Takayasu's arteritis

I. What every physician needs to know.

Takayasu’s arteritis (TA) is a large vessel vasculitis. It is also known as pulseless disease or aortic arch syndrome. It affects primarily the aorta and its primary branches. It results from idiopathic inflammation of the artery wall, causes uniform vascular stenosis, dilatation and aneurysm in 25%, and/or thrombosis.

II. Diagnostic Confirmation: Are you sure your patient has Takayasu's Arteritis?

The diagnosis of Takayasu’s arteritis can be confirmed with the American College of Rheumatology’s (ACR) classification criteria. These criteria help to differentiate Takayasu’s from other vasculitides. The six criteria are as follows:

Age of disease onset ≤ 40 years
Claudication of the extremities
Decreased brachial artery pulse
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Blood pressure difference >10 mmHg between arms
Bruit over subclavian arteries or aorta
Arteriogram abnormality

The patient has Takayasu’s if three of the above six criteria are met (sensitivity 90.5%, specificity 97.8%).

A. History Part I: Pattern Recognition:

Constitutional symptoms from systemic inflammation are common early in the disease process, and include weight loss, fevers, night sweats, malaise, myalgias. and arthralgias. With progression of disease comes vascular compromise, and symptoms include cold extremities and claudication. Involvement of the subclavian artery is most common, which can result in a subclavian steal. Involvement of the pulmonary artery may cause non-specific symptoms of chest pain, and dyspnea associated with pulmonary hypertension. Aortic dilatation can cause significant aortic regurgitation and symptoms of congestive heart failure.

If the carotid and vertebral arteries are affected, there may be symptoms of dizziness, syncope, stroke and/or headache, while involvement of mesenteric arteries may cause diarrhea and abdominal pain. Involvement of coronary arteries is possible, with resultant angina, ischemia or infarct of myocardium.

B. History Part 2: Prevalence:

Takayasu’s arteritis is primarily a disease of adolescent girls and young women, who account for 80-90% of cases. The prevalence is highest in the Asian population but it is seen in all races and geographic areas. South America has now been recognized as an area of high incidence. Specific genetic predisposition may be attributable to certain human leukocyte antigen B (HLA-B) types, but no specific environmental factors are known to contribute to disease pathogenesis.

C. History Part 3: Competing diagnoses that can mimic Takayasu's Arteritis.

The differential diagnosis of Takayasu’s arteritis is divided into several categories. Firstly, there are diseases of systemic inflammation with overlapping affected organs, like rheumatoid arthritis and systemic lupus erythematosus. Next, there are diseases of diseased blood vessels with overlapping findings, including severe atherosclerotic disease, syphilitic aortitis, and coarctation of the aorta.

Lastly, Takayasu’s arteritis needs to be differentiated from giant cell arteritis, the other large vessel vasculitis. The most discriminating factor between these two entities is age of onset. While Takayasu’s is a disease of young women, giant cell arteritis affects predominantly older patients. Similarly, Takayasu’s has a predilection for the Asian population not seen with giant cell arteritis. Lastly, although both diseases can have symptoms of arterial inflammation in the head and neck, upper extremity symptoms predominate in Takayasu’s.

D. Physical Examination Findings.

The physical exam in Takayasu’s arteritis may be quite abnormal; patients may appear chronically ill. Blood pressure should be measured in both arms, often a pressure differential of 10 mmHg is present. Hypertension is common, secondary to renal artery involvement. Commonly, there is tenderness over affected arteries, which may be evidenced on physical exam of the neck, shoulder, or arm. Synovitis of knees and wrists is seen early in disease. Pulselessness is also a common sign, and affects the upper extremities more than lower. Bruits are heard over affected vessels, and aortic regurgitation is common. Less commonly, there may be a rash of erythema nodosum, or characteristic ophthalmologic findings.

