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Bairagi RD, Reon RR, Hasan MM, Sarker S, Debnath D, Rahman MT, Rahman S, Islam MA, Siddique MAT, Bokshi B, Rahman MM, Acharzo AK. Ocular drug delivery systems based on nanotechnology: a comprehensive review for the treatment of eye diseases. DISCOVER NANO 2025; 20:75. [PMID: 40317427 PMCID: PMC12049359 DOI: 10.1186/s11671-025-04234-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/07/2025] [Indexed: 05/07/2025]
Abstract
Ocular drug delivery is a significant challenge due to the intricate anatomy of the eye and the various physiological barriers. Conventional therapeutic approaches, while effective to some extent, often fall short in effectively targeting ocular diseases, resulting in suboptimal therapeutic outcomes due to factors such as poor ocular bioavailability, frequent dosing requirements, systemic side effects, and limited penetration through ocular barriers. This review elucidates the eye's intricate anatomy and physiology, prevalent ocular diseases, traditional therapeutic modalities, and the inherent pharmacokinetic and pharmacodynamic limitations associated with these modalities. Subsequently, it delves into nanotechnology-based solutions, presenting breakthroughs in nanoformulations such as nanocrystals, liposomes, dendrimers, and nanoemulsions that have demonstrated enhanced drug stability, controlled release, and deeper ocular penetration. Additionally, it explores a range of nanosized carriers, including nano-structured lipid carriers, hydrogels, nanogels, nanoenzymes, microparticles, conjugates, exosomes, nanosuspensions, viral vectors, and polymeric nanoparticles, and their applications. Unique insights include emerging innovations such as nanowafers and transcorneal iontophoresis, which indicate paradigm shifts in non-invasive ocular drug delivery. Furthermore, it sheds light on the advantages and limitations of these nanotechnology-based platforms in addressing the challenges of ocular drug delivery. Though nano-based drug delivery systems are drawing increasing attention due to their potential to enhance bioavailability and therapeutic efficacy, the review ends up emphasizing the imperative need for further research to drive innovation and improve patient outcomes in ophthalmology.
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Affiliation(s)
- Rahul Dev Bairagi
- Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, 9208, Bangladesh
| | - Raiyan Rahman Reon
- Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, 9208, Bangladesh
| | - Md Mahbub Hasan
- Department of Biomedical Engineering, Khulna University of Engineering and Technology (KUET), Khulna, 9203, Bangladesh
| | - Sumit Sarker
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Bara Phool, Punjab, 140001, India
| | - Dipa Debnath
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology BHU, Varanasi, Uttar Pradesh, 221005, India
| | - Md Tawhidur Rahman
- Department of Pharmacy, Northern University of Bangladesh, Dhaka, 1230, Bangladesh
| | - Sinthia Rahman
- Department of Chemistry, University of Wyoming, Laramie, WY, USA
| | - Md Amirul Islam
- Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, 9208, Bangladesh
- Department of Pharmacy, East West University, Dhaka, 1212, Bangladesh
| | - Md Abu Talha Siddique
- Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA
| | - Bishwajit Bokshi
- Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, 9208, Bangladesh
| | - Md Mustafizur Rahman
- Pharmacy Discipline, School of Life Sciences, Khulna University, Khulna, 9208, Bangladesh
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Yang X, Xu F, Yu H, Li Z, Yu X, Li Z, Zhang L, Liu J, Wang S, Liu S, Hong J, Li J. Prediction of OCT contours of short-term response to anti-VEGF treatment for diabetic macular edema using generative adversarial networks. Photodiagnosis Photodyn Ther 2025; 52:104482. [PMID: 39826600 DOI: 10.1016/j.pdpdt.2025.104482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 12/25/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Diabetic macular edema (DME) stands as a leading cause for vision loss among the working-age population. Anti-vascular endothelial growth factor (VEGF) agents are currently recognized as the first-line treatment. However, a significant portion of patients remain insensitive to anti-VEGF, resulting in sustained visual impairment. Therefore, it's imperative to predict prognosis and formulate personalized therapeutic regimens. Generative adversarial networks (GANs) have demonstrated remarkably in forecasting prognosis of diseases, yet their performance is still constrained by the limited availability of real-world data and suboptimal image quality, which subsequently impacts the model's outputs. We endeavor to employ preoperative images along with postoperative OCT contours annotated and extracted via LabelMe and OpenCV to train the model in generating postoperative contours of critical OCT structures instead of previous whole retinal morphology, considerably alleviating the difficulty of output phase and diminishing the requisite quantity of training datasets. Our study reveals that the GAN could serve as an auxiliary instrument for ophthalmologists in determining the prognosis of individuals and screening patients with poor responses to anti-VEGF therapy.
