Aortitis

Introduction
Background

Aortitis is literally inflammation of the aorta, and it is representative of a cluster of large-vessel diseases that have various or unknown etiologies. While inflammation can occur in response to any injury, including trauma, the most common known causes are infections or connective tissue disorders. Infections can trigger a noninfectious vasculitis by generating immune complexes or by cross-reactivity. The etiology is important because immunosuppressive therapy, the main treatment for vasculitis, could aggravate an active infectious process.

Inflammation of the aorta can cause aortic dilation, resulting in aortic insufficiency. Also, it can cause fibrous thickening and ostial stenosis of major branches, resulting in reduced or absent pulses, low blood pressure in the arms, possibly with central hypertension due to renal artery stenosis. Depending on what other vessels are involved, ocular disturbances, neurological deficits, claudication, and other manifestations of vascular impairment may accompany this disorder.

Agents known to infect the aorta include Neisseria (eg, gonorrhea), tuberculosis, Rickettsia (eg, Rocky Mountain spotted fever) species, spirochetes (eg, syphilis), fungi (eg, aspergillosis, mucormycosis), and viruses (eg, herpes, varicella-zoster, hepatitis B, hepatitis C).

Immune disorders affecting the aorta include Takayasu arteritis, giant cell arteritis, polyarteritis nodosa, Behcet disease, Cogan syndrome, sarcoidosis, spondyloarthropathy, serum sickness, cryoglobulinemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, Henoch-Schönlein purpura, and postinfectious or drug-induced immune complex disease.

Also, anti-neutrophil cytoplasmic autoantibody (ANCA) can affect the large vessels, as in Wegener granulomatosis, polyangiitis, and Churg-Strauss syndrome. Other antibodies such as anti-glomerular basement membrane (ie, Goodpasture syndrome) and anti-endothelial (ie, Kawasaki disease) also can be culprits. Transplant rejection, inflammatory bowel diseases, and paraneoplastic vasculitis also may afflict the large vessels.

The cause or causes of giant cell or temporal arteritis, Takayasu arteritis, and polyarteritis nodosa are unknown.
Pathophysiology

The disease has 3 phases. Phase I is the prepulseless inflammatory period characterized by nonspecific systemic symptoms including low-grade fever, fatigue, arthralgia, and weight loss. Phase II involves vascular inflammation associated with pain (eg, carotidynia) and tenderness over the arteries. Phase III is the fibrosis stage, with predominant ischemic symptoms and signs secondary to dilation, narrowing, or occlusion of the proximal or distal branches of the aorta. Bruits frequently are heard, especially over carotid arteries and the abdominal aorta. The extremities become cool, and pain develops with use (ie, arm or leg claudication). Even in phase III, a significant number of patients seem to have insidious vascular inflammation, which has been demonstrated in surgical specimens and postmortem series.

In advanced cases, occlusion of the vessels to the extremities may result in ischemic ulcerations or gangrene, and with the involvement of cerebral arteries, strokes can occur. Because of the chronic nature of the disease, however, collateral circulation usually develops in the areas involved by vasculitis.

Pathologic changes involved in Takayasu arteritis are the same as for giant cell arteritis. Involved vessel walls develop irregular thickening and intimal wrinkling. Early in the disease, mononuclear infiltration with perivascular cuffing is seen. That extends to the media, followed by granulomatous changes and patches of necrosis and scarring (fibrosis) of all layers, especially the intima. Late stages have lymphocytic infiltration.

The distinction between Takayasu and giant cell arteritis is primarily the clinical pattern of vessels involved. Giant cell arteritis commonly involves the temporal artery, whereas Takayasu arteritis primarily involves the aorta, its main branches, and, in 50% of cases, the pulmonary artery. The initial vascular lesions frequently occur in or at the origin of the left subclavian artery, which can cause weakened radial pulse and easy fatigability in the left arm. As the disease progresses, the left common carotid, vertebral, brachiocephalic, right-middle or proximal subclavian, right carotid, and vertebral arteries, as well as the aorta, also are affected, as well as retinal vessels.

When the abdominal aorta and its branches, eg, the renal arteries, are involved, central hypertension may develop. Accurate blood pressure measurement may be difficult because of arterial lesions affecting supply to the extremities.

