanding ot Takayasu arteritis as a disorder of only locally limited involvement.^[4]

• References

Pathophysiology

Takayasu arteritis is an inflammatory disease of large- and medium-sized arteries, with a predilection for the aorta and its branches. Advanced lesions demonstrate a panarteritis with intimal proliferation.

Lesions produced by the inflammatory process can be stenotic, occlusive, or aneurysmal. All aneurysmal lesions may have areas of arterial narrowing. Vascular changes lead to the main complications, including hypertension, most often due to renal artery stenosis or, more rarely, stenosis of the suprarenal aorta; aortic insufficiency due to aortic valve involvement; pulmonary hypertension; and aortic or arterial aneurysm.

The renal arteries are involved in 24% to 68% of Takayasu arteritis cases. Renal artery involvement is often bilateral. Patients with renal artery involvement typically have coexistent stenosis of the perirenal aorta.^[5]

Congestive heart failure is a common finding, much more so than dilated cardiomyopathy, myocarditis, and pericarditis, which also have been reported. In patients in whom the pulmonary artery is involved, the right artery appears to be affected more than the left, with patients developing pneumonia, interstitial pulmonary fibrosis, and alveolar damage.

Other pathophysiologic consequences include hypotensive ischemic retinopathy, vertebrobasilar ischemia, microaneurysms, carotid stenosis, hypertensive encephalopathy, and inflammatory bowel disease. Rarely, Takayasu arteritis has also been associated with glomerulonephritis, systemic lupus erythematosus, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, Still disease, and ankylosing spondylitis.

• References

Etiology

The etiology of Takayasu arteritis is unknown. The underlying pathologic process is inflammatory, with several etiologic factors having been proposed, including infection with spirochetes, Mycobacterium tuberculosis, and streptococcal organisms, and circulating antibodies due to an autoimmune process. Genetic susceptibility factors have been identified.^{[6, 7]}

An antigen may stimulate aortic tissue, leading to the expression of heat shock protein–65, which, in turn, induces major histocompatibility (MHC) class I–related chain A (MICA). Natural killer cells and gamma-delta T cells expressing NKG2D receptors may infiltrate and recognize MICA on vascular smooth muscle cells, leading to acute inflammation. Proinflammatory cytokines are also released from the natural killer and T-cells, inducing the production of matrix metalloproteinases (MMPs) and amplifying the inflammatory response. This, in turn, would induce more MHC antigen and stimulate molecule expression on vascular cells, recruiting more mononuclear cells.

Histocompatibility complexes are activated through Toll-like receptors. Th1 lymphocytes, through interferon-gamma, activate macrophages, which, in turn, release vascular endothelial growth factor (VEGF). This ultimately results in smooth muscle migration and intimal proliferation. Th17 cells induced by the interleukin (IL)–23 microenvironment also contribute to vascular lesions through activation of infiltrating neutrophils.

The cellular infiltrate in Takayasu arteritis contains about 15% each of CD4⁺ and CD8⁺ T cells. IL-6 is a proinflammatory cytokine mainly synthesized by activated monocytes, macrophages, and T cells. IL-6 activates B cells and enhances T-cell cytotoxicity, natural killer cell activity, fibroblast proliferation, and acute-phase protein synthesis. Amplification of proinflammatory cytokine genes from aortic tissue reveals strong expression of IL-6 transcripts.

In a case report, M tuberculosis and its 65-kd heat shock protein was implicated in the etiology. Patients with Takayasu arteritis were found to have higher immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) titers against the M tuberculosis extract than did patients without the condition.^[8]

One article reported the presence of CD3⁺ T cells and IgG antibodies reactive to circulating antimycobacterial heat shock protein 65 (mHSP65) antibodies and to its human homologue, hHSP60.^[9] This suggests a possible cross-reactivity of immune response between mHSP65 and hHSP60. Case reports suggesting the role of antiendothelial cell, anticardiolipin, and antiaorta antibodies also exist.

The genetic susceptibility factor that has been most consistently associated with Takayasu arteritis is the human leukocyte antigen (HLA) allele HLA-B*52, which has been confirmed in several ethnicities. HLA-B*52 has a higher prevalence in Asians, which may help explain the greater frequency of Takayasu arteritis in this population.^{[6, 7]}  Carriage of HLA-B∗52 is associated with more severe disease, with a higher incidence of left ventricular wall abnormalities and aortic regurgitation and an earlier disease onset.^[10]

Other HLA alleles have also been implicated; for example, HLA-B∗39, HLA-DRB1∗1502, and HLA-DRB1∗0405 have also been associated with the disease in Japanese patients. HLA-B*39 is associated with renal artery stenosis.^[10]  In addition, genome-wide association studies have identified several non-HLA susceptibility loci.^[7]

One study demonstrated an association between several cases of Takayasu arteritis and CD36 deficiency (CD36d).^[11] The human CD36 antigen is a multifunctional membrane glycoprotein that belongs to the class B scavenger receptor family. It is expressed on monocytes, platelets, and endothelial cells, and contributes to myocardial fatty acid transport. In patients with CD36d, myocardial I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) uptake was absent.

• References

Epidemiology

Occurrence in the United States

Takayasu arteritis is estimated to affect 2.6 persons per million annually. The prevalence is 2.6-6.4 persons per million population. Any discrepancy in terms of pinpointing the prevalence is attributed to genetic factors and difficulty in diagnosis.

