Takayasu's arteritis

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Takayasu's arteritis
Microscopic takayasu.jpg
Takayasu's arteritis. Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
ICD-10 M31.4
ICD-9 446.7
OMIM 207600
DiseasesDB 12879
MedlinePlus 001250
MeSH D013625

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Brian Blank

Synonyms and Keywords: Aortic arch syndrome, nonspecific aortoarteritis, pulseless disease; TA

Overview

Takayasu's arteritis is an inflammatory disease of unknown etiology that affects mainly the aorta and its branches. Takayasu's arteritis is a form of large vessel granulomatous vasculitis characterized by massive intimal fibrosis and vascular narrowing. Due to obstruction of the main branches of the aorta, including the left common carotid artery, the brachiocephalic artery, and the left subclavian artery. Takayasu's arteritis can present as pulseless upper extremities (arms, hands, and wrists with weak or absent pulses on the physical examination) which may be why it is also commonly referred to as the "pulseless disease".

Historical Perspective

The first case of Takayasu’s arteritis was described in 1908 by Dr. Mikito Takayasu at the Annual Meeting of the Japan Ophthalmology Society.[1][2] Dr. Takayasu described a peculiar "wreathlike" appearance of blood vessels in the back of the eye (retina). Two Japanese colleagues at the same meeting (Dr. Onishi and Dr. Kagoshima) reported similar eye findings in patients whose wrist pulses were absent. It is now known that the blood vessel malformations that occur in the retina are a response (new blood vessel growth) to arterial narrowings in the neck, and that the absence of pulses noted in some patients occur because of narrowings of blood vessels to the arms. The eye findings described by Takayasu are rarely seen in patients from North America.

Classification

Four types of late-phase Takayasu arteritis are described on the basis of the sites of involvement.[3] The most common type is type III, which is found in as many as 65% of patients. The most commonly involved vessels include the left subclavian artery (50%), left common carotid artery (20%), brachiocephalic trunk, renal arteries, celiac trunk, superior mesenteric artery, and pulmonary arteries (50%). Infrequently, the axillary, brachial, vertebral, coronary, and iliac arteries are involved.

Type I

Classic pulseless type that involves the brachiocephalic trunk, carotid arteries, and subclavian arteries

Type II

Combination of type I and III

Type III

Atypical coarctation type that involves the thoracic and abdominal aorta distal to the aortic arch and its major branches

Type IV

Dilated type that involves extensive dilatation of the length of the aorta and its major branches

Pathophysiology

Although its cause is unknown, the condition is characterized by segmental and patchy granulomatous inflammation of the aorta and its major derivative branches. This inflammation leads to arterial stenosis, thrombosis, and aneurysms. There is also irregular fibrosis of the blood vessels due to chronic vasculitis, leading to sometimes massive intimal fibrosis (fibrosis of the inner section of the blood vessels). Prominent narrowing due to inflammation, granuloma, and fibrosis is often seen in arterial studies such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), or arterial angiography (DSA).

The genetic contribution to the pathogenesis of Takayasu's arteritis is supported by the genetic association with HLA-B∗52. A recent large collaborative study uncovered multiple additional susceptibility loci for this disease, increasing the number of genetic loci for this disease to five risk loci across the genome.[4] About 200,000 genetic variants were genotyped in two ethnically divergent Takayasu's arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. The study identified and confirmed two independent susceptibility loci within the HLA region (r2 < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10-16) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10-9; and rs189754752, OR = 2.47, p = 4.22 × 10-9). In addition, a genetic association was identified and confirmed between Takayasu's arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10-12). The risk allele in this locus results in increased mRNA expression of FCGR2A. In addition, a genetic association between IL12B and Takayasu arteritis was established (rs56167332, OR = 1.54, p = 2.18 × 10-8). A fifth genetic locus for the disease on chromosome 21q22 downstream of PSMG1 was also revealed (P=4.39X10-7).[4]

Epidemiology and Demographics

Race

Although Takayasu's arteritis has been reported worldwide, there is a predilection for young Asian women. In the Western world, atherosclerosis is a more frequent cause of obstruction of the aortic arch vessels than is Takayasu's arteritis.

Age

The age of onset is typically between 15 and 30 years.

Gender

Females are about 8–9 times more likely to be affected by Takayasu's arteritis than males.

