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A novel approach to imaging active Takayasu arteritis using somatostatin receptor PET/MRI ligandsJason M. Tarkin, MD PhD1,2; Christopher Wall, MD 1; Deepa Gopalan, MD3; Luigi Aloj, MD 4; Eric O. Aboagye, MD PhD; 5 Martin R. Bennett, MD PhD; 1 James E. Peters, MD PhD;6 James H.F. Rudd, MD PhD1; Justin C. Mason, MD PhD21Division of Cardiovascular Medicine, University of Cambridge, UK2Vascular Sciences, National Heart & Lung Institute, Imperial College London, UK3Department of Radiology, Cambridge University Hospitals NHS Trust, UK4Department of Radiology, University of Cambridge, UK 5Department of Surgery & Cancer, Imperial College London, UK6Department of Immunology and Inflammation, Imperial College London, UK7 Health Data Research UKCorrespondence to: Dr Jason M. TarkinDivision of Cardiovascular Medicine (Box 110)Addenbrooke’s Hospital, Hill’s RoadCambridge, UKCB2 2QQEmail: Jt545@cam.ac.ukTel: +44(0)1223331504Word count: 696Although 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is an important diagnostic test for Takayasu arteritis (TAK), ADDIN PAPERS2_CITATIONS <citation><priority>2</priority><uuid>E8149ABD-BFD6-44C1-BB90-23E6E09CDD24</uuid><publications><publication><subtype>400</subtype><title>18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis.</title><url> Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.</institution><startpage>439</startpage><endpage>449</endpage><bundle><publication><title>Arthritis &amp; rheumatology (Hoboken, N.J.)</title><uuid>936A5A64-869F-4AD1-8839-A18D63EBCDAC</uuid><subtype>-100</subtype><type>-100</type></publication></bundle><authors><author><lastName>Grayson</lastName><firstName>Peter</firstName><middleNames>C</middleNames></author><author><lastName>Alehashemi</lastName><firstName>Sara</firstName></author><author><lastName>Bagheri</lastName><firstName>Armin</firstName><middleNames>A</middleNames></author><author><lastName>Civelek</lastName><firstName>Ali</firstName><middleNames>Cahid</middleNames></author><author><lastName>Cupps</lastName><firstName>Thomas</firstName><middleNames>R</middleNames></author><author><lastName>Kaplan</lastName><firstName>Mariana</firstName><middleNames>J</middleNames></author><author><lastName>Malayeri</lastName><firstName>Ashkan</firstName><middleNames>A</middleNames></author><author><lastName>Merkel</lastName><firstName>Peter</firstName><middleNames>A</middleNames></author><author><lastName>Novakovich</lastName><firstName>Elaine</firstName></author><author><lastName>Bluemke</lastName><firstName>David</firstName><middleNames>A</middleNames></author><author><lastName>Ahlman</lastName><firstName>Mark</firstName><middleNames>A</middleNames></author></authors></publication></publications><cites></cites></citation>(1) 18F-FDG lacks inflammatory cell specificity and cannot accurately distinguish arteritis from metabolically active vascular remodelling. ADDIN PAPERS2_CITATIONS <citation><priority>0</priority><uuid>6F87CAE8-CEA5-46FE-A57C-F23685C87E7A</uuid><publications><publication><subtype>420</subtype><title>EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice.</title><url> of Rheumatology and Immunology, Medical University Graz, Graz, Austria.</institution><startpage>636</startpage><endpage>643</endpage><bundle><publication><title>Annals of the rheumatic diseases</title><uuid>F3A40D48-1F80-4415-A84A-903E13850BB6</uuid><subtype>-200</subtype><type>-200</type></publication></bundle><authors><author><lastName>Dejaco</lastName><firstName>Christian</firstName></author><author><lastName>Ramiro</lastName><firstName>Sofia</firstName></author><author><lastName>Duftner</lastName><firstName>Christina</firstName></author><author><lastName>Besson</lastName><firstName>Florent</firstName><middleNames>L</middleNames></author><author><lastName>Bley</lastName><firstName>Thorsten</firstName><middleNames>A</middleNames></author><author><lastName>Blockmans</lastName><firstName>Daniel</firstName></author><author><lastName>Brouwer</lastName><firstName>Elisabeth</firstName></author><author><lastName>Cimmino</lastName><firstName>Marco</firstName><