Between 1971 and 1983 in Olmsted County, Minnesota, three cases were recorded, thus establishing an annual incidence of 2.6 cases per million population.^[12]

International occurrence

Worldwide incidence of Takayasu arteritis is estimated at 2.6 cases per million per year. Although the disease has a worldwide distribution, it is observed more frequently in Asian countries such as Japan, Korea, China, India, Thailand, and Singapore, as well as in Turkey, Israel, and Central and South America. About 100-200 new cases of Takayasu arteritis are registered each year in Japan.^[4]

Estimates of the incidence rates in Europe  vary from 0.4 to 1.5 per million, while the prevalence ranges from 4.7 to 33 per million.^[13] It is unclear whether the variations reflect geographical and genetic differences among the populations or methodological differences in epidemiologic studies.^[13]

Race-, sex-, and age-related demographics

Takayasu arteritis is observed more frequently in patients of Asian or Indian descent. Japanese patients with Takayasu arteritis have a higher incidence of aortic arch involvement. In contrast, series from India report higher incidences of abdominal involvement.^{[4, 14]}

Approximately 80% of patients with Takayasu arteritis are women; however, the high female-to-male ratio seems to decrease west of Japan. In India, the female-to-male ratio is as low as 1.6:1.^[4]

Most patients with Takayasu arteritis are aged 4-63 years, with the mean age of onset being approximately 30 years. Fewer than 15% of cases present in individuals older than 40 years.

• References

Prognosis

Takayasu arteritis is associated with substantial morbidity and may be life-threatening. Its course usually extends for many years, with varying degrees of activity. Approximately 20% of patients have a monophasic and self-limited disease. In others, Takayasu arteritis is progressive or relapsing/remitting and requires immunosuppressive treatment.^{[15, 16, 17]}

A National Institutes of Health study of 60 patients with Takayasu arteritis showed that 20% of patients had a monophasic illness, self-limiting illness and therefore did not require immunosuppressive treatment. In the remaining 80% of patients, who did not have a monophasic illness and who experienced a single exacerbation, immunosuppressive therapy resulted in remission in 60%. Of these, one half experienced relapse after immunosuppressive therapy was stopped.

Complications

The overall morbidity in Takayasu arteritis depends on the severity of the lesions and their consequences. Complications of the disease include the following:

• Stroke
• Intracranial hemorrhage
• Seizures
• Graft stenosis and/or occlusion
• Ischemia
• Organ failure
• Complications of hypertension (eg, aortic dissection^[18] )
• Fetal injury
• Valvular heart disease
• Retinopathy
• Renovascular hypertension

Long-term use of corticosteroids can lead to infection, adrenal suppression, cataracts, hyperglycemia, hypertension (which complicates blood pressure control), osteoporosis, and aseptic necrosis.

Morbidity and mortality

Takayasu arteritis is a chronic relapsing and remitting disorder. The overall 10-year survival rate is approximately 90%; however, this rate is reduced in the presence of major complications.^[15]

The 5- and 10-year survival rates are approximately 69% and 36%, respectively, in patients with 2 or more complications. The 5- and 10-year survival rates associated with 1 or fewer complications are 100% and 96%, respectively.^[19]

Strict management of traditional cardiovascular risk factors such as dyslipidemia, hypertension, and lifestyle factors that increase the risk of cardiovascular disease is mandatory to minimize secondary cardiovascular complications. These complications are the major cause of death in Takayasu arteritis.

A 2008 study assessing quality of life with Takayasu arteritis showed worse scores for physical and mental health compared with many other chronic diseases associated with peripheral vascular disease. Disease remission is the only factor that positively influences physical and mental quality of life.^[20] Patients with rheumatoid arthritis or ankylosing spondylitis rated their quality of life as similar to those with Takayasu arteritis.^[21]

• References

History

The presentation of Takayasu arteritis is heterogeneous. Approximately 10% of patients with Takayasu arteritis are asymptomatic, and the diagnosis is suggested only by abnormal vascular findings on physical exam.^{[16, 22]} Constitutional symptoms may precede clinical vascular involvement.

Constitutional symptoms include the following:^{[19, 16, 22, 23]}

• Headache (50-70%)
• Malaise (35-65%)
• Arthralgias (28-75%)
• Fever (9-35%)
• Weight loss (10-18%)

Cardiac and vascular features include the following:^{[19, 16, 22, 23, 24]}

• Bruit, with the most common location being the carotid artery (80%)
• Blood pressure difference of extremities (45%-69%)
• Claudication (38-81%)
• Carotodynia or vessel tenderness (13-32%)
• Hypertension (28-53%; 58% with renal artery stenosis in one series)
• Aortic regurgitation (20-24%)
• Raynaud syndrome (15%)
• Pericarditis (< 8%)
• Congestive heart failure (< 7%)
• Myocardial infarction (< 3%)

Neurologic features include the following:^{[19, 16, 22, 23, 24]}

• Headache (50-70%)
• Visual disturbance (16-35%) - Strong association with common carotid and vertebral artery disease
• Stroke (5-9%)
• Transient ischemic attacks (3-7%)
• Seizures (0-20%)

Dermatologic manifestations include the following:^{[16, 23, 24]}

• Erythema nodosum (6-19%)
• Ulcerated subacute nodular lesions (< 2.5%)
• Pyoderma gangrenosum (< 1%)

