FDG-PET in Large Vessel Vasculitis

the detection of large vessel inflammation: the present literature This book represents the culmination of the efforts of a group of outstanding experts in vasculitis from all over the world, who have endeavored to draw themselves into this volume by keeping both the text and the accompanying figures and tables lucid and memorable. The book provides practical information about the screening approach to vasculitis by laboratory analysis, histopathology and advanced image techniques, current standard treatment along with new and more specific interventions including biologic agents, reparative surgery and experimental therapies, as well as miscellaneous issues such as the extra temporal manifestations of "temporal arteritis" or the diffuse alveolar hemorrhage syndrome. The editor and each of the authors invite you to share this journey by one of the most exciting fields of the medicine, the world of Vasculitis.

of the arteries originating from the aortic arch, particularly the superficial temporal artery; however, involvement of the entire aorta and of its main branches also occurs in about 15% 14 . Giant cell arteritis is common in the Caucasian population, with an incidence of about 18 per 100,000 over 50 years of age [15][16][17] and affects women twice as often as men [15][16][17] . Autopsy studies however suggest that it may be much more common than is clinically apparent 18 .

Takayasu's arteritis
Takayasu's arteritis is named after Mikito Takayasu, who in 1908 had reported the peculiar wreath-like arteriovenous anastomoses around the papillae in a young woman with pulseless disease 24 . This large vessel vasculitis primarily affects the aorta, its main branches, and the coronary and pulmonary arteries. The incidence rate of the disease is about 2 per 1,000,000 with its onset at a mean of 35 years of age [25][26][27] . Takayasu's arteritis occurs worldwide, although it is considered to be more common in the Orient 28 and is 10 times more prevalent in females than in males. The etiology of Takayasu's arteritis also remains unresolved, while the clinical course includes both an early and a late phase. Pathology studies in the early phase reveal granulomatous or diffuse productive www.intechopen.com inflammation in the media and adventitia, with secondary thickening of the intima and occasional perivascular inflammation 29 . In the clinic, it is commonly the setting of fever of unknown origin with non-specific systemic symptoms. Contrary to the early phase, pathology studies in the late phase show marked thinning of the media, with disruption of elastic fibers, fibrotic thickening of the adventitia, and marked intimal proliferation 29 . The resulting variable ischemic symptoms secondary to arterial stenosis, occlusion, or arterial dilatation and aneurysmal formation cause various clinical conditions, such as arm claudication, decreased arterial pulses, carotodynia, visual loss, stroke, aortic regurgitation and arterial hypertension 30 . Topological classification of Takayasu's arteritis is based on the vascular provinces that are affected 31 , with either affection of the branches of the aortic arch (Type I), the ascending aorta, aortic arch and its branches (Type IIa), the ascending aorta, aortic arch and its branches and the thoracic descending aorta (Type IIb), the thoracic descending aorta, abdominal aorta, and/or renal arteries (Type III), the abdominal aorta and/or renal arteries (Type IV) or combined features of types IIb and IV.

Diagnostic work-up in large vessel vasculitis
Giant cell arteritis and Takayasu's arteritis are both usually present with a wide clinical spectrum with no specific laboratory finding. The American College of Rheumatology has established a set of clinical, radiological and histological criteria to classify cases of biopsyproven arteritis ( Table 1) 32,33 . The presence of at least three of the described criteria is required for classifying a patient as having either Takayasu's arteritis or giant cell arteritis. These criteria provide a sensitivity of 93.5% with a specificity of 90.5% for diagnosing giant cell arteritis and a sensitivity of 91.2% with a specificity of 97.8% for diagnosing Takayasu's arteritis in biopsy-positive patients. Although these criteria were originally designed for research purposes to help distinguish between different types of vasculitis; they are in clinical practice also frequently used for diagnosing an individual patient 34 . Nevertheless, the fact that frequent symptoms of giant cell arteritis such as jaw claudication, diplopia, neck pain, and elevated C-reactive protein are not included in the criteria, limits their widespread clinical application. Criteria that are included, such as headache and scalp tenderness can also be due to various other diseases. A normal erythrocyte sedimentation rate does not rule out giant cell arteritis, as it has been found in up to 30% of patients with biopsy-proven giant cell arteritis 35,36 . Furthermore, several patients with giant cell arteritis do only display nonspecific symptoms that does not apply to any set of criteria. Systemic giant cell arteritis symptoms such as fever, anorexia, weight loss and malaise may focus the diagnostic work-up towards a suspected malignancy, especially in older patients 37 . Frequent clinical features of Takayasu's arteritis such as fever, postural dizziness, arthralgias, weight loss, headache, hypertension, elevated erythrocytes sedimentation rate and anemia were also not included in the classification criteria of the American College of Rheumatology. In contrast, angiographic findings and non-congruent blood pressure measurements between both arms are included as part of the diagnostic criteria although they may be false negative in early vasculitis 38,39 , or when the arteritis is restricted to the abdominal aorta, its branches, or to the pulmonary artery. The wide clinical spectrum and the diagnostic limitations of giant cell arteritis and Takayasu's arteritis frequently cause delay in their diagnosis and subsequent treatment. www.intechopen.com

[ 18 F]FDG-PET and [ 18 F]FDG-PET/CT
[ 18 F]FDG-PET is an operator-independent, non-invasive imaging modality which examines the regional distribution of fluorine-18-fluorodeoxyglucose. Deoxyglucose is labeled with the positron emitting radionuclide, 18  Modern PET-CT scanners combine PET scanners with a computed tomography scanner in a single gantry system. With these scanners, images are taken sequentially with both devices in the same session and the reading can be done with the single co-registered image. As a consequence, the functional image obtained by PET, can be correlated more precisely with the anatomic structures. PET/CT has shown an incremental diagnostic value over CT and PET alone and there is emerging evidence of a substantial impact of PET/CT imaging on patient management 40 .

