Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report

Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report Nozomu Hashiya, Ichiro Maruko, Yuri Miyaguchi, Ruka Maruko, Taiji Hasegawa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5355651/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Jan, 2025 Read the published version in BMC Ophthalmology → Version 1 posted 11 You are reading this latest preprint version Abstract Background To report a case of intraocular inflammation (IOI) after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration. Case presentation An 80-year-old man with diabetes mellitus had neovascular age-related macular degeneration refractory to treatment with aflibercept 2 mg. Despite ten injections of faricimab, the exudation remained, and we switched to brolucizumab, which resulted in a mild IOI. The IOI improved with only topical steroids, and we switched back to aflibercept 2 mg for the exudation. However, the exudation remained, and we decided to switch to aflibercept 8 mg after careful discussion with the patient. Two weeks later, he experienced minor ocular pain and photophobia. One month later, although a dry macula was achieved, severe visual impairment occurred due to anterior chamber inflammation, retinal vasculitis, and retinal vascular occlusion. We diagnosed the severe IOI following aflibercept 8 mg and immediately started steroid eye drops and a sub-Tenon injection of triamcinolone acetonide. Although the inflammation resolved, his visual acuity did not improve. Conclusions This case demonstrated a potential dose-dependent inflammatory response following aflibercept 8 mg, which did not occur with aflibercept 2 mg in patients with a history of intraocular inflammation. aflibercept 8 mg intraocular inflammation retinal vasculitis retinal vascular occlusion treatment-refractory neovascular age-related macular degeneration Figures Figure 1 Figure 2 Figure 3 Background Aflibercept 8 mg is a novel anti-vascular endothelial growth factor (VEGF) therapy recently approved in Japan to treat neovascular age-related macular degeneration (nAMD). Aflibercept 8 mg (0.07ml) is a new anti-VEGF drug with a higher concentration and improved stability, allowing four times the intravitreal molar dose compared to the aflibercept 2 mg (0.05ml). Since the introduction of brolucizumab and even faricimab, intraocular inflammation (IOI) after administration has been reported occasionally, and its safety has become a concern in recent years.[ 1 – 5 ] In the randomized, double-masked, non-inferiority phase 3 trial of aflibercept 8 mg in nAMD (PULSAR), aflibercept 8 mg and 2 mg had comparable safety profiles and a low incidence of IOI.[ 6 ] In the current study, we present a case of a patient with treatment-refractory nAMD who did not develop IOI with aflibercept 2 mg and developed IOI with perivascular hemorrhages and occlusive vasculitis after switching to aflibercept 8 mg. Case presentation An 80-year-old Japanese male with a history of diabetes mellitus had previously undergone cataract surgery and was being treated for glaucoma and nAMD in his left eye. He was previously treated with aflibercept 2 mg for nAMD but was referred to our hospital because the macular exudation did not improve. At the initial visit, the best-corrected visual acuity (BCVA) of the left eye was 20/63, and optical coherence tomography (OCT) showed the subretinal fluid (SRF) and a large sub-retinal pigment epithelium (RPE) fluid, so the patient was diagnosed as refractory to aflibercept 2 mg, and treatment was switched to faricimab. Despite ten injections of faricimab, the BCVA worsened to 20/100, and a large sub-RPE remained. We therefore switched to brolucizumab. Following two injections of brolucizumab, a slit-lamp examination revealed anterior chamber cells (1+) and fine corneal precipitates without hypopyon and ultra-widefield color fundus images (Optos California, Nikon) demonstrated retinal vascular occlusion and perivascular hemorrhage at the nasal periphery, which suggested the occurrence of a mild non-infections IOI (Fig. 1 ). The inflammation was quickly resolved with only 0.1% betamethasone eye drops. Since SRF remained on OCT after IOI was under control, we switched back to aflibercept 2 mg, which resulted in further BCVA loss to 20/200. Sixteen weeks after the final brolucizumab treatment and five weeks after switching to aflibercept 2 mg, when the IOI was confirmed to subside, we decided to switch to aflibercept 8 mg after careful discussion, expecting efficacy and safety. Two weeks later, he experienced minor ocular pain and photophobia but did not seek medical attention. At the one-month follow-up visit, BCVA decreased to 20/2000. Slit-lamp examination showed mild conjunctival injection, anterior chamber cells (1+), fine keratic precipitates (Fig. 2 a), and vitreous cells (1+) without hypopyon. Ultra-widefield color fundus images showed whitening of retinal vessels on the nasal side of the optic nerve and blot retinal hemorrhages around these vessels (Fig. 2 b). Ultra-widefield