Classification criteria

The American College of Rheumatology has established classification criteria for Takayasu arteritis (3 of 6 criteria are necessary). The presence of any 3 or more criteria yields a sensitivity of 90.5% and a specificity of 97.8%.^[25] The criteria are as follows:

• Age of 40 years or younger at disease onset
• Claudication of the extremities
• Decreased pulsation of one or both brachial arteries
• Difference of at least 10 mm Hg in systolic blood pressure between arms
• Bruit over one or both subclavian arteries or the abdominal aorta
• Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the upper or lower extremities that is not due to arteriosclerosis, fibromuscular dysplasia, or other causes

Stages

Takayasu arteritis progresses through 3 stages. Thus, symptoms that clinicians encounter depend on how soon the patient presents; most patients present late, delaying the diagnosis. In actual practice, however, most patients do not fall readily into such groupings, and this 3-stage scheme is an oversimplification of the complex clinical presentation. Symptoms encountered can occur early or late in the course of the disease. In the aforementioned NIH series, which included 60 patients observed over 20 years, only 33% of patients had constitutional symptoms (corresponding to stage 1); 18% of patients never progressed to the third stage.

The first stage is an early systemic stage during which the patient may complain of constitutional symptoms (eg, fatigue, malaise, giddiness, fever). This stage is considered to be prevasculitic.

The second stage is the vascular inflammatory stage when stenosis, aneurysms, and vascular pain (carotidynia) tend to occur.

Signs and symptoms characterizing the vascular inflammatory stage include fatigue, fevers, malaise, pain in extremities and joints, dyspnea, palpitations, headaches, rash (erythema nodosum or a lupuslike butterfly rash, which can be photosensitive), hemoptysis, ulceration, and weight loss. A single case of thoracic and lumbar spine pain has been reported. Symptoms of vascular insufficiency include arm numbness, claudication in the legs (rare), blurry vision, double vision (which can be posture dependent), amaurosis fugax, stroke, transient ischemic attacks, hemiplegia, seizures, and paraplegia.

The constitutional systemic symptoms and vascular symptoms may occur at the same time, rendering the classification into stages practically impossible.

The third stage is the burned-out stage, when fibrosis sets in, and generally is associated with remission. This stage does not occur in all patients, and even in patients who are in remission, relapses can occur. Presumably, the burned-out stage manifests with minimal symptoms, but little supportive evidence is found in the literature.

Takayasu arteritis in pregnancy

Special mention should be made regarding pregnant women. The inflammatory activity is not enhanced by the pregnancy, but the perinatal period may be complicated by the associated symptoms. Blood pressure may not be measurable due to pulselessness, thus making patient monitoring difficult, if not impossible. Often, calf pressures need to be obtained.

In pregnant women with Takayasu arteritis, uncontrolled blood pressure may lead to subarachnoid/intracranial hemorrhage and subsequent seizures, eye changes, preeclampsia, aortic regurgitation, syncope, fetal complications, and nephrotic syndrome.

• References

Physical Examination

A thorough physical examination is essential, with particular attention paid to peripheral pulses, blood pressure in all 4 extremities, and ophthalmologic examination. The most discriminatory finding is a systolic blood pressure difference (>10 mm Hg) between arms.

Hypertension due to renal artery involvement (and sometimes leading to hypertensive encephalopathy) is found in approximately 50% of patients. Carotidynia may be present. Aortic regurgitation is a common finding.

Absent or diminished pulses are the clinical hallmark of Takayasu arteritis, but pulses are normal in many patients and upper limbs are affected more often than lower limbs. When pulselessness occurs, patient monitoring can be difficult or impossible, and often, calf blood pressures must be obtained.

Ophthalmologic examination may show retinal ischemia, retinal hemorrhages, cotton-wool exudates, venous dilatation and beading, microaneurysms of peripheral retina, optic atrophy, vitreous hemorrhage, and classic, wreathlike peripapillary arteriovenous anastomoses (extremely rare).Fundus fluorescein angiography may show segmented retinal blood flow, also known as “boxcarring".^[26]

Skin changes resembling erythema nodosum or ulcerating nodular lesions may be seen.

Other significant findings include the following:

• Amaurosis fugax
• Focal neurologic deficits consistent with cerebral infarction or transient ischemic attack
• Vascular bruits, most commonly in the carotid and abdominal arteries but also in the subclavian and femoral arteries
• Myocardial infarction
• Dilated cardiomyopathy
• Eclampsia
• Subarachnoid hemorrhage, probably secondary to hypertension
• Leg edema due to renal failure secondary to renal artery stenosis and glomerulonephritis

Less common associations have been seen with the following:

• Ulcerative colitis
• Sensorineural hearing loss
• Pulmonary hemorrhage

A case report described sensorineural hearing loss associated with Takayasu arteritis.^[27] Whether a firm connection between the 2 syndromes exists, other than the inflammatory manifestations, has not been demonstrated. The pathologic etiology of the hearing loss was attributed to an immune-mediated process in the membranous labyrinth.

Another case report described the presence of Cogan syndrome with Takayasu arteritis.^[28] Cogan syndrome involves interstitial keratitis and a vestibuloauditory syndrome. Variations of this with other types of inflammatory eye disease and vestibuloauditory arteritis have also been reported.