Varying degrees of narrowing and occlusion or dilation of involved portions of the arteries result in a wide variety of symptoms.
Frequency
United States

In the United States and Europe, incidence is 1-3 new cases per year per million population. In a cohort of 1204 surgical aortic specimens described by Rojo-Leyva et al1 , 168 (14%) had inflammation and 52 (4.3%) were classified as having idiopathic aortitis. Among 383 individuals with thoracic aortic aneurysms, 12% had idiopathic aortitis.
International

Vasculitis has a worldwide distribution, with the greatest prevalence among Asians. An extensive epidemiological study conducted in Japan in 1984 identified 20 cases per million population. In 1990, Takayasu arteritis was added to the list of intractable diseases maintained by the Japanese Ministry of Health and Welfare; by the year 2000, 5000 patients were registered (the reported prevalence increased 2.5-fold).
Mortality/Morbidity

The 2 major predictors of poor outcome are complications (eg, Takayasu retinopathy, hypertension, aortic regurgitation, aneurysm) and progressive course.

* Patients with no complications or with mild to moderately severe complications have a 10-year survival rate of 100% and a 15-year survival rate of 93-96%. With notable complications or progression, the 10-year survival rate is 80-90% and the 15-year survival rate is 66-68 %.
* The occurrence of both a major complication and progressive course predicts the worst outcome (43% survival rate at 15 y).

Sex

Vasculitis is most common among women of reproductive age (female cases outnumber male at a ratio of 9:1).
Age

Aortitis is most commonly discovered at age 10-40 years.
Clinical
History

In 1905, at the 12th Annual Meeting of the Japanese Ophthalmology Society, Mikito Takayasu, an ophthalmologist, described a 21-year-old Japanese woman with a peculiar retinal arteriovenous anastomosis. At the same meeting, Onishi described a patient with similar funduscopic findings and absence of radial pulses. Giovan B. Morgagni, an Italian pathologist, reported the first case with signs and symptoms consistent with Takayasu arteritis. In 1948, Shimizu and Sano described a condition characterized by absent pulses, peripapillary arteriovenous anastomosis of the retina, and accelerated carotid sinus reflex, which they called pulseless disease. The name "Takayasu's disease" was applied by Caccamis in 1954, and that eponym held.

* Vanoli et al2 reported a study of 104 Italian patients (91 female, 13 male) with Takayasu arteritis. Median delay in diagnosis was 15.5 months. The main clinical features and laboratory findings were arterial bruit (90%), decreased or absent pulse (85%), blood pressure deference over 10 mm Hg (70%), claudication of extremities (45%), hypertension (40%), asthenia (50%), fever (30%), arthralgia/arthritis (25%), weight loss over 5 kg (20%), headache (20%), erythrocyte sedimentation rate greater than 30 mm/hr (85%), anemia (60%), and leukocytosis (20%). Vascular involvement based on full aortography revealed involvement of the left subclavian (65%), right subclavian (52%), left carotid (44%), abdominal aorta (39%), and right carotid (36%).
* Many patients have ischemia of the upper extremities that may manifest as arm claudication or numbness at the time of disease recognition. Claudication of the lower limbs is less common as a presenting symptom.
* Hall et al3 reported arthralgias or myalgias in about one half of patients at the early stage of disease. Symmetric inflammatory polyarthritides resembling rheumatoid arthritis were observed in 5 of 32 patients. Articular symptoms were either transient or continual for several months or longer. Myalgia sometimes dominates the clinical presentation and may mislead clinicians.
* Neurologic symptoms are generally caused by decreased cerebral blood flow in the carotid and vertebral arteries. Neurologic manifestations include vertigo, syncope, orthostasis, headaches, convulsions, transient ischemic attacks, stroke, and dementia. Seizures are often attributed to hypertensive encephalopathy. Because of central retinal hypoperfusion, visual impairment is most often bilateral and 48% of patients with vertebral artery involvement and 40% with common carotid artery involvement have visual aberrations.
* In a minority of cases (8-18% of pooled series), skin lesions resembling erythema nodosum or pyoderma gangrenosum were found over the legs. Upon biopsy, the lesions frequently showed vasculitis of the small vessels. Erythema nodosum is the predominant dermatologic finding in the United States and Europe, whereas pyoderma gangrenosum is found more frequently in Japan. Raynaud phenomenon has also been reported in 8-14% of patients.
* Angina pectoris occurs as a result of coronary artery ostial narrowing from aortitis or coronary arteritis and can lead to myocardial infarction, heart failure, or sudden death. Congestive heart failure may be caused by valvular disease. Aortic regurgitation that results from dilation of the aortic root is common.
* In cases of documented pulmonary artery involvement, fewer than 25% of patients had related clinical manifestations and only 20% had pulmonary hypertension. Pulmonary symptoms include cough, dyspnea, and hemoptysis.
* Abdominal pain, diarrhea, and gastrointestinal hemorrhage may result from mesenteric artery ischemia, but this is rare.
* Specific arteries that are inflamed may be tender to the touch (eg, carotid, temporal).