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Affiliation(s)
- Xueying Yang
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Fabao Xu
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Han Yu
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zhongwen Li
- Ningbo Eye Hospital, Wenzhou Medical University, Ningbo, PR China
| | - Xuechen Yu
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Zhiwen Li
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Li Zhang
- Department of Ophthalmology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China
| | - Jie Liu
- Department of Endocrinology, People's Hospital of Zoucheng, Jining, PR China
| | - Shaopeng Wang
- Zibo Central Hospital, Binzhou Medical University, Zibo, Shandong province, PR China
| | - Shaopeng Liu
- School of computer science, Guangdong Polytechnic Normal University, Guangzhou, PR China.
| | - Jiaming Hong
- School of Medical Information Engineering, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, PR China.
| | - Jianqiao Li
- Department of Ophthalmology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, PR China.
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Shimura M, Hirano T, Tsuiki E, Takamura Y, Morizane Y, Akiyama K, Yamamoto K, Hikichi TAIICHI, Koto T, Kinoshita T, Kusuhara S, Yoshida S, Sakamoto SI, Kimura K, Sugimoto M, Kida T, Mitamura Y, Takatsuna Y, Washio N, Osaka R, Ueda T, Minamoto A, Kogo J, Okamoto F, Enaida H, Sakanishi Y, Nagaoka T, Gomi F, Sasaki M, Terasaki H, Iwase TAKESHI, Tatsumi T, Nishi K, Shinoda K, Ueda S, Ueda-Consolvo T, Nakashizuka H, Murata T, Kitano S, Sakamoto T. ALTERATION OF TREATMENT CHOICES AND THE VISUAL PROGNOSIS FOR DIABETIC MACULAR EDEMA IN THE ERA OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR DRUGS: Analysis of the STREAT-DME 2 Study. Retina 2025; 45:335-344. [PMID: 39423137 PMCID: PMC11753449 DOI: 10.1097/iae.0000000000004301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
PURPOSE To assess the real-world outcome of best-corrected visual acuity after 2-year intervention for treatment-naive diabetic macular edema since the approval of anti-vascular endothelial growth factor therapy. METHODS A total of 1,780 treatment-naive eyes with diabetic macular edema for which intervention was initiated between 2015 and 2019, and which were followed for 2 years, were extracted from the longitudinal medical records of 37 retinal disease institutions in Japan. Interventions included anti-VEGF therapy, topical corticosteroid therapy, macular photocoagulation, and vitrectomy. The baseline and final best-corrected visual acuity, and the number and timing of interventions were recorded. Eyes were classified according to the year in which intervention was initiated. RESULTS Over a 2-year period, best-corrected visual acuity improved annually, finally reaching seven letters. The proportion of eyes in which good vision was maintained (best-corrected visual acuity >20/40) increased to 73.3% in the latest period. The administration of anti-VEGF therapy remained stable, accounting for approximately 90% of eyes. Notably, the proportion of eyes receiving anti-VEGF drugs as first-line treatment increased dramatically to approximately 80%. CONCLUSION Anti-VEGF therapy has become the first-line treatment since the approval of anti-VEGF drugs for diabetic macular edema. These findings reflect the evolution of diabetic macular edema treatment and highlight the superiority of anti-VEGF therapy and its increased uptake over time.