• References

Approach Considerations

Laboratory test results in individuals with Takayasu arteritis tend to be nonspecific. The erythrocyte sedimentation rate may be high, generally greater than 50 mm/h, in early disease but normal later. Leukocyte count may be normal or slightly elevated. A moderate, normochromic anemia may be present in individuals with active disease.^{[16, 22]}

Autoantibodies observed in other connective tissue diseases, including rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies, and antineutrophil cytoplasmic antibodies (ANCA), are as common as in the general population. Circulating antiendothelial antibodies may be present in high titers. This finding is considered nonspecific, because it is reported sporadically and may be present in other connective tissue diseases and in angiitis obliterans. Antiaorta antibodies may be present, but testing for them seldom is performed, if ever.

Some researchers found that the levels of soluble vascular cell adhesion molecule–1 (VCAM-1) were significantly higher in patients with Takayasu arteritis compared with normal, healthy controls and that they were also significantly higher in older patients than in younger ones, suggesting that VCAM-1 may serve as a marker of disease activity and progression with age. Tripathy et al reported that cell adhesion molecule levels remain elevated in patients with inactive Takayasu arteritis.^[32]

Hypoalbuminemia and increased levels of fibrinogen, alpha2-globulin, and gamma globulin are common. Urinalysis may be consistent with nephrotic syndrome.

HLA typing is not a standard diagnostic procedure for North American patients. Presumably, a finding of HLA-B*52 in such patients reinforces the diagnosis; it is not a definite diagnostic tool.

Imaging studies

Although conventional angiography has historically been the standard for diagnosis and evaluation of the extent of disease, computed tomography and magnetic resonance techniques have gained favor for initial evaluation, as they are less invasive than standard angiography and allow diagnosis of Takayasu arteritis earlier in the disease course.^{[33, 34]} Ultrasonography is useful for carotid assessment, while 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is useful for patients with no vascular signs or symptoms, fever of unknown origin, or an unexplained acute-phase response. (See the images below.)^{[35, 34, 33]}

View Image

MRI of thorax of 15-year-old girl with Takayasu arteritis. Note aneurysms of descending aorta. Image courtesy of Christine Hom, MD.

View Image

Coronal MRI of abdomen of 15-year-old girl with Takayasu arteritis. Note thickening and tortuosity of abdominal aorta proximal to kidneys. Image court....

For complete discussion, see Takayasu Arteritis Imaging

• References

Diagnostic Criteria

Ishikawa criteria

The Ishikawa criteria (1986) have been useful in defining Takayasu arteritis. One criterion is age younger than 40 years at diagnosis or at onset of characteristic signs and symptoms of 1-month duration.

Two major criteria involve lesions in the left and right midsubclavian artery, with the most severe stenosis or occlusion present in the mid portion of the artery from a 1 cm point proximal to the left and right, respectively, of the vertebral artery orifices to a 3-cm distal point to the orifice, as determined by angiography.

The minor criteria consist of annuloaortic ectasia or aortic regurgitation on angiography or echocardiography, and lesions of any of the following vessels:

• Pulmonary artery
• Left mid ̶ common carotid artery
• Distal brachiocephalic trunk
• Descending aorta
• Abdominal aorta

American College of Rheumatology criteria

The American College of Rheumatology (ACR; 1990) put forward the following diagnostic criteria:

• Angiographic criteria must show narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities
• These changes are not due to arteriosclerosis, fibromuscular dysplasia, or similar causes
• Changes are usually focal or segmental

These criteria probably allow greater flexibility to account for variability in actual clinical practice. In comparison to the Ishikawa criteria, which were established based on Japanese patients only, the ACR criteria may better reflect the North American population. The lesions can include stenosis, occlusion, or aneurysms.

The sensitivity and specificity of the American College of Rheumatology criteria are 90.5% and 97.9%, respectively.

• References

Assessing Disease Activity

Assessing disease activity in patients with Takayasu arteritis is frequently challenging, since clinical, biologic, and radiologic information do not always correlate. Prospective study criteria established by Kerr et al (National Institutes of Health) are used to assess disease activity in patients with Takayasu arteritis. New onset or worsening of 2 or more of the following features indicates active disease^[16] :

• Systemic features, such as fever and arthralgias (no identified cause)
• Elevated erythrocyte sedimentation rate
• Features of vascular ischemia or inflammation, such as claudication, diminished or absent pulse, bruit, carotodynia, or asymmetrical blood pressure in either the upper or lower limbs (or both)
• Typical angiographic features

Pentraxin-3 (PTX3), a member of the superfamily of acute-phase proteins such as C-reactive protein (CRP) and serum amyloid P, has been suggested as a possible biomarker for identifying disease activity in patients with an established diagnosis of Takayasu arteritis. In a cross-sectional, noninterventional study, PTX3 plasma levels were shown to be more accurate than the erythrocyte sedimentation rate (ESR) and CRP level for differentiating active from inactive disease in 57 patients with previously diagnosed Takayasu arteritis. PTX3 levels greater than 1 ng/mL were more accurate than normal thresholds of CRP and ESR for defining disease activity. Patients with unknown or equivocal disease status were excluded from the study.^[36]

Certainly, PTX3 plasma levels may play a future role as a possible disease marker. However as pointed out by the authors of the study, PTX3 needs to be assessed in a broader spectrum of patients whose disease activity is unknown or equivocal before recommending using it clinically.^[36]

Other measures of disease activity in Takayasu arteritis include the Birmingham Vasculitis Activity Score (BVAS), Disease Extent Index for Takayasu's Arteritis (DEI.Tak), and Indian Takayasu's Arteritis Score (ITAS). The ITAS seems to have good correlation; however, none of those scores has been validated.^{[37, 38]}

Imaging modalities for assessment of disease activity are limited by various factors, and no consensus has been reached on their sensitivity and specificity. Computed tomography angiography is limited by the amount of exposure to contrast. Magnetic resonance angiography is useful for providing information on vessel wall thickness, edema, and contrast enhancement; however, its ability to discriminate between acute versus inactive disease has been questioned.

