Aortitis 

Updated: Jul 11, 2019
Author: Justin D Pearlman, MD, ME, PhD, FACC, MA; Chief Editor: Richard A Lange, MD, MBA 

Overview

Background

Aortitis is histopathologic diagnosis of inflammation of the aorta,[1] and it is representative of a cluster of large-vessel diseases that have various or unknown etiologies. Although inflammation can occur in response to any injury, including trauma, the most common known causes are infections, immunologic, 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. Additionally, it can cause fibrous thickening of the aorta and ostial stenosis of major branches, resulting in reduced or absent pulses and/or low blood pressure in the upper extremities, 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. See the image below.

Aortitis. This chart represents the presence of an Aortitis. This chart represents the presence of an associated morbidity in Takayasu arteritis in the United States (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

Agents known to infect the aorta include Neisseria (eg, gonorrhea), tuberculosis, Rickettsia (eg, Rocky Mountain spotted fever) species, spirochetes (eg, syphilis), fungi (eg, aspergillus, 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) disorders 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) can also be culprits. Transplant rejection, inflammatory bowel diseases, and paraneoplastic vasculitis also may afflict the large vessels.

The European Society of Cardiology has issued guidelines on the diagnosis and treatment of aortic diseases.[2]

Pathophysiology

Aortitis has three phases. Phase I is the prepulseless inflammatory period characterized by nonspecific systemic symptoms which may include low-grade fever, fatigue, arthralgia, and weight loss, with elevated inflammation markers (sedimentation rate, C-reactive protein, plasma viscosity). Phase II involves vascular inflammation associated with pain (eg, carotidynia) and/or tenderness of the arteries. Phase III is permanent wall injury, which may present with ischemic symptoms and signs secondary to dilation, intramural tearing, 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 may become cool, or erythematous when dependent. There may be pain with use of the extremities (ie, arm or leg claudication). Even in advanced phase III, findings may be subtle leading to postmortem diagnosis.

In advanced cases, occlusion of the vessels to the extremities may result in ischemic skin changes, ulcerations or gangrene, and with the involvement of cerebral arteries, a stroke can occur. The chronic nature of the disease promotes development of collateral circulation to the areas affected by stage III vasculitis.

The distinction between Takayasu and giant cell arteritis is primarily the clinical pattern of vessels involved. 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.

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.[3] The initial vascular lesions with Takayasu arteritis frequently occur in or at the origin of the left subclavian artery, which can cause diminished radial pulse and easy fatigability with exertion 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, may be affected, as well as the retinal vessels. The image below illustrates the frequency of vascular involvement in Takayasu in patients in the United States.

Aortitis. The frequency of vascular involvement in Aortitis. The frequency of vascular involvement in Takayasu arteritis is depicted (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

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 blood flow to the extremities.

Etiology

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 have been detected in patients with Takayasu arteritis. In a study of 19 patients by Eichorn et al, antiendothelial antibodies were found in 18, and the titers were approximately 20 times higher than normal.[4] Chauhan et al showed that the antibodies are directed against 60-65 kd antigens and may induce expression of endothelial adhesion molecules, cytokine production, and apoptosis.[5] Whether this antibody is pathogenic or merely an epiphenomenon secondary to the vascular injury remains unclear. The presence of elevated anti-cardiolipin antibody titer also has been reported.

Cell-mediated immunological mechanisms are thought to be of primary importance. 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. 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 much higher.

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 histocompatibility 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.

Epidemiology

United States data

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 al, 168 (14%) had inflammation and 52 (4.3%) were classified as having idiopathic aortitis.[6] Among 383 individuals with thoracic aortic aneurysms, 12% had idiopathic aortitis.

International data

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).

Sex- and age-related demographics

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

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

Prognosis

Morbidity/mortality

Overall, 10-year survival rate has been reported as 80%-90%.The major predictors of poor outcome are late diagnosis, complications (eg, Takayasu retinopathy, hypertension, aortic regurgitation, aneurysm) and relentless progression, which may be associated with an infectious etiology. A case report identified rapid progression of fungal aortitis in just 10 days.[7] A similar rapid progression was observed with bacterial aortitis.[8]

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%. Complications or progression reduce the 15-year survival rate to 66%-68%.