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There is no specific lab test that can make the diagnosis of Takayasu’s; of the six ACR diagnostic criteria, none are lab criteria. However, a young female patient with vaso-occlusive disease and systemic inflammation should make a clinician consider Takayasu’s. Anemia of chronic inflammation is a common finding, and laboratory tests, which help to distinguish TA from rheumatoid arthritis or lupus may be warranted, specifically antinuclear antibody (ANA), rheumatoid factor (RF), and double stranded DNA (dsDNA). These tests are not typically abnormal in TA. In some studies, Anti-endothelial cell antibodies (AECA) is a common finding in TA, but this is not often used clinically.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

While traditional angiography is the gold standard of imaging tests, recent studies and recommendations indicate that other non-invasive modalities such as magnetic resonance imaging/angiography (MRI/A), computed tomography (CT) angiography, and ultrasound all have a role in diagnosis and serial assessment of the distribution and degree of vessel involvement and progression of TA. In the setting of renal failure, ultrasound of an affected large vessel (brachial or carotid) may help yield a diagnosis without the risk of more invasive studies. Positron Emission Tomography (PET) scanning may have superior sensitivity to MRI, however, due to its limited availability and non-validated diagnosis criteria, its role has not been established.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

The erythrocyte sedimentation rate (ESR) may be elevated in cases of TA. However, it is non specific, and there are cases where the ESR is normal. There is not histologic role or tissue used for this diagnosis.

III. Default Management.

Corticosteroid therapy is the first line therapy, with varied initial doses of prednisone 40-60 milligrams (mg). Due to low prevalence of disease, large trials of other immune modulating therapies are lacking. There are studies, which demonstrate the utility of methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, and tumor necrosis factor-alpha (TNF-alpha) inhibitors in the treatment of TA. At least one study also describes a role for minocycline in the treatment of TA, owing to its inhibition of matrix metalloproteinases. There is also a report of improved limb ischemia with sildenafil in TA. Cyclophosphamide is not typically used due to its toxicity and limited efficacy in TA.

A. Immediate management.

Like other large vessel vasculitides, namely giant cell arteritis, TA is quite steroid responsive. Once a diagnosis is made of TA, corticosteroid therapy should be initiated. If arterial stenosis worsens, another treatment option is percutaneous angioplasty, or revascularization with bypass grafts. This procedure is particularly effective when coupled with adjunctive immunosuppression. Stenting is less favorable due to high rates of re-occlusion. For many patients, surgical management is not necessary due to extensive collateralization in TA patients.

B. Physical Examination Tips to Guide Management.

As in many of the vasulitides, the clinical effect of treatment for TA is expected over weeks to months. Although an astute hospitalist may be able to make this diagnosis, it is unlikely that clinical improvement will occur over the course of a hospitalization. Arrangement for follow up with rheumatology is critical. Systemic effects of inflammation such as fatigue and fever should abate with treatment, but likely not during the time frame of an acute hospitalization.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

A few reports refer to monitoring of C-reactive protein (CRP) in the outpatient setting, as a surrogate for degree of inflammation. However, a study has shown that 50% of its patients had active disease progression with normal acute phase reactants (ESR, CRP). In addition, radiologic monitoring with CT or magnetic resonance imaging (MRI) may be warranted, and is a way to non-invasively assess vessel inflammation.

D. Long-term management.

Long-term management of TA includes immunosuppression with corticosteroid treatment, steroid sparing therapy like methotrexate or anti-TNF-alpha agents such as infliximab. Other long term agents include aspirin or other platelet inhibitors, which are thought to decrease platelet aggregation at the site of stenotic arteries and should be used in conjunction with corticosteroids. Post-discharge follow-up with a rheumatologist is vital.

Long-term management may also include revascularization or surgery, particularly in short stenotic segments. Utility of percutaneous revascularization can be limited, as the linear extent of inflammation in an affected vessel may be too long for angioplasty. If symptoms of aortic regurgitation become severe in the setting of aortic root disease, then valve replacement is a surgical treatment option.