middleNames>A</middleNames></author><author><lastName>Clark</lastName><firstName>Eric</firstName></author><author><lastName>Dasgupta</lastName><firstName>Bhaskar</firstName></author><author><lastName>Diamantopoulos</lastName><firstName>Andreas</firstName><middleNames>P</middleNames></author><author><lastName>Direskeneli</lastName><firstName>Haner</firstName></author><author><lastName>Iagnocco</lastName><firstName>Annamaria</firstName></author><author><lastName>Klink</lastName><firstName>Thorsten</firstName></author><author><lastName>Neill</lastName><firstName>Lorna</firstName></author><author><lastName>Ponte</lastName><firstName>Cristina</firstName></author><author><lastName>Salvarani</lastName><firstName>Carlo</firstName></author><author><lastName>Slart</lastName><firstName>Riemer</firstName><middleNames>H J A</middleNames></author><author><lastName>Whitlock</lastName><firstName>Madeline</firstName></author><author><lastName>Schmidt</lastName><firstName>Wolfgang</firstName><middleNames>A</middleNames></author></authors></publication></publications><cites></cites></citation>(2) This observation has led to the search for more specific and sensitive PET ligands. Macrophage activation antigen somatostatin receptor subtype-2 (SST2) PET represents a potential alternative imaging biomarker for defining disease activity in TAK, as macrophages are a major feature of the inflammatory infiltrate. We aimed to determine the ability of SST2 PET/magnetic resonance imaging (MRI) to detect arteritis in two patients with clinically active TAK.Case 1. A 47-year-old woman with a 20 year history of TAK presented with a 5 month history of recurrent chest pain, arthralgia and carotidynia. Immunosuppressive therapy had been finally weaned off 10 months earlier following long-standing remission. Prior investigations had identified diffuse left subclavian and mild right carotid arterial stenoses (Figure 1A), a non-obstructive ostial right coronary artery lesion and moderate aortic regurgitation with normal aortic root dimensions and left ventricular function. Examination revealed a long-standing reduced left radial pulse and a right carotid bruit. Blood pressure in the right arm was 130/80 mmHg, and in the left 120/70 mmHg. C-reactive protein (CRP) was raised at 31.6 mg/L (NR <5.0) and erythrocyte sedimentation rate (ESR) 67 mm/hr (NR 1-19). Indian Takayasu Activity Score (ITAS-A) was 7 and NIH score 3, indicating clinically active TAK. 18F-FDG-PET confirmed active TAK with increased tracer uptake in the ascending aorta (Figure 1C, 1F). MRI showed no evidence of progressive arterial injury. Despite treatment with depo-methylprednisolone 160 mg and azathioprine 150 mg daily, she remained symptomatic 5 months later, with elevated CRP (17.5 mg/L) and ESR (32 mm/hr). Vascular PET/MRI was performed as part of ongoing research study NCT04071691, using the SST2 ligand 68Ga-DOTATATE and a GE Signa PET/MRI scanner. Images acquired 50 min after an injected dose of 234 MBq in two 30 min bed positions covering the upper body were reconstructed with standard corrections applied. There was circumferential thickening of the ascending aorta on T1-weighted black blood MRI (Figure 1D), and corresponding avid PET signal (Figure 1B, 1E) with highest intensity (SUVmax 3.1; tissue-to-blood ratio [TBR]max 7.8) at the aortic base. The pattern of aortic 68Ga-DOTATATE binding was near identical to that seen on the prior 18F-FDG imaging.Case 2. A 29-year-old woman reported severe fatigue and episodes of sweating. A diagnosis of TAK had been made two years earlier based on constitutional symptoms and raised inflammatory markers, with peri-aortic thickening on CT scanning and low-level aortic 18F-FDG uptake on PET scanning two weeks after initiation of high-dose prednisolone. She continued azathioprine 150 mg daily and low-dose prednisolone maintenance therapy. On examination, pulses were present and symmetrical and blood pressure 90/60 mmHg. She had clinically active disease (CRP 21.5 mg/L, ESR 60 mm/hr, ITAS-A score 9 and NIH score 2). While previous MRI showed left subclavian and right vertebral artery stenoses (Figure 2A), there was no progressive arterial injury on repeat scanning despite active disease. Therapy was switched to prednisolone 20 mg once daily and methotrexate 20 mg once weekly. However, disease activity persisted with a further increase in CRP (39.6 mg/L) and ESR (106 mm/hr). Vascular PET/MRI was performed using another SST2 ligand, 18F-FET-βAG-TOCA, ADDIN PAPERS2_CITATIONS <citation><priority>0</priority><uuid>7E9EDC8D-5900-44F1-AA46-295C372755E6</uuid><publications><publication><subtype>400</subtype><title>Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors.</title><url> of Surgery and Cancer, Imperial College London, London, United Kingdom.</institution><startpage>1207</startpage><endpage>1213</endpage><bundle><publication><title>Journal of nuclear medicine : official publication, Society of Nuclear Medicine</title><uuid>4D9130E6-8BB5-4978-9A2D-A541B2A28734</uuid><subtype>-100</subtype><type>-100</type></publication></bundle><authors><author><lastName>Dubash</lastName><firstName>Suraiya</firstName><middleNames>R</middleNames></author><author><lastName>Keat</lastName><firstName>Nicholas</firstName></author><author><lastName>Mapelli</lastName><firstName>Paola</firstName></author><author><lastName>Twyman</lastName><firstName>Frazer</firstName></author><author><lastName>Carroll</lastName><firstName>Laurence</firstName></author><author><lastName>Kozlowski</lastName><firstName>Kasia</firstName></author><author><lastName>Al-Nahhas</lastName><firstName>Adil</firstName></author><author><lastName>Saleem</lastName><firstName>Azeem</firstName></author><author><lastName>Huiban</lastName><firstName>Mickael</firstName></author><author><lastName>Janisch</lastName><firstName>Ryan</firstName></author><author><lastName>Frilling</lastName><firstName>Andrea</firstName></author><author><lastName>Sharma</lastName><firstName>Rohini</firstName></author><author><lastName>Aboagye</lastName><firstName>Eric</firstName><middleNames>O</middleNames></author></authors></publication></publications><cites></cites></citation>(3) with an injected dose of 244.1 MBq. The major branches of the aortic arch were thickened on MRI (Figure 2C), with markedly increased PET signals in the brachiocephalic trunk, left common carotid, and bilateral subclavian arteries (Figure 2B, 2D). The maximum vascular PET signal (SUVmax 1.9; TBRmax 4.1) was at the proximal left common carotid artery. Treatment was subsequently escalated to tocilizumab to good effect. TAK is a granulomatous large-vessel vasculitis that typically affects young females resulting in arterial stenoses, aneurysms and occlusions. While 18F-FDG PET is useful for diagnosing TAK, ADDIN PAPERS2_CITATIONS <citation><priority>2</priority><uuid>E8149ABD-BFD6-44C1-BB90-23E6E09CDD24</uuid><publications><publication><subtype>400</subtype><title>18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis.</title><url> Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.</institution><startpage>439</startpage><endpage>449</endpage><bundle><publication><title>Arthritis &amp; rheumatology (Hoboken, N.J.)</title><uuid>936A5A64-869F-4AD1-8839-A18D63EBCDAC</uuid><subtype>-100</subtype><type>-100</type></publication></bundle><authors><author><lastName>Grayson</lastName><firstName>Peter</firstName><middleNames>C</middleNames></author><author><lastName>Alehashemi</lastName><firstName>Sara</firstName></author><author><lastName>Bagheri</lastName><firstName>Armin</firstName><middleNames>A</middleNames></author><author><lastName>Civelek</lastName><firstName>Ali</firstName><middleNames>Cahid</middleNames></author><author><lastName>Cupps</lastName><firstName>Thomas</firstName><middleNames>R</middleNames></author><author><lastName>Kaplan</lastName><firstName>Mariana</firstName><middleNames>J</middleNames></author><author><lastName>Malayeri</lastName><firstName>Ashkan</firstName><middleNames>A</middleNames></author><author><lastName>Merkel</lastName><firstName>Peter</firstName><middleNames>A</middleNames></author><author><lastName>Novakovich</lastName><firstName>Elaine</firstName></author><author><lastName>Bluemke</lastName><firstName>David</firstName><middleNames>A</middleNames></author><author><lastName>Ahlman</lastName><firstName>Mark</firstName><middleNames>A</middleNames></author></authors></publication></publications><cites></cites></citation>(1) it