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Affiliation(s)
- Masahiko Shimura
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Tokyo, Japan
| | - Takao Hirano
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Eiko Tsuiki
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | | | - Yuki Morizane
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kunihiko Akiyama
- Department of Ophthalmology, NHO Tokyo Medical Center, Tokyo, Japan
| | - Kaori Yamamoto
- Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan
| | | | - Takashi Koto
- Kyorin Eye Center, Kyorin University, School of Medicine, Tokyo, Japan
| | - Takamasa Kinoshita
- Department of Ophthalmology, Sapporo City General Hospital, Hokkaido, Japan
| | - Sentaro Kusuhara
- Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shigeo Yoshida
- Department of Ophthalmology, Kurume University School of Medicine, Fukuoka, Japan
| | | | - Kazuhiro Kimura
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Masahiko Sugimoto
- Department of Ophthalmology, Mie University Graduate School of Medicine, Mie, Japan
| | - Teruyo Kida
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka, Japan
| | - Yoshinori Mitamura
- Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yoko Takatsuna
- Department of Ophthalmology, Chiba Rosai Hospital, Chiba, Japan
| | - Noriaki Washio
- Department of Ophthalmology, Showa General Hospital, Tokyo, Japan
| | - Rie Osaka
- Department of Ophthalmology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tetsuki Ueda
- Department of Ophthalmology, Nara Medical University, Nara, Japan
| | - Akira Minamoto
- Department of Ophthalmology and Visual Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
| | - Jiro Kogo
- Department of Ophthalmology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Fumiki Okamoto
- Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroshi Enaida
- Department of Ophthalmology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yoshihito Sakanishi
- Department of Ophthalmology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Taiji Nagaoka
- Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, Tokyo, Japan
| | - Fumi Gomi
- Department of Ophthalmology, Hyogo Medical University, Hyogo, Japan
| | - Mariko Sasaki
- Department of Ophthalmology, Tachikawa Hospital, Tokyo, Japan
- Keio University School of Medicine, Tokyo, Japan
| | - Hiroto Terasaki
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - TAKESHI Iwase
- Department of Ophthalmology, Akita University Faculty of Medicine, Akita, Japan
| | - Tomoaki Tatsumi
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kosuke Nishi
- Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
| | - Kei Shinoda
- Department of Ophthalmology, Saitama Medical University, Saitama, Japan
| | - Shunichiro Ueda
- Department of Ophthalmology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tomoko Ueda-Consolvo
- Department of Ophthalmology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | | | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Nagano, Japan
| | - Shigehiko Kitano
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Hein M, Mehnert A, Josephine F, Athwal A, Yu DY, Balaratnasingam C. Predictors of Peripheral Retinal Non-Perfusion in Clinically Significant Diabetic Macular Edema. J Clin Med 2024; 14:52. [PMID: 39797135 PMCID: PMC11722121 DOI: 10.3390/jcm14010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 12/02/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Background/Objectives: Diabetic macular edema (DME) is a significant cause of vision loss. The development of peripheral non-perfusion (PNP) might be associated with the natural course, severity, and treatment of DME. The present study seeks to understand the predictive power of central macular changes and clinico-demographic features for PNP in patients with clinically significant DME. Methods: A prospective study using contemporaneous multi-modal retinal imaging was performed. In total, 48 eyes with DME from 33 patients were enrolled. Demographic, clinical history, laboratory measures, ultrawide field photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography results were acquired. Anatomic and vascular features of the central macula and peripheral retina were quantified from retinal images. Separate (generalized) linear mixed models were used to assess differences between PNP present and absent groups. Mixed effects logistic regression was used to assess which features have predictive power for PNP. Results: Variables with significant differences between eyes with and without PNP were insulin use (p = 0.0001), PRP treatment (p = 0.0003), and diffuse fluorescein leakage (p = 0.013). Importantly, there were no significant differences for any of the macular vascular metrics including vessel density (p = 0.15) and foveal avascular zone (FAZ) area (p = 0.58 and capillary tortuosity (p = 0.55). Features with significant predictive power (all p < 0.001) were subretinal fluid, FAZ eccentricity, ellipsoid zone disruption, past anti-VEGF therapy, insulin use, and no ischemic heart disease. Conclusions: In the setting of DME, macular vascular changes did not predict the presence of PNP. Therefore, in order to detect peripheral non-perfusion in DME, our results implicate the importance of peripheral retinal vascular imaging.
