Federico Tatò
email: federico.tato@t-online.de

Ulrich Hoffmann

Giant cell arteritis: a systemic vascular disease

Keywords: duplex sonography, extracranial involvement, fluorine-18-desoxyglucose positron emission tomography, giant cell arteritis, large-vessel vasculitis, magnetic resonance imaging , Haimhauserstrasse 4,

Giant cell arterits (GCA) is increasingly being recognized as a systemic vascular disease, not confined to the cranial arteries. Epidemiological studies have shown that almost one-third of the patients with GCA develop serious peripheral vascular complications during long-term follow up, and there is growing evidence that unrecognized extracranial involvement may be even more common. GCA of largeand medium-sized peripheral arteries typically leads to long tapering and occlusion of the arterial lumen due to concentric intimal thickening, sometimes accompanied by spontaneous dissection. Depending on the extent of the arterial obliteration and on the anatomy of the involved arterial segment, this may result in severe ischemia of the limbs during the acute phase of the disease. GCA of the aorta usually remains asymptomatic for many years, and leads to a markedly increased risk of aneurysms and dissections, particularly of the thoracic aorta. Evolving vascular imaging techniques such as duplex ultrasound, computer tomography (CT), magnetic resonance imaging (MRI), and fluorine-18-desoxyglucose positron emission tomography (18F-FDG-PET) have greatly improved our ability to detect and study arterial changes in large-artery vasculitis. Boosted by these advances in vascular imaging, vascular specialists are increasingly involved in the early diagnosis, follow-up and treatment of patients with large-vessel vasculitis.

Introduction

Giant cell arteritis (GCA) is the most common vasculitis of large and medium-sized arteries, affecting almost exclusively individuals over 50 years of age. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF][START_REF] Weyand | Giant-cell arteritis and polymyalgia rheumatica[END_REF] In this age-group the prevalence of GCA has been estimated at 200 per 100,000 persons in the United States, [START_REF] Lawrence | Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States[END_REF] and an even higher frequency has been reported in northern Europe. [START_REF] Noltorp | High incidence of polymyalgia rheumatica and giant cell arteritis in a Swedish community[END_REF][START_REF] Franzén | Giant cell arteritis and polymyalgia rheumatica in a region of Finland: an epidemiologic, clinical and pathologic study, 1984-1988[END_REF] As a result of the aging population in industrialized countries, increasing numbers of patients with GCA can be expected in the near future.

From the initial description by Hutchinson in 1890 and Horton in 1932 [START_REF] Hunder | The early history of giant cell arteritis and polymyalgia rheumatica: first description to 1970[END_REF] until recently, GCA was believed to be predominantly a localized disease, affecting primarily the cranial arteries, particularly the temporal artery (temporal arteritis) and the arteries of the retina and the optic nerve. This pat-tern of distribution explains many of the classical symptoms of GCA such as tender and swollen temporal arteries, temporal headache, jaw claudication and visual loss. Another characteristic feature of GCA is the frequent occurrence of systemic and musculoskeletal symptoms. Fatigue, weight loss, low-grade fever, polymyalgia rheumatica, arthralgia and tenosynovitis are observed alone or in combination in more than half of the patients with GCA. Laboratory signs of systemic inflammation are characteristic of the disease. An elevated erythrocyte sedimentation rate (ESR) and plasma Creactive protein (CRP) is almost always present. In addition, many patients have chronic anemia and reactive thrombocytosis. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF][START_REF] Weyand | Giant-cell arteritis and polymyalgia rheumatica[END_REF] As a consequence of these typical symptoms, most patients with GCA are initially seen by rheumatologists and ophthalmologists. Traditionally, vascular specialists have been involved in the management of patients with GCA only in exceptional cases with severe extracranial involvement leading to symptomatic peripheral or visceral ischemia. However, this pattern is gradually changing. GCA is increasingly been recognized as a generalized vascular disease potentially leading to serious peripheral arterial complications. Attentive clinical examination of the vascular system combined with modern vascular imaging techniques can contribute decisively to early diagnosis of GCA, to timely recognition of vascular complications, and to improved follow-up of disease activity during treatment. As a consequence, vascular specialists are increasingly involved in the long-term management of these patients. This review will focus on new developments in the diagnosis and treatment of GCA from the perspective of vascular medicine.

Epidemiology of extracranial GCA

Involvement of the aorta and its major branches was recognized early in a subset of patients with GCA. [START_REF] Hunder | Giant-cell arteritis producing an aortic arch syndrome[END_REF][START_REF] Klein | Large artery involvement in giant cell (temporal) arteritis[END_REF][START_REF] Perruquet | Aortic arch arteritis in the elderly[END_REF] The frequency of clinically manifest, extracranial large-artery involvement is usually quoted to be approximately 10-15%. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF][START_REF] Weyand | Giant-cell arteritis and polymyalgia rheumatica[END_REF] The true frequency of generalized vascular involvement is, however, controversial. In a population-based cohort followed for a period of 50 years, large-artery complications have been reported in 27% of the patients diagnosed with GCA, [START_REF] Neunninghoff | Incidence and predictors of large-artery complications (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years[END_REF] indicating that in the long run almost one-third of GCA patients may develop symptomatic extracranial involvement. Only very few studies have specifically looked for peripheral arterial involvement with a detailed vascular examination and imaging techniques. Large-vessel vasculitis may lead to thickening of the arterial wall without stenosis or to dilation of the artery and to the formation of aneurysms. [START_REF] Weyand | Medium-and large-vessel vasculitis[END_REF] Absent pulses arterial bruits or symptoms of ischemia may therefore be missing in many cases. Even if arterial obstructions occur, these may remain asymptomatic if they develop slowly. In our clinic we regularly see patients with high-grade stenosis or even occlusion of the subclavian or axillary artery who do not have upper limb claudication. This is particularly the case in elderly patients with reduced physical activity. Moreover, many patients with extracranial large-artery GCA do not have classical symptoms such as headache or jaw claudication, and almost half of these patients were found to have negative temporal artery biopsies. [START_REF] Barack | Disease pattern in cranial and largevessel giant cell arteritis[END_REF] It is therefore likely that extracranial involvement is underdiagnosed in patients with classical GCA or mistaken for an arteriosclerotic vascular disease in patients without temporal arteritis or typical symptoms of GCA.

Extracranial GCA may have a distribution and clinical presentation similar to Takayasu arteritis. [START_REF] Arend | The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis[END_REF][START_REF] Kerr | Takayasu arteritis[END_REF] Although histologically similar, GCA and Takayasu arteritis are considered distinct disease entities based on age of onset, distribution of vascular involvement, and clinical presentation. [START_REF] Michel | Clinical differentiation between giant cell (temporal) arteritis and Takayasu's arteritis[END_REF] Takayasu arteritis affects almost exclusively patients younger than 40 years, involves primarily the aorta and its major branches, and generally spares the cranial arteries. These criteria usually allow a clinical differentiation of these two vaculitides. More frequent recognition of aortic and largeartery involvement in GCA is, however, creating an increasing overlap between these disease entities.