18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a promising imaging modality, given its noninvasiveness and ability to visualize regional distribution in the vascular tree. No consensus has been reached on its sensitivity and specificity in determining acute versus inactive disease. Increased vascular uptake may be visible on an18F-FDG scan performed years after the acute phase.^[39]

Novel ligands such as radioactive PK11195 that bind to peripheral benzodiazepine receptors on activated monocyte/macrophages are under investigation to improve specificity of PET for active disease.^[37]

• References

Angiography

Angiography, the criterion standard for the diagnosis and evaluation of Takayasu arteritis, is used to evaluate only the appearance of the lumen and cannot be used to differentiate between active and inactive lesions. (See the images below.) Takayasu arteritis can be divided into the following 6 types based on angiographic involvement:^[3]

• Type I - Branches of the aortic arch
• Type IIa - Ascending aorta, aortic arch, and its branches
• Type IIb - Type IIa region plus thoracic descending aorta
• Type III - Thoracic descending aorta, abdominal aorta, renal arteries, or a combination
• Type IV - Abdominal aorta, renal arteries, or both
• Type V - Entire aorta and its branches

  View Image

  Complete occlusion of the left common carotid artery in a 48-year-old woman with Takayasu disease. Also note narrowing of the origin of the right subc....

  View Image

  Characteristic long, tapered narrowing of the distal aorta and iliac vessels. Image courtesy of Robert Cirillo, MD.

  View Image

  Image obtained in the same patient as in Image 2 reveals narrowing of the proximal descending aorta and right brachiocephalic artery. Image courtesy o....

  View Image

  Aortogram of a 15-year-old girl with Takayasu arteritis. Note large aneurysms of descending aorta and dilatation of innominate artery. Image courtesy ....

   

  

   

• References

Imaging Studies

Ultrasonography

Color Doppler ultrasonography provides details of the vascular wall, lumen, and flow and is a useful tool for screening and follow-up, particularly for carotid and subclavian arteries.

CT scanning

CT helical scanning angiography is a sensitive and specific diagnostic tool. CT scanning or ultrasonography may be used to assess the thickness of the aorta. One study found that multi-slice CT scanning was useful in detecting lesions.^[40]

MRA

The sensitivity of magnetic resonance angiography (MRA) is the same as or greater than that of angiography for revealing lesions in the aorta and its brachycephalic branches but is less sensitive for helping to detect smaller branch involvement. MRA that uses fast spin-echo sequences designed to enhance the detection of vessel wall edema shows promise in assessing disease activity before irreversible lesions develop.

Advances in technology have substantially improved the sensitivity and specificity of MRA, and the entire arterial vasculature can be displayed in less than 90 seconds. The risks are practically nonexistent.^[41]

PET scanning

The modality 18-F-FDG-PET has been shown to be useful in monitoring disease activity and response to treatment in preliminary studies. The presence or absence of FDG uptake correlates well with a patient’s clinical state and MRI findings. Its use in patients with Takayasu arteritis requires further investigation.

Several studies have shown that whole-body PET scanning demonstrates anatomic changes consistent with the diagnosis of Takayasu arteritis.^{[35, 34, 33]}

Other imaging modalities

Single-photon emission computed tomography (SPECT) scanning has been used to assess cerebral blood flow and may be useful in patients who undergo bypass surgery.

Gallium scanning has been used to assess inflammatory involvement of the vessels.

• References

Tissue Biopsy

In contrast to other vasculitides, tissue biopsy plays little to no role in the diagnosis of Takayasu arteritis, as histologic examination of the great vessels is usually possible only at the time of vascular procedures or postmortem. Biopsy of medium- to large-sized vessels may be diagnostic in early stages of the disease; however, in the chronic phase, diagnosis based on biopsy alone is inadequate. Whenever possible, the feasibility of submitting arterial tissue should be discussed with the attending surgeon prior to any surgical revascularization procedure.

• References

Histologic Findings

Takayasu arteritis is characterized by a special pattern of histopathologic changes. The early stage consists of a continuous or patchy granulomatous inflammatory reaction involving macrophages, lymphocytes, and multinucleated giant cells. Inflammation initially occurs in the vasa vasorum, with the artery wall becoming irregularly thickened and the lumen becoming narrowed. Takayasu arteritis progresses to a sclerotic stage, with intimal and adventitial fibrosis and scarring of the media. Lesions are initially inflammatory and later become occlusive.

In the early phase of Takayasu arteritis, histologic features include granulomatous changes in the media and adventitia of the aorta and its branches, followed by intimal hyperplasia, medial degeneration, and adventitial fibrosis of the sclerotic type. The duration is variable. Inflammatory cells—predominantly CD4 and CD8 lymphocytes, macrophages, plasma cells, histiocytes, and giant cells—invade the adventitia and media but not the intima.

