Pediatric Takayasu Arteritis 

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.^[1] (See Pathophysiology and Epidemiology.)

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).^[2] (See Pathophysiology, Etiology, and Epidemiology.)

The initial complaints may be 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. (See Presentation, DDx, and Workup.)

Upon histologic examination, the aorta demonstrates evidence of 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. 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.

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 and morbidity resulting from treatment medications - Take this into account with long-term treatment plans

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.

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.^[3]

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 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. 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 found in 90% of patients with Takayasu arteritis. Patients often have poststenotic dilatations and other aneurysmal areas. 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, carotidynia, and claudication 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 or aneurysm 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. Humoral immunity is also believed to be involved in this disease; antiaortic antibodies and antiendothelial cell antibodies have been found in patients with Takayasu arteritis. Immunoglobulin G (IgG), IgM, and properdin deposits are found in lesions from pathologic specimens.

Cytokine abnormalities include elevated tumor necrosis factor and interleukin (IL)–6. B cells may also play a role, 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 also increase total numbers of circulating B cells; reduction in disease activity is observed with successful depletion of B cells with anti-CD20.^[4]

Takayasu arteritis has been reported in identical twins, leading to the hypotheses that there is a hereditary basis for the disease. In Japan and Korea, Takayasu arteritis is associated with human leukocyte antigens (HLAs)-A10, B5, Bw52, DR2, and DR4. These associations have not been confirmed in Western studies. Takayasu arteritis is associated with HLA-B22 in the United States.

Although early reports associated tuberculosis with Takayasu arteritis, these involved populations endemic for tuberculosis, and population studies have not borne out this association. Others report an increased incidence of positive purified protein derivative relative to control patients. The true nature of the association with tuberculosis (if any) is unclear. Patients with Takayasu arteritis do not improve with antituberculous treatment. In a subset of patients with Takayasu arteritis, active tuberculosis may perpetuate disease activity through chronic antigen stimulation.

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).

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.^[5] 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.

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.^[3]

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.^[6]

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%.^[7] 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.

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.