eMedicine Specialties > Neurology > Inflammatory and Demyelinating Diseases

Takayasu Arteritis

Gabriel Bucurescu, MD, MS, Staff Neurologist, Neurology Service, Philadelphia Veterans Affairs Medical Center

Updated: Sep 17, 2009

Introduction

Background

Takayasu arteritis (TA) is a chronic inflammatory disease of the large arteries, usually affecting the aorta and its large branches and the pulmonary arteries. It is one of the vasculitides and can manifest systemically, involving any or all of the major organ systems. The brain is a prime target.

Dr Mikito Takayasu first described TA in 1905, when he described a patient with a wreathlike coronary anastomosis of retinal vasculature surrounding the papilla. Since then, the disease has been reported in all parts of the world, although it appears to be more prevalent in Asians.

Pathophysiology

TA is an inflammatory disease of large- and medium-sized arteries, with a predilection for the aorta and its branches. Advanced lesions demonstrate a panarteritis with intimal proliferation.

Lesions produced by the inflammatory process can be stenotic, occlusive, or aneurysmal. All aneurysmal lesions may have areas of arterial narrowing. Vascular changes lead to the main complications, including hypertension, most often due to renal artery stenosis or, more rarely, stenosis of the suprarenal aorta; aortic insufficiency due to aortic valve involvement; pulmonary hypertension; and aortic or arterial aneurysm. Congestive heart failure is a common finding, much more so than dilated cardiomyopathy, myocarditis, and pericarditis, which also have been reported. In patients in whom the pulmonary artery is involved, the right artery appears to be affected more than the left, with patients developing pneumonia, interstitial pulmonary fibrosis, and alveolar damage.

Other pathophysiologic consequences include hypotensive ischemic retinopathy, vertebrobasilar ischemia, microaneurysms, carotid stenosis, hypertensive encephalopathy, and inflammatory bowel disease. Rarely, TA has also been associated with glomerulonephritis, systemic lupus, polymyositis, polymyalgia rheumatica, rheumatoid arthritis, Still disease, and ankylosing spondylitis.

Frequency

United States

• The prevalence is 2.6-6.4 persons per million population. The discrepancy is attributed to genetic factors and difficulty in diagnosis.
• Between 1971-1983 in Olmstead County, Minnesota, 3 cases were recorded, thus giving an annual incidence of 2.6 cases per million population.

International

• Worldwide incidence is estimated at 2.6 cases per million per year.
• Many cases of TA are reported from Southeast Asia, where the condition is believed to be most common. However, it has been reported in all parts of the world and in all racial groups.
• The prevalence in Sweden is similar to that in the United States (ie, 2.6-6.4 persons per million population).
• In the United Kingdom, the annual incidence is 0.15 case per million.

Mortality/Morbidity

• Because TA is rare, data on mortality and morbidity are limited. The site of the lesions and the degree of involvement determine the extent and the clinical severity. A National Institutes of Health (NIH) study of 60 patients with TA prospectively demonstrated a 3% mortality rate. This result was similar to data from Japan and China but markedly different from other reports (which reported mortality as high as 35%). Such disparity may reflect differences in access to care, definitions of disease activity, and indications for treatment.
• The same NIH study showed that 20% of patients had a monophasic illness, which was self-limiting; they did not require immunosuppressive treatment. In the remaining 80% of patients who did not have a monophasic illness and experienced one exacerbation, immunosuppressive therapy resulted in remission in 60%. Of these, one half experienced relapse after immunosuppressive therapy was stopped. The overall morbidity depends on the severity of the lesions and their consequences.

Race

Cases have been reported worldwide, but TA is most common in Southeast Asia and the Indian subcontinent.

Sex

TA is primarily a disease of young women. Men are rarely affected.

Age

TA primarily affects young women, especially those in the childbearing ages. Peak onset is in individuals in their 30s. Less than 15% of cases present in individuals older than 40 years.

Clinical

History

TA progresses through 3 stages. Thus, symptoms that clinicians encounter depend on how soon the patient presents; most patients present late, delaying the diagnosis. However, in actual practice, most patients do not fall readily into such groupings, and this 3-stage scheme is an oversimplification of the complex clinical presentation. Symptoms encountered can occur early or late in the course of the disease. In the NIH series including 60 patients observed over 20 years, only 33% of patients had constitutional symptoms (corresponding to stage 1); 18% of patients never progressed to the third stage.