Natural History, Complications and Prognosis

Natural History

Those with the disease often notice symptoms between 15 and 30 years of age. Some people develop an initial "inflammatory phase" characterized by systemic illness with signs and symptoms of malaise, fever, night sweats, weight loss, joint pain, fatigue, and fainting. Fainting may result from subclavian steal syndrome or carotid sinus hypersensitivity.[5] There is also often anemia and marked elevation of the ESR or C-reactive protein (nonspecific markers of inflammation). The initial "inflammatory phase" is often followed by a secondary "pulseless phase". The "pulseless phase" is characterized by vascular insufficiency from intimal narrowing of the vessels manifesting as arm or leg claudication, renal artery stenosis causing hypertension, and neurological manifestations due to decreased blood flow to the brain. Of note is the function of renal artery stenosis in causation of high blood pressure: Normally perfused kidneys produce proportionate amount of a substance called renin. Stenosis of the renal arteries causes hypo-perfusion (decreased blood flow) of the juxtaglomerular apparatus, resulting in exaggerated secretion of renin, and high blood levels of aldosterone, eventually leading to water and salt retention and high blood pressure. The neurological symptoms of the disease vary depending on the degree, and the nature of the blood vessel obstruction and can range from lightheadedness, to seizures in severe cases. One rare but important feature of the Takayasu's arteritis is ocular involvement in form of visual field defects, vision loss, or retinal hemorrhage. Some individuals with Takayasu's arteritis may present with only late vascular changes, without a preceding systemic illness. In the late stage, weakness of the arterial walls may give rise to localized aneurysms. As with all aneurysms, possibility of rupture and vascular bleeding is existent and requires monitoring. Raynaud's phenomenon is commonly found in this disease, mainly due to decreased circulation of the blood to the arms.

Complications

Cardiac complications of Takayasu arteritis may include aortic regurgitation, myocarditis and congestive heart failure.

Prognosis

Five year survival in Takayasu arteritis is over 90%, but Takayasu arteritis is associated with significant morbidity.

Symptoms

The disease can be divided into two phases: a pre-pulseless phase and subsequent pulseless phase. In the initial phase is pre-pulseless phase, patients present with non-specific constitutional symptoms of vasculitis, which may include any of the following:

With progression of the disease and involvement of the branches of aorta,[6] specific symptoms secondary to narrowing/occlusion of the branches of aorta become evident.

  • Carotid and vertebral arteries: headache, vertigo, syncope, convulsions and dementia
  • Coronary arteries: chest pain, angina which may progress to myocardial infarction
  • Ascending aorta: aortic regurgiatation

Involvement of the subclavian artery is common and may lead to subclavian steal syndrome.[7] In this syndrome, the stenosis of the subclavian artery, proximal to the origin of vertebral artery leads to the retrograde flow of blood from the vertebral artery back to subclavian artery during exercise, secondary to vasodilation of blood vessels. The retrograde flow of blood from the vertebral artery back towards subclavian compromises blood flow in the posterior cerebral bed, leading to various neurological symptoms including presyncope/syncope.

Additional findings include skin lesions resembling erythema nodosum, erythema multiforme, pyoderma gangrenosum. In advanced stages of the disease, the occlusion of the vessels in the extremities may lead to ischemic ulcerations.

Diagnosis

Initially, a diagnosis of TA can be missed for months or years because its symptoms can be nonspecific (fever, lethargy, etc.). The American College of Rheumatology (ACR) has established diagnostic criteria for Takayasu arteritis. The patient needs to meet 3 out of 6 criteria for the diagnosis of Takayasu's arteritis:[8]

  • Age at the onset of disease <40 years
  • Claudication of the extremities
  • Decreased or absent brachial artery pulse in one or both arms
  • Difference of at least 10 mmHg in systolic blood pressure between the arms
  • Bruit over either one or both subclavian arteries or abdominal artery
  • Evidence of narrowing of aorta or its primary branches on arteriography, not due to atherosclerosis, fibromuscular dyaplasia, or other causes

Physical Examination

While Takayasu arteritis is sometimes referred to as the "pulseless disease", it is important to note that a missing peripheral pulse usually occurs late in the course of TA. More often individuals with TA present with an asymmetric pulse.[9]

Imaging Studies

The diagnosis of TA is sometimes made when a widened mediastinum is noted on a chest x ray. A follow-up CT scan will often demonstrate a widened aortic arch. [9]

Computed Tomography and Magnetic Resonance Angiography

Computed Tomography (CT) and Magnetic Resonance Angiography (MRA) are the gold standrad imaging modalities for TA and may demonstrate mural thickening of the aorta and luminal narrowing. Use of contrast may reveal inflammatory lesions prior to the development of stenoses; these lesions may be missed by angiography. Aortic lesions including stenosis, dilatation, wall thickening, and mural thrombi are well visualized on MRI, which is less adequate in visualizing distal lesions of the subclavian vessels and common carotids. [10] Non-contrast T2-weighted STIR images may be used to monitor edema in the aortic wall, which may be a surrogate for inflammation; edema may present more than 94% of patients with clinically active disease. One disadvantage of MRA is that pressure differentials cannot be measured across lesions in which imaging findings regarding their hemodynamic significance are inconclusive.