Distribution and manifestations of extracranial involvement

Extracranial GCA has most frequently been reported in the aortic arch and in the subclavian and axillary arteries. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF][START_REF] Weyand | Giant-cell arteritis and polymyalgia rheumatica[END_REF][START_REF] Klein | Large artery involvement in giant cell (temporal) arteritis[END_REF][START_REF] Perruquet | Aortic arch arteritis in the elderly[END_REF] Published data on the distribution of extracranial involvement vary, depending on the methodology of the studies. In the retrospective cohort analyzed by Nuenninghoff et al., 10 18% of the GCA patients experienced a large-artery complication due to aortic aneurysm and/or dissection. In the same study, symptomatic stenosis of the subclavian, axillary and/or brachial arteries occurred in 4%, and of the iliac and/or femoral arteries in 0.6%. This low rate of symptomatic peripheral artery stenoses may not reflect the true frequency of peripheral artery involvement. In 72 cases with histologically documented extracranial GCA, Lie found an involvement of the ascending aorta and the aortic arch in 39%, of the subclavian and axillary arteries in 26%, and of the femoropopliteal arteries in 18%. [START_REF] Lie | Aortic and extracranial large vessel giant cell arteritis: a review of 72 cases with histopathological documentation[END_REF] This study suggests that extracranial GCA involvement of the arteries of the arms and legs may in fact be as common as involvement of the aorta.

GCA of the aorta typically remains asymptomatic during the early phase of the disease and causes serious late complications due to aneurysms and dissections. In a retrospective cohort from Minnesota, patients with GCA were 17.3 times more likely to develop thoracic aortic aneurysms and 2.4 times more likely to develop abdominal aortic aneurysms than individuals of the same age without GCA. [START_REF] Evans | Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis: a population-based study[END_REF] Thoracic aneurysms appear to be particularly dangerous in GCA. Of 41 patients with GCA and thoracic aneurysm, 16 developed an acute aortic dissection and eight died. [START_REF] Evans | Thoracic aortic aneurysm and rupture in giant cell arteritis: a descriptive study of 41 cases[END_REF] In this study the median time between diagnosis of GCA and occurrence of thoracic aneurysm was 7 years. Yearly transthoracic echocardiography and two-view chest radiograph (Figure 1A-C) have therefore been suggested as a screening approach in all patients with GCA. [START_REF] Bongartz | Large-vessel involvement in giant cell arteritis[END_REF] Unlike aortic involvement, GCA of the peripheral arteries causes luminal narrowing and may cause symptoms of peripheral ischemia during the acute phase of the disease. The most typical extracranial manifestation of GCA is long tapering or occlusion of the axillary artery leading to missing arm pulses, decreased blood pressure measurements, axillary bruits, and arm claudication (Figure 2). Symptomatic stenoses of the subclavian and axillary arteries have been reported in 3-15% of patients with GCA. [START_REF] Klein | Large artery involvement in giant cell (temporal) arteritis[END_REF] The true frequency of involvement of these arterial segments is, however, unknown since asymptomatic lesions may be rather common. Fortunately, obstruction of the proximal arteries to the arm rarely causes limb-threatening ischemia. Even total occlusions of the subclavian and/or axillary artery may be well tolerated due to sufficient collateralization, and frequently do not require surgical or percutaneous vascular interventions. We have observed severe upper limb ischemia only in rare cases with extensive involvement of the brachial arteries. Inflammatory stenoses of the subclavian artery are almost always distal to the origin of the vertebral artery. Therefore, patients with GCA only rarely develop a subclavian steal phenomenon.

Iliac and femoropopliteal involvement causing ischemic symptoms of the legs has been described in several case reports, [START_REF] O'brien | Peripheral arterial insufficiency due to giant cell arteritis[END_REF][START_REF] Vasquez | Superior and inferior limb ischemia in giant cell arteritis: angiography follow-up[END_REF][START_REF] Hello | Lower limb giant cell arteritis and temporal arteritis: follow-up of 8 cases[END_REF][START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF] but the true frequency of this manifestation is unknown. GCA may cause extensive obstructions of the femoropopliteal and crural arteries, resulting in claudication and even critical limb ischemia. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF] In our experience, severe ischemia requiring vascular surgery or catheter intervention is more frequent in GCA of the lower limbs than of the upper limbs. It is very likely that femoropopliteal GCA is underdiagnosed owing to the similarity and overlap of the arterial occlusions with arteriosclerotic peripheral arterial disease in these elderly patients. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF]

Pathogenesis

GCA is a panarteritis characterized by infiltration of all layers of the arterial wall by T-lymphocytes and macrophages. Multinuclear giant cells are typically found in the proximity of the fragmented internal elastic membrane. Activated CD4+ T cells are the central inflammatory cell in large-vessel vasculitis. Recent studies suggest that the inflammatory process starts in the adventitia, where resident dendritic cells become activated and trigger T-cell response by antigen presentation. [START_REF] Weyand | Medium-and large-vessel vasculitis[END_REF] The antigens responsible for these events are still unknown. Autoantigens as well as infectious agents and toxins have been suggested. Activated CD4+ T cells induce inflammatory infiltrates and activate macrophages mainly through secretion of interferon-γ. Macrophages play a key role in the secretion of cytokines causing systemic inflammation (e.g. interleukin-1 and interleukin-6) and in the local proliferation and damage within the arterial wall. Macrophages in the media cause damage to the arterial wall through secretion of metalloproteinases and reactive oxygen intermediates. [START_REF] Weyand | Correlation of the topographical arrangement and the functional pattern of tissue-infiltrating macrophages in giantcell arteritis[END_REF][START_REF] Rodríguez-Pla | Metalloproteinase-2 and -9 in giant cell arteritis. Involvement in vascular remodeling[END_REF] These processes lead to fragmentation of the internal elastic lamina, to weakening of the arterial wall, and are probably the basis for development of aneurysms and dissections. When GCA causes arterial stenosis and ischemia, this is due to marked, concentric thickening of the intima. Intimal thickening results from the proliferation of myofibroblasts and secretion of extracellular matrix. Platelet-derived growth factor, [START_REF] Kaiser | Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis[END_REF] vascular endothelial growth factor (VEGF), [START_REF] Kaiser | Formation of new vasa vasorum in vasculitis: production of angiogenetic cytokines by multinucleated giant cells[END_REF] and metalloproteinases [START_REF] Rodríguez-Pla | Metalloproteinase-2 and -9 in giant cell arteritis. Involvement in vascular remodeling[END_REF] produced by activated macrophages and giant cells play a crucial role in the induction of intimal thickening.

Many questions about the pathogenesis of GCA are still unanswered. Particularly, the initial trigger of the disease remains elusive. Advances in the understanding of the cellular mechanisms of largevessel vasculitis have, however, provided increasingly detailed explanations for the concentric arterial wall thickening and the tendency to dissection and aneurysm formation typically observed in extracranial GCA. These insights will hopefully generate new therapeutic strategies in the near future.

Physical examination and basic vascular tests in patients with GCA

The classical physical sign of GCA is the swollen, tender temporal artery with decreased or absent pulsation. The specificity of this physical finding for a positive biopsy may be as high as 99%, but the sensitivity is far lower, and an apparently normal temporal artery on physical examination does not rule out a positive biopsy result. [START_REF] Gabriel | The use of clinical characteristics to predict the results of temporal artery biopsy among patients with suspected giant cell arteritis[END_REF][START_REF] Salvarani | Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis?[END_REF] Rare, but characteristic complications of extensive involvement of the branches of the external carotid arteries are necrosis of the tongue or of the scalp (Figure 3).