• The first stage is an early systemic stage during which the patient may complain of constitutional symptoms (eg, fatigue, malaise, giddiness, fever). This stage is considered to be prevasculitic.
• The second stage is the vascular inflammatory stage, when stenosis, aneurysms, and vascular pain (carotidynia) tend to occur.
  • Symptoms characterizing the vascular inflammatory stage include fatigue, fevers, malaise, pain in extremities and joints, dyspnea, palpitations, headaches, rash (erythema nodosum or a lupuslike butterfly rash, which can be photosensitive), hemoptysis, ulceration, and weight loss. A single case of thoracic and lumbar spine pain has been reported. Symptoms of vascular insufficiency include arm numbness, claudication in the legs (rare), blurry vision, double vision (which can be posture dependent), amaurosis fugax, stroke, transient ischemic attacks (TIAs), hemiplegia, seizures, and paraplegia.
  • The constitutional systemic symptoms and vascular symptoms may occur at the same time, rendering the classification into stages practically impossible.
• The third stage is the burned-out stage, when fibrosis sets in, and generally is associated with remission.
  • This stage does not occur in all patients, and even in patients who are in remission, relapses can occur.
  • Presumably, the burned-out stage manifests with minimal symptoms, but little supportive evidence is found in the literature.
• Special mention should be made regarding pregnant women.
  • The inflammatory activity is not enhanced by the pregnancy, but the perinatal period may be complicated by the associated symptoms.
  • Blood pressure may not be measurable due to pulselessness, thus making patient monitoring difficult, if not impossible. Often, calf pressures need to be obtained.
  • In pregnant women with TA, uncontrolled blood pressure may lead to subarachnoid/intracranial hemorrhage and subsequent seizures, eye changes, preeclampsia, aortic regurgitation, syncope, fetal complications, and nephrotic syndrome.

Physical

• The main finding is absent pulse(s) or a pulse discrepancy of greater than 30 mm Hg between the right and left arms.
• Other significant findings include the following:
  • Vascular bruits, most commonly in the carotid and abdominal arteries but also in the subclavian and femoral arteries
  • Focal neurologic deficits consistent with cerebral infarction or TIA
  • Hypertension, sometimes leading to hypertensive encephalopathy, usually due to renal artery stenosis
  • Amaurosis fugax
  • Retinal ischemia and microaneurysms
  • Myocardial infarction
  • Dilated cardiomyopathy
  • Eclampsia
  • Subarachnoid hemorrhage, probably secondary to hypertension
  • Leg edema due to renal failure secondary to renal artery stenosis and glomerulonephritis
• Less common associations have been seen with the following:
  • Ulcerative colitis
  • Sensorineural hearing loss
  • Pulmonary hemorrhage
• Blood pressure may not be measurable due to the pulselessness, making patient monitoring difficult or impossible. Often, calf blood pressures must be obtained.
• A case report of sensorineural hearing loss associated with TA also has been reported.¹ Whether a firm connection between the two syndromes exists, other than the inflammatory manifestations, has not been demonstrated. The pathologic etiology of the hearing loss was attributed to an immune-mediated process in the membranous labyrinth.
• A case report of Cogan syndrome with TA also has been reported.² Cogan syndrome, first described in 1945, involves interstitial keratitis and a vestibuloauditory syndrome. Variations of this with other types of inflammatory eye disease and vestibuloauditory arteritis have been reported.

Causes

The etiology is unknown. The underlying pathologic process is inflammatory, with several etiologic factors having been proposed, including spirochetes, Mycobacterium tuberculosis, streptococcal organisms, and circulating antibodies due to an autoimmune process.

An antigen may stimulate aortic tissue, leading to the expression of heat shock protein-65, which, in turn, induces major histocompatibility (MHC) class I–related chain A (MICA). Natural killer cells and gamma-delta T cells expressing NKG2D receptors may infiltrate and recognize MICA on vascular smooth muscle cells, releasing porfrin and leading to acute inflammation. Proinflammatory cytokines are also released from the natural killer and T-cells, inducing the production of matrix metalloproteinases (MMPs) and amplifying the inflammatory response. This, in turn, would induce more MHC antigen and stimulate molecule expression on vascular cells, recruiting more mononuclear cells.

