Chapter 31. Takayasu Arteritis

Takayasu arteritis, named for the Japanese ophthalmologist who first described the ocular manifestations in 1908, is a large-vessel vasculitis of unknown cause that chiefly affects women during their reproductive years. The disease often presents two challenges. First, the diagnosis can be delayed for months or even years due to the rarity of the disease, the young age of the (typical) patient, and the protean presenting manifestations. Second, treatment is a challenge. Although Takayasu arteritis is a chronic disease, it usually pursues a waxing and waning course that requires careful monitoring to determine when the disease is active and medical therapy is needed. Treatment with glucocorticoids usually succeeds in halting progression of the vasculitis. Indeed, because of the advances in medical therapy and surgical treatment of vascular complications, such as aortic regurgitation, survival of patients with Takayasu arteritis has increased dramatically.

• Causes vasculitis of the aorta and its major branches.
• Preferentially affects young women.
• Often presents with absent pulse, bruit, claudication, hypertension, or fever of unknown origin.
• Erythrocyte sedimentation rate is usually elevated.
• Most patients respond to prednisone.

Although Takayasu arteritis has been most extensively reported in Japan, Korea, China, Southeast Asia, and Mexico, cases have been described worldwide. In North America, the annual incidence is about 1–3 cases per million people. Takayasu arteritis affects women eight times more frequently than men. The average age of diagnosis is in the mid-20s but the disease may begin as early as age 7 or as late as age 70. Symptoms develop before age 20 in nearly one third of patients and after age 40 in about 10%. The age of onset tends to be later in European countries.

The cause of Takayasu arteritis remains elusive. The geographic clustering of cases suggests important genetic or environmental factors, but few have been identified. HLA associations have been found in Japanese patients (who preferentially express Bw52, DR2, Dw12, and DQw1), but not in other populations. The predominance of Takayasu arteritis in women of childbearing age suggests that female hormones may play a permissive role, as in systemic lupus erythematosus. An animal model of Takayasu arteritis has been produced with a herpes virus. In that model, the media of the aorta provides an immunoprivileged site for persistent herpes virus infection, which results in chronic inflammation (arteritis).

However initiated, Takayasu arteritis appears to be propagated by a T-cell–driven immune response that results in a granulomatous inflammation affecting all layers of the vessel. Indeed, the histopathology of Takayasu arteritis cannot be distinguished from that of temporal arteritis (also called giant cell arteritis; see Chapter 30). The inflammatory injury mediated by activated T cells, macrophages, and cytokines often results in proliferation of the intima and of smooth muscle cells in the media, leading to occlusion and stenosis of the artery. Transmural inflammation can also cause aneurysmal dilation of the vessel. Overproduction of inflammatory cytokines, such as interleukin-6, results in fever and other constitutional symptoms.

Symptoms and Signs

Although the presenting features of Takayasu arteritis vary greatly, they can be categorized into two broad groups: those caused by vascular damage (ie, occlusion, stenosis, or dilation of blood vessels), and those caused by systemic inflammation (Table 31–1). The separation of these presenting features is not always neatly maintained; many patients have both vascular complications and constitutional symptoms, and others have a biphasic presentation, with constitutional symptoms dominating early and vascular features becoming more salient later.

Among the vascular manifestations, bruit, claudication, hypertension, light-headedness (associated with vertebral or carotid artery disease), unequal blood pressures in the extremities, carotidynia, aortic regurgitation, and loss of a pulse are most common. Bruits develop most frequently over the carotid arteries, but also often develop in the supraclavicular or infraclavicular space (reflecting subclavian disease), along the flexor surface of the upper arm (from axillary artery disease), or in the abdomen (from renal or mesenteric artery vasculitis). Many patients have multiple bruits. Upper extremity claudication—commonly manifested in young women by fatigue and pain in the arm while exercising or blow-drying hair—develops more often than lower extremity claudication. A widened pulse pressure and diastolic murmur along the right sternal border may signal the aortic regurgitation that develops in 20% of patients. Other cardiac manifestations include angina (most commonly from stenotic lesions at or near the ostia of the coronary arteries), mitral regurgitation (secondary to left ventricular dilatation from aortic regurgitation), or congestive heart failure (early in the course caused by myocarditis or late in the course caused by chronic aortic with or without mitral regurgitation). Stroke affects a significant minority of patients. Glomerulonephritis is quite rare in this form of large vessel vasculitis; renal disease usually results from hypertension which in turns develops because of stenosis of the renal arteries.

The visual symptoms that were first described in 1908 occur rarely today. When present, visual symptoms chiefly result from retinal ischemia produced by narrowing or occlusion of the carotid arteries. Some patients may have such limited blood flow through their carotids and vertebral arteries that merely turning and tilting their head causes light-headedness, dizziness, or visual loss.