fluorescein angiography showed delayed filling of peripheral retinal veins, multiple retinal vein stenoses in the early phase (Fig. 2 c), and mild retinal vein leakage in the late phase (Fig. 2 d). We diagnosed the IOI following aflibercept 8 mg and immediately started steroid eye drops and a sub-Tenon injection of triamcinolone acetonide (20 mg/0.5 mL). The inflammation resolved, but his BCVA did not improve. Although IOI developed after aflibercept 8 mg, macular exudation, including large sub-RPE fluid, improved on OCT significantly (Fig. 3 a, b). The dry macula could be maintained for eight weeks, but due to re-exudation, the patient was switched to ranibizumab after ten weeks, which settled down without inflammation. Discussion and conclusions This report presents a case of intraocular inflammation associated with aflibercept 8 mg administration, accompanied by retinal vasculitis and retinal vascular occlusion, in a Japanese patient with treatment-refractory nAMD. The patient initially showed refractory to aflibercept 2 mg and faricimab and developed mild IOI when switched to brolucizumab. The inflammation was controlled with only 0.1% betamethasone eye drops and then switching back to aflibercept 2 mg. However, after switching to aflibercept 8 mg, more severe IOI developed, characterized by retinal hemorrhage and vascular occlusion. This case may reveal a potential dose-dependent relationship, where inflammation did not occur with aflibercept 2 mg but was triggered by the higher 8 mg dose. Increasing the molar dose of intravitreal anti-VEGF therapy may enhance its efficacy and durability. It may result in an extension of dosing intervals and a reduction in the frequency of hospital visits. However, these benefits must be carefully considered against safety concerns, particularly those associated with higher doses. Clinical trials, such as the phase 2 CANDELA study[ 7 ] and the phase 3 PULSAR study,[ 6 ] have generally demonstrated comparable safety profiles between aflibercept 2 mg and 8 mg. For instance, the CANDELA trial reported only one case of mild iritis in the aflibercept 8 mg group, which resolved with topical treatment.[ 7 ] Similarly, in the PULSAR trial, although IOI occurred in both groups, were mild to moderate and did not require discontinuation of administration.[ 6 ] These results only show that severe IOI is infrequent but do not indicate that aflibercept 8 mg is without any risk at all. Calculations show that brolucizumab has the highest molar concentration of anti-VEGF currently available, followed by aflibercept 8 mg.[ 8 , 9 ] It may not be a coincidence that this case showed intraocular inflammation with both drugs. However, there was no report on the IOI of aflibercept 8 mg in the US, even though it has already been approved by the Food and Drug Administration (FDA) in August 2023. In Japanese populations, the incidence of IOI, particularly with brolucizumab, has been reported to be higher compared to global averages.[ 2 , 4 ] Previous studies have shown IOI rates of 9–10% in Japanese nAMD patients treated with brolucizumab, with approximately one-third of these cases developing into retinal vasculitis or vascular occlusion.[ 2 ] Additionally, a one-year study found that a history of IOI and/or retinal occlusion, along with female gender, were significant risk factors for IOI after brolucizumab treatment.[ 4 ] These findings highlight the need for cautious patient selection, thorough education, and proactive management of inflammation when using brolucizumab or other anti-VEGF therapies in this demographic.[ 10 ] Recently there has been a report from Japan of an IOI after aflibercept 8 mg, where a small study in Japanese subjects reported IOI in 3 of 35 eyes (8.6%) treated with aflibercept 8 mg.[ 11 ] The limited sample size requires further investigation to determine whether the incidence is indeed elevated in the Japanese population. A larger multi-center analysis is needed better to understand the risk profile of aflibercept 8 mg, as higher rates of IOI have been observed with brolucizumab in Japan. Despite the occurrence of IOI, it is noteworthy that this patient sustained a dry macula for over two months, which is longer than previous treatments. This may suggest that aflibercept 8 mg may offer superior efficacy compared to aflibercept 2 mg, faricimab, and brolucizumab in the management of treatment-refractory nAMD. However, the potential dose-dependent inflammation requires a careful risk-benefit analysis, especially in patients with a history of ocular inflammation. Further research is needed to identify patient populations that may benefit from its enhanced efficacy without incurring significant inflammatory risks. In conclusion, this case highlights the need for careful monitoring in patients with a history of IOI and suggests a potential for a dose-dependent inflammatory response to aflibercept 8 mg. When using high-dose anti-VEGF therapy, these considerations should be taken into account to optimize patient safety and minimize the risk of complications. Abbreviations VEGF vascular endothelial growth factor nAMD neovascular age-related macular degeneration IOI intraocular inflammation BCVA best-corrected visual acuity OCT optical coherence tomography SRF subretinal fluid RPE retinal pigment epithelium FDA Food and Drug Administration Declarations Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Acknowledgements None. