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The increasing availability and improvement of imaging techniques are deeply influencing diagnosis and work-up of patients affected with vasculitis, particularly those with large vessel vasculitis (LVV). Fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET), especially when integrated with computed tomography (CT), is taking hold as a useful diagnostic technique to examine the aorta and the other large vessels in giant cell arteritis (GCA) with concomitant large vessel involvement (LV-GCA). In this paper we examined the progresses performed in this field in the last twenty years and the evidence available so far according to two different points of view ('pros' and 'cons'), in order to give a comprehensive answer to a still open question about the role of PET/CT in the diagnosis and follow-up of GCA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recent analysis of archived temporal arteries (TAs) acquired from 13 pathology laboratories in the US, Canada, Iceland, France, Germany and Israel from patients with pathologically-verified giant cell arteritis (GCA-positive) and TAs from patients with clinical features and laboratory abnormalities of GCA but whose TAs were pathologically negative (GCA-negative) revealed VZV antigen in most TAs from both groups. Despite formalin-fixation, VZV DNA was also found in many VZV-antigen positive sections that were scraped, subjected to DNA extraction, and examined by PCR with VZV-specific primers. Importantly, in past studies, the pathological diagnosis (GCA-positive or -negative) was known to the neurovirology laboratory. Herein, GCA-positive and GCA-negative TAs were provided by an outside institution and examined by 4 investigators blinded to the pathological diagnoses. VZV antigen was found in 3/3 GCA-positive TAs and in 4/6 GCA-negative TAs, and VZV DNA in 1/3 VZV antigen-positive, GCA-positive TAs and in 3/4 VZV antigen-positive, GCA-negative TAs. VZV DNA was also detected in one GCA-negative, VZV-antigen negative TA. Overall, the detection of VZV antigen in 78% of GCA-positive and GCA-negative TAs is consistent with previous reports on the prevalence of VZV antigen in patients with clinically suspect GCA., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To identify laboratory predictors of a positive temporal artery biopsy., Design: Cross-sectional study using retrospective electronic data base review., Participants: There were 3001 patients who had a temporal artery biopsy., Methods: The electronic database of a large health maintenance organization was searched for all patients who had a temporal artery biopsy performed from 1997 to 2006., Main Outcome Measures: Odds ratios for erythrocyte sedimentation rate, C-reactive protein (CRP), and platelet count values associated with a positive temporal artery biopsy., Results: Four hundred fifty-nine cases of biopsy-proven giant cell arteritis were identified. The odds of a positive biopsy were 1.5 times greater with an erythrocyte sedimentation rate of 47 to 107 mm/hr, 5.3 times greater with a CRP >2.45 mg/dL, and 4.2 times greater with platelets >400,000/μL., Conclusions: In this largest population-based giant cell arteritis study in the United States to date, we reaffirm Hayreh's finding of the significance of a CRP level >2.45 mg/dL in predicting a positive biopsy. Our findings support the literature suggesting that CRP and thrombocytosis may be stronger predictors of positive biopsy than erythrocyte sedimentation rate., Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Endothelin (ET)-1 has been implicated in the atherosclerotic process and during inflammation. Similarity in the development process of giant cell arteritis (GCA) and atherosclerosis exists. Several ET receptor antagonists have been developed, principally to target cardiovascular disease states. High doses of corticosteroids currently are used in the treatment of GCA, whereas other treatments are not as reliably effective. The present study was performed to elucidate the role for ET-1, ET(A), and ET(B) receptors in GCA., Design: Experimental, retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue., Participants: The study included 10 patients with GCA and 10 control patients with clinically suspected GCA but diagnosed not to have GCA., Methods: Immunohistochemistry, with anti ET-1, anti-ET(A), and anti-ET(B) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries., Main Outcome Measures: Endothelin-1, ET(A), and ET(B) receptor immunostaining intensities were quantified., Results: Temporal arteries from the patients with GCA showed the typical histologic features, including intimal thickening, disruption or loss of the elastic lamina, and inflammatory infiltrates of lymphocytes, macrophages, and multinucleated giant cells. These features were associated with increased ET-1 and ET(B) receptor immunoreactivity in the medial layer of the temporal arteries and endothelial cells in patients with GCA compared with the controls. The increased ET-1 and ET(B) receptor immunoreactivity occurred in vascular smooth muscle cells (SMCs) and multinucleated giant cells. The ET-1 and ET(B) receptor immunoreactivity correlated with the degree of systemic inflammation. No changes were observed in ET(A) receptor expression in SMCs or endothelial cells compared with controls., Conclusions: The results suggest a role for ET-1 and ET(B) receptors in GCA. Inhibiting the ET system may provide a corticosteroid-sparing alternative in the treatment of GCA., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To correlate the pathologic findings of temporal artery biopsies in patients clinically defined as positive, presumed, or negative for giant cell arteritis (GCA)., Design: Retrospective case series., Participants and Controls: Patients evaluated for GCA., Methods: Temporal artery biopsies examined between 1989 and 2007 were studied. Clinical information and residual tissue for immunohistochemical staining was identified in 107 patients. Clinical information was used to make a diagnosis of "positive," "presumed," or "negative" GCA. The biopsies were reviewed in a masked fashion and classified as "positive," "indeterminate," or "negative" based on published, classic pathologic diagnosis (CPD) criteria. All biopsies were immunostained for CD3 and CD68 and graded as "negative," "mildly" (+), "moderately" (++), or "markedly" (+++) positive. Clinical and pathologic results were correlated and a modified pathologic diagnosis classification (MPD) scheme was developed. The modified scheme was compared in a masked fashion with the final clinical diagnosis and positive and negative predictive values (PVs) were calculated., Main Outcome Measures: Pathologic diagnosis and final clinical diagnosis., Results: Using the MPD classification, there were 25%, 16%, and 61% positive, indeterminate, and negative biopsies, respectively. There was excellent correlation between the modified pathologic criteria and final clinical diagnosis (correlation coefficient 0.997; P<0.0001; kappa = 0.81). The positive PVs for CPD and MPD were 85% and 96%, respectively. The negative PVs for CPD and MPD were 64% and 61%, respectively. Positive and negative biopsies strongly correlated with clinical diagnoses of positive and negative for GCA, respectively, whereas indeterminate cases moderately correlated with presumed GCA. The diagnosis did not change from the original biopsy in 11 patients who had a second biopsy. Immunostaining for CD 68 was helpful in several indeterminate cases., Conclusions: We recommend using the modified histologic classification of temporal artery biopsies. There are indeterminate cases that cannot be further defined using current pathologic classification criteria. A second biopsy has very limited value. Immunostaining for CD68 may be helpful in indeterminate cases, although the diagnosis in these cases is based on clinical judgment.

