{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:22:25Z","timestamp":1786980145778,"version":"build-2736575974"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T00:00:00Z","timestamp":1738972800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,2,8]],"date-time":"2025-02-08T00:00:00Z","timestamp":1738972800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2025,5]]},"DOI":"10.1007\/s00417-025-06755-3","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T20:45:17Z","timestamp":1738961117000},"page":"1259-1267","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Systemic counterregulatory response of angiopoietin-2 after intravitreal injections with faricimab for nAMD"],"prefix":"10.1007","volume":"263","author":[{"given":"Anna Lena","family":"Huber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Beirer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Frede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Kirchmair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Angermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matus","family":"Rehak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Zehetner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2244-8645","authenticated-orcid":false,"given":"Yvonne","family":"Nowosielski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,8]]},"reference":[{"issue":"1","key":"6755_CR1","doi-asserted-by":"publisher","first-page":"1967714","DOI":"10.1080\/19420862.2021.1967714","volume":"13","author":"M Surowka","year":"2021","unstructured":"Surowka M, Schaefer W, Klein C (2021) Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins. MAbs 13(1):1967714. https:\/\/doi.org\/10.1080\/19420862.2021.1967714","journal-title":"MAbs"},{"issue":"4","key":"6755_CR2","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/j.ajo.2004.11.064","volume":"139","author":"R Hera","year":"2005","unstructured":"Hera R, Keramidas M, Peoc\u2019h M, Mouillon M, Romanet JP, Feige JJ (2005) Expression of VEGF and angiopoietins in subfoveal membranes from patients with age-related macular degeneration. Am J Ophthalmol 139(4):589\u201396. https:\/\/doi.org\/10.1016\/j.ajo.2004.11.064","journal-title":"Am J Ophthalmol"},{"issue":"9","key":"6755_CR3","first-page":"1912","volume":"40","author":"A Otani","year":"1999","unstructured":"Otani A, Takagi H, Oh H, Koyama S, Matsumura M, Honda Y (1999) Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci 40(9):1912\u201320","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"6755_CR4","doi-asserted-by":"publisher","first-page":"45081","DOI":"10.1038\/srep45081","volume":"27","author":"DS Ng","year":"2017","unstructured":"Ng DS, Yip YW, Bakthavatsalam M et al (2017) Elevated angiopoietin 2 in aqueous of patients with neovascular age related macular degeneration correlates with disease severity at presentation. Sci Rep 27:45081. https:\/\/doi.org\/10.1038\/srep45081","journal-title":"Sci Rep"},{"key":"6755_CR5","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.2147\/DDDT.S368963","volume":"29","author":"AA Nair","year":"2022","unstructured":"Nair AA, Finn AP, Sternberg P Jr (2022) Spotlight on faricimab in the treatment of wet age-related macular degeneration: Design, development and place in therapy. Drug Des Devel Ther 29:3395\u20133400","journal-title":"Drug Des Devel Ther"},{"issue":"3","key":"6755_CR6","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1080\/02713683.2017.1403632","volume":"43","author":"I Waltl","year":"2018","unstructured":"Waltl I, Zehetner C, Seifarth C et al (2018) Effects of intravitreal aflibercept on galectin-1 and vascular endothelial growth factor-a plasma levels in patients with diabetic retinopathy. Curr Eye Res 43(3):368\u2013375","journal-title":"Curr Eye Res"},{"issue":"3","key":"6755_CR7","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1097\/IAE.0000000000003344","volume":"42","author":"R Angermann","year":"2022","unstructured":"Angermann R, Huber AL, Nowosielski Y et al (2022) Changes in systemic levels of vascular endothelial growth