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author information Authors and Affiliations Department of Ophthalmology, Tokyo Women’s Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo, 162-8666, Japan Authors’ contributions NH conceived the study concept and design, analyzed and interpreted the data, and drafted the manuscript. IM contributed to data analysis and substantial revision of the manuscript. YM and RM were involved in data acquisition. TH provided critical input on study conception and manuscript drafting. TI advised on the study concept. All authors read and approved the final manuscript. Corresponding Author: Correspondence to Ichiro Maruko Ethics approval and consent to participate This retrospective study was conducted in accordance with the tenets of the Declaration of Helsinki. The institutional review board at Tokyo Women’s Medical University School of Medicine approved the study, which included OCT observation of eyes with macular and retinal disorders, observational study of age-related macular degeneration, and similar disorders. Consent for publication The patients have consented to the submission of this case report to the journal for publication. Written informed consent was obtained for all presented case details and accompanying images. Competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author(s) have made the following disclosure(s): funding statement Dr. Hashiya receives lecturing and travel fees from Senju Pharmaceutical, Chugai Pharmaceutical, Kowa, Novartis Pharma, and AMO. Dr. Maruko receives lecturing and travel fees from Bayer Pharmaceuticals, Novartis Pharma, Japan Alcon, Santen, Senju Pharmaceutical, Topcon, Chugai Pharmaceutical, Canon, Nidek, and Nikon. He holds a patent. Dr. Miyaguchi has nothing to disclose. Dr. Ruka Maruko receives lecturing and travel fees from Chugai Pharmaceutical and Kyowa Kirin. Dr. Hasegawa receives lecturing and travel fees from Novartis Pharma, Alcon Pharma, Santen, Kowa, Senju Pharmaceutical, R.E. Medical, Nikon Health Care Japan, JFC Sales Plan, Otsuka Pharmaceutical, and Japan Beringer Ingelheim. Dr. Iida receives grants from Nidek, Topcon, Santen, Novartis Pharma, Senju Pharmaceutical, Japan Alcon, HOYA, and AMO, consultant fees from Bayer Pharmaceuticals, Novartis Pharma, Chugai Pharmaceutical, Japan Beringer Ingelheim, and Janssen Pharma, and received lecturing and travel fees from Bayer Pharmaceuticals, Novartis Pharma, Japan Alcon, Santen, Senju Pharmaceutical, Topcon, Chugai Pharmaceutical, Canon, Nidek, Otsuka Pharmaceutical, Nikon, and Kyowa Kirin. He holds a patent. References Baumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, Rich R, Chaudhry N, Lakhanpal RR, Oellers PR et al. Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab. Ophthalmology 2020, 127(10). Maruko I, Okada AA, Iida T, Hasegawa T, Izumi T, Kawai M, Maruko R, Nakayama M, Yamamoto A, Koizumi H et al. Brolucizumab-related intraocular inflammation in Japanese patients with age-related macular degeneration: a short-term multicenter study. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2021. Kurup SK, Tabbaa T, Echegaray JJ, Oliver AL. Intraocular inflammation secondary to intravitreal brolucizumab treated successfully with Sub-Tenon triamcinolone: A case report. Am J Ophthalmol Case Rep. 2022;25:101289. Inoda S, Takahashi H, Maruyama-Inoue M, Ikeda S, Sekiryu T, Itagaki K, Matsumoto H, Mukai R, Nagai Y, Ohnaka M, et al. INCIDENCE AND RISK FACTORS OF INTRAOCULAR INFLAMMATION AFTER BROLUCIZUMAB TREATMENT IN JAPAN: A Multicenter Age-Related Macular Degeneration Study. Retina. 2024;44(4):714–22. Thangamathesvaran L, Kong J, Bressler SB, Singh M, Wenick AS, Scott AW, Arévalo JF, Bressler NM. Severe Intraocular Inflammation Following Intravitreal Faricimab. JAMA Ophthalmol. 2024;142(4):365–70. Lanzetta P, Korobelnik JF, Heier JS, Leal S, Holz FG, Clark WL, Eichenbaum D, Iida T, Xiaodong S, Berliner AJ, et al. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet. 2024;403(10432):1141–52. Wykoff CC, Brown DM, Reed K, Berliner AJ, Gerstenblith AT, Breazna A, Abraham P, Fein JG, Chu KW, Clark WL, et al. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmol. 2023;141(9):834–42. Veritti D, Sarao V, Gorni G, Lanzetta P. Anti-VEGF Drugs Dynamics: Relevance for Clinical Practice. Pharmaceutics 2022, 14(2). Veritti D, Sarao V, Di Bin F, Lanzetta P. Pharmacokinetic and Pharmacodynamic Rationale for Extending VEGF Inhibition Increasing Intravitreal Aflibercept Dose. Pharmaceutics 2023, 15(5). Holz FG, Iida T, Maruko I, Sadda SR, A CONSENSUS ON RISK MITIGATION FOR BROLUCIZUMAB IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Patient Selection, Evaluation, and Treatment. Retina. 