Pediatric Takayasu Arteritis

Updated: Nov 03, 2015
  • Author: Christine Hom, MD; Chief Editor: Lawrence K Jung, MD  more...
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Overview

Background

Takayasu arteritis is a chronic inflammatory disease of the aorta and its major branches. The disorder is a large vessel vasculitis of unknown origin that most often affects young women in the second and third decades of life (see the image below). [1] (See Pathophysiology, Etiology, and Epidemiology.) It is defined as arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually is in patients younger than 50 years. [2]

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

Takayasu arteritis has been reported in pediatric patients as young as age 6 months and in adults of every age. In children, Takayasu arteritis is one of the more common etiologies of renovascular hypertension. [3] (See Pathophysiology and Epidemiology.)

The initial complaints in children are typically nonspecific constitutional signs and symptoms (eg, fever, weight loss, lethargy). Because these complaints lack specificity, the correct diagnosis may be delayed for months or years. The classic pulseless disease is more common in adults and represents later disease. (See Presentation, DDx, and Workup.)

Upon histologic examination, the aorta demonstrates evidence of granulomatous inflammation. Mixed areas of stenosis or aneurysm formation are found on angiography or magnetic resonance angiography (MRA). Vascular insufficiency related to stenosis and thrombosis of affected vessels may cause renovascular hypertension, neurologic symptoms, or lower extremity claudications. (See Workup.)

Cardiac involvement may include aortic regurgitation and congestive heart failure resulting from myocarditis or increased afterload. Aortic root dilatation contributes to the aortic regurgitation. Often, the diagnosis of Takayasu arteritis is made when a widened mediastinum is appreciated on chest radiography and a tumor is suspected. Computed tomography (CT) scanning instead reveals a widened aortic arch. The wreathlike anastomoses of the retina described by Dr. Mikito Takayasu are seen in only 16% of adults and less frequently in children.

Despite the term pulseless disease, which is a synonym for Takayasu arteritis, the predominant finding in individuals with Takayasu arteritis is asymmetrical pulse. Absent peripheral pulses occur late in the course of the disease. Although 5-year survival rates exceed 90%, the disease has a high incidence of residual morbidity. (See Prognosis, Presentation, and Workup.)

Complications

Complications of Takayasu arteritis include the following:

  • Congestive heart failure due to aortic insufficiency, myocarditis, and/or hypertension
  • Aortic aneurysms, thrombus formation, and rupture
  • Ischemic stroke
  • Myocardial infarction
  • Hypertension
  • Clinically silent progressive disease (despite normal acute phase reactants)
  • Morbidity resulting from treatment medications - Must be considered in planning long-term treatment

Patient education

Review signs of corticosteroid excess (ie, Cushing syndrome) with the patient and his or her family, refer patients for psychosocial counseling, and reinforce medication compliance.

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Pathophysiology

Takayasu arteritis is characterized by granulomatous inflammation of the aorta and its major branches, leading to stenosis, thrombosis, and aneurysm formation. The lesions of Takayasu arteritis are segmental with a patchy distribution. [4]

Mononuclear infiltration of the adventitia occurs early in the course of the disease, with cuffing of the vasa vasorum. Granulomatous changes may be observed in the tunica media, with Langerhans cells and central necrosis of elastic fibers and smooth muscle cells. A panarteritis with infiltrates of both B and T lymphocytes, plasma cells, histiocytes, and giant cells is present. Later, fibrosis of the media and acellular thickening of the intima may compromise the vessel lumen. Platelet-derived growth factor (PGDF) is released, with subsequent myofibroblast proliferation, which further thickens the vessel wall. Matrix metalloproteinases weaken the arteries, allowing aneurysm formation. There is no inflammatory infiltrate of the intima; changes are thought to be reactive to inflammation in the media and adventitia. Wrinkling of the intima is visible upon gross examination.

Stenoses are the most common lesion, found in 90% of patients with Takayasu arteritis. Patients often have poststenotic dilatations and other aneurysmal areas, reported up to 45%. Stenotic arterial segments result in varied ischemic symptoms. These symptoms may range from abdominal pain after eating secondary to narrowing of the mesenteric arteries to renovascular hypertension to claudication of extremities.

In children, Takayasu arteritis is one of the more common etiologies of renovascular hypertension. Endothelial activation leads to a hypercoagulable state predisposing the patient to thrombosis. Congestive heart failure in individuals with Takayasu arteritis may occur as a result of hypertension, aortic root dilation, or myocarditis.

Transient ischemic attacks, cerebrovascular accidents, mesenteric ischemia, and carotidynia may occur. Symptoms of vascular compromise may be minimized by the development of collateral circulation, with a more insidious onset of stenosis. Vessel wall dissection may occur in areas weakened by inflammation.

One hypothesis for granulomatous vasculitis development is that antigens deposited in vascular walls activate CD4+ T cells, followed by the release of cytokines chemotactic for monocytes. These monocytes are transformed into macrophages that mediate endothelial damage and granuloma formation in the vessel wall. A mouse model supports this hypothesis. When syngeneic T cells sensitized to vascular smooth muscle cells were injected into mice, a granulomatous vasculitis of the pulmonary arterioles occurred in 20% of the mice.

