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Inflammation of the aortic wall may occur in noninfectious diseases, such as Takayasu disease, giant-cell arteritis, IgG-related diseases, the spondyloarthropathies, Behçet syndrome, relapsing polychondritis, Cogan syndrome, rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, idiopathic retroperitoneal fibrosis, as isolated aortitis, and other disorders.217,218 Only the most common of these uncommon entities are discussed in detail.
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A possible role for infectious agents—including bacteria, viruses, and mycobacterium—in instigating arteritides of various sorts has been postulated.219
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The prototypical nonspecific aortitis, Takayasu arteritis was named for the Japanese ophthalmologist who first called attention to the funduscopic findings.220,221 Because of its predilection for the brachiocephalic vessels, this arteritis has been labeled pulseless disease and aortic arch syndrome. The classic form occurs with greatest frequency in Asian countries, but patients with a similar nonspecific aortitis are encountered worldwide. The etiology is unknown; no infectious agent has been identified, and identification of endothelial antibodies in 18 of 19 patients with this disease supports an autoimmune mechanism. This finding is nonspecific.
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Recently, a genetic underpinning for Takayasu disease has been discovered, with mutations in the HLA-B and IL12B genes.222,223 Continued progress in genetic understanding promises to clarify whether Takayasu and other, nonspecific arteritidies are one and the same or different diseases.
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Histologic examination during active stages of the disease discloses a granulomatous arteritis similar to giant-cell arteritis and to the aortitis associated with the seronegative spondyloarthropathies and Cogan syndrome. In later stages, medial degeneration, fibrous scarring, intimal proliferation, and thrombosis result in narrowing of the vessel, yet there remains a lack of adequate histopathologic criteria for the differential diagnosis of noninfectious arteritides, including Takayasu disease and giant-cell aortitis.224 Aneurysm formation is less common than stenosis, but aneurysm rupture is an important cause of death in patients with Takayasu arteritis. Angiographically, the left subclavian artery is narrowed in approximately 90% of patients. The right subclavian artery, left carotid artery, and brachiocephalic trunk follow closely in frequency of stenosis. Thoracic aortic lesions occur in 66% of patients, the abdominal aorta is involved in 50%, and aortoiliac involvement is seen in approximately 12%. Pulmonary arteritis occurs in about half of patients and may be associated with pulmonary hypertension.
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In 70% to 80% of patients, clinical manifestations of the illness appear during the second or third decade of life, but onset in childhood and in middle life has been reported. Women are affected eight to nine times more often than men.225
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During the early or “prepulseless” phase, symptoms include fever, night sweats, malaise, nausea, vomiting, weight loss, rash, arthralgia, and Raynaud phenomenon. Splenomegaly may occur, and laboratory findings may include acceleration of the erythrocyte sedimentation rate, elevated levels of C-reactive protein, anemia, and plasma protein abnormalities. However, it should be recognized that a minority of patients may not experience any of the signs or symptoms listed above and may present with discrepancy of arm blood pressures, absent pulse(s), the presence of a supraclavicular or cervical bruit, or incidental findings on imaging performed for another reason.
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When arterial obstruction develops, upper-extremity claudication may occur as a consequence of subclavian artery stenosis. Stroke, transient cerebral ischemia, dizziness, or syncope usually indicate stenosis of the brachiocephalic arteries or subclavian steal. The retinopathy that first drew the attention of Takayasu is believed to result from retinal ischemia. Hypertension, observed in more than 50% of the cases, may be severe and occurs due to stenosis of the aorta proximal to the renal arteries or involvement of the renal arteries themselves.226
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Cardiac manifestations result from severe hypertension, dilatation of the aortic root producing valvular insufficiency, or coronary artery stenosis (Fig. 93–43). Angina pectoris, MI, and heart failure have been reported. Clinical pericarditis has been observed infrequently, but healed pericarditis is often encountered at necropsy. Involvement of the visceral arteries may result in splanchnic ischemia, and aortoiliac obstruction may produce intermittent claudication in the lower limbs.