2022;42(9):1629–37. Matsumoto H, Hoshino J, Numaga S, Mimura K, Asatori Y, Akiyama H. Retinal vasculitis after intravitreal aflibercept 8 mg for neovascular age-related macular degeneration. Jpn J Ophthalmol 2024. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 23 Jan, 2025 Read the published version in BMC Ophthalmology → Version 1 posted Editorial decision: Revision requested 18 Nov, 2024 Reviews received at journal 16 Nov, 2024 Reviewers agreed at journal 08 Nov, 2024 Reviewers agreed at journal 07 Nov, 2024 Reviews received at journal 06 Nov, 2024 Reviewers agreed at journal 31 Oct, 2024 Reviewers invited by journal 31 Oct, 2024 Editor invited by journal 30 Oct, 2024 Editor assigned by journal 30 Oct, 2024 Submission checks completed at journal 30 Oct, 2024 First submitted to journal 29 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5355651","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":375859398,"identity":"fd61c236-f6ed-4ff1-b94b-2196ce1f1418","order_by":0,"name":"Nozomu Hashiya","email":"","orcid":"","institution":"Tokyo Women's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Nozomu","middleName":"","lastName":"Hashiya","suffix":""},{"id":375859399,"identity":"3a264896-2529-4af3-ba01-b236aa9c73cb","order_by":1,"name":"Ichiro 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Maruko","email":"","orcid":"","institution":"Tokyo Women's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruka","middleName":"","lastName":"Maruko","suffix":""},{"id":375859404,"identity":"7fd28b2d-8286-4e00-b88e-e9fc0eaa9689","order_by":4,"name":"Taiji Hasegawa","email":"","orcid":"","institution":"Tokyo Women's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Taiji","middleName":"","lastName":"Hasegawa","suffix":""},{"id":375859405,"identity":"33b827e2-5d27-4125-8897-a222df17e690","order_by":5,"name":"Tomohiro Iida","email":"","orcid":"","institution":"Tokyo Women's Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Iida","suffix":""}],"badges":[],"createdAt":"2024-10-29 15:38:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5355651/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5355651/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12886-024-03827-6","type":"published","date":"2025-01-23T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":69912144,"identity":"12364021-b7db-455d-a28c-015c80a2730d","added_by":"auto","created_at":"2024-11-26 14:00:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2630204,"visible":true,"origin":"","legend":"\u003cp\u003eFundus findings on ultra-widefield fundus photography after intravitreal injection of brolucizumab.\u003c/p\u003e\n\u003cp\u003eUltra-widefield fundus photography shows partial retinal vascular occlusion (white arrowhead) and perivascular hemorrhage (white arrows) without retinal vessel whitening, suggesting mild intraocular inflammation.\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-5355651/v1/08f918e427cfeee553926833.png"},{"id":69912145,"identity":"5ed7f6aa-7ede-45ca-880c-3710ba54e8f2","added_by":"auto","created_at":"2024-11-26 14:00:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":11521891,"visible":true,"origin":"","legend":"\u003cp\u003eSlit-lamp examination and ultra-widefield fundus photography and ultra-widefield fluorescein angiography after intravitreal injection of aflibercept 8 mg.\u003c/p\u003e\n\u003cp\u003e(a) Slit-lamp examination shows fine keratic precipitates and anterior chamber cells (1+) without hypopyon.\u003c/p\u003e\n\u003cp\u003e(b) Ultra-widefield fundus photography shows whitening of retinal vessels at the nasal periphery (white arrowhead), and blot retinal hemorrhages around the peripheral vessels and vitreous opacities were also observed.\u003c/p\u003e\n\u003cp\u003e(c) Ultra-widefield fluorescein angiography in the early phase showed a filling delay of peripheral retinal veins (white arrowheads) and multiple focal stenoses of retinal veins (white arrows).\u003c/p\u003e\n\u003cp\u003e(d) Ultra-widefield fluorescein angiography in the late phase shows mild leakage from retinal veins and staining in the venous wall (white arrows).\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-5355651/v1/be49c5a6490c4fb53ed9e55d.png"},{"id":69912143,"identity":"3f3c4995-5154-4f71-8f6f-9543b2df9eb2","added_by":"auto","created_at":"2024-11-26 14:00:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2213442,"visible":true,"origin":"","legend":"\u003cp\u003eOptical coherence tomography (OCT) before and after intravitreal injection of aflibercept 8 mg.\u003c/p\u003e\n\u003cp\u003e(a) OCT demonstrated subretinal fluid (SRF) and a large sub-retinal pigment epithelium (RPE) fluid before intravitreal injection of aflibercept 8 mg.\u003c/p\u003e\n\u003cp\u003e(b) OCT showed significant improvement, with the disappearance of SRF and a reduction in sub-RPE fluid size after intravitreal injection of aflibercept 8 mg.