Vasculitis: Takayasu Arteritis

Does this patient have Takayasu arteritis?

Takayasu arteritis is a primary systemic vasculitis that predominantly affects the large vessels that include the aorta, its major branches, and the pulmonary arteries. Vessel inflammation results in stenoses or aneurysms of the affected arteries.

Epidemiology

Takayasu arteritis is estimated to affect 2.6 in 1 million people. Takayasu arteritis occurs throughout the world although it may vary in different populations. In studies from Asia and the United States, women are affected 9 times more often than men, although in other countries, the male/female distribution is equal. The average age of onset in studies from Asia is 15-25 years although series from other countries have revealed an average age of onset in the 40s.

Symptoms and signs

Approximately 10% of patients with Takayasu arteritis have a monophasic asymptomatic illness in which the consequences of disease are detected at a later point. The remaining 90% of patients present to medical attention as a result of either systemic or vascular symptoms. Systemic symptoms occur to 20-80% of patients and are characterized by fatigue, malaise, weight loss, arthralgias, and myalgias. Vascular symptoms occur in up to 90% of patients and common features often reflect hypoperfusion of the affected vascular territory. This can include claudication of the upper and/or lower extremities, consequences of central nervous system hypoperfusion including transient ischemic attacks, strokes, light-headedness, syncope, headache, and visual symptoms.

When the renal arteries are affected, patients may present with severe hypertension that may be resistant to medical management. Cardiac manifestations can include angina, myocardial infarction, and arrhythmias. Aneurysmal dilation of the aortic root can result in valvular insufficiency with congestive heart failure. Pulmonary artery involvement can be under appreciated and may present with features suggestive of a pulmonary embolism. Gastrointestinal manifestations with intestinal ischemia and infarction can occur but are less common because of the availability of collateral circulation through other arteries supplying the gastrointestinal organs.

Retinal disease as was originally reported by Dr. Takayasu is rare and occurs as a result of vascular compromise in the internal carotid circulation with central retinal hypoperfusion. Extravascular features can also be seen uncommonly in Takayasu arteritis, including manifestations involving the skin, kidney and nerve.

Physical examination

All patients with Takayasu arteritis should undergo 4 extremity blood pressure measurements at the time of each clinic visit. In patients who have stenotic lesions affecting the subclavian/axillary/brachial vessels, blood pressure measurements in the affected upper extremity will not be accurate. Other findings can include vascular bruits heard over the large arteries, diminished or absent peripheral pulses, and cardiac murmurs. Tenderness to palpation may be present over affected vessels and carotidynia in particular can be detected in up to 30% of patients.

Differential diagnosis

The differential diagnosis for Takayasu arteritis includes diseases that can affect the large vessels. These may be often be differentiated from Takayasu arteritis based upon the presence of extravascular features. These include:

Atherosclerosis
Other inflammatory diseases associated with primary or secondary vasculitis: giant cell arteritis, focal isolated aortitis, Cogan syndrome, Behçet’s disease, IgG4 related disease, sarcoidosis, relapsing polychondritis, rheumatoid arthritis, seronegative spondyloarthropathies, systemic lupus erythematosus
Infections: mycotic aneurysms, syphilis, tuberculosis, HIV, leprosy
Heritable disorders of connective tissue: Marfan’s syndrome, Ehler-Danlos syndrome (type IV, VI), Loeys-Dietz syndrome, neurofibromatosis, pseudoxanthoma elasticum
Fibromuscular dysplasia
Congenital
Radiation injury

Controversies in the differential diagnosis

There remains a great deal of overlap between Takayasu arteritis, giant cell arteritis, and focal isolated aortitis in terms of the vessels that are affected and the histologic findings. Because of this, some investigators feel that these diseases represent differing phenotypes along a single spectrum of disease.

What tests to perform?

Laboratory testing

There are no laboratory tests that can confirm a diagnosis of Takayasu arteritis. Typical laboratory findings are indicative of a generalized inflammatory process and include elevations in erythrocyte sedimentation rate and C-reactive protein as well as findings on complete blood counts that include leukocytosis, anemia, and/or anemia. Laboratory testing should also include measurements of renal and hepatic function as blood vessels supplying these organs can be affected in Takayasu arteritis. There are no serologic abnormalities seen in Takayasu arteritis and this form of vasculitis is not associated with antineutrophil cytoplasmic antibodies (ANCA).

