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Rheumatology Advance Access originally published online on October 13, 2006
Rheumatology 2007 46(1):6-15; doi:10.1093/rheumatology/kel323
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEWS

Takayasu's arteritis—recent advances in imaging offer promise

J. Andrews and J. C. Mason1

Consultant Rheumatologist, Northwick Park Hospital and Honorary Senior Lecturer, Imperial College London and 1Reader, Imperial College London and Honorary Consultant Rheumatologist, Hammersmith Hospital, London, UK.

Correspondence to: Dr Justin Mason, PhD, FRCP, Eric Bywaters Centre, Cardiovascular Medicine Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. E-mail: justin.mason{at}imperial.ac.uk


   Abstract
Top
 Abstract
Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 
Takayasu's arteritis (TA), a rare large vessel vasculitis of unknown aetiology, remains a difficult disease to manage with diagnosis often delayed until the late occlusive stage when irreversible vascular damage has occurred. Recent studies suggest that non-invasive imaging modalities including magnetic resonance imaging, ultrasound and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) allow diagnosis of TA earlier in the disease course than standard angiography and provide a means for monitoring disease activity. Choice of appropriate therapy for TA is limited by a lack of evidence and a combination of corticosteroids and immunosuppressive drugs is most commonly used. Novel therapeutic approaches such as the use of anti-tumour necrosis factor {alpha} (TNF-{alpha}) inhibitors and drug-eluting arterial stents show promise for improving the prognosis in severe disease. In addition, strict management of traditional cardiovascular risk factors such as dyslipidaemia, hypertension and lifestyle factors is mandatory to minimize secondary cardiovascular complications, which are the major cause of death in this disease.

KEY WORDS: Takayasu's arteritis, Vasculitis, Disease activity, Non-invasive imaging


   Introduction
Top
 Abstract
 Introduction
Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 
Takayasu's arteritis (TA), first described in 1908 and named in 1942 [1, 2], is a rare idiopathic chronic inflammatory disease of unknown aetiology, resulting in a granulomatous panarteritis of the aorta and its major branches. The arteritis associated with TA is characterized by adventitial thickening and cellular infiltration of the tunica media, with local destruction of vascular smooth muscle cells and elastin. Intimal hyperplasia, the result of myofibroblast proliferation, is followed by fibrosis of the tunica media and intima, leading to stenosis and on occasion thrombosis [3]. In ~20% of lesions, local destruction of the medial layer predominates and this, combined with an inadequate fibrotic response, results in dilatation and aneurysm formation. Initial inflammatory changes are associated with vasa vasoritis and proliferation of the vaso vasorum [4], and these vessels represent the portal of entry for inflammatory cells to the vessel wall [5]. Immunophenotypic analysis has identified T ({alpha}/ß and {gamma}/{delta}) and B lymphocytes and these may form nodules in the adventitia. T-cells co-localize with dendritic cells while granulocytes, macrophages and occasional giant cells are also seen (Fig. 1) [6, 7].


Figure 1
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  		FIG. 1. Histological specimen from the aorta of a patient with TA. This surgical specimen taken from the wall of the aorta shows: (A) vaso vasorum and adventitial hyaline fibrosis and (B) an associated mononuclear infiltrate involving the adventitial and medial layers.

 
TA typically presents with non-specific systemic signs and symptoms such as arthralgia, fever, fatigue, headaches, rashes (including erythema nodosum) and weight loss. Chronic inflammation of the aorta and its major branches, including subclavian, common carotid, coronary, pulmonary and renal arteries, may result in localized stenoses, vascular occlusion, dilatation and aneurysm formation (for detailed reviews see [8–11]). In addition to substantial morbidity, mortality has been reported to be as high as 35% at 5 yrs [8]. Notwithstanding this, a small percentage of patients experience a self-limiting monophasic inflammatory episode, which does not require chronic immunosuppressive therapy and does not progress to the occlusive stage [8].

This review will concentrate on the problems faced by rheumatologists in the diagnosis and management of TA, with specific focus on (1) the benefits and limitations of novel non-invasive imaging modalities and (2) the current treatments employed and prospects for the future.


   Clinical challenges in TA
Top
 Abstract
 Introduction
 Clinical challenges in TA
Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 
Initial diagnosis
The management of TA remains a complex clinical challenge from the onset. The non-specific nature of the symptoms at presentation, combined with the absence of physical signs, typically results in a delayed diagnosis and failure to initiate adequate treatment early in the disease course. In one series, 20% of patients remained undiagnosed up to 3 yrs following the onset of symptoms [8], findings that reflect our own experience.

In contrast to giant cell arteritis, biopsy material is rarely available in patients presenting with TA and this limits diagnostic accuracy. Likewise, there are no specific laboratory abnormalities to aid diagnosis. Hoffman examined multiple serological tests including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tissue factor, von Willebrand factor, sICAM-1, sVCAM-1 and sE-selectin and found that no test reliably distinguished between healthy volunteers and patients with active TA [12]. Patients may have a mild normochromic normocytic anaemia and hyperglobulinaemia but may not have a raised acute phase response, even in the early inflammatory stages. Complement activity is typically normal and disease-specific autoantibodies are characteristically absent. Anti-endothelial antibodies (AECA) may be present, occasionally in high titre, however, AECA also occur in a variety of other conditions where vascular inflammation is prominent including systemic lupus erythematosus (SLE) [13, 14].