\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-5355651/v1/bbc396c5d11471aa775c677d.png"},{"id":74858350,"identity":"5c67c491-f0bb-4bc3-af96-e9b6de51e066","added_by":"auto","created_at":"2025-01-27 16:08:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17982864,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5355651/v1/109b469a-4d98-4cdd-b707-b98d60888e58.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003eAflibercept 8 mg is a novel anti-vascular endothelial growth factor (VEGF) therapy recently approved in Japan to treat neovascular age-related macular degeneration (nAMD). Aflibercept 8 mg (0.07ml) is a new anti-VEGF drug with a higher concentration and improved stability, allowing four times the intravitreal molar dose compared to the aflibercept 2 mg (0.05ml). Since the introduction of brolucizumab and even faricimab, intraocular inflammation (IOI) after administration has been reported occasionally, and its safety has become a concern in recent years.[\u003cspan additionalcitationids=\"CR2 CR3 CR4\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In the randomized, double-masked, non-inferiority phase 3 trial of aflibercept 8 mg in nAMD (PULSAR), aflibercept 8 mg and 2 mg had comparable safety profiles and a low incidence of IOI.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] In the current study, we present a case of a patient with treatment-refractory nAMD who did not develop IOI with aflibercept 2 mg and developed IOI with perivascular hemorrhages and occlusive vasculitis after switching to aflibercept 8 mg.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eAn 80-year-old Japanese male with a history of diabetes mellitus had previously undergone cataract surgery and was being treated for glaucoma and nAMD in his left eye. He was previously treated with aflibercept 2 mg for nAMD but was referred to our hospital because the macular exudation did not improve. At the initial visit, the best-corrected visual acuity (BCVA) of the left eye was 20/63, and optical coherence tomography (OCT) showed the subretinal fluid (SRF) and a large sub-retinal pigment epithelium (RPE) fluid, so the patient was diagnosed as refractory to aflibercept 2 mg, and treatment was switched to faricimab. Despite ten injections of faricimab, the BCVA worsened to 20/100, and a large sub-RPE remained. We therefore switched to brolucizumab. Following two injections of brolucizumab, a slit-lamp examination revealed anterior chamber cells (1+) and fine corneal precipitates without hypopyon and ultra-widefield color fundus images (Optos California, Nikon) demonstrated retinal vascular occlusion and perivascular hemorrhage at the nasal periphery, which suggested the occurrence of a mild non-infections IOI (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The inflammation was quickly resolved with only 0.1% betamethasone eye drops. Since SRF remained on OCT after IOI was under control, we switched back to aflibercept 2 mg, which resulted in further BCVA loss to 20/200. Sixteen weeks after the final brolucizumab treatment and five weeks after switching to aflibercept 2 mg, when the IOI was confirmed to subside, we decided to switch to aflibercept 8 mg after careful discussion, expecting efficacy and safety.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTwo weeks later, he experienced minor ocular pain and photophobia but did not seek medical attention. At the one-month follow-up visit, BCVA decreased to 20/2000. Slit-lamp examination showed mild conjunctival injection, anterior chamber cells (1+), fine keratic precipitates (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), and vitreous cells (1+) without hypopyon. Ultra-widefield color fundus images showed whitening of retinal vessels on the nasal side of the optic nerve and blot retinal hemorrhages around these vessels (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Ultra-widefield fluorescein angiography showed delayed filling of peripheral retinal veins, multiple retinal vein stenoses in the early phase (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec), and mild retinal vein leakage in the late phase (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). We diagnosed the IOI following aflibercept 8 mg and immediately started steroid eye drops and a sub-Tenon injection of triamcinolone acetonide (20 mg/0.5 mL). The inflammation resolved, but his BCVA did not improve. Although IOI developed after aflibercept 8 mg, macular exudation, including large sub-RPE fluid, improved on OCT significantly (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, b). The dry macula could be maintained for eight weeks, but due to re-exudation, the patient was switched to ranibizumab after ten weeks, which settled down without inflammation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDiscussion and conclusions\u003c/h2\u003e \u003cp\u003eThis report presents a case of intraocular inflammation associated with aflibercept 8 mg administration, accompanied by retinal vasculitis and retinal vascular occlusion, in a Japanese patient with treatment-refractory nAMD. The patient initially showed refractory to aflibercept 2 mg and faricimab and developed mild IOI when switched to brolucizumab. The inflammation was controlled with only 0.1% betamethasone eye drops and then switching back to aflibercept 2 mg. However, after switching to aflibercept 8 mg, more severe IOI developed, characterized by retinal hemorrhage and vascular occlusion. This case may reveal a potential dose-dependent relationship, where inflammation did not occur with aflibercept 2 mg but was triggered by the higher 8 mg dose.