Aortitis

 

INTRODUCTION

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

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

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

Immune disorders affecting the aorta include 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).

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:

  • In the US: In the United States and Europe, incidence is 1-3 new cases per year per million population.
  • Internationally: 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 most commonly is 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.

  • 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. 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.
  • Neurological symptoms generally are caused by decreased cerebral blood flow in the carotid and vertebral arteries. Neurological manifestations include vertigo, syncope, orthostasis, headaches, convulsions, transient ischemic attacks, stroke, and dementia. Seizures often are attributed to hypertensive encephalopathy. Because of central retinal hypoperfusion, visual impairment most often is 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 are found over the legs. Upon biopsy, the lesions frequently show vasculitis of small vessels. Erythema nodosum is the predominant dermatological finding in the United States and Europe, whereas pyoderma gangrenosum is found more frequently in Japan. Raynaud phenomenon also has been reported in 8-14% of patients.
  • Angina pectoris occurs as a result of coronary artery ostial narrowing from aortitis or coronary arteritis, and this can lead to myocardial infarction, heart failure, or sudden death. Congestive heart failure may be caused by valvular disease. Aortic regurgitation resulting 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 al, anti-endothelial antibodies were found in 18, and the titers were approximately 20 times higher than normal.
    • 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.

 

DIFFERENTIALS

Churg-Strauss Syndrome
Giant Cell Arteritis
Mycosis Fungoides
Polyarteritis Nodosa
Renal Arteriovenous Malformation
Renal Artery Aneurysm
Renal Artery Stenosis
Sarcoidosis
Syphilis
Systemic Lupus Erythematosus
Tuberculosis


Other Problems to be Considered:

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, 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. High index of suspicion is essential, not just in young women—recently, a highly esteemed senior American rabbi died from severe vasculitis because the correct diagnosis was not considered in time. 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.

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 3 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 of Takayasu arteritis may help differentiation.

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, 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.


WORKUP

Lab 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 al, 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.

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.
  • 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 al, 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.
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 al 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 published, and the lower toxicity of mycophenolate mofetil makes this regimen an attractive alternative.
  • No reliable method of determining the activity of arteritis is established, and no single test should be relied upon.
    • 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:

  • 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.

Drug Category: Corticosteroids -- These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
Drug Name
 Prednisone (Deltasone) -- 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.
Adult Dose 1 mg/kg/d, not to exceed 60 mg/d, for 1-3 mo; taper slowly over several months as symptoms and laboratory test results improve
Pediatric Dose Not established
Contraindications Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
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
Pregnancy B - Usually safe but benefits must outweigh the risks.
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
Drug Category: Immunosuppressants -- A substantial percentage of patients with aortitis or other forms of vasculitis require additional immunosuppressive agents (eg, cyclophosphamide, methotrexate, mycophenolate mofetil).
Drug Name
 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.
Adult Dose 0.3 mg/kg/wk PO
Pediatric Dose Not established
Contraindications Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
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
Pregnancy D - Unsafe in pregnancy
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)
Drug Name
 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.
Adult Dose 1 g PO bid
Pediatric Dose Not established
Contraindications Documented hypersensitivity
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
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Increases risk for infection; increases toxicity in patients with renal impairment; caution in patients with active peptic ulcer disease
Drug Name
 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.
Adult Dose 2 mg/kg/d PO
Pediatric Dose Not established
Contraindications Documented hypersensitivity, severely depressed bone marrow function
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
Pregnancy D - Unsafe in pregnancy
Precautions Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

 

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

Medical/Legal 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.

 

PICTURES

 
Caption: Picture 1. Aortitis. Leukocyte infiltration of the vasovasorum of the aorta accompanies arteritis obliterans and ischemic necrosis of the media in a case of syphilitic aortitis.
Picture Type: Photo
Caption: Picture 2. Aortitis. Granulomatous arteritis with thrombosis of a cerebral vessel may present as a neurological defect with no obvious vascular disease by history or physical.
Picture Type: Photo