eMedicine Specialties > Cardiology > Peripheral Vascular Disease

Aortitis

Masato Okada, MD, FACP, FACR, FAAAAI, Consulting Staff, Section of Allergy and Rheumatology, Department of Medicine, St Luke's International Hospital, Tokyo
Justin D Pearlman, MD, PhD, ME, MA, Director of Dartmouth Advanced Imaging Center, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center

Updated: Mar 25, 2008

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.
- 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.
- 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.
- 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 exceedingly high.
- 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.

Differential Diagnoses

Behcet Disease	Renal Artery Aneurysm
Churg-Strauss Syndrome	Renal Artery Stenosis
Giant Cell Arteritis	Sarcoidosis
Inflammatory Bowel Disease	Syphilis
Kawasaki Disease	Systemic Lupus Erythematosus
Mycosis Fungoides	Takayasu Arteritis
Paraneoplastic Syndromes	Tuberculosis
Polyarteritis Nodosa	Wegener Granulomatosis
Renal Arteriovenous Malformation

Workup

Laboratory Studies

Elevated acute phase reactants, such as ESR and 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.
In one study by Eichorn et al⁴, high titers of serum anti-endothelial cell antibodies were detected in patients with Takayasu arteritis. 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 elastic proteinase that can degrade elastin in large vessel walls. A variety of inflammatory cytokines are known to induce the enzyme. Matsuyama et al⁶ 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). Magnetic resonance angiography (MRA) and CT angiography (CTA) may be of similar value. CTA must be performed with a high-resolution (spiral/helical or Ultrafast) CT scanner. MRA and CTA are replacing the conventional aortography as the diagnostic tools of Takayasu arteritis. The recent advance in this field is fluorodeoxyglucose-PET (FDG-PET), which seems to have a role in monitoring the activity of aortitis.
CTA and MRA are less invasive than conventional angiography, and they may reveal vascular wall thickening during the early phase of disease. In a study by Yamada et al⁷, 25 patients with symptoms suggestive of Takayasu arteritis underwent both conventional angiography and CT helical scanning angiography. CT angiography 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. 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.
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.
Careful interpretation of the chest x-ray also is very important, because some findings, such as widened mediastinum (ie, wide aorta), can be clues to the diagnosis of Takayasu arteritis.
Ultrasonographic studies might be useful to follow the diameter and wall thickness changes in specific regions of accessible arterial vessels.
A new classification of angiographic findings in patients with Takayasu arteritis was proposed at the International Conference on Takayasu Arteritis, as follows:
- 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, and type IV is observed in India and Thailand but is very rare in the United States and Japan.
Webb et al showed that FDG-PET had high sensitivity (92%) and specificity (100%) for active inflammation in Takayasu arteritis. Andrews et al⁸ and Meller et al⁹ 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.

Histologic Findings

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 Images 1-2.

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

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

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.
- 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 this regimen, but the remaining patients and patients whose disease relapses with the tapering must receive immunosuppressants.
- Weekly doses of methotrexate are thought to be less toxic than daily doses of cyclophosphamide. In a study by Hoffman et al¹⁰ of 16 patients whose disease was resistant to corticosteroid therapy, weekly methotrexate (mean dose 17.1 mg; range 10-25 mg) produced remissions in 81%. 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 promising case report of 3 patients with resistant disease who were treated with mycophenolate mofetil (1 g PO bid) has been published¹¹, and the lower toxicity of mycophenolate mofetil makes this regimen an attractive alternative.
- Anti-tumor necrosis factor agents (anti-TNFs), etanercept and infliximab, were administered to patients with active and relapsing Takayasu arteritis despite glucocorticoid therapy. Only 1 out of 15 patients did not respond and 10 patients achieved sustained remission.¹² 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 al¹³ reported that 46 out of 168 patients (27%) had large-artery complication. 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 al¹⁴ administered minocycline, 100 mg bid, for 3 months to 11 patients who had active Takayasu arteritis despite prednisolone therapy. Nine out of 11 patients were considered to be in remission at the end of the study.
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 might provide additional information to monitor the activity of aortitis.
- According to vascular specimens obtained at the time of bypass surgery and sequential angiographic studies, 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 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.