Purpose: Currently, giant cell arteritis (GCA) is primarily treated with corticosteroids or immunomodulating agents, but there is interest in identifying other noncorticosteroid alternatives. Similarities exist in the injury pathways between GCA and atherosclerosis. Angiotensin II is a vasoactive peptide involved in vessel inflammation during atherosclerosis, and angiotensin II receptor inhibitors are effective in preventing atherosclerosis. The present study was performed to elucidate the role of angiotensin type 1 (AT(1)) and type 2 (AT(2)) receptors in GCA., Design: Experimental retrospective immunohistochemical study of temporal arteries using archival formalin-fixed, paraffin-embedded tissue., Participants: Ten patients with GCA and 10 control patients, who were clinically suspected of having GCA but were diagnosed as not having GCA, were included., Methods: Immunohistochemistry, using anti-AT(1) and anti-AT(2) antibodies, was performed on formalin-fixed and paraffin-embedded temporal arteries., Main Outcome Measures: AT(1) and AT(2) receptor immunostaining intensity was quantified., Results: Hematoxylin-eosin-stained sections of temporal arteries from patients with GCA showed intimal hyperplasia, internal elastic lamina degeneration, and band-shaped infiltrates of inflammatory cells, including lymphocytes, histocytes, and multinucleated giant cells. AT(1) receptor staining was primarily observed in the medial layer of the temporal arteries and was higher in the patients with GCA than in the control patients. This was a result of increased AT(1) receptor immunostaining of both vascular smooth muscle cells and infiltrating inflammatory cells. Only faint immunostaining was seen for AT(2) receptors, primarily in the endothelial cells, and to a lesser extent on the smooth muscle cells. Immunostaining with antibodies for the AT(2) receptor was similar in the patients with GCA and in controls., Conclusions: These results suggest that AT(1) receptors play a role in the development of GCA. Inhibition of the angiotensin system may thus provide a noncorticosteroid alternative for the treatment of GCA., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Arterial wall damage in giant cell arteritis (GCA) is mediated by several different macrophage effector functions, including the production of metalloproteinases and lipid peroxidation. Tissue-invading macrophages also express nitric oxide synthase (NOS)-2, but it is not known whether nitric oxide-related mechanisms contribute to the disease process. Nitric oxide can form nitrating agents, including peroxynitrite, a nitric oxide congener formed in the presence of reactive oxygen intermediates. Protein nitration selectively targets tyrosine residues and can result in a gain, as well as a loss, of protein function. Nitrated tyrosine residues in GCA arteries were detected almost exclusively on endothelial cells of newly formed microcapillaries in the media, whereas microvessels in the adventitia and the intima were spared. Nitration correlated with endothelial NOS-3 expression and not with NOS-2-producing macrophages, which preferentially homed to the hyperplastic intima. The restriction of nitration to the media coincided with the production of reactive oxygen intermediates as demonstrated by the presence of the toxic aldehyde, 4-hydroxynonenal. Depletion of tissue-infiltrating macrophages in human temporal artery-SCID mouse chimeras disrupted nitrotyrosine generation, demonstrating a critical role of macrophages in the nitration process that targeted medial microvessels. Thus, protein nitration in GCA is highly compartmentalized, reflecting the production of reactive oxygen and reactive nitrogen intermediates in the inflamed arterial wall. Heterogeneity of microvessels in NOS-3 regulation may be an additional determinant contributing to this compartmentalization and could explain the preferential targeting of newly generated capillary beds.