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Patients in whom severe aortitis is evident at the time of diagnosis face a 25% to 30% risk of ischemic events or death over the next 5 years. Those without ischemic complications at presentation tend to fare better over 5 to 10 years. Severe hypertension and cardiac involvement are associated with a shortened life expectancy.
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The American College of Rheumatology has identified six major criteria for the diagnosis of Takayasu arteritis.227 Onset of illness by 40 years of age avoids overlap with giant-cell arteritis. Other criteria include upper-extremity claudication; diminished brachial pulses; greater than 10 mm Hg difference between systolic blood pressure in the arms; subclavian or aortic bruit; and narrowing of the aorta or a major branch. The presence of three of these six criteria carries high diagnostic accuracy.
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Arteriography typically shows long areas of smooth narrowing interspersed with areas that appear normal. Aneurysm and occlusions are also common. Duplex ultrasound MR angiography or CT scans may show wall thickening resulting from inflammation and edema of the media and adventitia. MR or CT angiography of the entire aorta and iliac vessels is recommended for all patients with suspected Takayasu disease to define the extent of disease, identify aneurysms, and estimate the activity of disease. A “macaroni sign” on echocardiographic evaluation has recently been described, signifying the thick wall of the vessel with the small, linear residual lumen.228 Positron emission tomography (PET) scanning is showing promise for diagnosis by identifying “hot spots” at sites of active Takayasu lesions.229
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Corticosteroid therapy appears effective in suppressing inflammation during the active phase, and favorable results have been reported with immunosuppressive and cytotoxic agents.230 The mainstay of medical treatment continues to be administration of corticosteroids.230 However, the use of biologic targeted treatments (infiximab, rituximab, toclizumab) has been quite effective and safe in patients refractory to standard therapy or in those who are glucocorticoid dependent.231 Operative treatment may be used to relieve symptoms caused by arterial obstruction, and percutaneous angioplasty and stenting are associated with mixed results. When performed for stenosis, the restenosis rate is substantial in both open and endovasculuar surgery.232,233,234 These procedures are best reserved for patients in whom the acute inflammatory stage of the disease has been controlled.217
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Giant-cell arteritis (temporal arteritis, polymyalgia rheumatica) involves extracranial arteries, including the aorta, in 10% to 13% of cases. A peak incidence late in life sets giant-cell arteritis apart from other nonspecific arteritides. Recent evidence suggests that giant-cell arteritis is occurring even later in life than in prior decades.235 Similar to Takayasu disease, giant-cell arteritis may produce narrowing of the brachiocephalic arteries, aneurysms of the ascending aorta, aortic dissection, and aortic regurgitation.236 Despite clinical, angiographic, and pathologic similarities to Takayasu arteritis, giant-cell arteritis almost always occurs in individuals older than 50 years of age. Although the most common presentation involves polymyalgia rheumatica with temporal arteritis, any large artery may be involved.
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Treatment of giant-cell arteritis usually involves oral prednisone in an initial dose of 40 to 60 mg/d. Induction therapy with intravenous steroids has been found beneficial in a randomized trial. During clinical follow-up, CT or MR angiography or [18F]-fludeoxyglucose PET/MRI237 can be of value in monitoring improvement in arterial abnormalities with therapy. In unresponsive cases (< 10%) and in those who relapse as the dose is tapered, cytotoxic agents such as cyclosporine, azathioprine, and methotrexate may be helpful. One randomized, double-blind trial found a significant reduction in the rate of relapse and the cumulative mean dose of corticosteroid medication with methotrexate compared with placebo in corticosteroid-treated patients,238 but another study did not.239,240
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For patients with symptomatic ascending aortic involvement in giant-cell arteritis (pain, inflammation), we have, anecdotally, had excellent results with surgical aortic resection—often permitting dramatic reduction or elimination of corticosteroid treatment.
