Review
Takayasu arteritis revisited: Current diagnosis and treatment

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Abstract

Takayasu arteritis (TA) is a rare nonspecific inflammatory disease of unknown cause, predominantly affecting the aorta and its main branches, coronary arteries, and pulmonary arteries of young females. It induces a variety of nonspecific inflammatory symptoms and ischemic symptoms due to stenotic lesions. Further progression of TA causes destruction of the arterial wall media, leading to aortic regurgitation and aneurysms or rupture of the involved arteries. Although serological tests specific for TA are not available, new better biomarkers are emerging such as pentraxin3 and matrix metalloproteinases. Recent advances in imaging modalities including magnetic resonance angiography, computed tomography (CT), sonography, and fluorodeoxy glucose positron emission tomography/CT (FDG-PET/CT) allow earlier and accurate diagnosis of TA. Duration between onset of the disease and diagnosis has become much shorter during the last decade. Medical treatment for TA is also changing. In addition to the traditional glucocorticoids and immunosuppressants, many new biological agents are being applied to patients with TA refractory to conventional treatment with favorable results. As for treatment for vascular complications, efficacy of endovascular treatment is still a matter of controversy because of the high rate of restenosis at an early stage after the procedure. Based on these advances, the prognosis and quality of life of TA patients have improved to a great deal. However, there are many issues that remain to be solved in the management of TA.

Introduction

In 1908, a Professor of Ophthalmology at Kanazawa University, Mikito Takayasu, reported a case of a 22-year old female patient who demonstrated a ‘peculiar ocular fundus characterized as bizarre change of central vessels of the retina by coronary anastomosis’ [1]. This was the first description of Takayasu arteritis. Similar cases were then repeatedly reported in Japan and other countries [2]. In 1951, Shimizu et al. reported 25 cases of ocular coronary anastomosis, weakness or deficit of radial pulses, and increased carotid arterial reflexes [3]. Since publication of this report, the disease came to be known as ‘pulseless disease’. This disease became a target of investigation by many researchers in fields of clinical as well as basic science, including ophthalmologists, rheumatologists, vascular surgeons, neurosurgeons, cardiologists, radiologists, immunologists and pathologists. In Japan, this disease is usually called aortitis syndrome after the series of investigations by Ueda et al. [4].

Management of Takayasu arteritis is changing. Recent advances in diagnostic clinical tests, especially imaging modalities and new biomarkers including reports from our laboratory [5], [6], have improved the accuracy of diagnosis, and new immunosuppressive agents are increasingly applied to this disease. Although guidelines for the management of TA were published recently [7], the clinical utility of these new technologies has not been settled yet.

The goal of this review is to revisit clinical management of TA. In particular, current advances in this field are reviewed based on our experience with more than 150 patients with TA at a single institution [8].

Section snippets

Epidemiology

In Japan, all cases of TA are registered by the Government. More than 5000 cases are registered and the number of patients increases by 200 to 400 every 3 years [7]. However, the annual rate of increase has become blunted in recent years. Peak age of onset is the latter half of teens and early twenties in female patients. No such peak exists in male patients [9].

A world-wide survey of TA revealed that cases are prevalent in Asia and Middle Eastern countries. Curiously, the male-to-female ratio

Pathology

Pathologically, the nature of this disease is a pan-arteritis mainly affecting the aorta, pulmonary artery and their major branches. The etiology of this disease is still unknown, although, it is generally accepted that a T cell-mediated autoimmune reaction against components of the vessel walls, especially the vasa vasorum, causes the chronic inflammation of large vessels [11], [12].

The first step of the pathological change in TA is granulomatous inflammation of vascular adventitia and outer

Genetic background

This disease is apparently not a genetic disorder. However, epidemiology of TA revealed its genetic background [9], [18]. There are risk alleles in HLA [19], [20], [21]. About a half of Japanese patients with TA have the HLA B52 allele [22], [23]. Also, it is obvious that some, but not many, patients show familial history of the same disease among siblings or between mother and daughter. The genetic background is currently under investigation, but it may be that it is the susceptibility to this

Signs and symptoms

Clinical signs and symptoms originate from both the systemic inflammation and from local vascular complications. The main clinical manifestations have not changed for decades, but serious complications such as visual loss, severe hypertension, end-stage renal disease, and strokes are becoming less frequent, probably because of recent advances in imaging tests which allow relatively early diagnosis. The most frequently observed systemic inflammatory symptoms are low or high grade fever, and

Diagnosis

There are no blood tests specific for TA. The most useful markers for diagnosis of TA are nonspecific inflammatory biomarkers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Conventional inflammatory markers include fibrinogen, white blood cell counts, complements (C3, C4, CH50), and immunoglobulin G. CRP is useful for following patients up after steroid treatment [24], [25]. Many other biomarkers are reported to be associated with active TA: matrix

Imaging tests

Recent advances in imaging modalities allow not only early diagnosis but also detailed assessment of vascular lesions (Fig. 2). It is now possible to evaluate localization of active inflammation by these imaging tests.

Treatment

Treatment of TA consists of two parts; induction and maintenance of remission and management of arterial complications. Remission is currently considered disappearance of symptoms and normalization of inflammatory biomarkers.

Conclusion

In general, the prognosis and vascular complications of TA are improving. Fatal or serious complications have diminished during the last decade [8]. TA is a rare disease accompanied by a variety of nonspecific clinical symptoms, that may sometimes make it difficult to diagnose in its early stages. Multiple biomarkers for its diagnosis and evaluation of activity are being developed but more specific markers are desirable. Although PTX-3 and MMPs have been proposed, their role in the assessment

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