A recent study, looking for novel disease biomarkers related to pathogenesis, analysed plasma and serum levels of matrix metalloproteinase (MMP)-2, -3 and -9 [15]. The results, although preliminary, are of interest. MMP-2 was elevated in TA patients vs controls but was not related to disease activity. In contrast, MMP-3 and MMP-9 were only elevated in patients with active disease, as defined by the National Institute of Health (NIH) criteria [8], and fell as disease activity was controlled by corticosteroids. The study is small and lacks correlative data between CRP and the MMPs, which limits the impact of the results. Nonetheless, the data is intriguing and suggests that analysis of these MMPs may be useful in diagnosis (MMP-2) and monitoring of TA (MMP-2, MMP-3). Further confirmatory studies are required, alongside prospective studies to establish whether MMP-3 and MMP-9 levels correlate with disease prognosis.

Diagnostic criteria
The principle limitation of current criteria for the diagnosis of TA is that patients with early phase non-occlusive disease may fail to fulfil them. The American College of Rheumatology (ACR) classification remains the most widely applied, with 3 or more of the criteria associated with a sensitivity of 90.5% and a specificity of 97.8% (Table 1) [16]. The Ishikawa classification criteria were published in 1988 [17] and in modified form in 1996 (Table 2) [18]. The authors reported that the latter, when applied to 106 patients with angiographically proven TA and 20 controls, had a diagnostic sensitivity and specificity of 92.5 and 95%, respectively, superior to both the original Ishikawa (60.4 and 95%) and the ACR criteria (77.4 and 95%).


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  		TABLE 1. ACR criteria for the diagnosis of TA [16]

 

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  		TABLE 2. Modified version of the Ishikawa diagnostic criteria for TA (abbreviated) [18]

 
Disease monitoring
Clinical analysis of TA disease activity, response to treatment and detection of relapse remains sub-optimal. Kerr and colleagues [8] defined active TA as the new onset or worsening of two or more of the following features: fever or arthralgia; raised ESR (>20 mm/h); features of vascular ischaemia or inflammation such as claudication, diminished or absent pulse, bruit, vascular pain, asymmetric blood pressure (BP) in upper or lower limbs or typical angiographic features; however, this definition has not been widely validated and is limited in scope. The Birmingham Vasculitis Activity Score (BVAS), a reliable indicator of disease activity for primary systemic vasculitis, lacks sensitivity for the large vessel vasculitides and is rarely useful for clinical practice.

At the Third International Conference on Giant Cell Arteritis and Polymyalgia Rheumatica held in Cambridge in July 2005, Dr Sivakumar, on behalf of the IRVAS group, presented a new clinical index of disease severity and extent in TA (the DEI-TAK) which uses the BVAS index as its template [19]. The index is based on the findings from 143 Indian patients with TA and contains 59 items in 11 organ-based scoring systems with emphasis on the cardiovascular system (19 items). Under the direction of Professor Paul Bacon, DEI-TAK is now being applied by interested physicians and will hopefully prove to be a useful clinical tool in patients with TA.

The ESR and CRP may be helpful in assessing disease activity and response to treatment in some patients. However, analysis of the acute phase response is often an unreliable indicator [12] and normal acute phase reactants may lead the clinician to a false sense of security. In a review of patients with clinically inactive disease (based on the absence of systemic clinical features, a normal ESR and stable angiographic findings), new angiographic changes were detected in 60% and surgical aortic biopsy specimens revealed histological evidence of ongoing vascular inflammation in 44% [8, 20]. Although some of the angiographic progression may be explained by persistent fibrotic scarring post-inflammation, these data demonstrate the limitation of current clinical parameters. A recent study reported elevated serum IL-18 in patients with TA vs controls, with maximal levels seen in those with active TA [21]. The close correlation of IL-18 levels with the ESR, suggest that measurement of IL-18 will not add anything in terms of monitoring disease activity. However, if it can be shown that IL-18 is present in the arterial wall and plays a role in disease pathogenesis, it may become a novel therapeutic target.


   Clinical imaging in TA
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 
Considerable advances have been made in recent years in vascular imaging. Thus magnetic resonance imaging and angiography (MRI/MRA), computed tomography (CT) and CT angiography, positron emission tomography (PET), CT-PET and high-resolution ultrasound (US) are becoming more widely available for the investigation of patients presenting with symptoms suggestive of a large vessel vasculitis.

Conventional angiography
Percutaneous intravascular angiography has been the gold-standard investigation for the diagnosis of TA, providing high-quality images of the arterial lumen. Lesions often occur at or close to the point of origin of the primary branches of the aorta. Localized narrowing or irregularity of the arterial lumen are the earliest lesions detectable by angiography, and these may proceed to stenosis or complete occlusion (Fig. 2). Vessels may also be dilated or aneurysmal—either saccular or fusiform. One of the most characteristic angiographic findings is the presence of ‘skip lesions’, where stenoses, or less frequently aneurysms, alternate with segments of uninvolved blood vessel.