Almost half of patients experience constitutional or musculoskeletal symptoms. These constitutional and musculoskeletal features dominate the presentation in approximately one third of all cases of Takayasu arteritis. Asthenia, weight loss, fever, myalgia, and arthralgia occur commonly. Prominent back pain, especially in the thoracic region, develops in a few patients. This pain resembles that seen in older patients with thoracic dissection and probably results from stimulation of nociceptive nerve fibers along the inflamed aorta.

Laboratory Findings

Takayasu arteritis does not cause any specific blood test or urinary abnormalities but usually produces nonspecific findings of inflammation. Nearly 80% of patients have elevated erythrocyte sedimentation rates (ESR) or C-reactive protein (CRP) values, especially during phases of active disease. Unfortunately, no blood test accurately measures disease activity. For example, the ESR is normal in 30% of patients with active disease and is elevated in 40% of patients with inactive disease. Recent studies have suggested that pentraxin-3 may more accurately reflect disease activity than either ESR or CRP. Anemia develops in 50% of patients, with hematocrits typically in the high 20s or low 30s. Anemic patients commonly have slightly low mean corpuscular volume (eg, high 70s). Thrombocytosis, which develops in one-third of patients, is often mild but may exceed 800,000/mcL. Less than 10% of patients with Takayasu arteritis have an elevated serum creatinine. About one quarter will have mild proteinuria or hematuria. Renal abnormalities usually result from hypertension; glomerulonephritis from Takayasu arteritis very rarely occurs.

Imaging Studies

Magnetic resonance imaging (MRI), computed tomography (CT), vascular ultrasonography, and conventional aortography are abnormal in virtually all patients with Takayasu arteritis. MRI appears most sensitive in that it can detect the inflammatory thickening of the aorta or its branches (Figure 31–1) that precedes changes in the caliber of the vessels’ lumen. Conventional angiography, although unhelpful in determining the thickness of the vessel wall, provides the most detailed images of the stenoses, occlusions, dilatation, and other vascular wall irregularities characteristic of Takayasu arteritis (Figure 31–2). Advances in CT and three-dimensional image reconstruction have allowed CT angiography to replace the more invasive conventional angiograms.

The most frequently affected vessels are the aorta, subclavian arteries, and carotid arteries (Table 31–2). Involvement of the aorta above and below the diaphragm occurs most commonly. The distribution of vascular involvement varies in people from different countries: whereas disease of the ascending aorta and great vessels is most common in patients from Japan, involvement of the abdominal aorta and renal arteries is most common in patients from India and Korea. In the extra-aortic vessels, long segments of stenosis are more frequent than dilation or aneurysm. Takayasu arteritis is one of the few forms of vasculitis that can affect, albeit rarely, the pulmonary arteries. Positron emission tomography scanning offers the theoretical advantage of allowing quantification of the degree of vascular inflammation. Indeed, positron emission tomography scanning appears to be sensitive in detecting vascular inflammation in patients with Takayasu arteritis, but the cost and level of radiation exposure pose important limitations. No imaging technique has been proven to be reliable in measuring disease activity. The initial enthusiasm for the ability of MRI to measure disease activity has not been substantiated by long-term follow-up studies.

Specific Tests

Biopsies of the aorta or other actively affected arteries show a granulomatous vasculitis with giant cells.

The biggest impediment to diagnosing Takayasu arteritis is that few physicians are familiar enough with this rare disease to recognize its presenting manifestations. The American College of Rheumatology has developed six criteria for classification of Takayasu arteritis (Table 31–3). In practice, the diagnosis of Takayasu arteritis requires demonstrating vasculitis of the aorta or its major branches by imaging tests (Figure 31–3; also see Figures 31–1 and 31–2) or biopsy, and excluding the diseases that can produce similar abnormalities (Table 31–4).

Of the other vasculitides, giant cell arteritis (see Chapter 30) is the form most likely to be confused with Takayasu arteritis. Both diseases cause a granulomatous panarteritis and an elevated ESR. In contrast to Takayasu arteritis, giant cell arteritis exclusively affects patients over the age of 50 and chiefly involves extracranial branches of the carotid artery (such as the temporal artery). Cogan syndrome is a rare disease characterized by vestibular-auditory abnormalities (often producing deafness and vertigo) and ocular inflammation (especially keratitis or inflammation of the cornea). A minority of patients with Cogan syndrome have medium- or large-vessel vasculitis, or both. A few other diseases can affect the aorta or its branches, but almost never do they convincingly mimic Takayasu arteritis (see Table 31–4). Relapsing polychrondritis, which results in characteristic changes in cartilage, may also affect the aorta. Rheumatoid arthritis and ankylosing spondylitis rarely affect the thoracic root. Buerger disease—a form of medium-vessel vasculitis associated with smoking—may affect the femoral, brachial, and axillary arteries, as can ergotism. Syphilitic aortitis can be excluded by appropriate serologic studies. Neurofibromatosis and congenital coarctation may affect the abdominal aorta and mesenteric great vessels. Radiation-induced damage can affect any vessel including the aorta. Atherosclerosis of the aorta and major branches rarely develops before age 50 and does not produce the long, smoothly tapered and stenotic segments of arteries that are so characteristic of Takayasu arteritis. Inflammatory abdominal aortic aneurysm is an unusual form of atherosclerosis characterized by marked thickening of the abdominal aorta, often associated with retroperitoneal inflammation. Almost all of the patients with this disorder are smokers. Patients with inflammatory abdominal aortic aneurysm often have mild anemia and modest elevations of the ESR. Marfan syndrome does not produce inflammatory symptoms or signs. Aortitis, especially of the abdominal aorta, can also be a manifestation of IgG4-related systemic disease.