The occurrence of both a major complication and progressive course predicts the worst outcome (43% survival rate at 15-years).

Cases that are diagnosed late may enter a fulminant course leading quickly to death unless very aggressive immunotherapy is instigated promptly.

Complications

Complications include aortic insufficiency, angina pectoris, myocardial infarction, stroke, limb ischemia, renal artery hypertension, and all consequences of vascular disease.

 

Presentation

History

In 1905, Mikito Takayasu, an ophthalmologist, described a 21-year-old Japanese woman with a peculiar retinal arteriovenous anastomosis, and Onishi described a patient with similar funduscopic findings and absence of radial pulses. Giovan 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.

In a study of 104 Italian patients (91 female, 13 male) with Takayasu arteritis there was a median delay in diagnosis of 15.5 months.[9] The main clinical features and laboratory findings were arterial bruit (90%), decreased or absent pulse (85%), limb blood pressure difference 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%) arteries.[9]

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 al reported arthralgias or myalgias in about one half of patients at the early stage of disease.[10] 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, headache, convulsion, transient ischemic attack, 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 on the lower extremities. 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.

Patients with noninfectious aortitis may present with atypical symptoms that result in diagnostic delay. Spanish researchers suggested "red flags" for the presence of aortitis may include atypical features of polymyalgia rheumatica, unexplained low back or limb pain, and constitutional symptoms in association with elevated levels of acute phase reactants.[11]

Angina pectoris may occur 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 Examination

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. Maneuvers can distinguish aortitis-induced pressure drop and/or pulse weakness from scalenus anticus syndrome, in which arm elevation and turning of the head precipitate symptoms.

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%).[12] A diastolic decrescendo murmur may signal aortic valve insufficiency. 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 diminish the blood pressure in the arms, the pressure in all limbs must be checked, and occasionally measuring central arterial pressure by catheterization may be required to assess hypertension.

Synovitis mimicking rheumatoid arthritis may be noticeable over larger joints, such as the knees or wrists, early in the course of disease.

 

DDx

Diagnostic Considerations

Scalenus anticus syndrome and chronic regional pain syndrome/sympathetic dysfunction can cause asymmetry of pulses. With scalenus anticus, the neck muscles have focal tenderness, and position of neck and arm can change the pulse strength. With sympathetic dysfunction, a thermal map may identify >1°C difference between the arms exacerbated by exposure to cold or wind, and bone scan may show focal activity in small bones of the wrist. In advanced cases, asymmetry of nail and hair growth may be noted.

To make the diagnosis of arteritis at the early stage, a high index of suspicion for vasculitis is necessary,[1, 13, 14] especially in patients with nonspecific inflammatory manifestations such as fatigue, malaise, joint aches, and low-grade fever but no specific clinical picture of other autoimmune diseases or infections. Carotidynia presenting as neck pain can be an important clue. C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) often are elevated, which supports the presence of an ongoing inflammatory process.

In the prepulseless phase, vascular changes may be too subtle to cause obvious extremity ischemia or arm claudication. With awareness of the disease, however, careful examination of the arteries at this stage may lead to the detection of reduction in one or more pulses; differences in blood pressure between the arms; or bruits over the neck, supraclavicular areas, axillae, or abdomen.

The American College of Rheumatology published the classification criteria of Takayasu arteritis as follows: (1) age 40 years or younger at disease onset; (2) claudication of extremities; (3) decreased brachial artery pulse; (4) systolic blood pressure difference of greater than 10 mm Hg between arms; (5) bruit over subclavian arteries or abdominal aorta; and (6) arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities that is not caused by arteriosclerosis, fibromuscular dysplasia, or similar causes.

The presence of at least three criteria reportedly yields a sensitivity of 90.5% and a specificity of 97.8%, although, being a clinical syndrome, the estimate of sensitivity is questionable.