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IgG4-Related Diseases
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IgG-related diseases are a relatively recently recognized immune-mediated condition that may involve nearly every organ system.241,242 Hallmarks of this disease are tumor-like swelling of the involved organs, dense lymphoplasmacitic infiltrate that contains IgG4-positive plasma cells, and storiform fibrosis. Usually there are elevated IgG levels in the serum. A number of conditions are considered part of IgG-related diseases, such as autoimmune pancreatitis, sclerosing mesenteritis, Mikulicz syndrome (salivary and lacrimal glands), Riedel thyroiditis, eosinophilic angiocentric fibrosis, Küttner tumor (submandibular glands), inflammatory pseudotumor, mediastinal fibrosis, and hypocomplementemic tubulointerstitial nephritis.242 The vascular involvement includes IgG4-related retroperitoneal fibrosis, IgG4-related abdominal aortitis, and IgG4-related perianeurysmal fibrosis or inflammatory aortic aneurysms.243 It is now recognized that IgG4-related disease may be the cause of idiopathic retroperitoneal fibrosis (previously called Ormonds disease) in up to two-thirds of cases.244
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Presentations of periaortitis may be nonspecific, leading to a delay in the diagnosis. The most common symptoms are pain in the lower abdomen, flanks, and back. The aorta may be extremely tender to palpation. The thoracic aorta may also be involved leading to aneurysm or dissection.245 Although Takayasu arteritis and giant-cell arteritis affect the primary aortic branches, IgG4-related disease generally spares the branches off the aortic arch.242
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It is important to diagnose IgG4-related diseases early, as effective therapy is available. Glucocorticoids are first-line agents. There are no studies that have evaluated the usual steroid-sparing agents (methotrexate, azathioprine). There are no randomized trials using B-cell depletion therapy (targeting a subset of plasma cells that produce the IgG4) with agents such as rituximab, but this agent seems to be quite effective in treating some patients with IgG4-related diseases who do not respond to glucocorticoids.242
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HLA-B27–Associated Spondyloarthropathies
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Aortitis is present in a substantial portion of patients with ankylosing spondylitis and Reiter syndrome; more than 90% have the histocompatibility antigen HLA-B27. Aortic involvement is most common in those with spondylitis of long duration, peripheral joint complaints in addition to spondylitis, and iritis.246 Inflammation of the aortic root and surrounding tissues, manifest by aortic valve regurgitation or cardiac conduction abnormalities in patients with the HLA-B27 histocompatibility antigen, may also occur without spondyloarthropathies. Although the majority of cases occur in the aortic root and ascending aorta, occasionally isolated abdominal aortitis may occur.247 Histologically, the aortic lesion in this setting resembles the inflammation seen in syphilis, with focal destruction of medial elastic tissue and thickening of the intima and adventitia. Aortic dissection has been reported.248
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Primary infection of the aortic wall is a rare cause of aortic aneurysms, which are more often saccular than fusiform. Infectious or “mycotic” aneurysms may arise secondarily from an infection occurring in a preexisting aneurysm of another cause. Staphylococcus, Salmonella, and Pseudomonas species are the most frequent pathogens causing primary aortic infections.248 Many cases arise as complications of infective endocarditis or arterial catheterization. An intrinsically abnormal aorta, however, may become infected as a consequence of bacteremia. Such infection produces suppurative aortitis, leading to weakness of a portion of the aortic wall. In these cases, aneurysms are typically saccular, yet there is a comparatively high propensity to rupture. Infection of the aorta related to endovascular stents is a new and increasing clinical entity that is difficult to treat.49,250
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Treponemal infection produces chronic aortitis in approximately 10% of patients with untreated tertiary syphilis and is the primary cause of death in about the same proportion of cases, but there is evidence of the process at autopsy in about half of patients who have had untreated syphilis for more than 10 years.251 During the spirochetemic phase of primary syphilis, Treponema pallidum organisms lodge in the adventitia of the vasa vasorum and initiate an inflammatory response characterized by perivascular lymphocytic and plasma cell infiltrate. This is followed by obliterative endarteritis, resulting in patchy medial necrosis, elastic fiber fragmentation, weakening of the aortic wall, and aneurysm formation. The intima of the aorta has a characteristic wrinkled appearance, frequently with superimposed atherosclerotic plaques. Because the infection is seeded through the vasa vasorum, the process is most severe in the ascending aorta and the arch, where the density of these vessels is greatest. Luetic aneurysms are typically saccular and involve the ascending aorta whether or not the transverse and descending portions are also affected. Aortic aneurysms resulting from cardiovascular syphilis follow interruption of the elastic fibers as a result of periaortitis and mesoaortitis, which thicken, but weaken, the aortic wall. Rupture is the major complication, but the enlarging aneurysm may also compress or erode adjacent structures of the mediastinum. Because the inflammatory process tends to interrupt the medial layer by transverse scars, dissection is distinctly uncommon.