• In a case report, the role of M tuberculosis and its 65-kd heat shock protein has been implicated in the etiology. Patients with TA were found to have higher immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA) titers against the M tuberculosis extract than patients without the condition.³
• One article reports the presence of CD3⁺ T cells and IgG antibodies reactive to circulating antimycobacterial heat shock protein 65 (mHSP65) antibodies and to its human homologue, hHSP60.⁴ This suggests a possible cross reactivity of immune response between mHSP65 and hHSP60.
• Other case reports involving the role of antiendothelial cell, anticardiolipin, and antiaorta antibodies also exist.
• In Japanese patients, human leukocyte antigen Bw52 (HLA-Bw52), which is in linkage disequilibrium with human leukocyte antigen DR4 (HLA-DR4), has been observed with increased frequency. Patients with the Bw52 genotype had a higher rate of aortic regurgitation. However, studies of HLA antigens in North American populations have not confirmed this. A study comparing HLA-B alleles in Mexican patients with TA and tuberculosis showed distinct specific alleles. TA was characterized by HLA-B39, -B44 and -B52, whereas pulmonary tuberculosis by HLA-B35, extrapulmonary tuberculosis by HLS-B39 and -B40.⁵
• One study demonstrated an association between several cases of TA and CD36 deficiency (CD36d).⁶ The human CD36 antigen is a multifunctional membrane glycoprotein that belongs to the class B scavenger receptor family. It is expressed on monocytes, platelets, and endothelial cells, and contributes to myocardial fatty acid transport. In patients with CD36d, myocardial I-15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (BMIPP) uptake was absent.

Differential Diagnoses

Other Problems to Be Considered

Cogan syndrome
Dilated cardiomyopathy
Erythema nodosum
Relapsing polychondritis
Amaurosis fugax
Ocular pathology
Giant cell arteritis
Other arteritides
Other large vessel diseases (eg, neurofibromatosis of the abdominal aorta)
Carotid disease and stroke
Reversible posterior leukoencephalopathy syndrome
Common variable immunodeficiency syndrome
Keratouveitis
Posterior scleritis
Polymyalgia rheumatica
Subclavian steal syndrome
Raynaud phenomenon

Workup

Laboratory Studies

• Laboratory tests in individuals with Takayasu arteritis (TA) tend to be nonspecific. The erythrocyte sedimentation rate (ESR) may be high, generally greater than 50 mm/h, in early disease but normal later. Leukocyte count may be normal or slightly elevated. A moderate, normochromic anemia may be present in individuals with active disease.
• Autoantibodies observed in other connective tissue diseases, including rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies, and antineutrophil cytoplasmic antibodies (ANCA), are as common as in the general population. Circulating antiendothelial antibodies may be present in high titers. This finding is considered nonspecific, because it is reported sporadically and may be present in other connective tissue diseases and in angiitis obliterans. Antiaorta antibodies may be present, but testing for them seldom is performed, if ever.
• Some researchers have found that the levels of soluble vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in patients with TA compared with normal healthy controls, and they were also significantly higher in older than younger patients, suggesting that VCAM-1 may serve as a marker of disease activity and progression with age.
• Hypoalbuminemia and increased levels of fibrinogen, alpha2-globulin, and gamma globulin are common.
• Urinalysis may be consistent with nephrotic syndrome.
• HLA typing has not confirmed any definite association in North American patients. Presumably, a finding of HLA-Bw52 in such patients reinforces the diagnosis; it is not a definite diagnostic tool.