Figure 2
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  		FIG. 2. Intra-arterial aortography of a patient with TA. Note the complete occlusion of the left common carotid and subclavian arteries.

 
Based on the location of vessel involvement, a five-type angiographic classification system was proposed by the International Cooperative Study on Takayasu's arteritis in 1997 (Table 3) [22]. Involvement of coronary or pulmonary arteries is designated by adding a C(+) or P(+) to one of the five types. Diffuse disease affecting the aorta and its branches above and below the diaphragm is the most common pattern of disease worldwide [23]. It is also important to note that intra-arterial angiography allows accurate assessment of central aortic pressures and imaging of the coronary arteries, which are not readily available with current non-invasive approaches.


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  		TABLE 3. Angiographic classification of TA [22]

 
Limitations of angiography
Despite its benefits, intra-arterial angiography is invasive, may aggravate local disease and only provides data on luminal anatomy. This inability to evaluate changes in the arterial wall may result in a normal angiogram in patients with early phase disease. Furthermore, the nature of the procedure and the necessity for exposure to contrast media and radioactivity significantly limits its use as a tool for monitoring patients with TA. Thus, in recent years considerable interest has focused on the assessment of novel imaging modalities for the diagnosis and management of TA. These include high-resolution Doppler US, electron beam CT (EBCT), MRI and 18F-fluorodeoxyglucose PET (18F-FDG-PET) [24, 25]. The novel imaging methods have the potential to establish an early diagnosis and to improve assessment of disease activity. This in turn may allow more accurate tailoring of treatment, so maximizing efficacy and minimizing toxicity. However, despite the fact that in many institutions, including our own, these techniques have begun to supersede conventional angiography, the lack of prospective studies for the evaluation of the novel modalities, and the persistent difficulty in confirmation of the findings through histological analysis, must be recognized.

Magnetic resonance imaging
Increasing use is being made of MRI/MRA in the diagnosis and management of TA [24]. The combination of multiplanar cardiac MRI using T1- and T2-weighted sequences in coronal and oblique sagittal planes, combined with contrast-enhanced 3D MRA has been reported to display equivalent diagnostic accuracy to invasive angiography [26, 27].

A specialized MR unit with a dedicated study protocol can provide a highly informative arterial survey of the vessels typically involved in TA including pulmonary arteries [27, 28]. MR provides high-resolution imaging of anatomical features such as mural thickening, luminal changes and aneurysm formation, while avoiding the risks associated with arterial puncture, iodinated contrast load and radiation exposure (Fig. 3). In addition, as subtle vessel wall thickening occurs early in the pre-stenotic inflammatory stage of the disease, specific MR sequences such as delayed contrast-enhanced MRI may allow the detection of TA, at a potentially reversible stage, provided the diagnosis is considered early enough [29]. Moreover, comparative studies with intra-arterial angiography are encouraging. Direct comparison of the findings from angiography and MRA in a study of 30 TA patients has revealed agreement in excess of 90% for the identification of normal and abnormal vessels [30, 31].


Figure 3
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  		FIG. 3. MRI of a patient with extensive TA involvement of the abdominal aorta. There is severe stenosis of the subdiaphragmatic aorta, the coeliac trunk is occluded and the superior mesenteric artery (SMA) has a stenotic origin with post-stenotic dilatation. The right renal artery has an anomalous origin near the SMA, the left kidney is small and supplied by a collateral following the occlusion of the left renal artery.

 
An additional advantage of the non-invasive/non-radioactive nature of MRI is the potential it offers as a means for assessment of disease activity and response to treatment. However, this application needs to be further explored in prospective studies, with data to date limited. A study of seven patients using inversion recovery prepared gradient-echo MR sequences, with nulling of blood and fat signals, demonstrated marked delayed enhancement on contrast-enhanced images in five patients, which was confined to areas of aortic thickening and associated with a raised CRP. The remaining two patients had evidence for aortic thickening with no delayed enhancement and a normal CRP [29]. Tso et al. reported on 16 patients in whom repeat scans were performed and found four new occlusions, seven stenoses and one dilatation. They identified new lesions in three patients, in the absence of concurrent arterial wall oedema, and in five patients following the appearance of oedema [32]. Although therapy may have had an important modifying influence, the data suggest that there is no close correlation between the presence/absence of vessel wall oedema detected by MR and disease progression [32]. In our retrospective study of six patients, we identified one patient in whom there was detectable reduction in vessel wall thickening and an increase in the vascular lumen of the left subclavian artery following immunosuppressive therapy [33] and similar findings have been reported elsewhere [34]. Although somewhat limited by their small size, these preliminary studies illustrate the potential of MR in the ongoing assessment of disease progress in terms of anatomical change in affected vessels.