Palpation of pulses, auscultation of peripheral arteries, and bilateral measurements of systolic brachial and ankle artery pressures are simple clinical tests capable of identifying many patients with suspected extracranial involvement. Absent pulses, a difference in systolic blood pressure between arms of more than 10-15 mmHg, or an abnormal ankle/ brachial index (< 0.9) indicate hemodynamically significant arterial obstructions. Arterial bruits are the earliest abnormal physical finding due to arterial stenosis, and may be present before the onset of any other symptom. Only 4-5% of GCA patients have been reported to have a diminished radial pulse or a systolic blood pressure difference of more than 10 mmHg between both arms, but 14% had bruits of the subclavian or brachial artery. [START_REF] Michel | Clinical differentiation between giant cell (temporal) arteritis and Takayasu's arteritis[END_REF] Typical localizations of arterial bruits in GCA are the carotid arteries, the supra-and infraclavicular region, over the axillary and brachial arteries, and over the orbits. Auscultation of the axillary fossa is particularly useful, since arterial bruits in this region are highly suggestive of large-vessel vasculitis, and almost never due to arteriosclerosis. An abnormal vascular examination of the lower extremities is far less specific for extracranial GCA due to the high frequency of arteriosclerotic peripheral arterial disease in the lower limbs of this elderly population. Differentiation between arteriosclerosis and vasculitis always requires further imaging studies in this arterial region.

Physical examination is not highly sensitive for aortic aneurysms, although more than 75% of abdominal aortic aneurysms with a diameter above 5 cm can be palpated. [START_REF] Lederle | Does this patient have abdominal aortic aneurysm?[END_REF] A diastolic murmur of aortic regurgitation may be the only clinical sign of a thoracic aortic aneurysm and should prompt further evaluation.

Blood inflammatory markers

A marked elevation of the ESR is typical for GCA, and an ESR above 50 mm/h is one of the five American College of Rheumatology 1990 criteria for the classification of this disease. [START_REF] Hunder | The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis[END_REF] However, a normal or only slightly elevated ESR does not rule out GCA. In a population-based study, ESR was < 30 mm/h in 3.6%, < 40 mm/h in 5.4%, and < 50 mm/h in 10.8% of patients with untreated GCA. [START_REF] Salvarani | Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurrence in a population based study[END_REF] Compared with ESR, CRP levels have the advantage of being unaffected by age and sex and of responding more rapidly to inflammation. There is some evidence that an elevated CRP may be slightly more sensitive than ESR for the diagnosis of active GCA. [START_REF] Hayreh | Giant cell arteritis: validity and reliability of various diagnostic criteria[END_REF] However, GCA patients with normal CRP but elevated ESR have been reported. [START_REF] Parikh | Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis[END_REF] In a recent study, only one of 119 patients (0.8%) with biopsy-proven GCA was found to have both normal ESR and CRP. [START_REF] Parikh | Prevalence of a normal C-reactive protein with an elevated erythrocyte sedimentation rate in biopsy-proven giant cell arteritis[END_REF] The authors of this study conclude that the use of both tests provides a slightly greater sensitivity for the diagnosis of GCA than the use of either test alone. With this approach, untreated GCA patients without detectable systemic inflammation appear to be very rare.

The use of blood markers of inflammation for the follow-up of disease activity during treatment is more complicated. Studies in Takayasu arteritis have shown that approximately 40% of patients thought to be in remission based on normal ESR and/or CRP have histological signs of active arteritis. [START_REF] Kerr | Takayasu arteritis[END_REF] These results cast doubt on the validity of currently used blood markers of inflammation for the assessment of disease activity in glucocorticoidtreated large-vessel vasculitis. Interleukin-6 (IL-6) is a promising biologic marker of disease activity, which has been shown to be markedly elevated in GCA before treatment as well as during relapses. [START_REF] Salvarani | Laboratory investigations useful in giant cell arteritis and Takayasu's arteritis[END_REF] In one study, 89% of flares of GCA during treatment were accompanied by increased IL-6, whereas only 58% of these patients had an ESR above 30 mm/h. [START_REF] Weyand | Treatment of giant cell arteritis. Interleukin-6 as a biologic marker of disease activity[END_REF] These findings indicate that IL-6 may be a highly sensitive marker of disease activity in GCA. However, the value of this marker for the practical management of GCA patients has still to be demonstrated in clinical trials.

Vascular imaging

Duplex sonography

Duplex sonography is today the first-line vascular imaging technique for the detection of large-vessel vasculitis. Interest in duplex sonography for the diagnosis of GCA was first triggered by sonographic studies of the temporal artery. [START_REF] Schmidt | Color duplex ultrasonography in the diagnosis of temporal arteritis[END_REF] Ultrasound transducers with frequencies of at least 10 MHz allow non-invasive imaging of the temporal artery with a degree of spatial resolution unachievable with any other of the currently available imaging techniques. Characteristic signs for temporal arteritis are segmental, concentric, hypoechogenic thickening of the arterial wall ('halo sign'), which may lead to luminal stenosis or total occlusion (Figure 4A andB). Sensitivity and specificity of duplex ultrasound for the diagnosis of GCA is still a matter of debate. [START_REF] Salvarani | Is duplex ultrasonography useful for the diagnosis of giant-cell arteritis?[END_REF][START_REF] Schmidt | Duplex ultrasonography in temporal arteritis[END_REF] Sensitivities above 75% and specificities above 95% have been reported in some studies. [START_REF] Schmidt | Color duplex ultrasonography in the diagnosis of temporal arteritis[END_REF][START_REF] Schmidt | Duplex ultrasonography in temporal arteritis[END_REF] Whether duplex ultrasound is indeed more sensitive than the clinical examination of the temporal artery, has however been questioned, and duplex ultrasound has not yet replaced temporal artery biopsy as a diagnostic criterion for GCA in clinical practice. [START_REF] Hunder | The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis[END_REF] Much of the controversy regarding the reliability of duplex sonography for the detection of temporal arteritis may be due to differences in methodology between published studies. In our experience, duplex sonography of the temporal artery is best performed with a 12-15-MHz ultrasound transducer. Under these conditions, and with sufficient experience of the examiner, we regularly detect bioptically confirmed temporal arteritis in clinically unremarkable temporal arteries. As has been suggested in a recent metaanalysis, [START_REF] Karassa | Meta-analysis: test performance of ultrasonography for giant-cell arteritis[END_REF] we consider duplex ultrasound of the temporal arteries a valuable diagnostic test, when used in combination with the clinical probability. Moreover, ultrasound-guided mapping of the temporal arteries has the potential to improve the diagnostic yield of the biopsy.