has more limited value for tracking therapeutic responses or detecting residual arteritis and the risk of progressive arterial injury; highlighting a need for more specifically targeted PET ligands. ADDIN PAPERS2_CITATIONS <citation><priority>3</priority><uuid>F9EB5CC0-6B7F-46D2-A196-695EF8E6A61E</uuid><publications><publication><subtype>420</subtype><title>EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice.</title><url> of Rheumatology and Immunology, Medical University Graz, Graz, Austria.</institution><startpage>636</startpage><endpage>643</endpage><bundle><publication><title>Annals of the rheumatic diseases</title><uuid>F3A40D48-1F80-4415-A84A-903E13850BB6</uuid><subtype>-200</subtype><type>-200</type></publication></bundle><authors><author><lastName>Dejaco</lastName><firstName>Christian</firstName></author><author><lastName>Ramiro</lastName><firstName>Sofia</firstName></author><author><lastName>Duftner</lastName><firstName>Christina</firstName></author><author><lastName>Besson</lastName><firstName>Florent</firstName><middleNames>L</middleNames></author><author><lastName>Bley</lastName><firstName>Thorsten</firstName><middleNames>A</middleNames></author><author><lastName>Blockmans</lastName><firstName>Daniel</firstName></author><author><lastName>Brouwer</lastName><firstName>Elisabeth</firstName></author><author><lastName>Cimmino</lastName><firstName>Marco</firstName><middleNames>A</middleNames></author><author><lastName>Clark</lastName><firstName>Eric</firstName></author><author><lastName>Dasgupta</lastName><firstName>Bhaskar</firstName></author><author><lastName>Diamantopoulos</lastName><firstName>Andreas</firstName><middleNames>P</middleNames></author><author><lastName>Direskeneli</lastName><firstName>Haner</firstName></author><author><lastName>Iagnocco</lastName><firstName>Annamaria</firstName></author><author><lastName>Klink</lastName><firstName>Thorsten</firstName></author><author><lastName>Neill</lastName><firstName>Lorna</firstName></author><author><lastName>Ponte</lastName><firstName>Cristina</firstName></author><author><lastName>Salvarani</lastName><firstName>Carlo</firstName></author><author><lastName>Slart</lastName><firstName>Riemer</firstName><middleNames>H J A</middleNames></author><author><lastName>Whitlock</lastName><firstName>Madeline</firstName></author><author><lastName>Schmidt</lastName><firstName>Wolfgang</firstName><middleNames>A</middleNames></author></authors></publication></publications><cites></cites></citation>(2) We have previously shown the ability of SST2 PET imaging using 68Ga-DOTATATE for marking high-risk atherosclerotic plaques. ADDIN PAPERS2_CITATIONS <citation><priority>6</priority><uuid>33E2FB5F-178D-4CCC-99C3-E88CFC75B53A</uuid><publications><publication><subtype>400</subtype><title>Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging.</title><url> of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.</institution><startpage>1774</startpage><endpage>1791</endpage><bundle><publication><title>Journal of the American College of Cardiology</title><uuid>E5A45714-E3A1-4408-976E-F4F13C0E98A5</uuid><subtype>-100</subtype><type>-100</type></publication></bundle><authors><author><lastName>Tarkin</lastName><firstName>Jason</firstName><middleNames>M</middleNames></author><author><lastName>Joshi</lastName><firstName>Francis</firstName><middleNames>R</middleNames></author><author><lastName>Evans</lastName><firstName>Nicholas</firstName><middleNames>R</middleNames></author><author><lastName>Chowdhury</lastName><firstName>Mohammed</firstName><middleNames>M</middleNames></author><author><lastName>Figg</lastName><firstName>Nichola</firstName><middleNames>L</middleNames></author><author><lastName>Shah</lastName><firstName>Aarti</firstName><middleNames>V</middleNames></author><author><lastName>Starks</lastName><firstName>Lakshi</firstName><middleNames>T</middleNames></author><author><lastName>Martin-Garrido</lastName