Imaging Studies

• Angiography is the criterion standard.
• The Ishikawa criteria (1986) have been useful in defining TA.
  • One criterion is age younger than 40 years at diagnosis or at onset of characteristic signs and symptoms of 1-month duration in the patient's history.
  • Two major criteria involve the left and right midsubclavian artery, with the most severe stenosis or occlusion present in the mid portion from a point 1 cm proximal to the left and right, respectively, vertebral artery orifices to that 3 cm distal to the orifice as determined by angiography.
  • The minor criteria consist of annuloaortic ectasia or aortic regurgitation as shown by angiography or echocardiography and pulmonary artery, left mid common carotid, distal brachiocephalic trunk, descending aorta, or abdominal aorta lesions.
• The American College of Rheumatology (ACR; 1990) states the following:
  • Angiographic criteria must show narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities.
  • These changes are not due to arteriosclerosis, fibromuscular dysplasia, or similar causes.
  • Changes are usually focal or segmental.
  • These criteria probably allow greater flexibility to account for variability in actual clinical practice.
  • In comparison to the Ishikawa criteria, which were established based on Japanese patients only, the ACR criteria may better reflect the North American population.
  • The lesions can include stenosis, occlusion, or aneurysms.
• Computed tomography (CT) scanning or ultrasound may be used to assess thickness of the aorta. One study found that multi-slice CT was useful in detecting lesions.⁷
• Magnetic resonance angiography (MRA), especially whole-body studies, can be used to assess the vasculature. Recent advances in technology have substantially improved sensitivity and specificity, and the entire arterial vasculature can be displayed in less than 90 seconds. The risks are practically nonexistent, and the versatility of the images obtained will likely lead to increased use over conventional angiography.⁸
• Gallium scanning has been used to assess inflammatory involvement of the vessels.
• Single-photon emission computed tomography (SPECT) scanning has been used to assess cerebral blood flow and may be useful in patients who undergo bypass surgery. Several recent studies have shown that the use of whole-body positron emission tomography (PET) scanning provides useful information demonstrating anatomic changes consistent with the diagnosis of TA.
• Ultrasonography has been used to determine flow characteristics in stenosed vessels.
• Recent reports of the use of positron emission tomography (PET) in various vasculitic conditions, including TA, demonstrate abnormal uptake patterns of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) in the walls of the involved vessels. 18F-FDA accumulates in inflammatory cells due to augmented oxidative metabolism, and this may be of value in diagnosis in the early stages of the disease and for evaluating response to therapy.

Procedures

• Few procedures are necessary. Grafts have been used to bypass regions of severe stenosis or occlusion. Usually, the graft is a saphenous vein graft. Examples of grafts performed include bypass of renal artery stenosis for renal salvage; bypass of innominate or carotid artery; and bypass between subclavian-axillary and common carotid arteries. Extraintracranial bypass operations generally are performed for stenosis of the internal carotid or middle cerebral arteries.
• Other procedures include aneurysm clipping and revascularization.
• Angioplasty and stenting have been used to treat recurrent stenosis.

Histologic Findings

• Lesions are initially inflammatory and later become occlusive. In the early phase of TA, histologic features include granulomatous changes in the media and adventitia of the aorta and its branches, followed by intimal hyperplasia, medial degeneration, and adventitial fibrosis of the sclerotic type. The duration is variable. Inflammatory cells—predominantly CD4 and CD8 lymphocytes, macrophages, plasma cells, histiocytes, and giant cells—invade the adventitia and media but not the intima.
• In the vasoocclusive stage, the lesions are characterized by occlusion and signs of ischemia. The adventitia and media are replaced by fibrous scarring, the vasa vasorum are obliterated, and the intima undergoes irregular thickening. Medial degeneration, disruption of the elastic lamellae, and thrombosis can occur. Aneurysms can form, but no aneurysms attributed to TA have been identified in the intracranial circulation. The literature reports a few cases of intracranial aneurysms that are considered to be incidental.
• The ground substance in the intima is increased markedly, histochemically showing a basophilic acid mucopolysaccharide in a state of gelatinous swelling.
• An increase in CD4 and decrease in CD8 lymphocytes, along with reduced B lymphocytes, have suggested a defect in T-cell regulation (cell-mediated immunity). Biopsy samples exhibit infiltrates of lymphocytes and monocytes in both the vessel walls and a peripheral nerve vasculitis. Lymphocytes and monocytes are attracted to the vessel wall either by an infectious agent or an autoimmune response, modulated by intercellular adhesion molecules (ICAMs).