E. Common Pitfalls and Side-Effects of Management.

Therapy with corticosteroids is likely to be long-term, and may require PCP prophylaxis if using >20 mg of prednisone for >2 weeks, or stress dose steroids if acquired adrenal insufficiency occurs, particularly in the setting of superimposed illness. The hospitalist should anticipate these common pitfalls of chronic corticosteroid use, as well as exacerbation of bone disease and diabetes. Consultation with rheumatology should happen early on in disease management.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

There is no standard adjustment of corticosteroid dose for a patient with renal insufficiency.

B. Liver Insufficiency.

There is no standard adjustment of corticosteroid dose for a patient with liver disease.

C. Systolic and Diastolic Heart Failure.

There is no standard adjustment of corticosteroid dose for a patient with heart failure. However, exacerbation of heart failure should alert the physician to the possibility of disease progression and echocardiogram evaluation. Worsening aortic or coronary vessel inflammation could manifest as heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease.

While there is no standard adjustment of corticosteroid dose in the setting of coronary artery or peripheral artery disease, the clinician should be alert to signs and symptoms of worsening vascular disease, as this may be a sign of disease progression or treatment failure.

E. Diabetes or other Endocrine issues.

Increasing glucose levels and careful diabetes management with long-term steroid use should be anticipated. Additionally, monitoring of bone disease is particularly important in the setting of ongoing corticosteroid use in TA.

F. Malignancy.

There is no specific adjustment of corticosteroid dose for patients with concurrent malignancy.

G. Immunosuppression (HIV, chronic steroids, etc).

TA is rare in patients with underlying HIV, and has only been rarely reported.

H. Primary Lung Disease (COPD, Asthma, ILD).

There is no standard adjustment of corticosteroid dose for a patient with underlying lung disease.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

Although there are no specific guidelines for alteration of corticosteroid dose in the setting of concurrent psychiatric disease, greater monitoring is warranted given known psychiatric side effects of corticosteroid therapy.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

One clinical hallmark of late TA is pulselessness. Signout should include a description of the patient’s pulse exam such that the next examiner may easily detect a change in condition. Other possible significant clinical manifestations include subclavian steal syndrome, and limb ischemia. Appropriate documentation of these findings are critical for safe transitions of care.

B. Anticipated Length of Stay.

Because the clinical manifestations of TA are myriad, there is no a priori way to predict a length of stay. For example, a patient with minor symptoms of pulse asymmetry may require a shorter stay than a patient with the same disease process who suffers from mesenteric ischemia or severe aortic regurgitation.

C. When is the Patient Ready for Discharge.

Because the clinical manifestations of TA are myriad, there is no a priori way to describe a readiness for discharge or specific discharge criteria. Appropriate discharge should be guided by the specific symptoms and findings driving the hospitalization. For instance, a patient admitted with hemoptysis secondary to pulmonary artery involvement should have resolution of bloody sputum, stable oxygenation, and stable hemoglobin. A patient with TA and symptomatic limb ischemia would necessarily have a different set of discharge criteria.

D. Arranging for Clinic Follow-up.

N/A

1. When should clinic follow up be arranged and with whom.

First follow up should be with rheumatology, for maintenance and monitoring of immunosuppresion. If the patient already has an endocrinologist who follows diabetes and/or bone disease, appropriate follow up should be arranged with that provider as well. The primary care physician should always be contacted and close follow up facilitated.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Signs of systemic inflammation may be checked regularly, and may help to gauge disease remission. ESR, CRP and complete blood count (CBC) could be ordered prior to discharge as a baseline for long-term monitoring.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

ESR, CRP, and CBC are likely to be monitored over the long term as markers of systemic inflammation. These elevated markers may abate with appropriate treatment.

E. Placement Considerations.

Patients with TA are typically young women, highly functional and unlikely to require placement, particularly in the early stages of disease.