Surgical Care

According to the experience at the Cleveland Clinic Foundation, vascular interventions for Takayasu arteritis resulted in a high failure rate: eleven out of 31 bypass grafts, 3 of 7 percutaneous transluminal angioplasty, and 5 of 7 stents restenosed or occluded.¹⁵

Angioplasty or bypass grafts or stents may be necessary once arterial stenosis has occurred.
Surgical repair or angioplasty are necessary in cases described as follows:
- 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 angioplastic dilation 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 cases of atherosclerosis. Bypass grafting can abolish the possibility of restenosis resulting from continued inflammation in a treated segment.

Consultations

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, Wegener granulomatosis, 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

Activity

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

Medication

No reliable method exists for determining the activity of arteritis. According to vascular specimens obtained at the time of bypass surgery and sequential angiographic studies, 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 and homocysteine levels should be monitored, especially if the patients require long-term corticosteroid therapy.

Corticosteroids

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 reversing increased capillary permeability and suppressing PMN 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 immunosuppressants. 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 include aseptic necrosis of hip, corticosteroid dependence, and ulcers.

Dosing

Adult

1 mg/kg/d PO, not to exceed 60 mg/d, for 1-3 mo; taper slowly over several months as symptoms and laboratory test results improve

Pediatric

Not established

Interactions

Estrogens may decrease clearance; may cause digitalis (ie, digoxin) toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Immunosuppressants

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)

Unknown mechanism of action in treatment of inflammatory reactions. May affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).
Weekly doses thought to be less toxic than daily doses of cyclophosphamide. In one study of 16 patients whose disease was resistant to corticosteroid therapy, weekly methotrexate (mean dose 17.1 mg; range 10-25 mg) produced 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.

Dosing

Adult

0.3 mg/kg/wk PO

Pediatric

Not established

Interactions

Coadministration with NSAIDs may be fatal
Oral aminoglycosides may decrease absorption and blood levels; charcoal lowers levels; etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels
Probenecid, salicylates, procarbazine, and sulfonamides (including TMP-SMX) may increase effects and toxicity; may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Monitor CBCs monthly and liver and renal functions every 1-3 mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels is increased, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurological systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Mycophenolate (CellCept)

Inhibits purine synthesis and proliferation of human lymphocytes. Promising published case report of 3 patients with resistant disease treated with mycophenolate mofetil. Reduced toxicity makes this regimen an attractive alternative.

Dosing

Adult

1 g PO bid

Pediatric

Not established

Interactions

May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decrease absorption and reduce levels (do not administer together); probenecid may increase levels; salicylates may increase toxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection; increases toxicity in patients with renal impairment; caution in patients with active peptic ulcer disease

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.

Dosing

Adult

2 mg/kg/d PO

Pediatric

Not established

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity, severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Anti-tumor necrosis factor agents

These agents are disease modifying drugs.

Etanercept (Enbrel)

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

Dosing

Adult

25 mg SC 2 times/wk with or without concomitant administration of MTX

Pediatric

<4 years: Not established
4-17 years: 0.4 mg/kg SC 2 times/wk (72-96 h apart); not to exceed 25 mg/dose
>17 years: Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity, sepsis, concurrent live vaccination

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Serious infections may develop and the therapy should be discontinued if they occur; possible adverse effects include injection site pain, redness and swelling at injection site, and headaches; rare cases of lupuslike symptoms and heart failure have been reported (discontinue treatment if symptoms develop)

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.

Dosing

Adult

3 mg/kg IV (in combination with methotrexate therapy); follow by additional 3 mg/kg at 2 and 6 wk after first dose; repeat q8wk thereafter

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

TNF-a modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF alpha-blockers compared with controlled groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections

Antibiotics

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.

Dosing

Adult

100 mg, PO bid

Pediatric

<8 years: Not recommended
>8 years: 4 mg/kg PO initially, followed with 2 mg/kg q12h

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines; hepatitis or lupuslike syndromes may occur

Follow-up

Further Inpatient Care

Catheterization to assess systemic and pulmonary hypertension, coronary and renal artery disease, and other specific sites of suspected obstruction
Arterial wall biopsy

Further Outpatient Care

Monitor periodically for complications and for progression of the inflammatory processes. Clinical evaluation with careful history review for any new or progressive signs is vital. Periodic examinations should include funduscopic examination, checking pulses and pressures 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.

Complications

Aortic insufficiency, angina pectoris, myocardial infarction, stroke, limb ischemia, renal artery hypertension, and all consequences of vascular disease

Prognosis

Overall, 10-year survival rate has been reported as 80-90%. Two major predictors of outcome are incidence of complications (eg, Takayasu retinopathy, hypertension, aortic regurgitation, aneurysm) and a progressive course.
Patients with no complications or with mild to moderately severe complications had a 10-year survival rate of 100% and a 15-year survival rate of 93-96%. Complications or progression reduces the 15-year survival rate to 66-68%.
The presence of both a major complication and progressive course nets a 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.