The contribution of duplex sonography is even more important for diagnosis, assessment of severity and follow-up in extracranial GCA. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF][START_REF] Schmidt | Color duplex ultrasonography in large-vessel giant cell arteritis[END_REF][START_REF] Schmidt | Involvement of peripheral arteries in giant cell arteritis: a color Doppler sonography study[END_REF][START_REF] Reinhard | Involvement of the vertebral arteries in giant cell arteritis mimicking vertebral dissection[END_REF][START_REF] Kolossvary | Bilateral axillobrachial and external carotid artery manifestation of giant cell arteritis: important role of color duplex ultrasonography in the diagnosis[END_REF][START_REF] Schmidt | Use of ultrasonography and positron emission tomography in the diagnosis and assessment of large-vessel vasculitis[END_REF] In the subclavian, axillary, and brachial arteries as well as in the cervical arteries, GCA has a typical sonographic appearance with concentric, hypoechogenic wall thickening of long arterial segments eventually leading to tapering of the arterial lumen (Figure 5) or to hypoechogenic occlusion. These arteries are easily accessible for duplex sonography with a 5-10-MHz transducer, thus allowing highresolution imaging of the arterial wall, and exact quantification of the degree of stenosis. In our experience, no additional information is gained by angiography. In extracranial GCA involving the arteries to the arms and/or the cervical arteries, we therefore do not recommend conventional angiography, except in rare cases in which a revascularization procedure is considered. The sonographic appearance of these arteries combined with elevated laboratory markers of systemic inflammation can be considered pathognomonic for large-vessel vasculitis.

The thickening of the arterial wall may decrease during treatment and become more echogenic. [START_REF] Schmidt | Use of ultrasonography and positron emission tomography in the diagnosis and assessment of large-vessel vasculitis[END_REF] However, some degree of thickening and stenosis usually persists even in patients in complete remis-sion, and recanalization of occluded arterial segments does not occur. The sonographic appearance of the arterial wall is therefore an unreliable parameter for the assessment of disease activity. Sequential sonographic follow-up of patients with extracranial GCA is nonetheless essential to rule out a progression of stenoses or involvement of previously normal arterial segments during treatment.

Less is known about the sonographic appearance of GCA of the femoropopliteal and crural arteries. Only very few studies report the sonographic appearance of lower limb GCA. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF][START_REF] Schmidt | Involvement of peripheral arteries in giant cell arteritis: a color Doppler sonography study[END_REF] Moreover, interpretation of vascular imaging is hampered by the high rate of concomitant arteriosclerosis in this vascular region. Undoubtedly, femoropopliteal GCA may have the same sonographic appearance as in the arteries of the upper limbs and the cervical arteries. Figure 6 shows the typical hypoechogenic, concentric wall thickening in the superficial femoral artery of a 67-year-old patient with GCA. During the course of the disease this patient necessitated femoropopliteal bypass surgery due to the development of critical limb ischemia, and GCA was histologically confirmed at the sites of bypass anastomosis. Totally occluded femoropopliteal arteries also have a typical sonographic appearance in GCA with a very hypoechogenic, occluded lumen surrounded by a concentric, slightly less hypoechogenic thickening of the arterial wall. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF] This sonographic appearance is distinctively different from the hypoechogenic occlusions in arterial embolism or thrombosis. In addition, we have observed a tendency to spontaneous dissection in patients with severe, occlusive femoropopliteal GCA. Figure 7 shows an example of a spontaneous dissection of the superficial femoral artery in a 65-year-old woman with critical ischemia of her left foot due to histologically confirmed extracranial GCA. The proneness of extracranial GCA to dissections is known from aortic aneurysms. However, spontaneous femoropopliteal dissection has not previously been reported as a manifestation of GCA.

A major advantage of duplex ultrasound over angiographic techniques is its ability to visualize the pathological thickening of the arterial wall, even if it does not cause arterial narrowing. By systematically performing a complete vascular ultrasound in all our patients with GCA, we are just starting to appreciate the variety of vascular morphology in large-vessel vasculitis. A frequent finding we have observed in these patients is a nonocclusive, concentric thickening of the arterial wall of medium echogenicity, accompanied by beaded, highly echogenic inclusions lining the innermost arterial layer (Figure 8A andB). Interestingly, we find this characteristic appearance almost Figure 8 Duplex sonography of the superficial femoral artery of a 56-year-old woman presenting with a 3-month history of fever of unknown origin. The longitudinal view (A) and cross-section (B) show marked thickening of the arterial wall of medium echogenicity and beaded, highly echogenic inclusions lining the innermost arterial layer. The arterial wall thickening did not lead to stenosis of the lumen, and the patient had normal pulses and systolic ankle pressures. 18F-FDG-PET confirms marked tracer-uptake in the femoropopliteal arteries consistent with large-vessel vasculitis (C). exclusively in the femoropopliteal arteries of patients with a non-occlusive course of the disease. The histological correlate to these sonographic changes is still unknown.

Computer tomography and magnetic resonance imaging

Computer tomography (CT) [START_REF] Park | Takayasu arteritis: evaluation of mural changes in the aorta and pulmonary artery with CT angiography[END_REF][START_REF] Yamada | Takayasu arteritis: evaluation of the thoracic aorta with CT angiography[END_REF][START_REF] Yoshida | The spectrum of findings in supra-aortic Takayasu's arteritis as seen on spiral CT angiography and digital subtraction angiography[END_REF] and magnetic resonance imaging (MRI) [START_REF] Choe | Takayasu's arteritis: assessment of disease activity with contrast-enhanced MR imaging[END_REF][START_REF] Tso | Takayasu arteritis. Utility and limitations of magnetic resonance imaging in diagnosis and treatment[END_REF][START_REF] Meller | Value of F-18 FDG hybrid camera PET and MRI in early Takayasu aortitis[END_REF][START_REF] Desai | Delayed contrast-enhanced MRI of the aortic wall in Takayasu's arteritis: initial experience[END_REF][START_REF] Narvaez | Giant cell arteritis and polymyalgia rheumatica: usefulness of vascular magnetic resonance imaging studies in the diagnosis of aortitis[END_REF][START_REF] Markl | High resolution 3T MRI for the assessment of cervical and superficial cranial arteries in giant cell arteritis[END_REF] have been shown to detect the inflammation in the arterial wall as well as luminal narrowing and aneurysms in patients with large-vessel vasculitis. In addition, CT-and MR-angiography (MRA) can provide detailed non-invasive information on the luminal anatomy, and the distribution of arterial stenoses and occlusions. Particularly, MRA is steadily replacing conventional angiography for obtaining a comprehensive overview of the involved vascular regions in large-vessel vasculitis.