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Affiliation(s)
- Martin Hein
- Lions Eye Institute, Perth, WA 6009, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA 6009, Australia
| | - Andrew Mehnert
- Lions Eye Institute, Perth, WA 6009, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA 6009, Australia
| | | | - Arman Athwal
- School of Engineering Science, Simon Fraser University, Burnaby, BC V5A 1S6, Canada
- Department of Medical Physics and Biomedical Engineering, University College London, London WC1E 6BT, UK
| | - Dao-Yi Yu
- Lions Eye Institute, Perth, WA 6009, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA 6009, Australia
| | - Chandrakumar Balaratnasingam
- Lions Eye Institute, Perth, WA 6009, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, WA 6009, Australia
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, WA 6009, Australia
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Chalasani M, Maatouk C, Markle J, Singh RP, Talcott KE. Predictors of Vision Loss After Lapse in Antivascular Endothelial Growth Factor Treatment in Patients With Diabetic Macular Edema. JOURNAL OF VITREORETINAL DISEASES 2024:24741264241305123. [PMID: 39678936 PMCID: PMC11645682 DOI: 10.1177/24741264241305123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Abstract
Purpose: To identify baseline characteristics that predict visual outcomes after a lapse in treatment among patients with diabetic macular edema (DME) who received intravitreal antivascular endothelial growth factor injections. Methods: In this retrospective study, patients with DME who had lapses in treatment of 3 months or longer were separated into 2 groups (stable vision, n = 201; vision loss, n = 61) based on an Early Treatment Diabetic Retinopathy Study vision loss threshold of 10 letters. Stepwise backward logistic regression was used to analyze baseline factors associated with vision loss and to create a predictive algorithm. Results: In the final regression model, the length of lapse in treatment (odds ratio [OR]; 1.15, 95% CI, 1.07-1.25), diabetic foot disease (OR, 3.02; 95% CI, 1.09-8.2), and Medicaid insurance (OR, 4.60; 95% CI, 1.20-18.7) were positively associated with vision loss (P < .05). Time since diagnosis of diabetic retinopathy (OR, 0.95; 95% CI, 0.91-0.99) was negatively associated with vision loss (P < .05). The final prediction model had a sensitivity of 20% and a specificity of 84%, with an area under the curve of 65%. Conclusions: For patients with DME at high risk for a lapse in treatment, baseline characteristics can help predict vision loss and guide management.
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Affiliation(s)
- Meghana Chalasani
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Christopher Maatouk
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Ophthalmology, University of Chicago Medical Center, Chicago, IL, USA
| | - Jonathan Markle
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Rishi P. Singh
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
- Cleveland Clinic Martin Hospitals, Cleveland Clinic Florida, Stuart, FL, USA
| | - Katherine E. Talcott
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA
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Shimura M, Sasaki S, Nonaka R, Kashiwagi I, Yasuda K, Noma H, Takagi H. Changes in Aqueous Angiopoietin-1/2 Concentrations During the Induction Phase of Intravitreal Faricimab Injections for Diabetic Macular Edema. Transl Vis Sci Technol 2024; 13:35. [PMID: 39723678 DOI: 10.1167/tvst.13.12.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2024] Open
Abstract
Purpose The purpose of this study was to investigate the dynamic changes in aqueous concentrations of angiopoietin (Ang)-1/2 and vascular endothelial growth factor (VEGF) during injection in treatment-naïve patients with diabetic macular edema (DME) receiving faricimab during the induction phase (3 consecutive monthly doses) and retrospectively analyze the data. Methods Thirty-five eyes of 26 patients (age = 63.1 ± 12.9 years) with treatment-naïve DME received faricimab injections monthly, 3 consecutive times. Additionally, 59 eyes of 59 patients (age = 63.9 ± 8.8 years) who underwent cataract surgery were recruited as controls. Aqueous humor samples were collected from each injection or surgery and stored at -80°C, and the concentration of each cytokine was quantified using a multiple enzyme-linked immunosorbent assay (Luminex). The clinical parameters of best-corrected visual acuity (BCVA) and central foveal thickness (CFT) at each visit were also recorded. Results Three induction phases of faricimab significantly suppressed each aqueous cytokine, rapidly for VEGF, gradually for Ang-2, and slightly for Ang-1. The Ang-1/2 ratio was lower (<1.0) at baseline and gradually increased, but did not reach a control ratio of 1.58. The baseline CFT correlated with VEGF, but not with the Ang-2, Ang-1, or Ang-1/2 ratios. After three injections, CFT did not correlate with VEGF, but it positively correlated with Ang-2 and negatively correlated with Ang-1, and it strongly negatively correlated with the Ang-1/2 ratio. Conclusions The Ang-1/2 ratio in the aqueous humor significantly negatively correlated with the degree of residual edema after faricimab treatment for DME. Translational Relevance The Ang-1/2 ratio in aqueous humor is thus a useful biomarker of the treatment response for DME.