Fibromuscular dysplasia, Ehlers-Danlos syndrome, and Marfan syndrome are associated with noninflammatory lesions that can mimic arteritis in angiographic findings. Fibromuscular dysplasia most commonly affects the renal arteries and leads to stenotic changes. Other sites, including carotid arteries and mesenteric arteries, can be involved, but the lesion usually is more focal. Ehlers-Danlos syndrome and Marfan syndrome also cause aortic aneurysm and aortic root dilatation, respectively. Their systemic manifestations and lack of typical clinical symptoms differentiate them from Takayasu arteritis.

Infectious diseases, including syphilis, tuberculosis, and mycosis, should be excluded as causes of aortic aneurysms. The progression of these infections can be indolent and, unless they are considered as differential diagnoses, missing them is easy. The clinician should keep in mind that, after the infection is stopped, he or she still may have to treat consequent inflammatory processes.

Other systemic vasculitides and granulomatous diseases, such as giant cell (temporal) arteritis, sarcoidosis, systemic lupus erythematosus (SLE), and Behçet disease, can manifest with aortic lesions. Age younger than 40 years at onset of disease is the single most discriminatory variable between Takayasu arteritis and giant cell (temporal) arteritis, which typically occurs in older individuals.

Important considerations

Elevations of acute phase reactants, such as ESR and CRP level are nonspecific and insensitive markers of the activity of Takayasu arteritis. False reassurance to patients based solely on these values can lead to medicolegal troubles. Careful monitoring of the disease with regular follow-up and appropriate imaging studies (including CT scan or MRI if necessary) is recommended.

Patients should be informed about the possibility of late complications (eg, aortic aneurysms), even in cases of successful treatment of patients whose disease is in early stages.

Pregnancy has not been shown to alter prognosis significantly, although hypertension and heart failure can worsen during the third trimester. The disease does not seem to be associated with increased incidence of neonatal death.

Differential Diagnoses

 

Workup

Laboratory Studies

Elevated acute phase reactants, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level, are nonspecific indicators of inflammation. Kerr et al questioned the value of these tests for monitoring the activity of Takayasu arteritis after seeing poor predictive value in relation to the status of surgical specimens.[12]

In a study by Eichorn et al, high titers of serum anti-endothelial cell antibodies were detected in patients with Takayasu arteritis.[4] The value of this titer in diagnosis and its usefulness as a marker of disease activity have not been completely established.

Matrix metalloproteinase (MMP) is a proteinase that can degrade elastin in large vessel walls. A variety of inflammatory cytokines are known to induce the enzyme. Matsuyama et al[15] reported that plasma level of MMP-9 and MMP-3 were useful markers of activity of Takayasu arteritis.

Imaging Studies

Early abnormalities in patients with Takayasu arteritis are limited to the arterial wall. Aortography and arteriography, which had been considered the diagnostic tests for Takayasu arteritis, can demonstrate luminal changes such as stenosis, occlusion, or aneurysmal dilatation, but they are not useful for detecting early mural findings (eg, tree-bark, endothelial wrinkling). In selected patients, conventional arteriography still may be necessary at the time of diagnosis of the late occlusive phase to provide additional information about the degree and extent of the arteritis.

Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) are replacing conventional aortography as the diagnostic tools of Takayasu arteritis. CTA and MRA are less invasive than conventional angiography, and they may reveal vascular wall thickening during the early phase of disease. CTA must be performed with a high-resolution (spiral/helical or Ultrafast) CT scanner.

In a study by Yamada et al comprising 25 patients with symptoms suggestive of Takayasu arteritis who underwent both conventional angiography and CT helical scanning angiography, CTA was 95% sensitive and 100% specific for the diagnosis of Takayasu arteritis, and it was more sensitive than conventional angiography in detecting vessel mural changes.[16] These modalities also can play roles in the follow-up of patients, because MRI and CT scans are able to show reduction of wall thickening after initiation of treatment.

Multimodality imaging is useful for identifying acute and chronic mural changes due to inflammation, edema, and fibrosis, and for characterizing structural luminal changes.[17] The recent advance in this field is fluorodeoxyglucose-PET (FDG-PET), which may have a role in early diagnosis and monitoring the activity of aortitis.[18, 19, 20, 21] A prospective study suggests that assessment of aortitis with semi-quantitative analysis of 180-minute (18)F-FDG PET/CT acquisition images is highly accurate.[22] Webb et al showed that FDG-PET had high sensitivity (92%) and specificity (100%) for active inflammation in Takayasu arteritis. Andrews et al[23] and Meller et al[24] concluded that FDG-PET was useful to detect active inflammation of large vessels, and that MRA was able to show progression of vascular wall thickening. See the image below.