Decorin is a small extracellular chondroitin/dermatan sulfate proteoglycan that has previously been shown to be involved in the angiogenesis-like behavior of endothelial cells (ECs) in vitro. There is also evidence that decorin plays a role in angiogenesis in vivo. In this study we sought to further explore the involvement of decorin in angiogenesis in vivo, especially in that associated with inflammation. We found by CD31 immunostaining of ECs that in giant cell arteritis there are capillary blood vessels not only in the adventitia as in uninvolved temporal artery wall, but also in the media and the external zone of the thickened intima. Localization of decorin by antiserum LF-30 in adjacent sections showed that in normal temporal artery wall decorin resides mainly in the media and the adventitia, whereas in inflamed temporal artery wall decorin is distributed throughout the vessel wall including the intima. Furthermore, the most intense reaction for decorin was evident in ECs of capillary neovessels within the media and the thickened intima of inflamed temporal artery wall. Decorin was also found in capillary ECs in certain pathological and physiological conditions in which the pivotal role of angiogenesis is more generally accepted. Pyogenic granulomas, granulation tissue of healing dermal wounds, and ovaries at different phases of follicle and corpus luteum formation all contained widely distributed CD31-positive capillaries. Decorin, on the other hand, was found in capillary ECs in pyogenic granulomas and granulation tissue, but not in those in the ovaries. The assessment of the degree of inflammation in the specimens with the presence of CD68-positive macrophages showed that the pyogenic granuloma, granulation tissue, and giant cell arteritis specimens were rich in macrophages around the decorin-positive capillaries. In contrast, the ovarian specimens were populated with fewer macrophages and even they were not located in close vicinity of capillaries negative for decorin. Our results confirm that decorin is involved in angiogenesis in vivo and, particularly, in conditions in which the inflammatory component is dominant.

Inflammation of the arterial wall in giant cell arteritis induces a series of structural changes, including the formation of new vasa vasorum. To study the regulation of neoangiogenesis in giant cell arteritis, temporal arteries were examined for the extent and localization of microvessel generation and for the production of angiogenic factors. In normal arteries, vasa vasorum were restricted to the adventitia, but in inflamed arteries, capillaries emerged in the media and the intima. These capillaries displayed a distinct topography with a circumferential arrangement in the external one-third of the intima. Neovascularization was closely correlated with the formation of lumen-obstructing intima, the fragmentation of the internal elastic lamina, and the presence of multinucleated giant cells. Comparison of tissue cytokine transcription in temporal arteries of giant cell arteritis patients with and without up-regulated neoangiogenesis identified interferon-gamma and vascular endothelial growth factor but not fibroblast growth factor-2 as mediators associated with vasa vasorum proliferation. Giant cells and CD68-positive macrophages at the media-intima junction were found to be the major cellular sources of vascular endothelial growth factor. These data demonstrate that formation of new vasa vasorum in vasculitis is regulated by inflammatory cells and not by arterial wall cells, raising the possibility that it represents a primary disease mechanism and not a secondary hypoxia-induced event. Increased neovascularization in interferon-gamma-rich arteries suggests that the formation of new vasa vasorum is determined by the nature of the immune response in the arterial wall, possibly resulting from the generation and functional activity of multinucleated giant cells.

The elastin peptide level (EP) and elastase-type activity (EA) were investigated in 89 patients with different types of systemic vasculitis (polyarteritis nodosa-14, non-specific aortoarteritis-33, temporal arteritis-23 and thromboangiitis obliterans-18) and compared to the controls: 31 patients with leg atherosclerosis and 12 aged subjects with no evident vascular pathology. EP and EA levels in patients with thromboangiitis obliterans were significantly lower as compared to leg atherosclerosis and the aged control group (p < 0.02 for EA, p < 0.05 for EP). The increase of EP predominated in giant-cell arteritis as compared to the other vasculitic groups (18/56 vs. 5/32, p < 0.05); EA in these patients was the lowest. The activation of elastin degradation after corticosteroid treatment was demonstrated by an increase of EP in temporal arteritis (p < 0.05) and of EA in thromboangiitis obliterans (p < 0.03). We suggest that the determination of the above parameters of elastin degradation may be helpful in the search for differences in mechanisms of vascular damage between atherosclerosis and inflammatory vascular diseases.

Destruction (elastolysis) of the internal elastic lamina is frequently observed near early atherosclerotic plaques. Elastolysis and plaque formation are also found together in the temporal arteritis/polymyalgia rheumatica syndrome. Could it be that atherosclerosis and the syndrome are more closely akin than usually thought, with elastolysis acting as the pathogenetic link between them? A kinship of this nature is in accord with the growing recognition that elastin-related autoimmunity prevails in both these forms of vascular disease. A case can also be made out for the belief that the autoimmune reactions in internal vessels may be provoked by events in the integument where a slow but ultimately massive turnover of dermal and vascular elastic tissue takes place under the harmful influence of solar and other forms of actinic radiation.