factor after intravitreal injection of aflibercept or brolucizumab for neovascular age-related macular degeneration. Retina 1 42(3):503\u2013510. https:\/\/doi.org\/10.1097\/IAE.0000000000003344","journal-title":"Retina 1"},{"issue":"6","key":"6755_CR8","doi-asserted-by":"publisher","first-page":"e869","DOI":"10.1111\/aos.14691","volume":"99","author":"R Angermann","year":"2021","unstructured":"Angermann R, Rauchegger T, Nowosielski Y et al (2021) Systemic counterregulatory response of angiopoietin-2 after aflibercept therapy for nAMD: a potential escape mechanism. Acta Ophthalmol 99(6):e869\u2013e875. https:\/\/doi.org\/10.1111\/aos.14691","journal-title":"Acta Ophthalmol"},{"issue":"4","key":"6755_CR9","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1136\/bjophthalmol-2012-302451","volume":"97","author":"C Zehetner","year":"2013","unstructured":"Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach GF (2013) Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema. Br J Ophthalmol 97(4):454\u20139. https:\/\/doi.org\/10.1136\/bjophthalmol-2012-302451","journal-title":"Br J Ophthalmol"},{"issue":"2","key":"6755_CR10","doi-asserted-by":"publisher","first-page":"e154","DOI":"10.1111\/aos.12604","volume":"93","author":"C Zehetner","year":"2015","unstructured":"Zehetner C, Kralinger MT, Modi YS et al (2015) Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age-related macular degeneration: a randomised, prospective trial. Acta Ophthalmol 93(2):e154\u2013e159. https:\/\/doi.org\/10.1111\/aos.12604","journal-title":"Acta Ophthalmol"},{"key":"6755_CR11","doi-asserted-by":"publisher","first-page":"7058505","DOI":"10.1155\/2021\/7058505","volume":"15","author":"AL Huber","year":"2021","unstructured":"Huber AL, Angermann R, Nowosielski Y, Seifarth C, Kralinger MT, Zehetner C (2021) Effects of intravitreal aflibercept on the systemic insulin-like growth factor-I and vascular endothelial growth factor-a in patients with diabetic retinopathy and age-related macular degeneration. J Ophthalmol 15:7058505. https:\/\/doi.org\/10.1155\/2021\/7058505","journal-title":"J Ophthalmol"},{"issue":"6","key":"6755_CR12","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/j.oret.2017.03.003","volume":"1","author":"U Chakravarthy","year":"2017","unstructured":"Chakravarthy U, Bailey C, Brown D et al (2017) Phase I trial of anti-vascular endothelial growth factor\/anti-angiopoietin 2 bispecific antibody RG7716 for neovascular age-related macular degeneration. Ophthalmol Retina 1(6):474\u2013485","journal-title":"Ophthalmol Retina"},{"issue":"9","key":"6755_CR13","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1001\/jamaophthalmol.2020.2699","volume":"138","author":"AM Khanani","year":"2020","unstructured":"Khanani AM, Patel SS, Ferrone PJ, Osborne A, Sahni J, Grzeschik S, Basu K, Ehrlich JS, Haskova Z, Dugel PU (2020) Efficacy of every four monthly and quarterly dosing of faricimab vs ranibizumab in neovascular age-related macular degeneration: The STAIRWAY phase 2 randomized clinical trial. JAMA Ophthalmol 138(9):964\u2013972. https:\/\/doi.org\/10.1001\/jamaophthalmol.2020.2699","journal-title":"JAMA Ophthalmol"},{"issue":"1","key":"6755_CR14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12886-019-1278-8","volume":"20","author":"H Zhou","year":"2020","unstructured":"Zhou H, Zhao X, Yuan M, Chen Y (2020) Comparison of cytokine levels in the aqueous humor of polypoidal choroidal vasculopathy and neovascular age-related macular degeneration patients. BMC Ophthalmol 8 20(1):15. https:\/\/doi.org\/10.1186\/s12886-019-1278-8","journal-title":"BMC Ophthalmol 8"},{"issue":"1","key":"6755_CR15","doi-asserted-by":"publisher","first-page":"4423","DOI":"10.1038\/s41598-022-08492-7","volume":"15","author":"M Shahidatul-Adha","year":"2022","unstructured":"Shahidatul-Adha M, Zunaina E, Aini-Amalina MN (2022) Evaluation of vascular endothelial growth factor (VEGF) level in the tears and serum of age-related macular degeneration patients. Sci Rep 15(1):4423. https:\/\/doi.org\/10.1038\/s41598-022-08492-7","journal-title":"Sci