[ 18 F]FDG-PET scanning protocols for large vessel vasculitis
The

[ 18 F]FDG-PET and atherosclerosis
The accumulation of glucose analogues has not only been demonstrated in vasculitic vessels, but also in atherosclerotic plaques (Figure 1) 56 (Figure 2): a) Grade I: uptake present but lower than liver uptake, b) Grade II: similar to liver uptake, and c) Grade III: uptake higher than liver uptake. Proposed by Meller et al. 48 , this scale was subsequently validated to represent the severity of inflammation 49 . Fig. 2. The visual arteritis score as proposed by Meller et al. 48 . The severity of large vessel [18F]FDG-uptake is visually graded: A) Grade 1: uptake present but lower than liver uptake; B) Grade 2: similar to liver uptake; C) Grade 3: uptake higher than liver uptake (images derived from reference 49 ).

BC A
So far, this score has been employed in two reference collectives without clinical symptoms or laboratory signs of large vessel inflammation in order to determine the uptake in nonvasculitic vessels 48,49 . Grade I vessel uptake was frequently found in the thoracic part of the aorta which was most likely due to atherosclerosis. Accordingly, only Grade II or III [ 18 F]FDG-uptake in the thoracic aorta and any visible uptake in other segments should routinely be judged as active large vessel inflammation. In this manner, the majority of lesions can be ruled out as due to atherosclerosis. On the other hand, computed quantification of [ 18 F]FDG-uptake using the [ 18 F]FDG standardized uptake value (SUV) has not shown to be useful in discriminating atherosclerosis from vasculitis yet.

[ 18 F]FDG-PET for diagnosing giant cell arteritis
The diagnosis of giant cell arteritis is currently based mainly on clinical evaluation, laboratory results, and temporal biopsy, but a gold standard is lacking. Despite recent advances, no imaging modality has been included in the American College of Rheumatology diagnostic criteria for giant cell arteritis (Table 1). Nevertheless, [ 18 F]FDGwww.intechopen.com PET has indicated its usefulness clinically for a number of studies through better evidence, as compared to Takayasu's arteritis, due to the higher frequency of the disease ( Table 2). The uptake pattern in large vessels affected by giant cell arteritis was linear, continuous, and was predominantly of Grade II. The thoracic vessels were most frequently affected, followed by the abdominal vessels 48,49 . In the published studies, the ability of [ 18 F]FDG-PET to detect large vessel inflammation differed considerably. In studies employing patients with polymyalgia rheumatica and giant cell arteritis, sensitivities between 56% and 100% were reported 45,46,51,53 , with a specificity between 77% and 98% 51 . The large differences seen between the studies can partially be explained by dissimilar disease activity; as suggested by one study demonstrating that the sensitivity depends on the degree of inflammation ( Figure  4). C-reactive protein has shown to be a better predictor for the sensitivity of [ 18 F]FDG-PET in giant cell arteritis than the erythrocyte sedimentation rate 49 46 . The high [ 18 F]FDG uptake of the brain and the small diameter of the temporal arteries limited its sensitivity in the detection of cranial vessel involvement with the whole-body PET technique used. Newer generation PET/CT scanners offer an image resolution corresponding to a three-fold improvement compared to the technology used in the aforementioned study (2mm vs. 7mm), potentially allowing to image even smaller arteries as the temporal arteries. Further clinical studies must are warranted to clarify the potential role of PET in the non-invasive work-up of temporal vasculitis.

[ 18 F]FDG-PET for diagnosing Takayasu's arteritis
The diagnosis of Takayasu's arteritis frequently integrates imaging and angiographic (Table 1). However, angiographic alterations usually occur in the late phase of Takayasu's arteritis while metabolic changes are already present in the early phases. The data on the use of [ 18 F]FDG-PET in Takayasu's arteritis are less robust compared to those in giant cell arteritis (Table 2), accounting for the different prevalences of both vasculitides. During the early phase of Takayasu's arteritis, the [ 18 F]FDG uptake pattern is linear and continuous ( Figure 3A), while in the late phase the pattern can become patchier rather than continuous but still remains in a linear distribution 44 44 . Follow-ups in Takayasu's arteritis only based on clinical symptoms alone have shown to be of limited accuracy. In a previous report, biopsies showed active inflammation in 44% of patients thought to be in clinical remission 59 . However, [ 18 F]FDG-PET is able to detect more sites than just those that were clinically active 44 . This makes [ 18 F]FDG-PET a promising candidate to be regularly employed in the follow-up of Takayasu's arteritis (Figure 3) due its high sensitivity and the good correlation with the outcome 43,44,49 .

Conclusions
In conclusion, whole-body imaging with [ 18 F]FDG-PET is highly effective in assessing the extent of giant cell arteritis and Takayasu's arteritis, respectively. [ 18 F]FDG-PET has shown to have identified more affected vascular regions than morphologic imaging with Magnetic Resonance Imaging in both diseases. A unique feature and strength of FDG-PET is the opportunity to monitor disease activity non-invasively. In contrast to other imaging modalities PET allows for an immediate assessment of response to anti-inflammatory treatment and is suitable to guide therapy. Recent developments in PET technology such as integrated PET/CT machines and increased image resolution of the PET submodality imply significant improvements for vaculitis imaging with FDG. Further studies are warranted to evaluate the diagnostic benefit of these newer technical developments.
www.intechopen.com [ 18 F]FDG-PET has the clear potential to develop into a valuable tool in the diagnostic workup of both giant cell arteritis and Takayasu's arteritis, and may become a first-line investigation technique for non-invasive therapy monitoring. However, consensus regarding the imaging procedures as well as further clinical evidence is urgently needed.