Limitations of MRI
Despite the persistent advances in the quality and range of images available, a number of disadvantages associated with MR scanning persist, not least the fact that in many areas worldwide there are limited facilities for MRI of patients with large vessel vasculitis. MR remains time-consuming, operator-dependent and expensive, and standardized protocols have yet to be agreed upon by different centres. Furthermore, although MRI may reveal signs suggestive of vascular inflammation in TA, including arterial wall thickening, increased signal intensity and arterial wall oedema [35], no clear correlation with disease activity or progression has been demonstrated [36]. In the Tso study referred to earlier, MR identified vessel wall oedema in 94% of patients with definite active disease and in 56% of those with apparent clinical remission [32]. However, the authors were unable to demonstrate a consistent correlation between the oedema and disease progression. It has also been reported that MR may occasionally overestimate the degree of stenosis in branch arteries [29], and that limitations in resolution may result in relatively poor imaging of distal aortic branches [24].

High-resolution Doppler ultrasound
Although widely available, the use of high-resolution Doppler US is relatively under investigated in TA. US may lead to an earlier diagnosis in patients presenting with TA, through detection of pre-stenotic lesions in the common carotid and subclavian arteries [37, 38]. US is particularly good for the assessment of common carotid arteries, where it is up to 10-fold more sensitive than MRI, displaying a resolution of 0.1–0.2 mm [24]. In addition, Doppler US can be used for indirect measurement of arterial stiffness, which is commonly raised in patients with TA [39, 40]. In TA, the typical lesion identified by US is a long, smooth, homogeneous concentric thickening of the arterial wall, whereas in contrast an atherosclerotic plaque is shown to be non-homogeneous, often calcified and associated with an irregular vessel wall [24, 25, 41]. Comparative studies have shown that results obtained with US correlate closely with angiography and MRA, with agreement in excess of 95% reported [42]. In addition, US may on occasion be more sensitive than angiography, through its ability to detect the intimal-media thickening associated with early lesions [25, 43].

The high resolution of Doppler US raises the possibility that it may also offer a means by which disease activity and response to treatment can be monitored. Park and colleagues studied the common carotid artery and based on the ESR, CRP and CT angiography findings they graded lesions identified active or inactive [44]. Using high-resolution US they report a common carotid arterial wall thickness of 2.5–5.0 mm in active lesions compared with 1.1–2.0 mm in lesions considered inactive, corresponding to a vessel diameter of 10 mm or more in active disease and <7 mm in inactive disease. Hence, they suggest that US may represent a means by which TA disease activity can be monitored. In addition, US has identified reductions in arterial wall thickness in response to treatment and following resolution of disease activity [24, 43]. However, although US is the most sensitive non-invasive method for detection of abnormalities in the common carotid arteries [43], further prospective studies are required to show convincingly that it can be of use in estimating disease activity and outcome.

Limitations of Doppler US imaging
Doppler US is highly operator-dependent and few centres have radiologists with sufficient vascular expertise. Furthermore, while imaging is optimal in the common carotid and vertebral arteries, assessment of the proximal subclavian and distal internal carotid arteries is limited by overlying tissues, and high-resolution US of the aorta is not yet available [24]. As with the other forms of non-invasive imaging, US does not allow measurement of central aortic pressures. Finally, there is insufficient data available to conclude whether or not US has a place in disease monitoring.

CT angiography
EBCT angiography has been used to assess patients with TA. EBCT allows detection of arterial wall thickening in the pre-stenotic phase [45, 46] and can help distinguish TA from atherosclerosis [47]. EBCT compared well with angiography in the analysis of lesions in the common carotid, subclavian and brachiocephalic arteries [48]. However, there are insufficient data in the literature to decide whether EBCT has a place in disease activity monitoring, with conflicting results reported for the use of arterial wall enhancement as a means of analysis [47, 49]. Likewise, contrasting results have been reported for the use of EBCT in assessing changes in wall thickness following treatment [46].

Limitations of CT angiography
The main limitations associated with EBCT are the requirement for iodinated contrast administration and radiation exposure. The current resolution of EBCT is such that it is most effective in the assessment of the aorta and its proximal branches and offers relatively limited imaging of distal aortic branches

18F-Fluorodeoxyglucose positron emission tomography
Labelling of the glucose analogue deoxyglucose with Fluorine-18, a positron-emitting radionuclide, permits the identification of areas of high glucose metabolic activity. FDG uptake is related to both the metabolic rate of the cell and the abundance of glucose transporters and although phosphorylated by hexokinase, FDG is not metabolized [50, 51]. Constitutive uptake is seen in the brain, myocardium and genitourinary tract. Uptake may also be seen in the bone marrow, gastrointestinal tract, liver and spleen, although this is usually minimal and diffuse [51]. To minimize uptake in normal tissues and to optimize the signal, patients are fasted for a minimum of 4 h prior to performing the scan. The use of 18F-FDG-PET in pathology has been most widely studied in oncology and is an integral part of clinical practice. However, FDG uptake may also be increased at sites of inflammation and infection and although not as well characterized as in the analysis of tumours, 18F-FDG-PET is increasingly recognized to be a useful imaging modality in this setting [50].

