{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T15:22:29Z","timestamp":1772810549397,"version":"3.50.1"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K09751"],"award-info":[{"award-number":["21K09751"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To evaluate aqueous flare values in patients with neovascular age-related macular degeneration (nAMD) receiving anti-vascular endothelial growth factor (VEGF) therapy, including brolucizumab.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective study included 101 patients treated with intravitreal anti-VEGF injections at Jichi Medical University Hospital from March to July 2021. Aqueous flare values were measured in both affected and fellow eyes. The number of treated eyes was 28 for aflibercept and 73 for brolucizumab. Flare values were compared between affected and fellow eyes, and associations with age, gender, drug type, number of injections, disease duration, and time since last injection were analyzed. We also measured flare values from pre-filled syringes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In unilateral treatment cases, brolucizumab-treated eyes had significantly higher aqueous flare values than fellow eyes (6.7 vs. 6.2 photon counts\/ms,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0032), while no significant difference was observed with aflibercept (6.9 vs. 6.7 pc\/ms,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.55). Flare values increased significantly with age in the brolucizumab group (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.0076) but not in the aflibercept group (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.56). The number of brolucizumab injections did not alter flare values. Multivariate analysis identified age as the only significant factor associated with increased aqueous flare. The mean (standard deviation) flare values measured from pre-filled syringes were 430 (15.6) pc\/ms for Beovu\n                      <jats:sup>\u00ae<\/jats:sup>\n                      (brolucizumab) and 161.8 (31) pc\/ms for Eylea\n                      <jats:sup>\u00ae<\/jats:sup>\n                      (aflibercept).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In nAMD, aqueous flare values were higher in brolucizumab-treated eyes and increased with age but were unaffected by the number of injections. Different flare values of each drug might affect the aqueous flare values within hours after injection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00417-025-07047-6","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T09:36:30Z","timestamp":1764408990000},"page":"701-709","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Increased aqueous flare after intravitreal brolucizumab injections compared to aflibercept in neovascular age-related macular degeneration"],"prefix":"10.1007","volume":"264","author":[{"given":"Yuto","family":"Hashimoto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yusuke","family":"Arai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5331-4730","authenticated-orcid":false,"given":"Hidenori","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironobu","family":"Tampo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rika","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hironori","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hana","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryota","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoru","family":"Inoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshikatsu","family":"Kaburaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuo","family":"Yanagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"7047_CR1","doi-asserted-by":"publisher","first-page":"9054","DOI":"10.1074\/jbc.m109.072876","volume":"285","author":"L Borras","year":"2010","unstructured":"Borras L, Gunde T, Tietz J, Bauer U, Hulmann-Cottier V, Grimshaw JPA, Urech DM (2010) Generic approach for the generation of stable humanized single-chain Fv fragments from rabbit monoclonal antibodies. J Biol Chem 285:9054\u20139066. https:\/\/doi.org\/10.1074\/jbc.m109.072876","journal-title":"J Biol Chem"},{"key":"7047_CR2","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1016\/j.ophtha.2017.03.057","volume":"124","author":"PU Dugel","year":"2017","unstructured":"Dugel PU, Jaffe GJ, Sallstig P, Warburton J, Weichselberger A, Wieland M, Singerman L (2017) Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial. Ophthalmology 124:1296\u20131304. https:\/\/doi.org\/10.1016\/j.ophtha.2017.03.057","journal-title":"Ophthalmology"},{"key":"7047_CR3","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1016\/j.ophtha.2015.12.030","volume":"123","author":"FG Holz","year":"2016","unstructured":"Holz FG, Dugel PU, Weissgerber G, Hamilton R, Silva R, Bandello F, Larsen M, Weichselberger A, Wenzel A, Schmidt A, Escher D, Sararols L, Souied E (2016) Single-chain antibody fragment VEGF inhibitor RTH258 for neovascular age-related macular degeneration: a randomized controlled study. Ophthalmology 