Warning: Gadolinium-based contrast agents [gadopentetate dimeglumine (Magnevist), gadobenate dimeglumine (MultiHance), gadodiamide (Omniscan), gadoversetamide (OptiMARK), gadoteridol (ProHance)] have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. In December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. [11]

While computed tomography and MRA are the best imaging modalities, findings on other imaging modalities include:

Chest radiography

Chest radiographs may reveal widening of the ascending aorta, irregular descending aorta, aortic calcifications, and rib notching (late findings).

Duplex Doppler

This modality may be used to evaluate and monitor disease in the common carotids and subclavian arteries; however, this imaging study is not useful in evaluating the aorta.

Carotid Ultrasound

Carotid ultrasound demonstrates a homogenous circumferential thickening of the vessel wall that is distinguishable from atherosclerotic thickening.

Gallium-67 radionuclide scan

This scan may demonstrate increased uptake in the aorta and branches.

MRI

Shown below is an MRI of a 15 year-old female patient with known Takayasu arteritis, showing thickened, enhancing aortic wall, consistent with large vessel vasculitis.

Takayasu arteritis.JPG

Treatment

Medical Therapy

Most people with Takayasu’s arteritis respond to steroids such as prednisone. The usual starting dose is approximately 1 milligram per kilogram of body weight per day (for most people, this is approximately 60 milligrams a day). Because of the significant side effects of long-term high–dose prednisone use, the starting dose is tapered over several weeks to a dose that the physician feels is tolerable for the patient.

Promising results are achieved with mycophenolate and tocilizumab. If treatment is not kept to a high standard then long term damage or death can occur.

Stress is a major factor that should be avoided at all costs; if this is not taken into account the surge of adrenaline can have a damaging effect on the heart.

Surgery

Surgical options may need to be explored for those who do not respond to steroids. Re-perfusion of tissue can be achieved by large vessel reconstructive surgery such as bypass grafting. Grafting autologous tissue has the highest rates of success. Stenting often obviates the need for surgery.

Percutaneous transluminal coronary angioplasty (PTCA) is not as effective in the long term but has fewer risks.

References

  1. synd/2722 at Who Named It
  2. M. Takayasu. A case with peculiar changes of the central retinal vessels. Acta Societatis ophthalmologicae Japonicae, Tokyo 1908, 12: 554.
  3. "eMedicine - Arteritis, Takayasu : Article by Robert L Cirillo, Jr, MD, MBA". Retrieved 2007-07-19. 
  4. 4.0 4.1 Saruhan-Direskeneli, G (Jul 2, 2013). "Identification of Multiple Genetic Susceptibility Loci in Takayasu Arteritis". American journal of human genetics. 93 (2): 298–305. PMC 3738826Freely accessible. PMID 23830517. doi:10.1016/j.ajhg.2013.05.026.  Unknown parameter |coauthors= ignored (help)
  5. Shikino Kiyoshi, Takako Masuyama and Masatomi Ikusaka. FDG-PET of Takayasu Arteritis. JGIM 2014.
  6. Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M; et al. (1994). "Takayasu arteritis.". Ann Intern Med. 120 (11): 919–29. PMID 7909656. 
  7. Yoneda S, Nukada T, Tada K, Imaizumi M, Takano T (1977). "Subclavian steal in Takayasu's arteritis. A hemodynamic study by means of ultrasonic Doppler flowmetry.". Stroke. 8 (2): 264–8. PMID 15335. 
  8. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM et al. (1990) The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33 (8):1129-34. PMID: 1975175 PMID: 1975175
  9. 9.0 9.1 "Takayasu Arteritis: eMedicine Pediatrics: General Medicine". 
  10. Yamada I, Nakagawa T, Himeno Y: Takayasu arteritis: diagnosis with breath-hold contrast-enhanced three- dimensional MR angiography. J Magn Reson Imaging 2000; 11: 481
  11. www.fda.gov

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