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Imbalance Between Angiogenic and Anti-Angiogenic Factors in Sera from Patients with Large-Vessel Vasculitis L

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Imbalance Between Angiogenic and Anti-Angiogenic Factors in Sera from Patients with Large-Vessel Vasculitis L Imbalance between angiogenic and anti-angiogenic factors in sera from patients with large-vessel vasculitis L. Pulsatelli1, L. Boiardi2, E. Assirelli1, G. Pazzola2, F. Muratore2, O. Addimanda3,4, P. Dolzani 1, A. Versari5, M. Casali5, B. Bottazzi6, L. Magnani2, E. Pignotti3, N. Pipitone2, S. Croci7, A. Mantovani6,8,9, C. Salvarani2,10, R. Meliconi3,4 ABSTRACT Objective. Introduction Large-vessel vasculitides (LVV) are im- mune-mediated vascular diseases that typically affect the aorta and its major branches. Giant cell arteritis (GCA) and Takayasu’s arteritis (TAK) are the two major forms of LVV. GCA typically af- fects the extracranial branches of the Methods. carotid artery and is almost exclusive- ly seen in people aged over 50 years, while TAK commonly affects subjects under the age of 40 (1, 2). LVV are characterised by dysfunctional - tory lesions within the vessel wall. Vas- cular remodelling in response to aberrant immune response leads to occlusion of the lumen and ischaemic damage of me- dium-sized arteries, whereas in the aorta, aneurysm formation, rupture or dissec- Results. tion are more frequently seen (3-5). - In vasculitis immune-mediated mecha- nisms, a dual role of angiogenesis has - been hypothesised. Indeed, angiogen- esis might be primarily involved in - - quently, might be considered as a rescue CLINICAL AND EXPERIMENTAL RHEUMATOLOGY mechanism in ischaemic damage (6). The role of angiogenesis in LVV is also Key words: giant cell arteritis, - supported by histopathological analyses Takayasu’s arteritis, positron-emission - that have shown new capillary forma- tomography, angiogenic factors, - tion in the arterial media and intima, anti-angiogenic factors normally avascular (7, 8). In addition, a marked neoangiogenesis expanding the - capillary network of the adventitia was - recognised as a further pathogenic event. Adventitial vasa vasorum drive T cells and macrophages invasion of the vessel wall, and promote their differentiation. Recent studies have strengthened the role of interplay between tissue invasive T-cell and endothelial cells and stromal Conclusion. - cells in the vessel wall, ultimately lead- ing to formation of microvessels and Clinical and Experimental Rheumatology 2020 S-23 Angiogenesis-related factors in LVV / L. Pulsatelli et al. expansion of the intimal layer (9, 10). Materials and methods indicative of vasculitis. Disease was Angiogenesis is a complex and highly Between January 2003 and September least two new or worsened items (32). circulating factors as well as locally 2010, 47 patients with LVV (33 with For the purpose of this study, due to produced mediators (11, 12). TAK and 14 with GCA) who had been the heterogeneity of the angiographic Physiological formation of new blood referred to the Rheumatology Unit modalities, worsening of angiographic vessels derives from the net balance at the Arcispedale S. Maria Nuova in - between angiogenic inducers and in- Reggio Emilia, Italy were enrolled in ening of luminal changes in the affect- hibitors (positive and negative regula- the cross-sectional study. Patients were ed vessel or the appearance of new vas- tors of angiogenesis) (11, 12). diagnosed according to the ACR classi- cular lesions. MRA, CTA and/or colour A wide array of factors is involved in this Doppler ultrasound were used to assess process. Vascular endothelial growth (30), as appropriate. luminal changes. As a tertiary reference centre for vascu- Clinical and 18F-FDG PET/CT data (FGF), platelet-derived growth factor litis, we admit patients with suspected, from an additional 20 patients (5 with (PDGF), angiopoietins, soluble adhe- early, or established LVV for re-evalua- TAK and 15 with GCA) were also in- sion molecules (such as soluble vascular tion of treatment and/or disease activity. cluded in the cluster analysis (no serum cellular adhesion molecule sVCAM-1) Among our patients, 36 (11 GCA) samples were available from the pa- are recognised as positive regulators were on treatment: 19 received steroid tients in the latter group). of angiogenesis, whereas the major in- only (prednisone: 16.07±12.35 mg/ Written informed consent was obtained hibitors include endostatin, angiostatin, day, mean ± standard deviation), 13 from all patients according to the Dec- received immunosoppressive agents laration of Helsinky and the study was (methotrexate, azathioprine, mycophe- approved by the local ethics committee. of angiogenesis, and thrombospondin-2 nolate, cyclophosphamide) with or (11-15). without steroid, and 4 received biolog- VEGF, FGF and PDGF are expressed in vasculitic lesions (7, 8, 16, 17), as well 1 tocilizumab). Positron emission tomography scans as the up-regulation of circulating levels Patients with LVV are offered a stand- were performed using a hybrid PET/ of some proangiogenic