Rep"},{"issue":"2","key":"6755_CR16","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1007\/s00417-017-3846-z","volume":"256","author":"Z Ioanna","year":"2018","unstructured":"Ioanna Z, Christian S, Christian G, Daniel B (2018) Plasma levels of hypoxia-regulated factors in patients with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 256(2):325\u2013332. https:\/\/doi.org\/10.1007\/s00417-017-3846-z","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"11","key":"6755_CR17","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.15252\/emmm.201505889","volume":"8","author":"JT Regula","year":"2016","unstructured":"Regula JT, von Lundh P, Foxton R et al (2016) Targeting key angiogenic pathways with a bispecific crossMAb optimized for neovascular eye diseases. EMBO Mol Med 2 8(11):1265\u20131288. https:\/\/doi.org\/10.15252\/emmm.201505889","journal-title":"EMBO Mol Med 2"},{"issue":"9","key":"6755_CR18","doi-asserted-by":"publisher","first-page":"e55","DOI":"10.1097\/IAE.0000000000003184","volume":"41","author":"RN Achiron","year":"2021","unstructured":"Achiron RN, Achiron A, Tuuminen R (2021) Correspondence. Retina 1 41(9):e55\u2013e56. https:\/\/doi.org\/10.1097\/IAE.0000000000003184","journal-title":"Retina 1"},{"issue":"1","key":"6755_CR19","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.oret.2017.04.004","volume":"2","author":"T Cabral","year":"2018","unstructured":"Cabral T, Lima LH, Mello LGM et al (2018) Bevacizumab Injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmol Retina 2(1):31\u201337. https:\/\/doi.org\/10.1016\/j.oret.2017.04.004","journal-title":"Ophthalmol Retina"},{"issue":"4","key":"6755_CR20","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1167\/iovs.14-13897","volume":"55","author":"J Lee","year":"2014","unstructured":"Lee J, Park DY, Park DY et al (2014) Angiopoietin-1 suppresses choroidal neovascularization and vascular leakage. Invest Ophthalmol Vis Sci 7 55(4):2191\u20139. https:\/\/doi.org\/10.1167\/iovs.14-13897","journal-title":"Invest Ophthalmol Vis Sci 7"},{"issue":"1","key":"6755_CR21","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1186\/s40942-023-00507-3","volume":"9","author":"\u00d8K J\u00f8rstad","year":"2023","unstructured":"J\u00f8rstad \u00d8K, Foss S, Gj\u00f8lberg TT, Mester S, Nyquist-Andersen M, Sivertsen MS, Fossum D, Gleditsch E, Moe MC, Andersen JT (2023) Pharmaceutical compounding and storage of faricimab in a syringe for intravitreal injection do not impair stability and bi-specific binding properties. Int J Retina Vitreous 9(1):65. https:\/\/doi.org\/10.1186\/s40942-023-00507-3","journal-title":"Int J Retina Vitreous"},{"issue":"3","key":"6755_CR22","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.ophtha.2020.07.062","volume":"128","author":"MH Maloney","year":"2021","unstructured":"Maloney MH, Payne SR, Herrin J, Sangaralingham LR, Shah ND, Barkmeier AJ (2021) Risk of systemic adverse events after intravitreal bevacizumab, ranibizumab, and aflibercept in routine clinical practice. Ophthalmology 128(3):417\u2013424. https:\/\/doi.org\/10.1016\/j.ophtha.2020.07.062","journal-title":"Ophthalmology"},{"issue":"5\u20136","key":"6755_CR23","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1159\/000541662","volume":"247","author":"PAH Nichani","year":"2024","unstructured":"Nichani PAH, Popovic MM, Mihalache A, Pathak A, Muni RH, Wong DTW, Kertes PJ (2024) Efficacy and safety of intravitreal faricimab in neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion: A meta-analysis. Ophthalmologica 247(5\u20136):355\u2013372. https:\/\/doi.org\/10.1159\/000541662","journal-title":"Ophthalmologica"},{"key":"6755_CR24","doi-asserted-by":"publisher","first-page":"711","DOI":"10.2147\/DDDT.S40215","volume":"5","author":"F Semeraro","year":"2013","unstructured":"Semeraro F, Morescalchi F, Duse S, Parmeggiani F, Gambicorti E, Costagliola C (2013) Aflibercept in wet AMD: specific role and optimal use. Drug Des Devel Ther 5:711\u2013722. https:\/\/doi.org\/10.2147\/DDDT.S40215","journal-title":"Drug