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Aortic involvement may be asymptomatic or associated with aortic regurgitation, coronary ostial stenosis, or aortic aneurysm. Asymptomatic aortitis may sometimes be identified by linear calcification of the ascending aorta, evident on chest radiographs. Valvular regurgitation, present in 20% to 30% of patients with syphilitic aortitis, is mainly a consequence of aortic root dilatation. Syphilitic coronary ostial stenosis, only a century ago more common than coronary atherosclerosis as a cause of angina pectoris, occurs in 25% to 30% of such patients, most of whom also have aortic regurgitation. MI is rare. The least frequent manifestation of syphilitic aortitis is aneurysm formation, which occurs in 5% to 10% of affected patients. Although the prognosis for patients with uncomplicated syphilitic aortitis is comparable to that of the general population, the outlook is poor when syphilitic aneurysms of the aorta are large enough to produce symptoms. The diagnosis of cardiovascular syphilis may be difficult in patients older than 50 years of age, when hypertensive and atherosclerotic disease often coexist.
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The frequency of cardiovascular syphilis has fallen dramatically over recent decades as a consequence of early identification and treatment of the disease. However, a recent report indicates that syphilitic ascending aortic aneurysm is still surprisingly common and must remain in the consciousness of the caring medical and surgical teams.252
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Adequate antimicrobial therapy of early syphilis is the most important preventive measure, although whether such treatment retards the progression of disease once aortitis has developed has not been clearly established. Without surgical intervention, symptomatic syphilitic aortic aneurysms are associated with a high mortality.
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Recently, Roberts and colleagues253 described the features of syphilitic aortitis at surgery in the hope of permitting intraoperative identification and prompt institution of treatment. The distinguishing features include sparing of the aortic root, involvement of the tubular portion of the ascending aorta, uniform involvement of all of the surface area of the affected aortic portions, and inflammation in all three layers of the aortic wall. The aorta is said to have a “tree bark” appearance characteristic of syphilitic aortitis.
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Tuberculous aneurysms usually result from direct extension of infection from hilar lymph nodes and subsequent granulomatous destruction of the medial layer, leading to loss of aortic wall elasticity. The posterior or posterolateral aortic wall is usually the site of saccular aneurysm formation in these cases. Caseating granulomatous lesions affecting the medial layer of the aortic wall characterize the histology. Pseudoaneurysm formation,254 perforation, or aortoenteric fistula may result. Infection may occasionally invade the aortic valve ring and adjacent structures, producing a caseating paravalvular abscess. Rupture of tuberculous aortic lesions may occur. It is important to recognize that miliary tuberculous may manifest in a manner very similar to Takayasu arteritis. Therefore, if there is any suspicion that tuberculosis is present, testing should be performed before starting immunosuppressant medications.