In TA, abnormal 18F-FDG-PET uptake is seen in the wall of large vessels (>4 mm), if vascular inflammation is present (Fig. 4). We have recently reported on two retrospective studies, which explored the utility of 18F-FDG-PET scanning in TA. In the first, 12 patients had active disease and six had inactive, and there was one false-negative and no false-positive scans. Thus, 18F-FDG-PET had a sensitivity of 92% and a specificity of 100%, with a positive predictive value of 100% and a negative predictive value of 85% [52]. The second study, comparing angiography, MRI and 18F-FDG-PET in six TA patients, suggested that 18F-FDG-PET is an important new clinical tool for the diagnosis of TA and that it may have a place in the monitoring of disease activity and response to treatment [33].


Figure 4
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  		FIG. 4. 18F-FDG-PET scan of a patient with TA prior to and following treatment with corticosteroids and immunosuppression. (A) FDG-PET scan performed at presentation. Note the markedly abnormal uptake of 18F-FDG in the aortic arch and carotid arteries. (B) FDG-PET scan of the same patient in remission following treatment with prednisolone and intravenous cyclophosphamide. Note almost complete resolution of abnormal 18F-FDG uptake in these areas.

 
The principle advantage of 18F-FDG-PET is its ability to detect pre-stenotic disease in patients presenting with non-specific features commonly associated with early TA [53, 54]. However, critical analysis of the accuracy of 18F-FDG-PET in the assessment of disease activity and response to treatment is limited by the lack of available arterial biopsy material. Reduction in 18F-FDG-PET uptake at the site of aortitis has been correlated with both clinical improvement and a reduction in aortic wall thickness [55]. In addition, we and other groups have demonstrated a marked reduction in 18F-FDG-PET uptake at sites of inflammation following adequate immunomodulatory therapy, a response that typically correlates with changes in the acute phase response and disease activity index [33, 52, 56].

Co-registration of MR with FDG-PET has not yet been described in large vessel vasculitis but has been investigated in both oncology and neurosciences [57, 58]. However, a recent report has highlighted the benefit of co-registration of 18F-FDG-PET and enhanced CT images in TA [59]. In this study of 14 patients and six healthy controls, 18F-FDG-PET co-registration with CT images allowed localization of 18F-FDG accumulation to the aortic wall in patients with TA in whom 18F-FDG accumulation could not be identified anatomically with PET scanning alone. Co-registration of 18F-FDG-PET and CT may also offer a more accurate method for the detection of disease relapse. We have found 18F-FDG-PET scanning alone to be relatively insensitive in this scenario. Using co-registration of the images, Kobayashi et al. [59] were able to identify persistent vascular uptake of 18F-FDG-PET despite normalization of the acute phase response. We have made similar observations, suggesting that 18F-FDG-PET scanning represents a sensitive means for the detection of persistent disease activity, in those patients who appear clinically to be in remission while having histological evidence for persistent vascular wall inflammation [8]. However, further prospective studies to validate the role of 18F-FDG-PET scanning and to exclude alternative explanations for the persistent uptake including localization at sites of vascular remodelling, fibrosis or atherogenesis are required (see subsequent text).

Limitations of 18F-FDG-PET
Although 18F-FDG-PET is proving to be a sensitive and specific means through which vascular wall inflammation can be detected [33, 52, 59], limitations remain. First, it results in significant radiation exposure, is expensive and is limited to relatively few centres. Second, it lacks both histological confirmation of the findings in TA and a reliable standardized technique for quantification. Finally, 18F-FDG-PET may detect atherosclerosis [54], although this is more commonly seen in older patients and typically exhibits a vascular distribution distinct from TA. For example, TA typically affects the common carotid arteries while atherosclerosis is more typically seen in the internal carotid arteries. Moreover, an intense linear uptake of FDG is more characteristic of active vasculitis (Fig. 4). Nevertheless, particularly in older TA patients it may prove difficult to distinguish between FDG uptake due to active TA or subclinical atherosclerosis. Similarly, sites of vascular remodelling and fibrosis in TA are associated with increased metabolic activity and might take up FDG leading to detection of a low-level vascular signal difficult to distinguish from partially treated disease.

As yet, 18F-FDG-PET scanning has only been shown to be of use in the diagnosis of TA. Prospective studies are required to confirm its utility as a tool for the assessment of disease activity and for monitoring. Likewise, data are needed on the outcome of patients whose 18F-FDG-PET scan suggests persistent disease activity, so as to establish whether they are more likely to suffer a disease flare or to develop progressive vascular lesions.


   Medical management of TA
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 
Corticosteroids
Controlled trials providing an evidence base to support treatment choices for patients with TA are singularly lacking, even for the use of corticosteroids. When considering the efficacy of individual drugs, the stage of disease is likely to be important. Despite this, the majority of reports includes patients with late-stage disease and fixed fibrotic lesions. Although active vascular wall inflammation in the early phase would be expected to be more reversible than established late phase disease, data to support this hypothesis remain limited, with studies typically too small to subdivide patients. It has been suggested that 50% of patients respond to corticosteroid therapy alone [60], a view supported by an NIH study, which achieved remission at least once in 60% of patients treated with corticosteroids [8]. A Mayo Clinic study of 32 patients, 29 of whom were treated with corticosteroids, reported that systemic symptoms responded rapidly in all patients, with an associated fall in ESR [61]. Of 16 patients with an absent pulse, eight had a confirmed return of the pulse. Although Mwipatayi et al. [9] also noted a significant improvement in systemic symptoms and acute phase response in a retrospective study of 182 patients receiving corticosteroids, no improvement in stenotic lesions or return of absent pulses was noted. The efficacy of corticosteroids is also supported, albeit indirectly, by the observation that 50% of patients relapse during corticosteroid tapering [8]. However, there are no data to confirm that steroids or indeed other immunosuppressive therapy alter the outcome in TA.