In the vasoocclusive stage, the lesions are characterized by occlusion and signs of ischemia. The adventitia and media are replaced by fibrous scarring, the vasa vasorum are obliterated, and the intima undergoes irregular thickening. Medial degeneration, disruption of the elastic lamellae, and thrombosis can occur. Aneurysms can form, but no aneurysms attributed to Takayasu arteritis have been identified in the intracranial circulation. The literature reports a few cases of intracranial aneurysms that are considered to be incidental.

The ground substance in the intima is increased markedly, histochemically showing a basophilic acid mucopolysaccharide in a state of gelatinous swelling.

An increase in CD4 and decrease in CD8 lymphocytes, along with reduced B lymphocytes, have suggested a defect in T-cell regulation (cell-mediated immunity). Biopsy samples exhibit infiltrates of lymphocytes and monocytes in both the vessel walls and a peripheral nerve vasculitis. Lymphocytes and monocytes are attracted to the vessel wall either by an infectious agent or an autoimmune response, modulated by intercellular adhesion molecules (ICAMs).

• References

Approach Considerations

Medical management of Takayasu arteritis depends on the disease activity and the complications that develop. Some patients have only mild forms of Takayasu arteritis; others deteriorate considerably. The two most important aspects of treatment are controlling the inflammatory process and controlling hypertension.

Corticosteroids

Corticosteroids are the mainstay of therapy for active Takayasu arteritis. However, some patients may also require cytotoxic agents, to achieve remission and taper of long-term corticosteroid treatment.

Oral corticosteroids are started at 1 mg/kg daily or divided twice daily and tapered over weeks to months as symptoms subside.

Long-term, low-dose corticosteroid therapy may be required. Osteoporosis prevention when patients are started on corticosteroids should be seriously considered.

IL-6 receptor inhibitor

Evidence supports interleukin-6 (IL-6) as a major component in the inflammatory process of large-vessel vasculitis, and case reports and observational studies have shown that the humanized monoclonal antibody tocilizumab, which blocks the soluble IL-6 receptor, can produce clinical responses and have a steroid-sparing effect in patients with refractory Takayasu arteritis, including patients refractory to tumor necrosis factor (TNF) inhibitors.^[42]

A retrospective study by the French Takayasu Network that included 46 patients concluded that tocilizumab is efficient and may reduce the incidence of relapses. Overall disease activity decreased, the daily prednisone dose decreased from 15 mg at baseline to 5 mg at 6 months, and the overall tocilizumab failure-free survival rate was 81% at 12 months and 48% at 48 months.^[43]

A systematic review of tocilizumab therapy for Takayasu arteritis that included 105 patients, 76 of them with refractory disease, found that 85.7% of patients had an initial clinical response to within 3 months and 65.2% had radiological improvement; 90.4% were able to reduce their corticosteroid dose. Only 9% of patients experienced relapse while on therapy, but relapse after discontinuation of tocilizumab occurred in  46% of patients, at a median of 5 months.^[44]

The TAKT trial—a randomized, double-blind, placebo-controlled, phase 3 study of the steroid-sparing effect of tocilizumab—failed to meet the primary endpoint. However, the results suggest a favorable effect of tocilizumab over placebo for time to relapse of Takayasu arteritis and found no new safety concerns.^[42]   

B-cell depletion

Rituximab, a chimeric IgG1 antibody that binds to CD20 expressed on the surface of B cells, has been shown to improve clinical signs and symptoms of Takayasu arteritis.^[45] Although the pathogenesis of Takayasu arteritis is not believed to be mediated by the humoral immune system, B cells are believed to have an antibody-independent effect, which may modulate regulatory T-cell immune reactions against foreign and self-antigens. No large trial has proved this finding.

Cytotoxic agents

Cytotoxic agents are used for patients whose disease is steroid resistant or relapsing. These agents are usually continued for at least 1 year after remission and are then tapered to discontinuation. Methotrexate, azathioprine, and cyclophosphamide are among the drugs used in Takayasu arteritis, although success has also been reported with mycophenolate mofetil and tacrolimus.^[46] Cyclophosphamide should be reserved for patients with the most severe and refractory disease states.

Anti-tumor necrosis factor agents

Anti-TNF agents have shown encouraging results in a small number of patients with relapsing Takayasu arteritis.^[47]

In an uncontrolled series of 15 patients, adjunctive treatment with anti-TNF agents was effective in patients with active, relapsing Takayasu arteritis despite treatment with steroids and multiple other immunosuppressive agents.^[48] The initial dose of etanercept was 25 mg twice weekly (seven patients); infliximab (11 patients [three were switched from etanercept to infliximab]) was given at 3 mg/kg initially and at 2 weeks, 6 weeks, and then every 8 weeks thereafter. In nine of the 14 responders, an increase in the anti-TNF dosage was required to sustain remission.

The preliminary results of this study suggested that anti-TNF therapy may be a useful adjunct to corticosteroids in the treatment of patients with Takayasu arteritis.