Des Devel Ther"},{"issue":"5","key":"6755_CR25","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.3390\/pharmaceutics15051413","volume":"15","author":"L Ferro Desideri","year":"2023","unstructured":"Ferro Desideri L, Traverso CE, Nicol\u00f2 M, Munk MR (2023) Faricimab for the treatment of diabetic macular edema and neovascular age-related macular degeneration. Pharmaceutics 5 15(5):1413. https:\/\/doi.org\/10.3390\/pharmaceutics15051413","journal-title":"Pharmaceutics 5"},{"issue":"4","key":"6755_CR26","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1038\/s41371-022-00689-7","volume":"37","author":"N Ioakeimidis","year":"2023","unstructured":"Ioakeimidis N, Gourgouli I, Terentes-Printzios D et al (2023) Aortic stiffness and systemic inflammation changes predict clinical response to intravitreal anti-vascular endothelial growth factor therapy in patients with age-related macular degeneration. J Hum Hypertens 37(4):273\u2013278. https:\/\/doi.org\/10.1038\/s41371-022-00689-7","journal-title":"J Hum Hypertens"},{"issue":"5","key":"6755_CR27","doi-asserted-by":"publisher","first-page":"711","DOI":"10.4093\/dmj.2019.0119","volume":"44","author":"SMJ Cho","year":"2020","unstructured":"Cho SMJ, Lee H, Shim JS, Kim HC (2020) Sex-, age-, and metabolic disorder-dependent distributions of selected inflammatory biomarkers among community-dwelling adults. Diabetes Metab J 44(5):711\u2013725. https:\/\/doi.org\/10.4093\/dmj.2019.0119","journal-title":"Diabetes Metab J"},{"issue":"4","key":"6755_CR28","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1159\/000445388","volume":"235","author":"T Shiba","year":"2016","unstructured":"Shiba T, Takahashi M, Yoshida I, Taniguchi H, Matsumoto T, Hori Y (2016) Arteriosclerotic changes after Intravitreal injections of anti-vascular endothelial growth factor drugs in patients with exudative age-related Macular Degeneration. Ophthalmologica 235(4):225\u2013232. https:\/\/doi.org\/10.1159\/000445388","journal-title":"Ophthalmologica"},{"issue":"1","key":"6755_CR29","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/s41433-021-01416-1","volume":"36","author":"YY Chen","year":"2022","unstructured":"Chen YY, Lai YJ, Yen YF, Chou P (2022) Increased mortality after intravitreal injections of anti-VEGF for neovascular AMD among patients with prior stroke or acute myocardial infarction. Eye (Lond) 36(1):153\u2013159. https:\/\/doi.org\/10.1038\/s41433-021-01416-1","journal-title":"Eye (Lond)"},{"issue":"1","key":"6755_CR30","doi-asserted-by":"publisher","first-page":"7597","DOI":"10.1038\/s41598-023-34128-5","volume":"10","author":"YI Chou","year":"2023","unstructured":"Chou YI, Chang HY, Lin MY, Tseng CH, Wang TJ, Lin IC (2023) Risk analysis for patients with arterial thromboembolic events after intravitreal ranibizumab or aflibercept injections. Sci Rep 10(1):7597. https:\/\/doi.org\/10.1038\/s41598-023-34128-5","journal-title":"Sci Rep"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-06755-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-025-06755-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-06755-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T18:03:28Z","timestamp":1749492208000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-025-06755-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,8]]},"references-count":30,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5]]}},"alternative-id":["6755"],"URL":"https:\/\/doi.org\/10.1007\/s00417-025-06755-3","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,8]]},"assertion":[{"value":"25 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 February 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional ethical board of the Medical University of Innsbruck (Approval number 1317\/2022) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"Informed consent was obtained from all individual participants included in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers\u2019 bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}