Laboratories may play a role in the initial diagnostic process in considering other etiologies of large vessel vasculitis in the appropriate setting. Examples might include immunoglobulin subtyping to look at IgG4 level in patients who may be suspected to have IgG4 related disease, or infection linked investigations in patients who may have infectious aortitis. Laboratory testing does play a role in serial monitoring of patients who have an established diagnosis of Takayasu arteritis. Monthly laboratories are often performed to include erythrocyte sedimentation rate, C-reactive protein, complete blood count, and chemistries, which may also be influenced by toxicity monitoring performed for medications the patient is receiving.

Imaging

Imaging plays an important role in both the diagnosis and monitoring of patients with Takayasu arteritis. As the diagnosis of Takayasu arteritis is based upon the presence of compatible vascular lesions, vascular imaging represents the foundation on which a diagnosis of Takayasu arteritis is made. In patients suspected to have Takayasu arteritis the entire aorta and branch vessels should be imaged to examine for stenotic or aneurysmal lesions. Detailed imaging not only provides critical information on the distribution of vascular lesions which can support the diagnosis, it also provides important information about lesions in key territories that can influence outcome as well as providing a complete view of the large vessels for future disease monitoring.

The main imaging techniques that are performed include magnetic resonance arteriography (MRA), computed tomography arteriography (CTA), and catheter directed dye arteriography. Catheter directed dye arteriography allows precise luminal visualization and also provides a means to perform central pressure monitoring and vascular intervention. However, it has the disadvantage of being an invasive technique that can be associated with bleeding, vessel injury, or embolization and it involves X-ray exposure and contrast dye.

MRA and CTA both offer an advantage in being noninvasive techniques that can be performed serially. CTA involves X-ray exposure and both MRA and CTA are contraindicated in renal insufficiency. MRA also provides information on the vessel wall. Although information can be gained regarding vessel wall thickness and signal intensity, the utility of these parameters in assessing disease activity remains unclear. After diagnosis, imaging continues to be an important part of disease activity monitoring in which the presence of new vascular lesions in new territories is considered indicative of active disease. Monitoring by MRA or CTA should be performed at every 6-12 month intervals or at the time where there is suspicion of active disease based on other clinical features.

Other imaging techniques that have been utilized in Takayasu arteritis include ultrasound and positron emission tomography (PET). Ultrasound may be useful in selective clinical settings but may not provide sufficient precision to assess new vascular changes. PET is an emerging technology that is being studied in Takayasu arteritis although its current utility in clinical practice is unclear.

Biopsies

Because Takayasu arteritis affects the large blood vessels, biopsies are typically not performed for diagnostic purposes. Vascular tissue may be obtained in patients with Takayasu arteritis at the time of a vascular surgical procedure when this is being performed for therapeutic reasons. Although such interventions are ideally performed at a time of disease quiescence, active vasculitis has been seen in up to 44% even when the disease was thought to be clinically quiescent, demonstrating the insensitivity of our current means to accurately assess disease activity. The histologic findings in Takayasu arteritis are that of a panarteritis in which the inflammatory infiltrate is predominantly lymphocytic with scattered giant cells in the media and adventitia with granuloma formation. Later onset changes include disruption of the internal elastic lamina, neovascularization of the adventitia, and adventitial fibrosis.

Overall Interpretation of test results

The diagnosis of Takayasu arteritis is largely based on compatible vascular lesions in appropriate clinical setting which may include elevations in acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, and findings on complete blood count). As imaging techniques provide information on the location of vascular lesions, this can have prognostic value by demonstrating disease affecting critical vascular territories.

Controversies in diagnostic testing

While erythrocyte sedimentation rate and C-reactive protein can be useful markers of inflammatory disease, they may be elevated for other reasons such as infection and in some patients they may be normal even in the setting of pathologically documented active disease. On MRA or CTA imaging, worsening of either stenoses or aneurysms in a previously affected area can be difficult to interpret as this may reflect progressive damage from prior disease activity.

How should patients with Takayasu arteritis be managed?

Therapeutic overview of Takayasu arteritis

Treatment of Takayasu arteritis includes both medical and non-medical approaches. Glucocorticoids remain the foundation of medical treatment in Takayasu arteritis. Although other immunosuppressive agents are often used, almost all of this experience has come solely from case series and open-label studies such that the efficacy of these approaches compared to glucocorticoids alone is unknown. Although an increasing number of randomized trials have been performed in giant cell arteritis, the experience in this disease should not be extended to Takayasu arteritis, particularly as some series suggest a differing therapeutic response.

Treatment of Takayasu arteritis presents a number of complicated issues. The nature of the disease in impacting a young and predominantly female population has ramifications in terms of the short- and long-term toxicity of individual therapies. Accurate assessment of disease activity in Takayasu arteritis remains one of the greatest challenges in guiding treatment decisions and overall patient management.