In a review of nine patients with refractory Takayasu arteritis, Youngstein et al reported sustained responses to treatment with a TNF-α antagonist, an IL-6 receptor antagonist, or both. The mean duration of anti–TNF-α treatment was 42 months (maximum 8 years), and two patients maintained responses to IL-6 receptor inhibition at 19 and 20 months.^[49]

During treatment, none of the patients showed significant progression in arterial injury, and significant decreases occurred in C-reactive protein level, prednisolone dose, and Indian Takayasu arteritis activity. As five of the nine patients had failed cyclophosphamide, the investigators recommended that therapies targeting TNF-α and the IL-6 receptor be considered ahead of cyclophosphamide.^[49]

Cardiovascular procedures

Bypass graft surgery is the procedure with the best long-term patency rate. Percutaneous balloon angioplasty can provide good outcomes for short lesions. Angioplasty and stenting have been used to treat recurrent stenosis. Conventional stents seem to be associated with high failure rates in patients with Takayasu arteritis. Other procedures include aneurysm clipping and revascularization.

Cardiovascular risk factors

Strict management of traditional cardiovascular risk factors such as dyslipidemia, hypertension, and lifestyle factors that increase the risk of cardiovascular disease is mandatory to minimize secondary cardiovascular complications. These complications are the major cause of death in Takayasu arteritis.

Hypertension is treated with antihypertensive agents, and aggressive therapy is necessary to prevent complications. Low-dose aspirin may have a therapeutic effect in large vessel vasculitis.

Antiplatelet agents and heparin may prove useful in preventing stroke. Warfarin also has been used. The literature reports a case of improvement in renal and systemic function with low-dose intravenous (IV) heparin therapy (10,000 U/d) followed by oral anticoagulant and antiplatelet agents.

Pregnancy

Pregnancy is an important concern in Takayasu arteritis; these patients require aggressive treatment. Pregnancy may exacerbate hypertension and/or cardiovascular complications and can increase the risk for maternal and fetal morbidity and mortality. Pregnancy may be safer during presumed remission of Takayasu arteritis. Fetal monitoring is indicated in patients with suspected complications of pregnancy.

Inpatient care

Management of Takayasu arteritis is long-term. Inpatient care is limited to managing acute manifestations of the disease, which usually result in complications from organ failure, stroke, pregnancy, seizures, and intracranial hemorrhage. Intensive care unit (ICU) admission is indicated for patients with critical deterioration.

Diet and activity

Diet modification is necessary to manage hypertension or renal failure. Any activity limitations depend on the severity of the disease and complications.

Consultations

Consult with the following specialists as needed:

• Rheumatologist
• Cardiologist
• Vascular surgeon
• Imaging/interventional radiologist
• Obstetrician-gynecologist for pregnant patients

• References

Surgical Therapy

Critical stenotic lesions should be treated by angioplasty or surgical revascularization during periods of remission. Indications for surgical repair or angioplasty are as follows:

• Renovascular stenosis causing hypertension
• Coronary artery stenosis leading to myocardial ischemia
• Extremity claudication induced by routine activity
• Cerebral ischemia and/or critical stenosis of 3 or more cerebral vessels
• Aortic regurgitation
• Thoracic or abdominal aneurysms larger than 5 cm in diameter
• Severe coarctation of the aorta

Percutaneous transluminal coronary angioplasty is followed by restenosis at the angioplasty site within 1-2 years in a substantial number of patients.

Bypass graft surgery

Bypass graft surgery is the procedure with the best long-term patency rate. Bypass surgery has been performed on patients with critical thoracic aortic arch arterial stenosis, upper and lower extremity ischemia, cerebrovascular accidents, and renal artery stenosis. The procedures are generally case specific. Certain issues, such as the timing of surgery in relation to disease activity or the advisability of surgery in symptom-free patients, have not been resolved. Anastomotic stenoses or graft occlusion is a potential complication of surgery.

Grafts have been used to bypass regions of severe stenosis or occlusion. Usually, the graft is a saphenous vein graft. Examples of grafts performed include bypass of renal artery stenosis for renal salvage; bypass of innominate or carotid artery; and bypass between subclavian-axillary and common carotid arteries. Extraintracranial bypass operations generally are performed for stenosis of the internal carotid or middle cerebral arteries.

• References

Follow-Up

Bypass surgery has been performed on patients with critical thoracic aortic arch arterial stenosis, upper and lower extremity ischemia, cerebrovascular accidents, and renal artery stenosis. The procedures are generally case specific. Certain issues, such as the timing of surgery in relation to disease activity or the advisability of surgery in symptom-free patients, have not been resolved. Anastomotic stenoses or graft occlusion is a potential complication of surgery.

Grafts have been used to bypass regions of severe stenosis or occlusion. Usually, the graft is a saphenous vein graft. Examples of grafts performed include bypass of renal artery stenosis for renal salvage; bypass of innominate or carotid artery; and bypass between subclavian-axillary and common carotid arteries. Extraintracranial bypass operations generally are performed for stenosis of the internal carotid or middle cerebral arteries.

Follow-up should be with a rheumatologist who can follow disease activity and treat the patient medically as needed.

A follow-up examination of critical or near-critical stenosis and disease activity with angiography (or MRI or CT angiography) and possibly FDG-PET scanning may be necessary. Recognizing that Takayasu arteritis may progress in the absence of clinical findings is important. Periodic imaging may reveal an active disease that requires treatment with immunosuppressive agents.

• References

Medication Summary

The goals of therapy in Takayasu arteritis are to reduce inflammation and suppress autoimmune disease. To treat the active disease, corticosteroids are used and gradually tapered. Cytotoxic agents such methotrexate, azathioprine, and cyclophosphamide are the main therapeutic agents when the response to steroids is unsatisfactory. As previously mentioned, anti–tumor necrosis factor (anti-TNF) agents have shown encouraging results in a small number of patients with relapsing Takayasu arteritis.^[47]

• References

Prednisone

• Dosing, Interactions, etc.