123:1080\u20131089. https:\/\/doi.org\/10.1016\/j.ophtha.2015.12.030","journal-title":"Ophthalmology"},{"key":"7047_CR4","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ophtha.2019.04.017","volume":"127","author":"PU Dugel","year":"2020","unstructured":"Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG, HAWK and HARRIER Study Investigators (2020) HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of Brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127:72\u201384. https:\/\/doi.org\/10.1016\/j.ophtha.2019.04.017","journal-title":"Ophthalmology"},{"key":"7047_CR5","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/j.ophtha.2020.04.017","volume":"127","author":"CR Baumal","year":"2020","unstructured":"Baumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, Rich R, Chaudhry N, Lakhanpal RR, Oellers PR, Leveque TK, Rutledge BK, Chittum M, Bacci T, Ana Bety Enriquez AB, Sund NJ, Subong ENP, Albini TA (2020) Retinal vasculitis and intraocular inflammation after intravitreal injection of Brolucizumab. Ophthalmology 127:1345\u20131359. https:\/\/doi.org\/10.1016\/j.ophtha.2020.04.017","journal-title":"Ophthalmology"},{"key":"7047_CR6","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1159\/000444497","volume":"56","author":"S Demirel","year":"2016","unstructured":"Demirel S, Bilici S, Bat\u0131o\u011flu F, \u00d6zmert E (2016) Is there any difference between ranibizumab and aflibercept injections in terms of inflammation measured with anterior chamber flare levels in age-related macular degeneration patients: a comparative study. Ophthalmic Res 56:35\u201340. https:\/\/doi.org\/10.1159\/000444497","journal-title":"Ophthalmic Res"},{"key":"7047_CR7","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3109\/09273948.2015.1108445","volume":"25","author":"A Uzun","year":"2017","unstructured":"Uzun A, Yalcindag FN, Demirel S, Bat\u00fdo\u00f0lu F, Ozmert E (2017) Evaluation of aqueous flare levels following intravitreal ranibizumab injection for neovascular age-related macular degeneration. Ocul Immunol Inflamm 25:229\u2013232. https:\/\/doi.org\/10.3109\/09273948.2015.1108445","journal-title":"Ocul Immunol Inflamm"},{"key":"7047_CR8","doi-asserted-by":"publisher","first-page":"656774","DOI":"10.3389\/fphar.2021.656774","volume":"12","author":"J Dolar-Szczasny","year":"2021","unstructured":"Dolar-Szczasny J, Bucolo C, Zweifel S, Carnevali A, Rejdak R, Za\u0142uska W, Czarnek-Chudzik A, Toro MD (2021) Evaluation of aqueous flare intensity in eyes undergoing intravitreal bevacizumab therapy to treat neovascular age-related macular degeneration. Front Pharmacol 12:656774. https:\/\/doi.org\/10.3389\/fphar.2021.656774","journal-title":"Front Pharmacol"},{"key":"7047_CR9","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1097\/01.iae.0000237080.10627.b7","volume":"26","author":"C Kiss","year":"2006","unstructured":"Kiss C, Michels S, Prager F, Weigert G, Geitzenauer W, Schmidt-Erfurth U (2006) Evaluation of anterior chamber inflammatory activity in eyes treated with intravitreal bevacizumab. Retina 26:877\u2013881. https:\/\/doi.org\/10.1097\/01.iae.0000237080.10627.b7","journal-title":"Retina"},{"key":"7047_CR10","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1097\/iae.0000000000000334","volume":"35","author":"GR Blaha","year":"2015","unstructured":"Blaha GR, Brooks NO, Mackel CE, Pani A, Stewart AP, Price LL, Barouch FC, Chang J, Marx JL (2015) Changes in flare after intravitreal injection of three different anti-vascular endothelial growth factor medications. Retina 35:577\u2013581. https:\/\/doi.org\/10.1097\/iae.0000000000000334","journal-title":"Retina"},{"issue":"6","key":"7047_CR11","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1007\/s00417-024-06374-4","volume":"262","author":"Y Ichihashi","year":"2024","unstructured":"Ichihashi Y, Takamura Y, Hirano T, Shimura M, Yoneda K, Konno K, Yamada Y, Morioka M, Gozawa M, Matsumura T, Inatani M (2024) Flare levels after intravitreal injection of Brolucizumab for diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 262(6):1745\u20131753","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"4","key":"7047_CR12","doi-asserted-by":"publisher","first-page":"337","DOI":"10.4103\/sjopt.sjopt_119_22","volume":"36","author":"C Kesim","year":"2022","unstructured":"Kesim C, Chehab Z, Hasanreisoglu M (2022) Laser flare photometry in uveitis. Saudi J Ophthalmol 36(4):337\u2013343","journal-title":"Saudi J Ophthalmol"},{"key":"7047_CR13","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12237401","volume":"12","author":"H Matsubara","year":"2023","unstructured":"Matsubara H, Nagashima R, Chujo S, Matsui Y, Kato K, Kuze M, Kondo M (2023) Subclinical ocular changes after intravitreal injections of different anti-VEGF agents for neovascular age-related macular degeneration. J Clin Med 12:7401. https:\/\/doi.org\/10.3390\/jcm12237401","journal-title":"J Clin Med"},{"key":"7047_CR14","unstructured":"Food US, Administration D, Center for Drug Evaluation and Research (2020) Product quality review(s). Application number: 761125Orig1s000. Available at: (accessed 22 May 2025).