Specific medical therapies in Takayasu arteritis

Glucocorticoids

Glucocorticoids should be the first treatment initiated for patients with active Takayasu arteritis. They are rapidly acting and have been found to reduce the disease symptoms with some series demonstrating an improvement in blood flow and return of pulses. At initial diagnosis of active Takayasu arteritis, prednisone 1mg/kg/day is typically given for the first month followed by tapering over the next 6-9 months, although there have been no comparative trials to determine the optimal induction dose and duration.

Methotrexate

Methotrexate has been examined in open-label prospective trials in patients with resistant Takayasu arteritis. Methotrexate is usually given at doses of 15-25mg/week orally or subcutaneously. Side effects of methotrexate include bone marrow suppression, infection, hepatotoxicity, pneumonitis, teratogenicity, and stomatitis. Methotrexate is contraindicated in the setting of renal insufficiency, underlying chronic hepatic disease, severe chronic pulmonary impairment, and pregnancy. Folic acid 1mg daily is usually given together with methotrexate to reduce toxicity.

Azathioprine

Azathioprine has been examined in a small study in Takayasu arteritis where patients had improvement in symptoms and arteriographic stability over one year. Azathioprine can be associated with bone marrow suppression, infection, allergic reactions, elevated transaminases, and leukemia. Screening to assure adequate production of thiopurine methyltransferase, an enzyme involved in the metabolism of azathioprine, should be considered prior to initiation. Azathioprine is usually escalated to a dose of 2mg/kg/day.

Mycophenolate mofetil

Data with the use of mycophenolate mofetil remains small although this may be considered in selected setting. Mycophenolate mofetil is teratogenic and pregnancy testing must be performed prior to initiation in women of childbearing potential followed by a dedicated contraceptive plan. Other side effects of mycophenolate mofetil include bone marrow suppression, infection, and gastrointestinal toxicity.

Cyclophosphamide

As Takayasu arteritis predominantly occurs in young women and given its relapse potential, cyclophosphamide is rarely used. Toxicities of cyclophosphamide include bacterial and opportunistic infections, bone marrow suppression, infertility in men and women, teratogenicity, bladder injury, transitional cell carcinoma of the bladder, and myeloproliferative disease.

Tumor necrosis factor (TNF) inhibitors

A number of open-label studies have emerged suggesting a beneficial role of anti-TNF agents in Takayasu arteritis. These agents have not been examined in comparative studies and would typically be considered only in the setting of relapsing or resistant disease. Anti-TNF agents can have a number of side effects including an increased risk of infections including tuberculosis and opportunistic fungal infections, demyelinating disease, congestive heart failure, and development of antinuclear antibodies with a lupus-like reaction.

Tocilizumab

Tocilizumab has been of interest in Takayasu arteritis, particularly given the proven efficacy in giant cell arteritis. To date, the experience in Takayasu arteritis has been confined to case reports and small series, although a randomized trial has been in progress. Although many published reports describe a favorable response with tocilizumab in Takayasu arteritis, it carries side effect concerns that include cytopenias, hepatic toxicity, hyperlipidemia, gastrointestinal perforations, and an increased risk of infection. Given these issues and the absence of proven efficacy, use of tocilizumab should be considered only in selected rare instances in Takayasu arteritis.

Abatacept

The first randomized trial to be conducted in Takayasu arteritis examined the safety and efficacy of abatacept combined with glucocorticoids in patients with newly diagnosed or relapsing disease. In Takayasu arteritis, abatacept did not prolong the rate relapse-free survival or the median duration of remission. Although it was associated with a favorable safety profile, the absence of efficacy in the trial does not support the use of abatacept in the treatment of Takayasu arteritis. Of note is that a trial examining abatacept in giant cell arteritis that was conducted in parallel by the same investigator team using the same study protocol, found abatacept to be efficacious in giant cell arteritis. This observation of contrasting results raises intriguing questions about the relationship between these diseases and the current need to view them as therapeutically unique.

Rituximab

In contrast to small vessel vasculitides, such as granulomatosis with polyangiitis and microscopic polyangiitis, there has previously been limited interest in pursuing B cell-directed therapies in large vessel vasculitis. However, a small number of recent case reports have been published with the use of rituximab in Takayasu arteritis. Rituximab has also been examined in patients with IgG4-related disease including aortitis. It remains unclear whether larger studies of rituximab will be performed in Takayasu arteritis and at the current time, it is not recommended for treatment of these patients.

Anti-platelet therapy

Anti-platelet therapy has been found to provide benefit in retrospective studies in giant cell arteritis. In Takayasu arteritis, there has also been a small body of evidence that the use of antiplatelet therapy is associated with a lower frequency of ischemic events.