Treatment

Medical Care

Medical management of Takayasu arteritis (TA) depends on the disease activity and the complications that can develop. Some patients have only mild forms of TA; others deteriorate considerably. The two most important aspects of treatment are controlling the inflammatory process and controlling the hypertension. Corticosteroids are the most important therapeutic agents and are necessary in active disease. Therapy is continued until patients achieve remission.

• For patients who do not achieve remission on corticosteroids, cytotoxic agents such as methotrexate (0.3 mg/kg/wk) or cyclophosphamide (1 mg/kg/d) may prove effective; azathioprine (1 mg/kg) is another possible option. For relapses, combinations of the above can be tried. Success has also been reported with mycophenolate mofetil and tacrolimus hydrate.⁹
• Hypertension is treated with antihypertensive agents, and aggressive therapy is necessary to prevent complications.
• Antiplatelet agents and heparin may prove useful in preventing stroke. Warfarin also has been used. The literature reports a case of improvement in renal and systemic function with low-dose intravenous (IV) heparin therapy (10,000 U/d) followed by oral anticoagulant and antiplatelet agents.
• Anti–tumor necrosis factor (TNF) agents have recently shown encouraging results in a small number of patients with relapsing TA.¹⁰ Anti-TNF may be a useful adjunct to glucocorticoid therapy; however, to date, a controlled clinical trial is lacking.

Surgical Care

Bypass surgery has been performed on patients with critical thoracic aortic arch arterial stenosis, upper and lower extremity ischemia, cerebrovascular accidents, and renal artery stenosis. The procedures are generally case specific. Certain issues, such as the timing of surgery in relation to disease activity or the advisability of surgery in symptom-free patients, have not been resolved. Anastomotic stenoses or graft occlusion is a potential complication of surgery. Short lesions respond well to percutaneous transluminal angioplasty.

Consultations

• Cardiologist
• Rheumatologist
• Obstetrician-gynecologist for pregnant patients
• Vascular surgeon

Diet

Diet modification is necessary to manage hypertension or renal failure.

Activity

Any limitations depend on the severity of the disease and complications.

Medication

The goals of therapy are to reduce inflammation and suppress autoimmune disease. To treat the active disease, corticosteroids are used and gradually tapered. Cytotoxic agents are the main therapeutic agents when the response to steroids is unsatisfactory.

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)

Used in treatment of various allergic and inflammatory diseases. Also used as an immunosuppressant to treat autoimmune disorders. Decreases inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

0.05-2 mg/kg/d PO divided bid/qid for 1-3 mo; after obtaining a satisfactory response, taper slowly

Pediatric

4-5 mg/m²/d PO; alternatively, administer 1-2 mg/kg PO qd; taper over 2 wk as symptoms resolve

Interactions

Clearance may decrease when used concurrently with estrogens; when used concurrently with digoxin, may increase digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin also may increase metabolism of glucocorticoids (consider increase in maintenance dose); monitor patients for hypokalemia when taking this medication concurrently with diuretics

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin lesions

Precautions

Pregnancy

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

Precautions

Patients who receive glucocorticoids are at risk of multiple complications, including severe infections; abrupt discontinuation of glucocorticoids may cause an adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Cytotoxic agents

In patients not responding to prednisone, cyclophosphamide or methotrexate—either in combination with prednisone or alone—can be used to suppress the active disease.

Cyclophosphamide (Cytoxan)

Alkylating agent chemically related to nitrogen mustards. Mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells; used as second-line agent in treating exacerbations of immune-mediated processes.

Dosing

Adult

1 mg/kg/d IV

Pediatric

Administer as in adults

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects of cyclophosphamide; also may potentiate doxorubicin-induced cardiotoxicity; conversely, digoxin serum levels may be reduced; antimicrobial effects of quinolones also may be reduced
May increase cyclophosphamide half-life while decreasing metabolite concentrations; may increase effects of anticoagulants
Rates of metabolism and leukopenic activity of cyclophosphamide are increased by long-term administration of high doses of phenobarbital; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; also may prolong neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

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

Precautions

Regularly monitor patient's hematologic profile (particularly neutrophils and platelets) during treatment to determine degree of hematopoietic suppression; examine urine regularly for red cells, which may precede hemorrhagic cystitis

Methotrexate (Folex, Rheumatrex)

Mechanism of action in treatment of autoimmune diseases is unknown. May affect immune function. Effects can be observed as early as 3-6 wk following administration; used as second- or third-line drug to suppress active disease.