Although CT is excellent for the detection of arterial wall inflammation in the aorta and its proximal branches [START_REF] Park | Takayasu arteritis: evaluation of mural changes in the aorta and pulmonary artery with CT angiography[END_REF][START_REF] Yamada | Takayasu arteritis: evaluation of the thoracic aorta with CT angiography[END_REF][START_REF] Yoshida | The spectrum of findings in supra-aortic Takayasu's arteritis as seen on spiral CT angiography and digital subtraction angiography[END_REF] (Figure 9), it has the disadvantage of exposing the patient to iodinated contrast medium and radiation. This is particularly relevant in young patients with Takayasu arteritis. For these reasons, and due to the fast advances in MR-technology, MRI is becoming the preferred method for the evaluation of large-vessel vasculitis. Several studies have demonstrated that MRI is capable of detecting arterial inflammation even in peripheral arteries as small as the superficial temporal artery. [START_REF] Markl | High resolution 3T MRI for the assessment of cervical and superficial cranial arteries in giant cell arteritis[END_REF] In addition to increased arterial wall thickness, MRI detects edema [START_REF] Tso | Takayasu arteritis. Utility and limitations of magnetic resonance imaging in diagnosis and treatment[END_REF] and enhanced uptake of ferromagnetic contrast medium in the inflamed arterial wall. [START_REF] Desai | Delayed contrast-enhanced MRI of the aortic wall in Takayasu's arteritis: initial experience[END_REF] Edema appears hyperintense in T2-weighted and STIR images, and marked enhancement of the arterial wall becomes evident in gadolinium-assisted MRI (Figure 10). The degree of arterial wall edema and contrast enhancement has been shown to correlate with systemic inflammation [START_REF] Choe | Takayasu's arteritis: assessment of disease activity with contrast-enhanced MR imaging[END_REF][START_REF] Desai | Delayed contrast-enhanced MRI of the aortic wall in Takayasu's arteritis: initial experience[END_REF] and to regress during treatment. [START_REF] Tso | Takayasu arteritis. Utility and limitations of magnetic resonance imaging in diagnosis and treatment[END_REF][START_REF] Narvaez | Giant cell arteritis and polymyalgia rheumatica: usefulness of vascular magnetic resonance imaging studies in the diagnosis of aortitis[END_REF][START_REF] Aluquin | Magnetic resonance imaging in the diagnosis and follow up of Takayasu's arteritis in children[END_REF][START_REF] Bley | Influence of corticosteroid treatment on MRI findings in giant cell arteritis[END_REF] These studies suggest that MRI is superior to duplex ultrasound for the assessment and follow-up of disease activity.

CT and MRI have become indispensable for the evaluation of aortitis and aortic aneurysms in GCA and other inflammatory large-artery disorders such as Takayasu arteritis, periaortitis, and inflammatory aortic aneurysm. MRA is already being widely used for the evaluation of peripheral arterial disease. Today's high-end MR-scanners produce good quality angiographies that can clearly depict the typical tapered stenoses of large-vessel vasculitis (Figure 2). Morphological analysis of the arterial wall of medium-sized and small arteries is feasible with modern MR-technology, but these applications must still be considered experimental. Presently, duplex sonography is more widely available and offers superior resolution of the arterial wall and better quantification of the degree of stenosis in these peripheral arterial segments.

Digital subtraction angiography

Digital subtraction angiography (DSA) is still considered the gold standard for the diagnosis of obliterating arterial disease. A long, smooth or beaded appearance of arterial stenoses is suggestive of vasculitis on angiography. [START_REF] Stanson | Extracranial angiographic findings in giant cell (temporal) arteritis[END_REF] However, these findings are not specific. Beaded stenoses are also typical of fibromuscular dysplasia medial type, [START_REF] Slovut | Fibromuscular dysplasia[END_REF] and long, smooth arterial narrowing may be seen in other non-inflammatory conditions such as postinterventional myointimal hyperplasia, ergotism or after dissection. Angiographic diagnosis of femoropopliteal GCA is particularly difficult due to the similarity and overlap with arteriosclerotic peripheral arterial disease. Characteristic tapering of the artery or beaded configuration of the stenosis are missing in many patients. Extensive involvement of the deep femoral artery (Figure 11A) and spontaneous dissection (Figure 11B) may indicate GCA in this vascular region. The angiographic appearance of GCA may, however, be almost indistinguishable from arteriosclerotic vascular disease. This is particularly the case in patients with extensive obliteration of the femoropopliteal and crural arteries. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF] At our institution we perform DSA only in patients with severe ischemia, in whom we consider revascularization. With increasing use of duplex sonography, MRI and CT, DSA has become dis-pensable for the majority of patients with suspected extracranial GCA, and would therefore represent an unnecessary exposure of the patients to the risks of arterial puncture, iodinated contrast medium and radiation.

Fluorine-18-desoxyglucose positron emission tomography

Fluorine-18-desoxyglucose positron emission tomography (18F-FDG-PET) has recently shown promising results for the detection of arterial wall inflammation in large-vessel vasculitis. [START_REF] Schmidt | Use of ultrasonography and positron emission tomography in the diagnosis and assessment of large-vessel vasculitis[END_REF][START_REF] Blockmans | Clinical value of [18F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin[END_REF][START_REF] Turlakow | Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis[END_REF][START_REF] Belhocine | Imaging of large vessel vasculitis with 18FDG PET: illusion or reality? A critical review of the literature data[END_REF][START_REF] Webb | The role of 18F-FDG PET in characterising disease activity in Takayasu arteritis[END_REF][START_REF] Brodmann | The role of 2-18F-fluoro-D-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries[END_REF][START_REF] Blockmans | Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients[END_REF] 18F-FDG-PET can be used as a whole-body Figure 12 18F-FDG-PET in a 76-year-old man with bilateral stenoses of the axillary and superficial femoral arteries, and positive temporal artery biopsy. 18F-FDG-PET shows abnormal tracer uptake in the subclavian, axillary and carotid arteries, as well as in the abdominal aorta, the iliac and femoropopliteal arteries.

screening tool, and this method has the potential of detecting arteritis in very early stages, before the occurrence of manifest arterial stenosis. Accordingly, several studies have demonstrated the usefulness of 18F-FDG-PET for the detection of largevessel vasculitis in patients with fever of unknown origin or unexplained systemic inflammation but without clinically manifest vascular symptoms. [START_REF] Blockmans | Clinical value of [18F]fluoro-deoxyglucose positron emission tomography for patients with fever of unknown origin[END_REF][START_REF] Knockaert | Fever of unknown origin in adults: 40 years on[END_REF][START_REF] Meller | Early diagnosis and follow-up of aortitis with 18F-FDG PET and MRI[END_REF][START_REF] Tatò | Takayasu's arteritis without manifest arterial stenoses as a cause of fever of unknown origin[END_REF] 18F-FDG-PET was shown to have a sensitivity of 92% and a specificity of 100% for the initial diagnosis of Takayasu arteritis, and to correlate with clinical disease activity during follow-up. [START_REF] Webb | The role of 18F-FDG PET in characterising disease activity in Takayasu arteritis[END_REF] tracer uptake in the aorta and in peripheral arteries was detected by 18F-FDG-PET and also in patients with GCA. [START_REF] Tatò | Clinical presentation and vascular imaging in giant cell arteritis of the femoro-popliteal and tibio-peroneal arteries[END_REF][START_REF] Turlakow | Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis[END_REF][START_REF] Brodmann | The role of 2-18F-fluoro-D-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries[END_REF][START_REF] Blockmans | Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients[END_REF][START_REF] Meller | Early diagnosis and follow-up of aortitis with 18F-FDG PET and MRI[END_REF][START_REF] Blockmans | Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: evidence for inflammation of the aortic arch[END_REF] In a recent study, Blockmans et al. [START_REF] Blockmans | Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients[END_REF] found a positive vascular 18F-FDG uptake in 29 of 35 (83%) patients with biopsy proven GCA, who did not have clinical symptoms of peripheral ischemia. Increased 18F-FDG uptake was most frequent in the subclavian artery (74%), followed by the aorta (51%) and the femoral arteries (37%). This study reinforces impressively the assumption that GCA is a generalized vascular disease in the majority of patients (Figure 12). The interpretation of 18F-FDG-PET in GCA is, however, more difficult than in Takayasu arteritis. GCA patients are usually old and frequently have concomitant arteriosclerosis. Arteriosclerotic vascular disease has been shown to cause enhanced vascular 18F-FDG uptake. [START_REF] Yun | F-18 FDG uptake in the large arteries. A new observation[END_REF][START_REF] Lederman | Detection of atherosclerosis using a novel positron-sensitive probe and 18-fluorodeoxyglucose (FDG)[END_REF] Only very few studies of 18F-FDG uptake in vasculitis included an agematched control group. In one study, 67 18F-FDG uptake of the thoracic aorta and subclavian arteries was positive in 54% of GCA patients and in 2% of controls. However, 77% of the patients with GCA and 23% of controls had enhanced vascular 18F-FDG uptake in the femoral arteries. This study indicates that 18F-FDG-PET may have a good specificity for extracranial GCA of the aorta and the proximal arteries to the arms, but that positive results have to be interpreted with caution in the femoropopliteal region. Duplex ultrasound proved very useful for the interpretation of 18F-FDG-PET in our patients with GCA. In our experience, femoropopliteal 18F-FDG uptake can be regarded as an indication of extracranial GCA only in patients without generalized arteriosclerosis and with the typical sonographic signs of vasculitis (Figure 8A-C).