Aortitis. Diffuse stenosis from the aortic arch to Aortitis. Diffuse stenosis from the aortic arch to the abdominal aorta. The left common carotid artery is also stenotic (top arrow) and the left subclavian artery is not visualized (second arrow from the top).
Aortitis. Bilateral dilatation of the vertebral ar Aortitis. Bilateral dilatation of the vertebral arteries. Occlusion of the right internal carotid artery (left arrow). Severe stenosis of the left internal carotid artery are shown. Note the moderate stenosis of the left external carotid artery at the bifurcation with dilated collateral circulation.
Aortitis. This image reveals moderate stenosis of Aortitis. This image reveals moderate stenosis of the external iliac artery at the bifurcation and occlusion of the right femoral artery.

Ultrasonographic studies might be useful to follow the diameter and wall thickness changes in specific regions of accessible arterial vessels.

Catheterization may be performed to assess systemic and pulmonary hypertension, coronary and renal artery disease, and other specific sites of suspected obstruction.

The American College of Radiology has issued guidelines on the initial radiologic examination of patients with nontraumatic aortic disease.[21]

In 2002, a classification of angiographic findings in patients with Takayasu arteritis was proposed at the International Conference on Takayasu Arteritis, as follows[25] :

  • Type I involves branches of the aortic arch.
  • Type IIa involves the ascending aorta, aortic arch, and its branches.
  • Type IIb involves the type IIa region plus the thoracic descending aorta.
  • Type III involves the thoracic descending aorta, abdominal aorta, and/or renal arteries.
  • Type IV involves only the abdominal aorta and/or renal arteries.
  • Type V involves the whole aorta and its branches.

Type V is the most common finding. Type IV is observed in India and Thailand but is very rare in the United States and Japan.

Histologic Findings

An arterial wall biopsy may provide helpful information.

The histologic features of arteritis are characterized as focal panarteritis. The intima is markedly thickened by accumulation of mucopolysaccharides. The media and adventitia demonstrate mixed cellular infiltration with granuloma and giant cells. The lesions usually are focal skip lesions rather than the diffuse involvement observed in patients with syphilitic aortitis. See the images below.

Aortitis. This image demonstrates leukocyte infilt Aortitis. This image demonstrates leukocyte infiltration of the vasa vasorum of the aorta accompanies arteritis obliterans and ischemic necrosis of the media in a case of syphilitic aortitis.
Aortitis. Granulomatous arteritis with thrombosis Aortitis. Granulomatous arteritis with thrombosis of a cerebral vessel may present as a neurologic defect with no obvious vascular disease by history or physical examination.

Staging

A triphasic pattern of disease progression has been described, as follows:

  • 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 fibrotic stage, with predominant ischemic symptoms and signs secondary to dilation, narrowing, or occlusion of the proximal or distal branches of the aorta.

 

Treatment

Medical Care

The primary goals of therapy are to (1) stop progression of inflammatory disease, (2) treat complications, and (3) monitor for reactivation. If vasculitis stems from infection, eradicating the infection prior to initiating immune suppression therapy is generally vital.

The mainstay of therapy for arteritis is corticosteroids; however, a substantial percentage of patients require additional immunosuppressive agents such as cyclophosphamide, methotrexate, or mycophenolate mofetil.[26]

Daily prednisone in doses of 1 mg/kg, not to exceed 60 mg/d, should be given for 1-3 months to patients with active arteritis. When the symptoms and laboratory test results related to the inflammatory process improve, the prednisone should be tapered slowly over several months. The maximum reduction should be 10% of the daily amount per week. Long-term, low-dose prednisone therapy may be necessary to prevent progression of arterial stenoses.

As many as 75% of patients respond favorably to daily prednisone therapy, but the remaining patients whose disease relapses with corticosteroid tapering should receive additional immunosuppressants.