Dosing

Adult

0.3 mg/kg/wk PO

Pediatric

Not established

Interactions

Oral aminoglycosides may decrease absorption and blood levels of concurrent PO MTX; charcoal lowers plasma levels of both PO and IV MTX and may be particularly significant with high-dose therapies; etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives (found in some vitamins) may decrease response
NSAIDs administered concurrently with MTX can cause a fatal interaction
Indomethacin and phenylbutazone can increase MTX plasma levels (mechanism of action is unknown but may involve inhibition of renal prostaglandin synthesis or competitive renal secretion)
Phenytoin serum concentrations may be decreased by MTX; probenecid, salicylates, and sulfonamides (including TMP-SMZ) may increase therapeutic and toxic effects of MTX; inhibition of renal tubular secretion, competition for a common elimination pathway, or protein displacement may be the mechanisms; if protein displacement is the mechanism, it may involve displacement of the highly bound metabolic 7-hydroxymethotrexate, since the parent drug is only 50% bound; procarbazine may increase nephrotoxicity of MTX; MTX may increase plasma levels of thiopurines

Contraindications

Documented hypersensitivity; alcoholism, alcoholic liver disease, or other chronic liver disease; patients with laboratory evidence of immunodeficiency syndromes or preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia) should not take this medication

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor hematology at least monthly and liver and renal function every 1-3 mo during therapy; during initial or changing doses or periods of increased risk of elevated MTX blood levels (eg, dehydration), more frequent monitoring may be indicated
Stop MTX immediately if significant drop in blood count; aspirin, NSAIDs, or low-dose steroids may be continued, although possibility of increased toxicity with concomitant use of NSAIDs (eg, salicylates) is unknown

Antihypertensive agents

Can be used to treat hypertension associated with arteritis. On occasion, combinations are required. Therapy can be individualized.

Nifedipine (Procardia)

One of the more common channel blockers used for hypertension associated with arteritis.

Dosing

Adult

Immediate release dosage form: 10-30 mg PO tid; not to exceed 120-180 mg/d
Sustained-release dosage form: 30-60 mg PO qd; not to exceed 90-120 mg/d

Pediatric

0.25-0.5 mg/kg/dose PO tid/qid prn

Interactions

May cause severe hypotension when taken concurrently with fentanyl; cimetidine may increase toxicity of nifedipine

Contraindications

Documented hypersensitivity to agent or adenosine

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Lower extremity edema has been associated; rare instances of allergic hepatitis have been reported

Antiplatelet agents

Help prevent CVAs and improve renal and systemic function. A formulation of extended-release dipyridamole and aspirin (Aggrenox) also recently has become available.

Ticlopidine hydrochloride (Ticlid)

Interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interaction. Used as second-line antiplatelet therapy for patients who are intolerant to aspirin therapy or in whom such therapy fails.

Dosing

Adult

250 mg PO bid

Pediatric

Not established

Interactions

Corticosteroids and antacids may decrease effects; toxicity increases when taken concurrently with aspirin, theophylline, cimetidine, and NSAIDs

Contraindications

Documented hypersensitivity; caution in liver damage, neutropenia, or thrombocytopenia and with active bleeding disorders

Precautions

Pregnancy

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

Precautions

Discontinue if absolute neutrophil count falls to <1,200/µL or if platelet count falls to <80,000/µL

Clopidogrel (Plavix)

Thienopyridine derivative chemically related to ticlopidine that inhibits platelet aggregation; selectively inhibits ADP binding to its platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation.

Dosing

Adult

75 mg PO qd

Pediatric

Not established

Interactions

Concomitant administration of clopidogrel with naproxen associated with increased occult GI blood loss; administer NSAIDs and clopidogrel with caution
Prolongs bleeding time; safety of coadministration with warfarin has not been established, thus administer these 2 agents with caution

Contraindications

Documented hypersensitivity; active pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathologic conditions; caution in patients who have lesions with a propensity to bleed (eg, ulcers)
Cautiously use drugs such as aspirin and other NSAIDs that may increase such lesions in patients who are taking clopidogrel

Aspirin and extended-release dipyridamole (Aggrenox)

Drug combination with antithrombotic action.
Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis.
Dipyridamole is a platelet adhesion inhibitor that possibly inhibits RBC uptake of adenosine, itself an inhibitor of platelet reactivity. In addition, may inhibit phosphodiesterase activity leading to increased cyclic-3', 5'-adenosine monophosphate within platelets and formation of the potent platelet activator thromboxane A2.