Patients with predominantly constitutional symptoms are often evaluated for other conditions. For example, a woman with a hematocrit of 28, a mean corpuscular volume of 78 (reflecting anemia of chronic disease), and a platelet count of 980,000/mcL (nonspecifically reflecting inflammation)—not uncommon findings in Takayasu arteritis—will often unproductively undergo evaluation for gastrointestinal hemorrhage, iron deficiency anemia, or another hematologic disorder. Fatigue and weight loss might erroneously suggest a diagnosis of depression. Transient ischemic attacks in a young woman can be wrongly attributed to migraine. Fever and aortic regurgitation may initially suggest bacterial endocarditis. Measuring blood pressure in both arms, carefully palpating pulses in all extremities, and listening for bruits in the abdomen and chest and along the carotids and supraclavicular and axillary areas provide the best clinical tools in early diagnosis of Takayasu arteritis.

Although glucocorticoid therapy for Takayasu arteritis has not been tested in controlled trials, it appears very effective in suppressing vascular inflammation. Initial therapy consists of prednisone (1 mg/kg) for 1 month and then tapered to 10 mg/d over 4–6 months. This treatment nearly universally succeeds in eliminating constitutional and musculoskeletal symptoms within days to a few weeks. Anemia, thrombocytosis, and elevated ESRs also usually respond promptly. Remission, defined as resolution of signs, symptoms, and laboratory markers of inflammation, as well as lack of progression of angiographic abnormalities, is seen in most patients who receive glucocorticoid therapy. Unfortunately, many patients with Takayasu arteritis experience relapses of symptoms or progression of vascular disease that necessitate restarting high-dose prednisone therapy. Open studies suggest that methotrexate plus prednisone or mycophenolate mofetil plus prednisone may be more effective than prednisone alone in some patients. Small open trials also suggest that infliximab, an inhibitor of tumor necrosis factor, is an effective glucocorticoid-sparing agent. Because of its toxicity, cyclophosphamide is rarely used to treat Takayasu arteritis. Rituximab has been reported to be effective in a few small series of patients.

Complications of Takayasu arteritis, such as hypertension, congestive heart failure, angina, or aortic regurgitation, may benefit from other forms of medical therapy. Treating hypertension is especially tricky in patients with extensive Takayasu arteritis who may have two or more arterial beds with substantially different blood pressures. Reducing blood pressure to achieve a “normal” blood pressure in the legs may aggravate or cause upper extremity claudication. Often the physician must accept compromises in blood pressures that sustain perfusion of critical organs or tissues. Other complications that can be prevented or treated include osteoporosis. Patients taking prednisone long term can guard against osteoporosis by performing weight-bearing exercises and taking 400–800 units of vitamin D and 1200–1800 mg of calcium daily; whether a bisphosphonate or other agent to prevent osteoporosis is added depends on the patient’s menopausal status and overall risk of developing osteoporosis (see Chapter 58).

Interventional radiologists and surgeons also can play important roles in treatment. Surgery can be life-saving for treating aortic regurgitation, mitral regurgitation, severe coronary artery ostial lesions, and thoracic aortic aneurysms. Angioplasty and stenting have been successful in treating some cases of hypertension caused by renal artery stenosis. However, restenosis is common. Severely stenotic lesions of the subclavian or carotid arteries are often surprisingly well tolerated, especially when the patient is supported with effective medical therapy. For these vascular areas, the adage “less is more” often applies. Whenever possible, angioplasty or vascular surgery should be deferred until medical therapy has suppressed the inflammation.

Most patients have a chronic relapsing and remitting course requiring careful monitoring and adjustment of suppressive therapy. Judging the level of inflammation can be difficult and requires monitoring symptoms, signs, and laboratory markers of inflammation (eg, hematocrit and ESR). Some experts advocate annual MRI of the aorta and its branches since some patients show progression in the absence of obvious symptoms or signs of active disease. Pregnancy appears surprisingly well tolerated if the patient has inactive disease, is taking low doses of prednisone (ie, <15 mg), and has normal renal function.

Almost all patients experience permanent morbidity from Takayasu arteritis. Because of the morbidity, only about half of the patients are able to work. Survival rates have increased greatly recently so that 10-year survival rates of 80–90% have become common. Advances in diagnosis, medical and surgical treatment, and monitoring augur even better prognosis in the near future. Mortality has been caused chiefly by renal failure, stroke, cardiac failure, or infectious complications of immunosuppressive treatment.