Weekly doses of methotrexate are thought to be less toxic than daily doses of cyclophosphamide. In a study by Hoffman et al of 16 patients whose vascular disease was resistant to corticosteroid therapy, weekly methotrexate (mean dose 17.1 mg; range 10-25 mg) produced remissions in 81%.[27] Relapse occurred in 44% when the corticosteroids were tapered to or near discontinuation; reinstitution of corticosteroids led to remission, and 3 of 7 patients in this group successfully stopped glucocorticoid therapy.

A case report exists of three patients with resistant disease who showed treatment benefit with mycophenolate mofetil (1 g PO bid).[28] The lower toxicity of mycophenolate mofetil makes this regimen an attractive alternative.

Anti-tumor necrosis factor agents (anti-TNFs), etanercept and infliximab, have been administered to patients with active and relapsing Takayasu arteritis despite glucocorticoid therapy. Fourteen of 15 patients responded to therapy and 10 patients achieved sustained remission.[29] Larger and randomized controlled studies are necessary to determine the role of anti-TNFs in the management of aortitis.

Aortic involvement in temporal arteritis (giant cell arteritis) is not uncommon. Nuenninghoff at al reported that 46 of 168 patients (27%) had large-artery complications.[30] Eighteen percent of the patients had aortic aneurysm and/or aortic dissection, and 13% developed large-artery stenosis. Low-dose aspirin in addition to glucocorticoid is accepted as a standard in the initial treatment of giant cell arteritis because of the benefit in reducing the rate of visual loss and cerebrovascular accidents. Long-term, low-dose aspirin has not been shown to have any effect in aortic complication.

Matsuyama et al administered minocycline, 100 mg bid, for 3 months to 11 patients who had active Takayasu arteritis despite prednisolone therapy.[31] Nine of 11 patients were considered to be in remission at the end of the study.

For both Takayasu aortoarteritis and giant cell arteritis with or without aortic involvement, tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, seems to be effective.[32]

No reliable method of determining the activity of arteritis is established, and no single test should be relied upon. As mentioned above, FDG-PET and MMP-3 and MMP-9 serum levels might provide additional information to monitor the activity of aortitis.

To prevent progression of vascular lesions and to reduce the necessity of surgical procedures in the later stage, careful monitoring of disease activity with sequential imaging studies and more prolonged immunosuppressive treatments may be necessary.

As the prognosis of patients with arteritis improves, prevention of atherosclerotic disorders becomes more important. Treatment of hypertension and congestive heart failure should be instituted if these complications occur, and serum cholesterol levels and homocysteine levels should be monitored, especially if the patients require long-term corticosteroid therapy.[33]

Activity

Activity may be limited by claudication (ie, ischemic pain from limb use) or by aortic insufficiency and congestive heart failure.

Surgical Care

Angioplasty or bypass grafts or stents may be necessary once arterial stenosis has occurred. Unfortunately, according to the experience at the Cleveland Clinic Foundation, vascular interventions for Takayasu arteritis resulted in a high failure rate: 11 of 31 bypass grafts, 3 of 7 percutaneous transluminal angioplasty treatments, and 5 of 7 stents placed experienced restenosis or occlusion.[34]

Surgical repair or angioplasty may be necessary in patients with the following:

  • Significant hypertension resulting from renovascular stenosis

  • Myocardial ischemia secondary to coronary artery involvement

  • Disabling extremity claudication unresponsive to medical treatment

  • Cerebral ischemia

  • Aortic root dilatation leading to significant aortic regurgitation

  • Thoracic or abdominal aortic aneurysms larger than 5 cm in diameter

Stenoses or occlusions affecting lengthy portions of an artery may make angioplasty of an involved segment technically difficult. In addition, the heavily scarred arteries in patients with Takayasu arteritis sometimes are not managed as easily by angioplasty as are atherosclerotic lesions.