Dosing

Adult

25/200 mg PO bid

Pediatric

Not established

Interactions

Theophylline may decrease hypotensive effects of dipyridamole; antiplatelet activity of dipyridamole may increase heparin toxicity
Aspirin effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses > 2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs

Contraindications

Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; due to association of aspirin with Reye syndrome, do not use in children ( <16 y) with flu

Precautions

Pregnancy

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

Precautions

Aspirin may cause transient decrease in renal function and aggravate chronic kidney disease; avoid use in patients with severe anemia, with history of blood coagulation defects, or who are taking anticoagulants
Caution in hypotension; dipyridamole has peripheral vasodilating effects

Anticoagulants

In patients with renal failure due to crescentic glomerulonephritis and nephrotic syndrome, low-dose heparin followed by oral anticoagulation leads to improved renal and systemic function. It probably reduces the destructive effects of fibrin thrombi in the small vessels of the kidney.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders.
Tailor dose to maintain an INR in the range of 2-3.

Dosing

Adult

5-10 mg/d PO qd for 2-3 d; adjust dose according to desired INR

Pediatric

Not established

Interactions

Drugs that may decrease anticoagulant effects include griseofulvin, carbamazepine, glutethimide, estrogens, nafcillin, phenytoin, rifampin, barbiturates, cholestyramine, colestipol, vitamin K, spironolactone, oral contraceptives, and sucralfate
Medications that may increase anticoagulant effects of warfarin include oral antibiotics, capecitabine, phenylbutazone, salicylates, sulfonamides, chloral hydrate, clofibrate, diazoxide, anabolic steroids, ketoconazole, ethacrynic acid, miconazole, nalidixic acid, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenylbutazone, phenytoin, propoxyphene, sulfonamides, gemfibrozil, acetaminophen, and sulindac

Contraindications

Documented hypersensitivity; severe liver or kidney disease; open wounds or GI ulcers

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Do not switch brands after achieving therapeutic response; caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

Heparin

Augments activity of antithrombin III; does not actively lyse but is able to block further thrombogenesis; prevents reaccumulation of a clot after a spontaneous fibrinolysis.

Dosing

Adult

Loading dose: 40-170 U/kg IV
Maintenance infusion: 18 U/kg/h IV
Alternatively, start with 50 U/kg/h IV, followed by a continuous infusion of 15-25 U/kg/h; increase dose by 5 U/kg/h q4h prn using aPTT results

Pediatric

Loading dose: 50 U/kg/h IV
Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h IV q6-8h prn using aPTT results

Interactions

Digoxin, tetracycline, nicotine, and antihistamines may decrease effects; NSAIDs, aspirin, dipyridamole, dextran, and hydroxychloroquine may increase toxicity

Contraindications

Documented hypersensitivity; active bleeding and subacute bacterial endocarditis; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Some preparations contain the preservative benzyl alcohol; when used in large amounts, benzyl alcohol has been associated with fetal toxicity (gasping syndrome); preservative-free heparin is recommended in neonates; use with caution in patients who are diagnosed with shock or severe hypotension

Immunosuppressant agents

Inhibit key factors responsible for immune reactions.

Mycophenolate (Cellcept, Myfortic)

Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses denovo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.
Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic) is an enteric-coated product that delivers the active moiety.

Dosing

Adult

Mycophenolate mofetil: 1 g/d PO/IV q12h
Mycophenolic acid: 720 mg PO bid; administer on empty stomach 1 h before or 2 h after meals

Pediatric

Not established

Interactions

In combination with either acyclovir or ganciclovir may result in higher levels for both interacting drugs due to competition for renal tubular excretion; aluminum/magnesium present in some antacids, and cholestyramine containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live virus vaccine immune response; when administered in combination with theophylline may increase free fraction levels of theophylline; may reduce blood levels hormones contained in oral contraceptives and could reduce effectiveness

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

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

Precautions

Increases risk for infection (monitor blood count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increased free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut Myfortic tab; women of childbearing potential must have a negative serum or urine pregnancy test must be completed within one week of beginning MMF and must receive contraceptive counseling and use effective contraception; continue contraception for 6 wk following discontinuing

Tacrolimus (Prograf)

Suppresses humoral (T-lymphocyte) immunity.