><firstName>Abel</firstName></author><author><lastName>Manavaki</lastName><firstName>Roido</firstName></author><author><lastName>Yu</lastName><firstName>Emma</firstName></author><author><lastName>Kuc</lastName><firstName>Rhoda</firstName><middleNames>E</middleNames></author><author><lastName>Grassi</lastName><firstName>Luigi</firstName></author><author><lastName>Kreuzhuber</lastName><firstName>Roman</firstName></author><author><lastName>Kostadima</lastName><firstName>Myrto</firstName><middleNames>A</middleNames></author><author><lastName>Frontini</lastName><firstName>Mattia</firstName></author><author><lastName>Kirkpatrick</lastName><firstName>Peter</firstName><middleNames>J</middleNames></author><author><lastName>Coughlin</lastName><firstName>Patrick</firstName><middleNames>A</middleNames></author><author><lastName>Gopalan</lastName><firstName>Deepa</firstName></author><author><lastName>Fryer</lastName><firstName>Tim</firstName><middleNames>D</middleNames></author><author><lastName>Buscombe</lastName><firstName>John</firstName><middleNames>R</middleNames></author><author><lastName>Groves</lastName><firstName>Ashley</firstName><middleNames>M</middleNames></author><author><lastName>Ouwehand</lastName><firstName>Willem</firstName><middleNames>H</middleNames></author><author><lastName>Bennett</lastName><firstName>Martin</firstName><middleNames>R</middleNames></author><author><lastName>Warburton</lastName><firstName>Elizabeth</firstName><middleNames>A</middleNames></author><author><lastName>Davenport</lastName><firstName>Anthony</firstName><middleNames>P</middleNames></author><author><lastName>Rudd</lastName><firstName>James</firstName><middleNames>H F</middleNames></author></authors></publication></publications><cites></cites></citation>(4) In these first two cases of SST2 PET/MRI in large-vessel vasculitis, arteritis was accurately identified, suggesting this novel approach merits further evaluation. When compared to 68Ga-DOTATATE, the longer half-life and shorter positron range of 18F-FET-βAG-TOCA may offer wider availability and better image resolution for identifying active arteritis. Acknowledgments: J.M.T. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (211100/Z/18/Z) and the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). M.R.B is supported by the British Heart Foundation. J.E.P. is supported by a UKRI Innovation Fellowship at Health Data Research UK (MR/S004068/). J.H.F.R. is supported by the Higher Education Funding Council for England, the British Heart Foundation, NIHR Cambridge BRC and Wellcome Trust. E.O.A. and J.C.M. acknowledge support from the Imperial NIHR BRC.Disclosures: noneReferences ADDIN PAPERS2_CITATIONS <papers2_bibliography/>1.Grayson PC, Alehashemi S, Bagheri AA, Civelek AC, Cupps TR, Kaplan MJ, et al. 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol. 2018 Mar;70(3):439–49. 2.Dejaco C, Ramiro S, Duftner C, Besson FL, Bley TA, Blockmans D, et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. 2018. pp. 636–43. 3.Dubash SR, Keat N, Mapelli P, Twyman F, Carroll L, Kozlowski K, et al. Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors. J Nucl Med. 2016 Aug;57(8):1207–13. 4.Tarkin JM, Joshi FR, Evans NR, Chowdhury MM, Figg NL, Shah AV, et al. Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging. J Am Coll Cardiol. 2017 Apr 11;69(14):1774–91. Figure 1. Relapsing Takayasu arteritis Images from Case 1: MRI showing (A) left subclavian (solid arrow) and proximal right carotid (dashed arrow) arterial stenoses, and (D) aortic wall thickening (arrowhead); (B, E) 68Ga-DOTATATE PET/MRI and (C, F) 18F-FDG PET images in coronal (top) and axial (bottom) views demonstrating avid tracer signal (asterisks) in ascending aortaFigure 2. Treatment refractory Takayasu arteritis Images from Case 2: MRI showing (A) left subclavian artery stenosis (solid arrow) and (C)thickening of the major branches of the aortic arch (dashed arrows); 18F-FET-βAG-TOCAPET/MRI in (B) coronal and (D) axial views demonstrating avid tracer uptake (asterisks) in theaffected arteries ................
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