Non-medical therapy

Up to 70% of patients with Takayasu arteritis may require non-medical interventions for revascularization of stenosed or occluded vessels that produce ischemia or for the treatment of aneurysms. The most frequent indications including renovascular hypertension resistant to medical management, cerebral hypoperfusion, limb claudication affecting quality of life, repair of aneurysms, or valvular insufficiency. Interventional modalities can include bypass surgery or endovascular procedures including percutaneous transluminal angioplasty or stenting.

Although bypass surgery is more invasive, some studies have demonstrated a lower rate of restenosis as compared with stenting or angioplasty. Nonmedical interventions should ideally be undertaken during periods of disease quiescence out of concern of minimizing vascular complications.

Management of comorbidites

Hypertension has been reported in 30-90% of Takayasu arteritis patients in individual series and may be under appreciated due to stenoses affecting the upper extremity vessels. Careful management of hypertension is important in minimizing cerebrovascular, cardiac, and renal complications. Sudden drops in blood pressure should be avoided, particularly in those who have significant stenoses in the vessel supplying cranial blood flow. Monitoring and management of other cardiovascular risk factors such as hyperlipidemia, diabetes, and smoking cessation are also important.

What happens to patients with Takayasu arteritis?

Although remission can be achieved in over 90% of patients with Takayasu arteritis, sustained remission defined as the absence of clinical, laboratory, or radiographic evidence of active disease while receiving prednisone 10mg daily or less occurs in only 28% of patients. Relapses requiring an increase in glucocorticoids and/or other immunosuppressive therapy occur in 70-90% of patients.

Mortality – mortality due to active Takayasu arteritis is uncommon and series from North America demonstrated a 5-year survival rate of over 95%. In other series however mortality has been as high as 35%. Disease related causes of mortality include cerebrovascular events, myocardial infarction, congestive heart failure, aneurysm rupture, or renal failure.
Morbidity – Takayasu arteritis is associated with substantial morbidity. In one series, almost 50% of patients experienced permanent disability.
Pregnancy – as Takayasu arteritis predominantly affects women in childbearing years, the impact of disease on pregnancy is an important consideration. Published experience to date remains limited although favorable outcomes have been reported with careful follow-up, ideally by a high-risk obstetrician. Monitoring for hypertension is essential.
Pharmacologic considerations – as Takayasu arteritis primarily affects people less than the age of 50, the long-term toxicity of therapy remains an important consideration. Decisions regarding the duration of treatment must factor in the severity and damage related to the vasculitis, the effectiveness of treatment, and its side effects.

How to utilize team care?

Specialty consultations – patients with Takayasu arteritis are typically medically managed by rheumatologists. Multiple other specialty consultants may be involved in their care that can include vascular or cardiothoracic surgeons for vascular interventions, invasive radiologists for diagnostic procedures and endovascular interventions, cardiology, vascular medicine, ophthalmology, and many others.
Nurses – nurses can provide a meaningful role in the care of patients with Takayasu arteritis in performing 4 extremity blood pressure measurements during office visits, providing education about this disease and medications, and teaching about self administered medications.
Pharmacists – pharmacists can provide a meaningful role in the care of patients with Takayasu arteritis in reviewing the correct administration of her medication, answering questions about medication toxicities, and in reviewing medication profiles for possible interactions.
Dieticians – there are no specific dietary restrictions in patients with Takayasu arteritis. Because of the use of glucocorticoids dietary measures to reduce concentrated sweets and monitor caloric intake are important.
Therapists – physical and occupational therapy can play an important role in patients who have become debilitated from their illness. Patients can also develop a steroid myopathy with weakness in the proximal muscle groups during glucocorticoid treatment for Takayasu arteritis which can benefit from physical therapy. Strokes represent a potential complication of Takayasu arteritis for which physical, occupational, and speech therapy play an important role.

Are there clinical practice guidelines to inform decision making?

Applications – there are no general clinical practice guidelines to inform decision making in Takayasu arteritis. In 2011, the Italian Society of Rheumatology published recommendations regarding the treatment of primary large vessel vasculitis with biologic agents. These should be viewed within the context of the individual patient.
Limitations – the absence of randomized trials in Takayasu arteritis make it difficult to establish therapeutic guidelines.

Other considerations

ICD-10 code – Takayasu arteritis M31.4
Typical lengths of stay – this will vary based upon the reason for hospitalization. In Takayasu arteritis patients this can be for reasons of acute management of active disease, treatment of disease-related complications, or hospitalizations for surgical or other mechanical interventions.

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