Dosing

Adult

0.05 mg/kg/d IV or 0.15-0.3 mg/kg/d PO divided bid

Pediatric

0.1 mg/kg/d IV or 0.3 mg/kg/d PO

Interactions

Caution with drugs associated with renal dysfunction, including aminoglycoside, amphotericin B, cisplatin, and others (can enhance nephrotoxicity); concentrations may be increased in presence of diltiazem, nicardipine, nifedipine, verapamil, clotrimazole, fluconazole, itraconazole, ketoconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, cyclosporine, danazol, methylprednisolone, and protease inhibitors; concentrations may decrease when administered with carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin

Contraindications

Documented hypersensitivity (including hypersensitivity reactions to tacrolimus or HCO-60 [polyoxyl 60 hydrogenated castor oil])

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Insulin-dependent diabetes reported in 20% of patients using tacrolimus for transplants, which is reversible in 15% after 1 year and in 50% after 2 years; increased risk for African American and Hispanic patients; nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, tremor, headache, and increased risk of lymphomas and other malignancies (especially skin tumors) may occur; anaphylaxis, hypertension, myocardial hypertrophy, gastrointestinal abnormalities, arthralgias, cramps, asthma, and bronchitis have been reported with its use

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d

Pediatric

Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Contraindications

Documented hypersensitivity; low levels of serum thiopurine methyltransferase (TPMT)

Precautions

Pregnancy

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

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and monitor liver, renal, and hematologic function; pancreatitis rarely associated

Follow-up

Further Inpatient Care

• Management of Takayasu arteritis is long-term. Inpatient care is limited to managing acute manifestations of the disease, usually resulting in complications from organ failure, stroke, complications of pregnancy, seizures, and intracranial hemorrhage.
• ICU admission is indicated for patients with critical deterioration.
• Fetal monitoring is indicated in patients with suspected complications.

Further Outpatient Care

Monitoring long-term immunosuppressive therapy and hypertension control is necessary.

Complications

• Complications include stroke, intracranial hemorrhage, seizures, graft stenosis and/or occlusion, ischemia, organ failure, complications of hypertension, and fetal injury.
• Long-term use of corticosteroids can lead to infection, adrenal suppression, cataracts, hyperglycemia, hypertension (which complicates blood pressure control), osteoporosis, and aseptic necrosis.

Prognosis

Prognosis varies according to the severity of the disease and the response to therapy. In some series, mortality is high. Two main North American series showed survival figures of greater than 90%.

Patient Education

Patients need to understand the nature of the disease and the need to take medications to prevent complications. When in remission or in mild forms, patients are tempted to stop the antihypertensive drugs, thus increasing risk of serious neurologic and other systemic complications.

Miscellaneous

Medicolegal Pitfalls

Takayasu arteritis is rare and difficult to diagnose. Initially, symptoms are vague; disease may progress considerably until the angiogram is performed. Some individuals may find fault with the provider if they feel diagnosis was delayed.

Special Concerns

Pregnancy is an important concern; aggressively treat these patients.

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Keywords

aortic arch arteritis, aortitis syndrome, pulseless disease, brachiocephalic arteritis, occlusive thromboarteritis, nonspecific arteritis, occlusive thromboaortopathy, TA

Contributor Information and Disclosures

Author

Gabriel Bucurescu, MD, MS, Staff Neurologist, Neurology Service, Philadelphia Veterans Affairs Medical Center
Gabriel Bucurescu, MD, MS is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy Society
Disclosure: Nothing to disclose.

Medical Editor

Sydney Louis, MB, BCh, MD, Emeritus Professor, Department of Neurology, Brown University School of Medicine
Sydney Louis, MB, BCh, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

CME Editor

,, Kathy Roarty Placeholder
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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