Widespread use of 18F-FDG-PET is restricted by high costs, limited availability and the relatively high radiation burden. Moreover, the specificity of 18F-FDG uptake in peripheral arteries of patients with GCA requires further study. 18F-FDG-PET is nonetheless a very promising technique for the evaluation of large-vessel vasculits in selected patients. In vasculitis patients presenting with unspecific symptoms such as fever of unknown origin or chronic anemia and thrombocytosis, 18F-FDG-PET is already today an important diagnostic tool. 18F-FDG-PET may also become a very useful method for monitoring disease activity in patients with persistent systemic inflammation or with progression of the disease in spite of immunosuppressive treatment.

Medical treatment

When treating patients with GCA, the primary aim is to prevent progression of vascular damage and serious vascular complications by suppression of the inflammatory process. Glucocorticoids remain the mainstay of treatment in GCA. Virtually all patients respond to initial glucocorticoid treatment with quick resolution of systemic symptoms and normalization of the laboratory signs of inflammation. Many years of experience have shown that glucocorticoid treatment is effective in halting the inflammatory process and in preventing the progression of the disease. Prednisone is usually started at doses between 40 mg and 60 mg per day, although occasional patients require higher initial doses to attain remission. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF][START_REF] Weyand | Giant-cell arteritis and polymyalgia rheumatica[END_REF] In a recent study, induction treatment with a 3-day course of 15 mg/kg i.v. methylprednisolone was superior to standard treatment with oral prednisone started at 40 mg per day. [START_REF] Mazlumzadeh | Treatment of giant cell arteritis using induction therapy with high-dose glucocorticoids: a double-blind, placebocontroled, randomized, prospective clinical trial[END_REF] Initial treatment with high-dose i.v. glucocorticoid pulses resulted in a more stable remission, subsequently allowing more rapid tapering of oral glucocorticoids, and a lower cumulative glucocorticoid dose. Parenteral, high-dose glucocorticoids have previously been suggested for the initial treatment of GCA patients presenting with acute visual loss, 71 although this treatment regimen is controversial. [START_REF] Hayreh | Management of giant cell arteritis. Our 27-year clinical study: new light in old controversies[END_REF] Patients with extracranial GCA, who are at a high risk of severe peripheral arterial complications, might also benefit from a higher initial glucocorticoid dose. However, this hypothesis has not yet been investigated in a clinical study.

The initial prednisone dose should be continued until systemic symptoms have disappeared, and blood markers of inflammation have returned to normal. This usually takes 2-4 weeks. There is no consensus on how quick the prednisone dose should be tapered after initial remission is obtained. We usually reduce the dose by 10 mg every 2 weeks until the dosage reaches 20 mg/day, then by 2.5 mg every 2 weeks until a dosage of 10 mg/day. Below 10 mg/day we recommend a slower reduction by approximately 1 mg every 4 weeks. The aim is to achieve a low maintenance dosepossibly below 7 mg/daywithout inducing relapses. The total duration of glucocorticoid treatment is usually 2 years. Unfortunately, 30-50% of the patients will experi-ence relapses during reduction of the glucocorticoid dose. [START_REF] Salvarani | Polymyalgia rheumatica and giant-cell arteritis[END_REF] These patients require high doses of glucocorticoids over long periods of time, and are at great risk to suffer serious treatment-related side effects and complications. Adjunctive treatment with cyclophosphamide, dapsone, and azathioprine has been tested in individual patients and small trials, but the glucocorticoid-sparing effect of these drugs is not convincing. Methotrexate was studied in three randomized, double-blind, placebo-controlled trials. [START_REF] Spiera | A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA)[END_REF][START_REF] Hoffman | for the International Network for the Study of Systemic Vasculitides (INSSYS). A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis[END_REF][START_REF] Jover | Combined treatment of giant cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial[END_REF] Only one of these trials could demonstrate a benefit of methotrexate treatment. [START_REF] Jover | Combined treatment of giant cell arteritis with methotrexate and prednisone. A randomized, double-blind, placebo-controlled trial[END_REF] Anti-TNF-α agents have recently shown promising results in patients with difficult-to-treat Takayasu arterits. [START_REF] Hoffman | Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis[END_REF][START_REF] Tatò | Refractory Takayasu's arteriitis successfully treated with the human, monoclonal anti-tumor necrosis factor antibody adalimumab[END_REF] However, the first randomized, double-blind, placebo-controlled trial of infliximab in GCA was discontinued early due to lack of efficacy. [START_REF] Hoffman | Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis[END_REF] These studies emphasize that long-term medical treatment of patients with GCA remains a clinical challenge. We usually treat the first relapses by increasing the prednisone dose to 20-40 mg/day and attempt slow dose-reduction anew. After several relapses, methotrexate is considered the firstline corticosteroid-sparing agent by most clinicians, in spite of the weak evidence for its efficacy. It is our impression that patients with generalized disease and extensive extracranial involvement require higher glucocorticoid doses and more aggressive immunosuppressive treatment than patients with localized disease. Possibly, these patients may represent a subgroup which would benefit from anti-TNF-α treatment in a similar way as has been shown in Takayasu arteritis. [START_REF] Hoffman | Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis[END_REF][START_REF] Tatò | Refractory Takayasu's arteriitis successfully treated with the human, monoclonal anti-tumor necrosis factor antibody adalimumab[END_REF] However, prognosis and response to treatment has not yet been studied systematically in extracranial GCA.

Aspirin and anticoagulants have been shown to reduce the risk of ischemic complications in patients with newly diagnosed GCA. [START_REF] Nesher | Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis[END_REF][START_REF] Lee | Antiplatelet and anticoagulant therapy in patients with giant cell arteritis[END_REF] In addition to its antithrombotic effects, aspirin may have beneficial anti-inflammatory actions in large-vessel vasculitis. [START_REF] Weyand | Therapeutic effects of acetylsalicylic acid in giant cell arteritis[END_REF] Whether antithrombotic treatment has a clinically relevant effect on top of glucocorticoids in preventing disease progression and new ischemic events during treatment, is however unknown. It is probably prudent to treat patients with extracranial GCA with an anti-platelet agent in addition to glucocorticoids, particularly in cases with symptoms of ischemia. The potential benefit of antithrombotic treatment has, however, to be individually weighted against increased risk of bleeding.