Immunosuppressive therapy
In those patients who relapse on corticosteroid monotherapy or require doses associated with an unacceptable risk of serious side effects, it is common practice to add a further immunosuppressive drug as a steroid-sparing agent. However, once again data demonstrating the efficacy of such an approach remains sparse. In the study by Kerr [8], 25 patients had an immunosuppressive agent added. Eight patients (32%) achieved remission following addition of methotrexate (MTX), azathioprine (AZA) or cyclophosphamide (CYC) and a further four patients responded following a trial of a second agent. Although this approach may induce remission and act as a steroid-sparing agent, we remain largely ignorant as to its efficacy in preventing disease progression and there are no significant data to suggest that immunosuppressive drugs result in lesion regression. Indeed, serial angiograms have revealed progressive vascular lesions in patients treated with a combination of corticosteroids and an immunosuppressive drug [8, 9]. Notwithstanding this, it is important to recognize the need for further prospective studies using MRA, FDG-PET and US imaging to assess combination therapy on vascular wall inflammation in early-phase disease and to determine its efficacy in preventing the development of stenoses.

MTX is now the ‘first-choice’ second line immunosuppressive agent, based largely on familiarity among rheumatologists, small open label studies and anecdotal evidence [8, 9, 62–64]. MTX can induce remission in early disease [65] and improve remission rates in corticosteroid-resistant TA [62]. In the latter open-label study, 13 of the 16 patients achieved disease remission, as defined by the absence of signs of active disease and no new angiographic lesions [62]. Remission was maintained in 50% of patients over a follow-up period of 18 months.

A study of 15 patients with TA examined whether a combination of oral prednisolone (initially 1 mg/kg/day tapered to 5–10 mg/day) and AZA (2 mg/kg/day) could suppress disease activity in newly diagnosed patients. All achieved complete resolution of systemic symptoms, and repeat angiography at 1 yr revealed no new angiographic lesions. Although this study demonstrates the efficacy of AZA as a steroid-sparing agent, it remains possible that similar results would have been seen with the corticosteroids alone [66]. However, AZA remains a suitable alternative to MTX in TA.

Before the widespread usage of MTX, oral CYC was the agent of choice for corticosteroid-resistant TA. In an NIH study, the addition of oral CYC (2 mg/kg/day) induced remission in four of six patients and allowed a reduction of corticosteroid dose [60]. Concern regarding the toxicity associated with long-term CYC therapy has limited its use in TA, which is largely confined to the treatment of life-threatening disease or to those failing to respond to AZA or MTX. The use of CYC is typically restricted to 3–6 months, prior to switching to AZA or MTX. We favour pulsed intravenous CYC (750 mg/m2), with an initial infusion followed by a second 2 weeks later, and thereafter monthly for 6 months.

Experience with other immunosuppressive agents is limited, and reports often anecdotal. Mycophenolate mofetil (MMF) has shown some promise as an alternative to MTX in TA. In a report of three patients with refractory TA, MMF (2 g/day) appeared clinically efficacious and well-tolerated [67]. A recent study examined the effect of minocycline in 11 patients with active disease despite oral prednisolone. Minocycline 100 mg b.d. was given for 3 months without a change in prednisolone dose. Patients receiving minocycline displayed a significant reduction in disease activity and acute phase response [68]. However, further studies are required before either of these drugs is used in preference to MTX or AZA.

Data are emerging in support of tumour necrosis factor {alpha} (TNF-{alpha}) antagonists in the treatment of TA, with two case studies and an open-label trial reported [69–71]. In the latter, 15 TA patients, representative of the 25% of patients who develop intractable disease [8], were treated with either infliximab or etanercept. Ten patients achieved complete remission, as evidenced by the absence of new vascular lesions and withdrawal of corticosteroid therapy, and four partial remission with >50% reduction in the dose of corticosteroids. The response to treatment was maintained for up to 3.3 yrs. These encouraging data support the need for a randomized, controlled clinical trial of anti-TNF-{alpha} therapy in TA, particularly in light of the recent report of a lack of efficacy of this therapy in giant cell arteritis (GCA) [72].

Finally, when discussing the role of combination immunosuppressive therapy in TA, it is also important to remember the need to avoid over-treatment with immunosuppressive drugs in patients with prolonged inactive or ‘burnt-out’ disease. In these patients, prognosis depends more on the presence of complications such as systemic or pulmonary hypertension than on the risk of disease relapse.