\u00a0https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2020\/761125Orig1s000.pdf"},{"key":"7047_CR15","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.ejpb.2010.12.018","volume":"78","author":"M Veurink","year":"2011","unstructured":"Veurink M, Stella C, Tabatabay C, Pournaras CJ, Gurny R (2011) Association of ranibizumab (Lucentis\u00ae) or bevacizumab (Avastin\u00ae) with dexamethasone and triamcinolone acetonide: an in vitro stability assessment. Eur. J. Pharm. Biopharm. 78:271\u2013277. https:\/\/doi.org\/10.1016\/j.ejpb.2010.12.018","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"7047_CR16","volume":"57","author":"EL Nimz","year":"2016","unstructured":"Nimz EL, Van\u2019t Land CW, Yanez JA, Chastain LE (2016) Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. Invest Ophthalmol Vis Sci 57:4996","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"7047_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26020556","volume":"26","author":"K Nagaoka","year":"2025","unstructured":"Nagaoka K, Kimura N, Inoda S, Takayama T, Arai Y, Yanagi Y, Shimada T, Nagai R, Takahashi H, Aizawa K (2025) Comparative pharmacokinetic analysis of aflibercept and brolucizumab in human aqueous humor using nano-surface and molecular-orientation limited proteolysis. Int J Mol Sci 26:556. https:\/\/doi.org\/10.3390\/ijms26020556","journal-title":"Int J Mol Sci"},{"key":"7047_CR18","first-page":"237","volume":"33","author":"T Oshika","year":"1989","unstructured":"Oshika T, Kato S, Sawa M, Masuda K (1989) Aqueous flare intensity and age. Jpn J Ophthalmol 33:237\u2013242","journal-title":"Jpn J Ophthalmol"},{"key":"7047_CR19","doi-asserted-by":"publisher","first-page":"4701","DOI":"10.1007\/s10792-023-02870-4","volume":"43","author":"K Hoshi","year":"2023","unstructured":"Hoshi K, Kunikata H, Aizawa N, Yasuda M, Okabe T, Takizawa H, Abe T, Nakazawa T (2023) Baseline characteristics associated with the incidence of intraocular inflammation after the intravitreous injection of Brolucizumab. Int Ophthalmol 43:4701\u20134709. https:\/\/doi.org\/10.1007\/s10792-023-02870-4","journal-title":"Int Ophthalmol"},{"key":"7047_CR20","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1097\/IAE.0000000000001061","volume":"36","author":"A Hautam\u00e4ki","year":"2016","unstructured":"Hautam\u00e4ki A, Luoma A, Immonen I (2016) Anterior chamber flare during bevacizumab treatment in eyes with exudative age-related macular degeneration. Retina 36:2183\u20132190","journal-title":"Retina"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-07047-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-025-07047-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-07047-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T10:13:14Z","timestamp":1772791994000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-025-07047-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,29]]},"references-count":20,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["7047"],"URL":"https:\/\/doi.org\/10.1007\/s00417-025-07047-6","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,29]]},"assertion":[{"value":"9 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 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":"This retrospective study was approved by the Institutional Review Board of Jichi Medical University (Jichi-CU19-017). All procedures adhered to the tenets of the Declaration of Helsinki and followed institutional guidelines. Informed consent was obtained via an opt-out process, as disclosed on the Department of Ophthalmology website at Jichi Medical University. Where required, written informed consent was obtained from patients for procedures performed as part of their clinical care.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"YH, YA, Hironobu T, RK, Hironori T, HY, and RT: None. Hidenori T: Consultant fee from Boehringer; lecturer\u2019s fees from Santen, Senju, Novartis, Bayer, Boehringer, Chugai, Kyowa Kirin, MSD, Nikon and HOYA; grants from Novartis, Kyowa Kirin, Linical and Bayer; a founder of DeepEyeVision; patents outside this work. SI: Lecturer\u2019s fees from Chugai, Kyowa Kirin, Bayer, Senju, Macron, DeepEyeVision and Novartis and grants from HOYA, Santen, and Chugai outside this work. TK: Lecturer\u2019s fees from Santen, Tanabe-Mitsubishi, Kowa, Senju, Ono, Otsuka, Nippon Kayaku, Santen, Maruho, Rothniten, Bayer, and Chugai; grants from Santen, Senju, Tomei Corporation, Chugai, and Heiwa Medical Shokai, outside this work. YY: Consultant fees from Roche and Boehringer; lecture\u2019s fees from Chugai, Novartis, Bayer, Santen, Boehringer, Senju, and Astellas; stock option from DeepEyeVision outside this work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Commercial relationships disclosure"}},{"value":"The authors used ChatGPT-4o (OpenAI, San Francisco, CA, USA) to assist with language editing on June 19, 2025, during the preparation of this manuscript.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Language editing"}}]}}