Consultations

Consultations include the following:

  • Infectious disease - To eliminate possibility of Neisseria, Rickettsia, spirochete, fungal, or viral (herpes, hepatis B, hepatitis C) causes

  • Rheumatology - To investigate the many immunologic diseases that may result in vasculitis, including Henoch-Schönlein purpura, SLE, rheumatoid arthritis, cryoglobulinemia, serum sickness, granulomatosis with polyangiitis, Churg-Strauss syndrome, Goodpasture syndrome, and Kawasaki disease

  • Cardiology - To evaluate aortic insufficiency, congestive heart failure, ischemia, and stenoses, for consideration of valve replacement, aneurysm repair, angioplasty, or stent placement

  • Cardiovascular surgery - To evaluate carotid stenosis, aortic dilation, arterial bypasses, and/or perform diagnostic biopsy

Long-Term Monitoring

Monitor periodically for complications and for progression of the inflammatory processes. Clinical evaluation with careful history review for any new or progressive signs is essential.[1] Periodic examinations should include funduscopic examination, pulse and pressure assessments in all limbs, checking for bruits and signs of abdominal aneurysm, and neurologic examination. No particular blood test has proven reliable, but a variety may be useful if they happen to indicate increased activation.

Deterrence/Prevention

Aortic trauma with dissection, transplants, immune disorders including connective tissue diseases and inflammatory bowel diseases, infections, and medications that may induce immune complex disease should all raise suspicion for subsequent vasculitis. Vague constitutional symptoms, neck pain, or headaches likewise should raise suspicion for early diagnosis.

 

Medication

Medication Summary

No reliable method exists for determining the activity of arteritis. According to  sequential angiographic studies and vascular specimens obtained at the time of surgery, active vasculitis is present in approximately 50% of patients who lack symptoms of active inflammation or have a normal ESR. To prevent progression of vascular lesions and to reduce the necessity of surgical procedures in the later stage, careful monitoring of disease activity with sequential imaging studies and more prolonged immunosuppressive treatments may be necessary.

As the prognosis of patients with Takayasu arteritis improves, prevention of atherosclerotic disorders becomes more important. Treatment of hypertension and congestive heart failure should be instituted if these complications occur, and serum cholesterol levels should be monitored, especially if the patients require long-term corticosteroid therapy.

Corticosteroids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Mainstay of therapy. May decrease inflammation by reducing capillary permeability and suppressing leukocyte activity.

Daily doses should be given to patients with active Takayasu arteritis. As many as 75% of patients respond favorably to this regimen, but remaining patients, and patients who relapse with tapering, must receive additional immunosuppressants. When tapering steroids, maximum reduction should be 10% of daily amount per week. Long-term low-dose therapy may be necessary to prevent progression of arterial stenoses. Complications of corticosteroid therapy include aseptic necrosis of hip, corticosteroid dependence, and gastric ulcers.

Immunosuppressants

Class Summary

A substantial percentage of patients with aortitis or other forms of vasculitis require additional immunosuppressive agents (eg, cyclophosphamide, methotrexate, mycophenolate mofetil).

Methotrexate (Folex PFS, Rheumatrex)

The mechanism of action in treatment of inflammatory reactions is unknown. May affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).

Weekly doses of cyclophosphamide are thought to be less toxic than daily doses. In one study of 16 patients whose disease was resistant to corticosteroid therapy, weekly methotrexate (mean dose 17.1 mg; range 10-25 mg) induced remissions in 81%. Relapse occurred in 44% when corticosteroids were tapered to or near discontinuation. Reinstitution of corticosteroids led to remission, and 3 of 7 patients in this group successfully stopped glucocorticoid therapy.

Mycophenolate (CellCept)

Inhibits purine synthesis and proliferation of human lymphocytes. Reduced toxicity makes this regimen an attractive alternative.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Anti-tumor Necrosis Factor Agents

Class Summary

These agents are disease modifying drugs.

Etanercept (Enbrel)

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which decreases inflammatory and immune responses.

Infliximab (Remicade)

Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-a and inhibits its binding to TNF-a receptor. Reduces infiltration of inflammatory cells and TNF-a production in inflamed areas. Used with methotrexate in patients who have had inadequate response to methotrexate monotherapy.

Antibiotics

Class Summary

Empiric antimicrobial therapy should cover all likely pathogens in the context of the clinical setting.

Minocycline (Dynacin, Minocin)

Treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible chlamydia, rickettsia, and mycoplasma. Additionally, has anti-inflammatory properties.