Clinical Context:  The immunosuppressant prednisone is a first-line therapy administered for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity and CD4 counts.

• References

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

• References

Cyclophosphamide

• Dosing, Interactions, etc.

Clinical Context:  Cyclophosphamide may be added to steroid therapy if the patient has shown minimal response to steroid treatment or has been on a steroid for a prolonged period of time. Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells.

• References

Methotrexate (Trexall, Rheumatrex)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate may be added to treatment if steroid therapy has not been effective or if the patient has been on steroid treatment for a prolonged period of time. Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; the drug may affect immune function. Methotrexate ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Effects can be observed as early as 3-6 weeks following methotrexate's administration. Methotrexate is used as second- or third-line drug to suppress active disease.

• References

Class Summary

Cyclophosphamide or methotrexate—either in combination with prednisone or alone—can be used to suppress active disease in patients who are not responding to prednisone.

• References

Azathioprine (Imuran, Azasan)

• Dosing, Interactions, etc.

Clinical Context:  Azathioprine may be added to treatment if there has been no response to steroid therapy or if the patient has been on steroid treatment for a long period of time. Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, ribonucleic acid (RNA), and proteins. It may decrease the proliferation of immune cells, which results in lower autoimmune activity.

• References

Mycophenolate (CellCept, Myfortic)

• Dosing, Interactions, etc.

Clinical Context:  Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Mycophenolate inhibits antibody production.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (CellCept), is a prodrug that, once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (Myfortic), is an enteric-coated product that delivers the active moiety.

• References

Tacrolimus (Prograf)

• Dosing, Interactions, etc.

Clinical Context:  Tacrolimus suppresses humoral (T-lymphocyte) immunity.

• References

Infliximab (Remicade)

• Dosing, Interactions, etc.

Clinical Context:  Infliximab may be added to treatment if steroids and other immunosuppressant drugs are ineffective in achieving or maintaining remission. Infliximab is a chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to the TNF-α receptor. It reduces the infiltration of inflammatory cells and TNF-α production in inflamed areas.

• References

Tocilizumab (Actemra)

• Dosing, Interactions, etc.

Clinical Context:  Tocilizumab is an IL-6 receptor inhibitor. IL-6 inhibition results in a decreased C-reactive protein level to within the normal range, decreased values in other pharmacodynamic parameters (eg, rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and an increased hemoglobin value.

• References

Rituximab (Rituxan)

• Dosing, Interactions, etc.

Clinical Context:  Rituximab is a chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of B-lymphocytes.

• References

Class Summary

These agents inhibit key factors that mediate immune reactions.^[50]

• References

Etanercept (Enbrel)

• Dosing, Interactions, etc.

Clinical Context:  Etanercept may be added to treatment if steroids and other immunosuppressant drugs are ineffective in achieving or maintaining remission. Etanercept is a soluble p75 TNF receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.

• References

Class Summary

These agents play an important role in modulating the inflammatory process.

• References

Nifedipine (Procardia)

• Dosing, Interactions, etc.

Clinical Context:  Nifedipine is one of the more common channel blockers used for hypertension associated with arteritis.

• References

Class Summary

These drugs can be used to treat hypertension associated with arteritis. On occasion, combinations are required. Therapy can be individualized.

• References

Ticlopidine hydrochloride

Clinical Context:  Ticlopidine hydrochloride interferes with platelet membrane function by inhibiting adenosine diphosphate (ADP) ̶ induced platelet-fibrinogen binding and subsequent platelet-platelet interaction. It is used as a second-line antiplatelet therapy for patients who are intolerant to aspirin therapy or in whom such therapy fails.

• References

Clopidogrel (Plavix)

• Dosing, Interactions, etc.

Clinical Context:  Clopidogrel is a thienopyridine derivative chemically related to ticlopidine that inhibits platelet aggregation; it selectively inhibits ADP binding to its platelet receptor and subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

• References

Aspirin and extended-release dipyridamole (Aggrenox)

• Dosing, Interactions, etc.

Clinical Context:  This drug combination has antithrombotic action. Aspirin inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. It may be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Dipyridamole is a platelet adhesion inhibitor that possibly inhibits red blood cell uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, dipyridamole may inhibit phosphodiesterase activity leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2.

• References

Class Summary

These drugs help to prevent cerebrovascular accidents and improve renal and systemic function.

• References

Warfarin (Coumadin, Jantoven)

• Dosing, Interactions, etc.

Clinical Context:  Warfarin interferes with hepatic synthesis of vitamin K ̶ dependent coagulation factors. It is used for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.

Tailor the dose to maintain an international normalized ratio (INR) in the range of 2-3.

• References

Heparin

• Dosing, Interactions, etc.

Clinical Context:  Heparin augments the activity of antithrombin III. It does not actively lyse, but it is able to block further thrombogenesis. Heparin prevents reaccumulation of a clot after a spontaneous fibrinolysis.

• References

Class Summary

In patients with renal failure due to crescentic glomerulonephritis and nephrotic syndrome, low-dose heparin followed by oral anticoagulation leads to improved renal and systemic function. It probably reduces the destructive effects of fibrin thrombi in the small vessels of the kidney.

• References