Vascular interventions

The decision to perform invasive vascular procedures in patients with large-vessel vasculitis is always difficult. As a general rule, elective vascular reconstruc-tion should be postponed until the inflammatory activity is in remission. The largest body of experience on revascularization procedures in large-vessel vasculitis comes from Takayasu arteritis. Bypass surgery has been performed for many years in these patients with low perioperative mortality and acceptable long-term patency rates of 70-80%. [START_REF] Liang | Advances in the medical and surgical treatment of Takayasu arteritis[END_REF] Percutaneous transluminal angioplasty (PTA) and stenting is also feasible in stenotic lesions of Takayasu arteritis with good primary success. The 1-year patency of percutaneous interventions with or without stenting was below 60% in most published series. [START_REF] Liang | Advances in the medical and surgical treatment of Takayasu arteritis[END_REF][START_REF] Fava | Percutaneous transluminal angioplasty in patients with Takayasu arteritis: five year experience[END_REF] However, there has been no systematic study of the effect of the control of inflammation on the patency of vascular interventions.

Much less is known about the results of revascularization procedures in extracranial GCA. Stenoses of the subclavian and axillary artery leading to arm claudication are occasionally treated by PTA. In a recently published series of 29 stenoses and one occlusion of upper-extremity arteries, the authors report excellent technical success but a primary patency rate of only 65% in spite of ongoing immunosuppressive treatment. [START_REF] Both | Balloon angioplasty of arteries of the upper extremities in patients with extracranial giant-cell arteritis[END_REF] Only a few case reports refer to bypass surgery in GCA patients with upperlimb ischemia, and no data on long-term patency are available. [START_REF] Aburahma | Temporal arteritis: diagnostic and therapeutic considerations[END_REF][START_REF] Soury | Arterial lesions of the upper limbs in horton disease. Surgical revascularization by bilateral carotid-humeral bypass[END_REF] In our experience, stenoses and occlusions of the subclavian and axillary artery only exceptionally cause such severe symptoms as to require an intervention. Most patients become oligo-or asymptomatic within several months after initiation of glucocorticoid treatment. The degree of stenosis may decrease during treatment. However, improvement of symptoms due to collateralization occurs regularly and also in patients with irreversible stenoses or occlusions. For these reasons we recommend being very restrictive with revascularization procedures in the upper-limb arteries of GCA patients.

To our knowledge, no study of revascularization procedures in symptomatic GCA of the lower limbs has been published. Femoropopliteal and crural lesions were unsuitable for a percutaneous intervention in all our patients with severe lower-limb ischemia due to extracranial GCA. Very long high-grade stenoses or occlusions of the superficial femoral artery combined with extensive occlusions of the tibial and peroneal arteries were the predominant finding. Two of our patients with critical limb ischemia required a femoropopliteal and a femorotibial bypass for limb salvage with good short-term results. Experience is still lacking to allow general recommendations regarding lower-limb revascularization procedures in these patients. As for upperlimb ischemia, we suggest restrictive use of invasive vascular interventions in inflammatory iliac or femoropopliteal obstructions, as long as the hemodynamic situation is compensated, and the limb is not at risk. As in Takayasu arteritis, surgical revascularization is probably superior to percutaneous intervention in GCA patients with critical limb ischemia.

Aortic aneurysms of patients with GCA are generally treated according to the same recommendations as for arteriosclerotic aneurysms. Epidemiological data on the natural history of GCA-related aneurysms is insufficient to allow for specific recommendations in these patients. Unlike in arteriosclerosis, aneurysms of GCA patients affect more frequently the thoracic aorta and appear to be more prone to dissection. [START_REF] Evans | Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis: a population-based study[END_REF][START_REF] Evans | Thoracic aortic aneurysm and rupture in giant cell arteritis: a descriptive study of 41 cases[END_REF] These factors make screening more difficult, and suggest that follow-up examinations may be warranted at shorter intervals in these patients.

Future perspectives

Today, modern vascular diagnostic techniques allow us to perform detailed non-invasive studies of the true degree of extracranial involvement in patients with GCA. Preliminary data suggest that GCA may in fact be a generalized vascular disease in the majority of patients. Systematic studies are now needed to characterize the distribution of symptomatic and asymptomatic peripheral arterial involvement in these patients. These studies will help to clarify the impact of extracranial involvement on the course of the disease, the response to treatment, and the prognosis of these patients.

Increasing insight into the pathophysiology of large-vessel vasculitis will generate new treatment strategies, which will have to prove their ability not only to suppress laboratory signs of inflammation, but also to stop the progression of vascular damage. Subjective symptoms and global markers of inflammation such as ESR or plasma CRP have long been recognized as insufficient surrogate parameters for disease activity. Again, modern vascular diagnostics offers new opportunities to monitor non-invasively disease activity in the arterial wall, thus greatly facilitating the evaluation of the efficacy of new treatments.

It is very likely that peripheral arterial disease of the lower-limb arteries due to large-vessel vasculitis has long been underestimated or misinterpreted as an aggressive form of obliterating arteriosclerosis. Catastrophic outcomes are no rarity in these patients, and are usually the consequence of delayed diagnosis and treatment. Increasing engagement of vascular medicine in the interdisciplinary management of patients with large-vessel vasculitides will hopefully improve the prevention and treatment of serious vascular complications.

Figure 1

 1 Figure 1 Chest radiograph of a 70-year-old man at the time of diagnosis of GCA in 2002 (A). Four years later the chest radiograph of the same patient shows new mediastinal broadening (B). A CT scan demonstrates a large aneurysm of the thoracic aorta with a maximum diameter of 9.3 cm in the ascending segment (C).

Figure 2

 2 Figure 2 MR-angiography of a 62-year-old woman with extracranial GCA showing the typical, long tapering of the left axillary artery (arrows).

Figure 3

 3 Figure 3 An 82-year-old man with bioptically confirmed GCA of the temporal artery and necrosis of the scalp. The necrotic skin lesions show healing and scarring after several weeks of prednisone treatment.

Figure 4

 4 Figure 4 Duplex scan of the frontal branch of the left temporal artery of a 79-year-old woman with positive temporal artery biopsy. The scan performed with a 14-MHz transducer shows the typical, hypoechogenic thickening of the arterial wall ('halo sign') in longitudinal (A) and cross-section (B) views.

Figure 5

 5 Figure 5 Color-coded duplex sonography in a 68year-old woman with extracranial GCA. Longitudinal view of the left axillary artery showing tapering of the lumen due to concentric, hypoechogenic thickening of the arterial wall.

Figure 6

 6 Figure 6 Color-coded duplex sonography in a 67year-old man with extracranial GCA of the lower extremities. Longitudinal view of the left superficial femoral artery showing a high-grade stenosis due to hypoechogenic thickening of the arterial wall.

Figure 7

 7 Figure 7 Color-coded duplex sonography in a 65year-old woman with extracranial GCA of the upper and lower extremities. Longitudinal view of the left superficial femoral artery showing a spontaneous dissection of the arterial wall with two perfused lumens.