Physical

Patients frequently appear chronically ill. Mild to moderate fever may be present. Heart rate and rhythm are unaffected. Reduced blood pressure in one or both arms is common. Laterality of blood pressure (ie, a difference between left and right arms greater than 10 mm Hg) suggests vascular obstruction, and the difference may be greater than 30 mm Hg. Maneuvers can distinguish this pressure drop and/or pulse weakness from scalenus anticus syndrome, in which arm elevation and turning of the head are influential.

* Arterial pulse intensity in any of the limbs may be diminished, often asymmetrically. Bruits may be audible over the carotid arteries, abdominal aorta, and sometimes the subclavian and brachial arteries. In a North American study by Kerr et al, bruit was the most common clinical finding (80%), and the most common site was in the carotid vessels (70%). A diastolic decrescendo murmur may signal aortic valve insufficiency. The cardiac apex may be displaced laterally. Rales, edema, liver congestion, elevated venous pressure, and hepatojugular reflux, if present, signify the complication of heart failure.
* Hypertension develops in 33-76% of patients, most frequently resulting from narrowing of the renal artery, but narrowing and decreased elasticity of the aorta and branches also can be exacerbating factors. As narrowing or occlusion may lower the pressure in the arms, all limbs must be checked, and measuring central pressure by catheterization may be required to identify hypertension.
* Synovitis mimicking rheumatoid arthritis may be noticeable over larger joints, such as the knees or wrists, early in the course of disease.

Causes

The pathogenesis of Takayasu arteritis has not been elucidated completely. Genetic influences and immunological mechanisms have received the most attention. The associations of Takayasu arteritis with other autoimmune diseases, such as connective tissue diseases and ulcerative colitis, provide clinical support for the importance of autoimmunity in the pathogenesis.

* High titers of anti-endothelial antibodies were detected in patients clinically diagnosed as having Takayasu arteritis.
o In a study of 19 patients by Eichorn et al4 , anti-endothelial antibodies were found in 18, and the titers were approximately 20 times higher than normal. Chauhan et al5 showed that the antibodies are directed against 60-65 kd antigens and may induce expression of endothelial adhesion molecules, cytokine production, and apoptosis.
o The only patient who did not have a positive titer for the antibody had inactive disease. However, whether this antibody is pathogenic or merely an epiphenomenon secondary to the vascular injury remains unclear.
o The presence of elevated anti-cardiolipin antibody titer also has been reported.
* Cell-mediated immunological mechanisms are thought to be of primary importance.
o Histopathologic examination has shown heavily infiltrating cells in all layers of the aorta, including alpha-beta T cells, gamma-delta T cells, and natural killer (NK) cells.
o In comparison to the cells found in a patient with an atherosclerotic aortic aneurysm, the proportion of gamma-delta T cells (ie, cytotoxic cells) was exceedingly high.
o Enhanced expression of human leukocyte antigen (HLA) molecules and restricted usage of alpha-beta T-cell receptor genes and gamma-delta T-cell receptor genes in the infiltrating cells suggest the existence of a targeted specific antigen. Gamma-delta T cells can recognize the major histocompatability complex (MHC) class I (MIC) chain-related molecules MICA and MICB, whose expression is known to be increased by stress. The MICA gene was found to be located near the HLA-B gene. MICA-1.2 is strongly associated with Takayasu arteritis, even in the absence of HLA-B52, which is highly prevalent in Japanese patients. Expression of heat shock protein-65, a stress-induced protein, also is increased in the tissue. These findings suggest that unknown stress, such as infection, may trigger the autoimmune process involved in patients with Takayasu arteritis.

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