factors was ob- CT scanner (Discovery, GE) with 3.30 served in patients with LVV (6, 18-20). then yearly in order to obtain a compre- min-emission scan/bed and CT- attenu- On the other hand, pentraxin (PTX) hensive evaluation of the disease activ- ation correction. All subjects fasted for 3, the prototypical long PTX that has ity and extension by means of duplex been recognised as an antiangiogenic sonography, computerised tomography (37 Mbq of 18F-FDG/13 kilograms of factor by binding to FGF-2 and inhib- (CT), or magnetic resonance (MR), an- patient weight). Mean time from in- iting FGF-2-dependent endothelial cell giography (CTA, MRA), and 18F-FDG jection to acquisition was 60 minutes. proliferation and neovascularisation PET/CT. This protocol includes the de- Whole-body 18F-FDG PET/CT scan- (21-23), is to be up-regulated at both termination of erythrocyte sedimenta- ning was performed from mid-femora vascular and circulating levels in LVV tion rate (ESR) and C-reactive protein to external auditory meatus. Vascular (19, 24, 25) and also in small-vessel (CRP) at the time of 18F-FDG PET/CT uptake was visually graded using a vasculitis (26-28) evaluation. four-point scale (33, 34) ranging from In order to gain further insights into the A semi-quantitative clinical evaluation 0 to 3, where 0 = no uptake, 1 = low- molecular mechanisms driving angio- grade uptake (lower than liver uptake), genesis dysregulation in LVV, we in- the unit (considered as the baseline in 2 = intermediate-grade uptake (similar vestigated the serum levels of a panel this study) using the ITAS (31) and the to liver uptake) and 3 = high-grade up- of angiogenic inducers (VEGF, FGF-2, NIH/Kerr (32) indices. The ITAS lists take (higher than liver uptake). soluble vascular cellular adhesion mol- constitutional and organ manifestations Four aortic segments (ascending tho- ecule sVCAM-1, angiopoietin 1, -2,) with particular emphasis on cardiovas- racic aorta, aortic arch, descending tho- and inhibitors (angiostatin, endosta- racic aorta and abdominal aorta) and tin, PTX3) in patients with GCA and markers (ESR and CRP) and the physi- the carotid, subclavian, axillary, iliac TAK. Furthermore, we analysed the cian’s global opinion. A score is gen- and femoral arteries were evaluated bi- soluble factor levels according to dis- erated on the basis of present (=1) or laterally and 18F-FDG vascular uptake ease activity assessed by means of 18F- absent (=0) clinical manifestations, and Fluorodeoxyglucose-positron emission disease was considered active if one for vasculitis and scores of 0 and 1 tomography/computerised tomography or more organ system scores positive (18F-FDG PET/CT) and clinical indi- (31). The NIH/Kerr index assesses four Assessment of the 18F-FDG PET/CT ces including the National Institutes of items: constitutional manifestations, data was carried out by two nuclear medi- Health (NIH)/Kerr criteria and the In- raised ESR, manifestations of vascular cine specialists who were blinded to clini- dian Takayasu’s Activity Score (ITAS). ischaemia and angiographic features S-24 Clinical and Experimental Rheumatology 2020 Angiogenesis-related factors in LVV / L. Pulsatelli et al. Table I. Characteristics of normal controls (NC), giant cell arteritis (GCA) patients and Takayasu’s arteritis (TAK) patients at baseline. NC GCA NC TAK Two groups of healthy subjects, matched for age to the GCA and TAK No. of subjects 21 14 25 33 patients, respectively, were evaluated Age, mean (SD) 64 (10) 61 (8) 40 (9.0) 42 (14) Sex, no. female (%) 12 (57)a 8 (57) 17 (68)a 27 (81) as normal controls (NC). FDG-PET/CT scan, no. positive (%) NA 6 (43) NA 20 (61) Venous blood was drawn from all the Active disease according to Kerr score NA 7 (50) NA 16 (48) patients and all the NC between 8.00 no. positive (%) a.m. and 10.00 a.m. and collected in Active disease according to ITAS score, NA 7 (50) NA 15 (45) no. positive (%) tubes without anticoagulant. Serum ESR, median (range), mm/hr NA 12.5 (2.0-120.0) NA 28.0 (2.0-116.0) was separated by centrifugation for 10 CRP, median (range), mg/dl NA 0.64 (0.08-9.59) NA 0.87 (0.08-13.39) minutes 1000 x g. Samples were ali- No. of treated patients (%)b NA 11 (79) NA 25 (74) quoted and stored at -80°C until analy- 18F-FDG PET/CT: 18F-Fluorodeoxyglucose-positron emission tomography/computerised tomography; sis. Serum levels of VEGF, sVCAM-1, ITAS: Indian Takayasu’s activity score; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; FGF-2, endostatin, angiopoietin-1, an- NA: not applicable. giopoietin-2, angiostatin were evaluat- a ed using commercial sandwich enzyme (using Fisher’s exact test) (NC GCA: =1.000: NC . TAK: =0.353). bCorticosteroid with or without immunosuppressive drug (methotrexate/azathioprine/cyclophospha- immunoassay following the manufac- mide) /biological drugs. turer’s instructions. We used ELISA kits from R&D Systems, Minneapo- lis, MN, USA for detection of VEGF, sVCAM-1, FGF, Angiopoietin-1 An- giopoietin-2 and endostatin; serum angiostatin levels were measured us- ing ELISA kits from Cusabio College Park, MD, USA.
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