Management of cardiovascular risk
Patients with chronic rheumatic inflammatory diseases such as rhematiod arthritis (RA) and SLE are at increased risk of developing premature atherosclerosis and this also seems to be the case in TA [73–76]. Therefore, it is imperative that risk factors for cardiovascular disease such as hypertension, hyperlipidaemia and lifestyle factors such as smoking status are screened for and aggressively managed. Underlying systemic hypertension is often missed in TA, as the BP recorded in the upper limbs may underestimate the true central pressure, as a consequence of subclavian/axillary artery involvement. It is important to measure the BP in all four limbs and where possible to have patients regularly assessed in a vascular laboratory. As renovascular hypertension is prevalent in TA, drugs such as angiotensin converting enzyme inhibitors and angiotension II receptor antagonists are the anti-hypertensive agents of choice (although contraindicated if bilateral renovascular disease is present). In patients with renal artery stenosis, consideration should be given to interventional management (see subsequent text).

Intriguingly, low-dose aspirin may have a therapeutic effect in large vessel vasculitis, although whether this reflects an anti-platelet or anti-inflammatory effect is currently unknown [77]. HMG-CoA reductase antagonists (statins) are increasingly recognized to have pleiotropic actions, displaying vasculoprotective, anti-inflammatory and immunomodulatory effects in addition to their lipid-lowering properties [78, 79] and a modest disease-modifying effect has been reported in patients with RA [80]. This combination of actions suggests that statins may have disease-modifying and protective effects in TA. Our current practice is to adopt a pragmatic approach and prescribe concomitant low-dose aspirin and statin therapy, in addition to standard immunosuppressant therapy, in all patients with TA including those who are normolipidaemic, unless there is a contraindication. However, the efficacy and indeed safety of this approach remains to be determined.


   Interventional management of TA
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
Future developments
 Summary
 Acknowledgements
 References
 
An interventional approach in TA should not be undertaken lightly and for optimal results requires multidisciplinary input from rheumatology, interventional radiology and an experienced vascular surgeon. Revascularization should only be considered if stenotic or occlusive lesions lead to significant haemodynamic effects, or if aneurysmal enlargement results in a risk of rupture or dissection. Other indications include severe stenoses of the cervicocranial circulation considered to increase the risk of cerebrovascular accident, significant coronary artery disease, coarctation of the aorta, aortic regurgitation, severe limb claudication and significant renal artery stenosis. Good long-term outcomes have been achieved with surgical bypass procedures, with cumulative survival rates of 81.4 and 73.5% at 10 and 20 yrs, respectively [81, 82]. The restenosis rate reported by most authors is 20–30%. A Cleveland Clinic Series reported that of the 31 bypass procedures performed, restenosis, occlusion or the need for revascularisation occurred in 11 after a median follow-up period of 11 months [83].

A recent review of 106 TA patients undergoing surgery divided them into prognostic categories and suggested that patients with complicated and/or progressive disease derived the most benefit [82]. However, the authors also highlighted the potential risk of anastomotic aneurysms and suggest patients undergo regular screening for this complication [82, 84]. Weaver examined 27 patients with TA who underwent intervention for renal artery stenosis. Forty interventions were performed; 32 aortorenal bypass procedures, two repeat implantations, four nephrectomies and two transluminal angioplasty procedures. During follow-up (mean 68 months), three graft stenoses and three graft occlusions occurred. Intervention resulted in a significant decrease in BP and a reduction in the number of anti-hypertensive agents required per patient [85]. Although percutaneous transluminal angioplasty (PTA) has been used in TA, particularly for short focal lesions [86], only relatively short-term follow-up data are available and some centres have reported high-restenosis rates (44% at 12 months) [8, 83]. Experience with post-PTA stent insertion has also been reported, mainly as single case reports with generally favourable results. Notwithstanding this, the number of patients reported and the follow-up period remains limited with long-term data lacking [87]. Indeed, a recent study suggested that the long-term patency of stents was low with five of seven stents restenosed or occluded after 2–45 months [82].

Ideally, interventions should be performed when the disease is inactive to minimize the risk of surgical dehiscence. The question of how to therapeutically minimize complications including restenosis remains unresolved. However, a recent study using serial angiography suggests that intervention performed on patients with stable disease (using NIH criteria [8] and post-interventional treatment with corticosteroids and immunosuppressive drugs are independent variables for the maintenance of arterial patency [88].


   Future developments
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
Summary
 Acknowledgements
 References
 
Therapies
TA remains a clinical challenge at all stages of disease and treatment decisions are hampered by a dearth of evidence for and against specific therapies. This is a reflection of the nature of the condition and its rarity, which limits the feasibility of prospective controlled clinical trials. Although current treatment regimens adequately control vascular inflammation in the majority of patients, up to 25% will not respond [8] and there are precious few data to support the ability of any specific therapy to retard disease progression. An initial open label study suggests that TNF-{alpha} blockade may induce remission in those failing to respond to maximal conventional treatment [72]. However, disappointing recent results associated with the use of anti-TNF{alpha} therapy in other granulomatous vasculitides including Wegener's granulomatosis [89] and GCA [72], indicate the need for prospective controlled trials of anti-TNF-{alpha} therapy, both to confirm its efficacy and to increase the likelihood of adequate funding being made available for its use.