Figure 10

 10 Figure 10 Contrast-enhanced, T1-weighted MRI of the right popliteal region of a 73-year-old man with critical lower limb ischemia due to extracranial GCA showing concentric thickening and marked enhancement of the popliteal artery wall (arrow).

Figure 9

 9 Figure9Chest CT-scan of a 67-year-old man presenting with chronic anemia, thrombocytosis and markedly elevated erythrocyte sedimentation rate. The concentric wall-thickening in the ascending aorta with mural contrast enhancement (arrow) and aneurysm of the descending thoracic aorta (arrowhead) are consistent with aortitis.

Figure 11 (

 11 Figure 11 (A) Digital subtraction angiography (DSA) in a 70-year-old man with critical ischemia of the right leg due to bioptically confirmed femoropopliteal GCA. The angiogram shows complete obliteration of both the superficial and the deep femoral artery. (B) DSA of a 65-year-old woman with critical ischemia of the left leg due to bioptically confirmed femoropopliteal GCA. The thin superficial femoral artery shows a spiralling dissection (duplex sonography in Figure 7) in the proximal segment (arrow). The irregularities and segmental narrowing of the deep femoral artery (arrowhead) are also suggestive of largevessel vasculitis.

Vascular Medicine 2008; 13: 127-140


Jagjeeth Naik
email: jagnaik@hotmail.com

Umar Sadat

Jonathan R Boyle

Panel A Panel

Images in vascular medicine Management of giant cavernous renal arteriovenous malformation

A 69-year-old man was referred with weight loss, night sweats, raised inflammatory markers, and an abdominal bruit. He underwent a contrast-enhanced CT scan of the abdomen, which revealed a giant cavernous arteriovenous malformation (AVM) of the left renal artery and vein (Panel A). The left renal artery (RA) was the same size as the adjacent abdominal aorta (AA) and spiralling around a grossly dilated renal vein (Panel B; RV). Aetiology was thought to be congenital, as there was no antecedent history of trauma, biopsy or malignancy. An isotope renal scan showed equivalent function in both kidneys and creatinine levels were normal. Treatment was planned to prevent exacerbation of the existing car-diomegaly and risk of further high output cardiac failure. Three treatment options are described for this rare condition: endovascular repair, ligation of the fistula and nephrectomy.

Endovascular therapy 1 with coil embolization was felt to be inappropriate in this case due to the vessel calibre and the high-flow fistula (constituting a real danger of coil dislodgement and migration). Open ligation of the AVM is also reported in the literature, 2 but predominantly for fistulas originating in segmental branches of the renal artery as opposed to the main artery as in this case. Nephrectomy was therefore planned. An abdominal approach was used to control the vessels at the hilum (Panel C; artery slung).

Examination of the excised kidney and opening of the renal vein revealed the site of the AVM, which allowed the passage of a 4-mm catheter (Panel D).

Histology revealed normal endothelium. The patient was discharged on day 6 and at follow-up 6 months later he remains well with stable cardiac status and normal renal function.


Drosos Kotelis
email: drosos.kotelis@med.uni-heidelberg.de

Editor in Chief, Mark A Creager

Panel A

A 37-year-old woman presented with a 5-month history of hoarseness. She had no other clinically significant medical history or history of trauma. An ENT doctor diagnosed swelling of the right vocal chord. With the hoarseness being refractory to medical treatment, a chest computed tomography (CT) scan was performed which revealed distinct elongation and kinking of the bronchial arteries with multiple aneurysms near the right subclavian artery in a location that could cause compression of the recurrent laryngeal nerve (Panel A: posterior view). A contrast-enhanced whole-body magnetic resonance angiography ruled out intracranial, abdominal or acral aneurysm formation (Panel B). Given the uncertain origin of the aneurysms, selective angiography of the thoracic aorta and the supra-aortic vessels showed a total of five aneurysms along the aortic arch (Panel C): aneurysms numbers 1 and 3 were supplied from a bronchial artery and the right internal thoracic artery; aneurysms numbers 4 and 5 were found to originate from the right and the left subclavian artery respectively; aneurysm number 2 originated from the brachiocephalic trunk.

Considering the high risk of massive bleeding and neurologic injury with open surgical treatment, we decided to proceed with endovascular embolization. All five aneurysms were selectively embolized in two consecutive sessions using interlocking detachable coils (IDC; Boston Scientific Corporation, Natick, MA, USA) (Panel D).

At 6 months' follow-up, the CT angiogram showed complete thrombosis of all aneurysms, yet the patient is still suffering from hoarseness and vocal chord swelling.

The etiology of the aneurysm formation in this patient remains unknown, especially since were not able to gain material for histological examination. Bronchial artery aneurysms are rare and have been associated with atherosclerosis, trauma, inflammatory lung disease, bronchiectasis, tuberculosis, sepsis, and Osler-Weber-Rendu disease. [START_REF] Tanaka | Giant mediastinal bronchial artery aneurysm mimicking benign esophageal tumor: a case report and review of 26 cases from literature[END_REF] The patient's hoarseness may have been the symptom which led to the diagnosis and may be unrelated to the mediastinal aneurysms. Embolization appears to be a safe and reliable therapeutic option in the management of multiple mediastinal aneurysms. [START_REF] Vernhet | Bronchial aneurysms mimicking aortic aneurysms: endovascular treatment in two patients[END_REF] Long-term follow-up is needed however.

Vascular Medicine 2008; 13: 173-174


Ioannis Kaskarelis

Marios Patronis

Mihalis Argiriou

Charalambos Zisis
email: chzisis@hol.gr

come   L'archive ouverte pluridisciplinaire

Images in vascular medicine

Stent placement after iatrogenic carotid artery rupture Ioannis Kaskarelis 1 , Marios Patronis 2 , Mihalis Argiriou 2 and Charalambos Zisis 2

An 84-year-old male was admitted to our hospital with right common carotid artery rupture after an unsuccessful attempt at hemodialysis catheter placement in the right internal jugular vein. He was hemodynamically unstable (blood pressure 55/35 mmHg) and mechanically ventilated. His hematocrit had dropped from 38% to 23% in 3 hours. His computed tomogram (CT) of the chest showed extensive hemorrhagic infiltration around the right common carotid artery (Panel A, arrow), which expanded into the mediastinum. Leak of the artery with pseudoaneurysm formation, angiographically proven (Panel B), was successfully excluded with selfexpanding covered stent placement (Panel C). The patient was transferred to the intensive care unit where his hematocrit and hemoglobin stabilized. He had a complicated post-procedural course, and ultimately succumbed 5 days later to respiratory and metabolic complications.

Emergent carotid artery stenting has been reported in cases of acute carotid dissection with or without associated pseudoaneurysm, as well as in blunt carotid injury, and once in perforation complicating an elective carotid artery stenting procedure. [START_REF] Kadkhodayan | Angioplasty and stenting in carotid dissection with or without associated pseudoaneurysm[END_REF][START_REF] Dieter | Perforation complicating carotid artery stenting: the use of a covered stent[END_REF] To our knowledge, such a case of iatrogenic perforation with hemodynamic alteration of the patient and active extravasation from the perforated carotid artery, managed some hours later with covered stent placement, has not been described previously.

Vascular Medicine 2008; 13: 177-178