\u003c/p\u003e \u003cp\u003eIncreasing the molar dose of intravitreal anti-VEGF therapy may enhance its efficacy and durability. It may result in an extension of dosing intervals and a reduction in the frequency of hospital visits. However, these benefits must be carefully considered against safety concerns, particularly those associated with higher doses. Clinical trials, such as the phase 2 CANDELA study[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and the phase 3 PULSAR study,[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have generally demonstrated comparable safety profiles between aflibercept 2 mg and 8 mg. For instance, the CANDELA trial reported only one case of mild iritis in the aflibercept 8 mg group, which resolved with topical treatment.[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Similarly, in the PULSAR trial, although IOI occurred in both groups, were mild to moderate and did not require discontinuation of administration.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] These results only show that severe IOI is infrequent but do not indicate that aflibercept 8 mg is without any risk at all. Calculations show that brolucizumab has the highest molar concentration of anti-VEGF currently available, followed by aflibercept 8 mg.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] It may not be a coincidence that this case showed intraocular inflammation with both drugs. However, there was no report on the IOI of aflibercept 8 mg in the US, even though it has already been approved by the Food and Drug Administration (FDA) in August 2023.\u003c/p\u003e \u003cp\u003eIn Japanese populations, the incidence of IOI, particularly with brolucizumab, has been reported to be higher compared to global averages.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Previous studies have shown IOI rates of 9\u0026ndash;10% in Japanese nAMD patients treated with brolucizumab, with approximately one-third of these cases developing into retinal vasculitis or vascular occlusion.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Additionally, a one-year study found that a history of IOI and/or retinal occlusion, along with female gender, were significant risk factors for IOI after brolucizumab treatment.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] These findings highlight the need for cautious patient selection, thorough education, and proactive management of inflammation when using brolucizumab or other anti-VEGF therapies in this demographic.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Recently there has been a report from Japan of an IOI after aflibercept 8 mg, where a small study in Japanese subjects reported IOI in 3 of 35 eyes (8.6%) treated with aflibercept 8 mg.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] The limited sample size requires further investigation to determine whether the incidence is indeed elevated in the Japanese population. A larger multi-center analysis is needed better to understand the risk profile of aflibercept 8 mg, as higher rates of IOI have been observed with brolucizumab in Japan.\u003c/p\u003e \u003cp\u003eDespite the occurrence of IOI, it is noteworthy that this patient sustained a dry macula for over two months, which is longer than previous treatments. This may suggest that aflibercept 8 mg may offer superior efficacy compared to aflibercept 2 mg, faricimab, and brolucizumab in the management of treatment-refractory nAMD. However, the potential dose-dependent inflammation requires a careful risk-benefit analysis, especially in patients with a history of ocular inflammation. Further research is needed to identify patient populations that may benefit from its enhanced efficacy without incurring significant inflammatory risks.\u003c/p\u003e \u003cp\u003eIn conclusion, this case highlights the need for careful monitoring in patients with a history of IOI and suggests a potential for a dose-dependent inflammatory response to aflibercept 8 mg. When using high-dose anti-VEGF therapy, these considerations should be taken into account to optimize patient safety and minimize the risk of complications.