The experience of the EUVAS investigators in organizing clinical trials in the ANCA-associated vasculitides [90], demonstrates that such an approach will be required for TA. Experience in Italy suggests that a useful development might be the creation of national/international TA patient databases [91]. This would provide data on the total number of TA patients and annual incidence figures for new or relapsing cases, essential information for planning recruitment for future clinical trials.

The work of Connie Weyand and others is extending our understanding of vascular wall pathology in the large vessel vasculitides [6, 7, 92, 93]. These studies highlight the fact that myofibroblast proliferation is a major contributor to vascular stenosis in TA and that this is not adequately controlled by conventional therapy. These observations may ultimately lead to biological therapies designed to inhibit growth factors such as platelet-derived growth factor (PDGF), specific matrix metalloproteinases, or pivotal cytokines or cellular components such as interferon (IFN-{gamma} or dendritic cells [7]. In the short term, currently available drugs including rapamycin (sirolimus) and everolimus, which inhibit mammalian target of rapamycin (mTOR), a regulatory protein in the cell cycle [94], should be considered. They have been shown to be more effective than ciclosporin A and AZA in the inhibition of myointimal proliferation post-cardiac transplantation [95, 96]. Furthermore, rapamycin may induce expression of haem oxygenase-1 (HO-1) [97], which catalyses the breakdown of haem into carbon monoxide, biliverdin and bilirubin. HO-1 expression in vascular smooth muscle cells (VSMC) exerts anti-proliferative, pro-apoptotic effects, whereas, in contrast, it is pro-proliferative and anti-apoptotic in endothelial cells [98]. As described earlier the risk of restenosis following arterial stent insertion is increased in patients with TA. The use of drug-eluting stents to prevent restenosis has been pioneered in the treatment of coronary artery atherosclerosis. Stents incorporating rapamycin or tacrolimus have been shown to have lower restenosis rates than bare-metal (drug-free) stents [99] and this would seem to be a useful option in TA and merit further investigation. Of note, a recent report demonstrated markedly improved coronary artery patency following insertion of drug-eluting stents compared with a bare-metal stent in a patient with TA [100].

The presence of narrowed, stenotic or dilated arteries in patients with TA will result in disturbed local blood flow and increased areas exposed to oscillatory shear stress. In combination with endothelial dysfunction, these abnormalities are likely to be important in the accelerated atherosclerosis reported at autopsy in young female patients with TA [75]. We have recently shown that TA is associated with elevated aortic stiffness in the central aorta, which may persist when the disease is quiescent [40]. Thus when designing therapy for patients with TA, consideration should be given to combination therapy aimed at suppressing inflammation, inhibiting myofibroblast proliferation and modifying cardiovascular risk.

Disease monitoring
Despite current limitations including cost, availability and optimal imaging protocols, it is essential to embrace novel imaging technologies and to plan clinical trials in TA incorporating them. In particular, the co-registration of PET with CT and/or MR images seems to have great potential. These studies are required to substantiate provisional data suggesting that these approaches allow early diagnosis and facilitate monitoring of disease activity. Moreover, new prospective studies will help determine the effect of treatment on inflammation within the arterial wall and whether suppression of disease activity with current drug regimens alters disease progression.


   Summary
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
Acknowledgements
 References
 
TA is a rare large vessel vasculitis of unknown aetiology, which remains difficult to manage and is often only diagnosed in the late occlusive stage of the disease, when irreversible vascular damage has occurred. Recent studies suggest that novel non-invasive imaging methods such as 18F-FDG-PET, Doppler US and MRA, by allowing accurate assessment of the vascular wall, can identify the presence of vascular inflammation and/or wall thickening not detectable by conventional angiography. Although this is an important advance, as it may allow TA to be diagnosed in the early pre-stenotic phase and to be monitored more accurately, further prospective studies are required to confirm this. Thus, conventional angiography remains an important technique for the evaluation of TA patients.

The non-invasive imaging modalities discussed are expensive and, in the case of 18F-FDG-PET, often limited to patients suffering from malignancy. Moreover, data to date suggest that they are most effective when used in combination. However, TA is a disease of young patients with a mortality rate similar to that seen in many malignancies. Hence it is our view that every effort should be made to provide early access to adequate imaging for patients presenting with features consistent with TA. Although as yet there is little evidence that immunosuppressive therapy can prevent progression of the disease, the dramatic reduction in vascular inflammation post-treatment seen in studies utilizing 18F-FDG-PET [33] and CT-PET [59], suggest that early diagnosis and appropriate therapy may lead to reduction in the incidence of vascular occlusion. The next challenge is to use these techniques, combined with MRA and conventional angiography to establish this.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
References
 
We are grateful for the continuing help of Dr A. Al-Nahhas (Hammersmith Hospital, London) and Dr R. Mohiaddin (Royal Brompton Hospital, London) in providing FDG-PET and MRI studies for our TA patient cohort. We would like to thank Dr J. Boyle (Hammersmith Hospital) for assistance with histology and Dr R. Grocott-Mason (Hillingdon Hospital, Middlesex) for the angiogram.

The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Clinical challenges in TA
 Clinical imaging in TA
 Medical management of TA
 Interventional management of TA
 Future developments
 Summary
 Acknowledgements
 References
 

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