F. Prognosis and Patient Counseling.

The clinical course of TA is variable, as are many diseases of chronic inflammation. Some patients experience progressive inflammation even in the setting of treatment, while others have long periods of quiescence. Absence of progression, and fewer complications portend a better prognosis.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Screening for diabetes and bone disease is indicated for patients on prolonged corticosteroid treatment. Pneumocystis jirovecii prophylaxis should be considered.

VII. What's the evidence?

Weyand, CM, Goronzy, JJ. “Medium- and large-vessel vasculitis”. N Engl J Med. vol. 349. 2003 Jul 10. pp. 160-9.

Arend, WP, Michel, BA, Bloch, DA, Hunder, GG, Calabrese, LH, Edworthy, SM, Fauci, AS, Leavitt, RY, Lie, JT, Lightfoot, RW. “The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis”. Arthritis Rheum. vol. 33. 1990 Aug. pp. 1129-34.

Mason, JC. “Takayasu arteritis – advances in diagnosis and management”. Nat Rev Rheumatol. vol. 6. 2010 Jul. pp. 406-15.

Michel, BA, Arend, WP, Hunder, GG. “Clinical differentiation between giant cell (temporal) arteritis and Takayasu's arteritis”. J Rheumatol. vol. 23. 1996 Jan. pp. 106-11.

Kerr, GS. “Takayasu's arteritis”. Rheum Dis Clin North Am. vol. 21. 1995 Nov. pp. 1041-58.

Kissin, EY, Merkel, PA. “Diagnostic imaging in Takayasu arteritis”. Curr Opin Rheumatol. vol. 16. 2004 Jan. pp. 31-7.

Liang, P, Tan-Ong, M, Hoffman, GS. “Takayasu's arteritis: vascular interventions and outcomes”. J Rheumatol. vol. 31. 2004 Jan. pp. 102-6.

Park, MC, Lee, SW, Park, YB, Lee, SK, Choi, D, Shim, WH. “Post-interventional immunosuppressive treatment and vascular restenosis in Takayasu's arteritis”. Rheumatology (Oxford). vol. 45. 2006 May. pp. 600-5.

Salvarani, C, Cantini, F, Boiardi, L, Hunder, GG. “Laboratory investigations useful in giant cell arteritis and Takayasu's arteritis”. Clin Exp Rheumatol. 2003 Nov-Dec;21. pp. S23-8.

Schäcke, H, Döcke, WD, Asadullah, K. “Mechanisms involved in the side effects of glucocorticoids”. Pharmacol Ther. vol. 96. 2002 Oct. pp. 23-43.

Shingadia, D, Das, L, Klein-Gitelman, M, Chadwick, E. “Takayasu's arteritis in a human immunodeficiency virus-infected adolescent”. Clin Infect Dis. vol. 29. 1999 Aug. pp. 458-9.

Maksimowicz-McKinnon, K, Hoffman, GS. “Takayasu arteritis: what is the long-term prognosis?”. Rheum Dis Clin North Am. vol. 33. 2007 Nov. pp. 777-86.

Kerr, GS, Hallahan, CW, Giordano, J, Leavitt, RY, Fauci, AS, Rottem, M, Hoffman, GS. “Takayasu arteritis”. Ann Intern Med. vol. 120. 1994 Jun 1. pp. 919-29. (Acute phase reactants are not helpful for ongoing disease progression assessment.)

Liang, P, Hoffman, GS. “Advances in the medical and surgical treatment of Takayasu arteritis”. Curr Opin Rheumatol. vol. 17. 2005 Jan. pp. 16-24. (Bypass grafts are superior to stenting of vascular occlusions.)

Numano, F. “Differences in clinical presentation and outcome in different countries for Takayasu's arteritis”. Curr Opin Rheumatol. vol. 9. 1997 Jan. pp. 12-5. (Emerging epidemiologic changes in disease prevalence.)

Kissin, EY, Merkel, PA. “Diagnostic imaging in Takayasu arteritis”. Curr Opin Rheumatol. vol. 16. 2004 Jan. pp. 31-7. (Use of new imaging techniques, including PET, in monitoring disease activity.)

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