\u003c/p\u003e \u003c/div\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eVEGF\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evascular endothelial growth factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003enAMD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eneovascular age-related macular degeneration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eIOI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintraocular inflammation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBCVA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebest-corrected visual acuity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eOCT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoptical coherence tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSRF\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esubretinal fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRPE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eretinal pigment epithelium\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eFDA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood and Drug Administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Ophthalmology, Tokyo Women\u0026rsquo;s Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo, 162-8666, Japan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNH conceived the study concept and design, analyzed and interpreted the data, and drafted the manuscript. IM contributed to data analysis and substantial revision of the manuscript. YM and RM were involved in data acquisition. TH provided critical input on study conception and manuscript drafting. TI advised on the study concept. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding Author:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Ichiro Maruko\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study was conducted in accordance with the tenets of the Declaration of Helsinki. The institutional review board at Tokyo Women\u0026rsquo;s Medical University School of Medicine approved the study, which included OCT observation of eyes with macular and retinal disorders, observational study of age-related macular degeneration, and similar disorders.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patients have consented to the submission of this case report to the journal for publication. Written informed consent was obtained for all presented case details and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe author(s) have made the following disclosure(s): funding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Hashiya receives lecturing and travel fees from Senju Pharmaceutical, Chugai Pharmaceutical, Kowa, Novartis Pharma, and AMO.\u003c/p\u003e\n\u003cp\u003eDr. Maruko receives lecturing and travel fees from Bayer Pharmaceuticals, Novartis Pharma, Japan Alcon, Santen, Senju Pharmaceutical, Topcon, Chugai Pharmaceutical, Canon, Nidek, and Nikon. He holds a patent.\u003c/p\u003e\n\u003cp\u003eDr. Miyaguchi has nothing to disclose.\u003c/p\u003e\n\u003cp\u003eDr. Ruka Maruko receives lecturing and travel fees from Chugai Pharmaceutical and Kyowa Kirin.\u003c/p\u003e\n\u003cp\u003eDr. Hasegawa receives lecturing and travel fees from Novartis Pharma, Alcon Pharma, Santen, Kowa, Senju Pharmaceutical, R.E. Medical, Nikon Health Care Japan, JFC Sales Plan, Otsuka Pharmaceutical, and Japan Beringer Ingelheim.\u003c/p\u003e\n\u003cp\u003eDr. Iida receives grants from Nidek, Topcon, Santen, Novartis Pharma, Senju Pharmaceutical, Japan Alcon, HOYA, and AMO, consultant fees from Bayer Pharmaceuticals, Novartis Pharma, Chugai Pharmaceutical, Japan Beringer Ingelheim, and Janssen Pharma, and received lecturing and travel fees from Bayer Pharmaceuticals, Novartis Pharma, Japan Alcon, Santen, Senju Pharmaceutical, Topcon, Chugai Pharmaceutical, Canon, Nidek, Otsuka Pharmaceutical, Nikon, and Kyowa Kirin. He holds a patent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBaumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, Rich R, Chaudhry N, Lakhanpal RR, Oellers PR et al. Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab. Ophthalmology 2020, 127(10).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaruko I, Okada AA, Iida T, Hasegawa T, Izumi T, Kawai M, Maruko R, Nakayama M, Yamamoto A, Koizumi H et al. Brolucizumab-related intraocular inflammation in Japanese patients with age-related macular degeneration: a short-term multicenter study. \u003cem\u003eGraefe's archive for clinical and experimental ophthalmology\u0026thinsp;=\u0026thinsp;Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie\u003c/em\u003e 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKurup SK, Tabbaa T, Echegaray JJ, Oliver AL. Intraocular inflammation secondary to intravitreal brolucizumab treated successfully with Sub-Tenon triamcinolone: A case report. Am J Ophthalmol Case Rep. 2022;25:101289.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eInoda S, Takahashi H, Maruyama-Inoue M, Ikeda S, Sekiryu T, Itagaki K, Matsumoto H, Mukai R, Nagai Y, Ohnaka M, et al. INCIDENCE AND RISK FACTORS OF INTRAOCULAR INFLAMMATION AFTER BROLUCIZUMAB TREATMENT IN JAPAN: A Multicenter Age-Related Macular Degeneration Study. Retina. 2024;44(4):714\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThangamathesvaran L, Kong J, Bressler SB, Singh M, Wenick AS, Scott AW, Ar\u0026eacute;valo JF, Bressler NM. Severe Intraocular Inflammation Following Intravitreal Faricimab. JAMA Ophthalmol. 2024;142(4):365\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLanzetta P, Korobelnik JF, Heier JS, Leal S, Holz FG, Clark WL, Eichenbaum D, Iida T, Xiaodong S, Berliner AJ, et al. Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial. Lancet. 2024;403(10432):1141\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWykoff CC, Brown DM, Reed K, Berliner AJ, Gerstenblith AT, Breazna A, Abraham P, Fein JG, Chu KW, Clark WL, et al. Effect of High-Dose Intravitreal Aflibercept, 8 mg, in Patients With Neovascular Age-Related Macular Degeneration: The Phase 2 CANDELA Randomized Clinical Trial. JAMA Ophthalmol. 2023;141(9):834\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeritti D, Sarao V, Gorni G, Lanzetta P. Anti-VEGF Drugs Dynamics: Relevance for Clinical Practice. Pharmaceutics 2022, 14(2).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVeritti D, Sarao V, Di Bin F, Lanzetta P. Pharmacokinetic and Pharmacodynamic Rationale for Extending VEGF Inhibition Increasing Intravitreal Aflibercept Dose. Pharmaceutics 2023, 15(5).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHolz FG, Iida T, Maruko I, Sadda SR, A CONSENSUS ON RISK MITIGATION FOR BROLUCIZUMAB IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. Patient Selection, Evaluation, and Treatment. Retina. 2022;42(9):1629\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatsumoto H, Hoshino J, Numaga S, Mimura K, Asatori Y, Akiyama H. Retinal vasculitis after intravitreal aflibercept 8 mg for neovascular age-related macular degeneration. Jpn J Ophthalmol 2024.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"aflibercept 8 mg, intraocular inflammation, retinal vasculitis, retinal vascular occlusion, treatment-refractory, neovascular age-related macular degeneration","lastPublishedDoi":"10.21203/rs.3.rs-5355651/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5355651/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo report a case of intraocular inflammation (IOI) after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAn 80-year-old man with diabetes mellitus had neovascular age-related macular degeneration refractory to treatment with aflibercept 2 mg. Despite ten injections of faricimab, the exudation remained, and we switched to brolucizumab, which resulted in a mild IOI. The IOI improved with only topical steroids, and we switched back to aflibercept 2 mg for the exudation. However, the exudation remained, and we decided to switch to aflibercept 8 mg after careful discussion with the patient. Two weeks later, he experienced minor ocular pain and photophobia. One month later, although a dry macula was achieved, severe visual impairment occurred due to anterior chamber inflammation, retinal vasculitis, and retinal vascular occlusion. We diagnosed the severe IOI following aflibercept 8 mg and immediately started steroid eye drops and a sub-Tenon injection of triamcinolone acetonide. Although the inflammation resolved, his visual acuity did not improve.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case demonstrated a potential dose-dependent inflammatory response following aflibercept 8 mg, which did not occur with aflibercept 2 mg in patients with a history of intraocular inflammation.\u003c/p\u003e","manuscriptTitle":"Intraocular inflammation after intravitreal injection of aflibercept 8 mg for treatment-refractory neovascular age-related macular degeneration: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-26 14:00:37","doi":"10.21203/rs.3.rs-5355651/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-18T08:49:27+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-16T10:08:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312723432474549151199933872449897343303","date":"2024-11-08T07:54:15+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"65781651704965081789252201902845854025","date":"2024-11-07T13:03:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-11-06T21:11:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"313999000911762880655397694926127131972","date":"2024-10-31T21:57:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-10-31T09:31:04+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-10-30T07:52:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-30T04:19:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-30T04:17:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2024-10-29T15:32:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85aef8c6-64d9-4306-a5c5-7b0ddf8ddd88","owner":[],"postedDate":"November 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-01-27T16:00:29+00:00","versionOfRecord":{"articleIdentity":"rs-5355651","link":"https://doi.org/10.1186/s12886-024-03827-6","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2025-01-23 15:57:18","publishedOnDateReadable":"January 23rd, 2025"},"versionCreatedAt":"2024-11-26 14:00:37","video":"","vorDoi":"10.1186/s12886-024-03827-6","vorDoiUrl":"https://doi.org/10.1186/s12886-024-03827-6","workflowStages":[]},"version":"v1","identity":"rs-5355651","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5355651","identity":"rs-5355651","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}