Human studies suggesting endothelial cell activation have demonstrated increased expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with Takayasu arteritis. Evidence for an autoimmune etiology is supported by circulating antiaortic antibodies and antiendothelial cell antibodies found in the sera of patients with Takayasu arteritis. Immunoglobulin G (IgG), IgM, and properdin deposits are found in lesions from pathologic specimens. Autoreactive T cells TH1 and TH17 are increased in active Takayasu arteritis, along with decreased numbers of FOXP3-positive T-reg cells.

Cytokine abnormalities include elevated tumor necrosis factor and interleukin IL–6. More recently, B cells are identified as contributing to Takayasu arteritis, with plasmablast expansion in patients with active Takayasu arteritis. This increase in B cells is not seen in inactive disease. IL-6 and B-cell activating factor (BAFF) also increase total numbers of circulating B cells; reduction in disease activity is observed with successful depletion of B cells with anti-CD20 and increase in B cells observed with relapse. [5]

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Epidemiology

Occurrence in the United States

In Minnesota's Olmstead County, incidence of Takayasu arteritis was estimated at 2.6 cases per million. However, the applicability of this number to the diverse population of the United States as a whole is uncertain.

International occurrence

Takayasu arteritis is common in developing countries, where the disease is closely associated with tuberculosis. The nature of this association is unclear because most patients with Takayasu arteritis in the United States do not have tuberculosis. In contrast, many physicians in developing countries assume that tuberculosis is present in every patient with Takayasu arteritis.

In endemic areas, active tuberculosis may perpetuate Takayasu disease activity through molecular mimicry or chronic antigen stimulation. Quantitative interferon assays may be useful in identifying these patients. In a series of 66 Turkish patients with Takayasu arteritis, 37% of active patients had a positive QuantiFERON (interferon release assay) test, compared with only 17% of patients in remission. There was no difference in tuberculin skin test (TST). There is no change in activity with tuberculosis therapy.

Race-related demographics

Takayasu arteritis is more common in Asian populations but has been described in patients of all races. Japanese patients with Takayasu arteritis have a higher incidence of aortic arch involvement. In contrast, series from India report higher incidences of thoracic and abdominal involvement. In US patients with Takayasu arteritis, the most commonly involved vessels are the left subclavian, superior mesenteric, and abdominal aorta.

In US children with Takayasu arteritis, lesions of the thoracic and abdominal aorta, rather than lesions of the aortic arch, are most common. However, all patterns of vascular involvement have been observed in every country.

Sex-related demographics

In adults, females account for 80-90% of patients with Takayasu arteritis. Pediatric studies are more varied. Although sex distribution usually mirrors the 80-90% female preponderance observed in adults, series of studies of Takayasu arteritis in childhood from India and South Africa reported a 2:1 female-to-male ratio. However, these are countries in which Takayasu arteritis is associated strongly with tuberculosis, and additional etiologic and pathophysiologic factors may be present.

Age-related demographics

Takayasu arteritis is the most common large vessel vasculitis of adolescence. Takayasu arteritis is an uncommon vasculitis in children. [6] The most common are postinfectious vasculitides, Henoch-Schönlein purpura, polyarteritis nodosa, and Kawasaki disease. Most cases of Takayasu arteritis present in persons aged 10-30 years. In a series of patients with Takayasu arteritis, 20-35% were younger than 20 years at diagnosis. The youngest patient reported was aged 6 months.

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Prognosis

Takayasu arteritis is a chronic, relapsing disease. More than half of patients with Takayasu arteritis achieve control on corticosteroids alone; however, their relapse rate is high and they require long periods of steroid treatment. [4]

Overall prognosis in individuals with Takayasu arteritis relates to the degree of vascular and end-organ damage, specifically retinal vasculopathy, aortic insufficiency, aortic aneurysms, and hypertension. Survival rate at 15 years is as high as 95%.

Among patients with Takayasu arteritis who are treated with glucocorticoids, 60% respond; however, as many as 40% relapse on tapering of steroids. In a Cleveland Clinic series of 75 patients, 93% achieved remission, but only 28% of patients were able to maintain 6 months of remission when steroids were tapered to 10 mg or less. [7]

Patients refractory to glucocorticoids have been offered azathioprine, methotrexate, cyclosporine, cyclophosphamide, TNF inhibition, mycophenolate mofetil, rituximab, [8] and tocilizumab, [9, 10] with varying success. These drugs can be steroid sparing and disease controlling in a subset of refractory patients, but the disease remains chronic and not cured. Patients discontinuing their medications typically flare within a few weeks.

Morbidity and mortality

Because Takayasu arteritis is rare in the United States, accurate survival data are uncertain. One study reported a survival rate of 85-95% at 15 years. In a 1994 study, only 2% of deaths were attributed directly to Takayasu arteritis. Japanese studies support 90-95% survival rates.

In contrast, in a series involving 26 Mexican children aged 3-15 years, the 5-year survival rate was only 35%. [11] Deaths resulted from rupture of aorta or aneurysms (2), stroke (2), cardiac failure (2), and peritonitis and ventricular fibrillation.

Morbidities in persons with Takayasu arteritis are related to ischemia and hypertension and include congestive heart failure, transient ischemic attacks, stroke, and visual disturbances. Pulmonary artery disease occurs in up to 50% of adult series.

Chronic, low-grade dissection of the aorta may cause recurrent chest pain for years. Upon autopsy, children with Takayasu arteritis who have died from acute rupture of the aorta have often been found to have evidence of multiple small dissections that did not progress.

An increased incidence of atherosclerotic vascular disease is independent of coronary risk factors; this is due to chronic systemic inflammation.

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