Miscellaneous

Medicolegal Pitfalls

Elevations of acute phase reactants, such as ESR and CRP level, not only are nonspecific but also are 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.
Failure to diagnose aortitis often arises from the fact that the clinician fails to consider it in the differential diagnosis.

Special Concerns

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.

Multimedia

Media file 1: Leukocyte infiltration of the vasovasorum of the aorta accompanies arteritis obliterans and ischemic necrosis of the media in a case of syphilitic aortitis.

Media file 2: Granulomatous arteritis with thrombosis of a cerebral vessel may present as a neurological defect with no obvious vascular disease by history or physical.

Media file 3: Diffuse stenosis from the aortic arch to the abdominal aorta. The left common carotid artery are also stenotic and the left subclavian artery is not visualized.

Media file 4: Dilatation of the bilateral vertebral arteries. Occlusion of the right internal carotid artery. Severe stenosis of the left internal carotid artery. Moderate stenosis of the left external carotid artery at the bifurcation with dilated collateral circulation.

Media file 5: Moderate stenosis of the external iliac artery at the bifurcation and occlusion of the right femoral artery.

Media file 6: Frequency of vascular involvement (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

Media file 7: Presence of associated morbidity in Takayasu arteritis in the United States (adapted from combined reports by Maksimowicz-McKinnon et al and Kerr).

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Keywords

aortitis, Takayasu's arteritis, Takayasu arteritis, pulseless disease, pulselessness, giant cell arteritis, polyarteritis nodosa, Kawasaki disease, large vessel arteritis, vasculitis

Contributor Information and Disclosures

Author

Masato Okada, MD, FACP, FACR, FAAAAI, Consulting Staff, Section of Allergy and Rheumatology, Department of Medicine, St Luke's International Hospital, Tokyo
Masato Okada, MD, FACP, FACR, FAAAAI is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Physicians, and American College of Rheumatology
Disclosure: Nothing to disclose.

Coauthor(s)

Justin D Pearlman, MD, PhD, ME, MA, Director of Dartmouth Advanced Imaging Center, Professor of Medicine, Professor of Radiology, Adjunct Professor, Thayer Bioengineering and Computer Science, Dartmouth-Hitchcock Medical Center
Justin D Pearlman, MD, PhD, ME, MA is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Federation for Medical Research, International Society for Magnetic Resonance in Medicine, and Radiological Society of North America
Disclosure: Nothing to disclose.

Medical Editor

Russell F Kelly, MD, Program Director, Assistant Professor, Department of Internal Medicine, Division of Cardiology, Cook County Hospital, Rush Medical College
Russell F Kelly, MD is a member of the following medical societies: American College of Cardiology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Ronald J Oudiz, MD, Director of Pulmonary Hypertension, Associate Professor, Department of Medicine, Division of Cardiology, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA
Ronald J Oudiz, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, and American Heart Association
Disclosure: Actelion Grant/research funds Clinical Trials + honoraria; Encysive Grant/research funds Clinical Trials + honoraria; Gilead Grant/research funds Clinical Trials + honoraria; Pfizer Grant/research funds Clinical Trials + honoraria; United Therapeutics Grant/research funds Clinical Trials + honoraria

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Chief Editor

George A Stouffer III, MD, Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

Further Reading

eMedicine Specialties > Cardiology > Peripheral Vascular Disease

Aortitis

Introduction

Background

Pathophysiology

Frequency

United States

International

Mortality/Morbidity

Sex

Age

Clinical

History

Physical

Causes

Differential Diagnoses

Other Problems to Be Considered

Workup

Laboratory Studies

Imaging Studies

Histologic Findings

Staging

Treatment

Medical Care

Surgical Care

Consultations

Activity

Medication

Corticosteroids

Prednisone (Deltasone, Orasone, Sterapred)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Immunosuppressants

Methotrexate (Folex PFS, Rheumatrex)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Mycophenolate (CellCept)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Cyclophosphamide (Cytoxan)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Anti-tumor necrosis factor agents

Etanercept (Enbrel)

Dosing

Adult

Pediatric

Interactions

Contraindications

Precautions

Pregnancy

Precautions

Infliximab (Remicade)

Dosing

Adult

Pediatric