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Affiliation(s)
- Masahiko Shimura
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Shotaro Sasaki
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Ryota Nonaka
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Ikumi Kashiwagi
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Kanako Yasuda
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Hidetaka Noma
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
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Boyer DS, Steinle NC, Pearlman JA, Stone CM, Crawford C, Gupta S, Dugel PU, Baldwin ME, Leitch IM. Phase 1b Dose Escalation Study of Sozinibercept Inhibition of Vascular Endothelial Growth Factors C and D With Aflibercept for Diabetic Macular Edema. Transl Vis Sci Technol 2024; 13:32. [PMID: 39699889 DOI: 10.1167/tvst.13.12.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2024] Open
Abstract
Purpose Sozinibercept inhibits vascular endothelial growth factors (VEGFs) C and D. This study evaluated outcomes following switching from anti-VEGF-A monotherapy to intravitreal injections of three dose levels of sozinibercept in combination with aflibercept in patients with diabetic macular edema (DME). Methods A phase 1b, open-label, multicenter dose-escalation study with a 24-week follow-up. Patients received 3 loading doses of aflibercept (2 mg) in combination with sozinibercept (0.3, 1, or 2 mg) once every 4 weeks and were followed through week 24. The primary endpoint was safety, and secondary endpoints included mean change from baseline in best-corrected visual acuity (BCVA) and anatomic changes on imaging. Results Nine patients received sozinibercept in combination with aflibercept after a mean (SD) of 6.3 (2.4) injections of previous anti-VEGF-A. Sozinibercept combination therapy was well tolerated with no dose-limiting toxicities. Mean change in BCVA at week 12 was +7.7 letters (95% confidence interval [CI], 2-13.3) from baseline (65 letters [SD 5.5]) with a dose response for increasing doses of sozinibercept. At week 12, central subfield thickness (CST) was decreased by -71 µm (95% CI, -117 to -26) from baseline (434 µm [SD 58]), and 6 of 9 (67%) patients had a ≥50% reduction in excess foveal thickness. Conclusions In prior-treated patients with center-involved DME, switching to sozinibercept in combination with aflibercept was well tolerated with improved visual and anatomic outcomes. Translational Relevance This first-in-human study builds upon basic research by providing safety and preliminary efficacy of sozinibercept (anti-VEGF-C/-D) in combination with aflibercept for DME.
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Affiliation(s)
- David S Boyer
- Retina-Vitreous Associates Medical Group, Beverly Hills, CA, USA
| | | | | | | | | | - Sunil Gupta
- Retina Specialty Institute, Pensacola, FL, USA
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Li M, Li W, Wang X, Wu G, Du J, Xu G, Duan M, Yu X, Cui C, Liu C, Fu Z, Yu C, Wang L. Identification and Activity Study of an Impurity Band Observed in the nrSDS-PAGE of Aflibercept. Pharm Res 2024; 41:2031-2042. [PMID: 39322793 DOI: 10.1007/s11095-024-03773-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
BACKGROUND Aflibercept is a biopharmaceutical targeting vascular endothelial growth factor (VEGF) that has shown promise in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) in adults. Quality control studies of aflibercept employing non-reduced SDS-PAGE (nrSDS-PAGE) have shown that a significant variant band (IM1) is consistently present below the main band. Considering the quality control strategy of biopharmaceuticals, structural elucidation and functional studies are required. METHODS In this study, the variant bands in nrSDS-PAGE were collected through electroelution and identified by peptide mass fingerprinting based on liquid chromatography-tandem MS (LC-MS/MS). This variant was expressed using knob-into-hole (KIH) design transient transfection for the detection of ligand affinity, binding activity and biological activity. RESULTS The variant band was formed by C-terminal truncation at position N99 of one chain in the aflibercept homodimer. Then, this variant was successfully expressed using KIH design transient transfection. The ligand affinity of the IM1 truncated variant was reduced by 18-fold, and neither binding activity nor biological activity were detected. CONCLUSIONS The efficacy of aflibercept is influenced by the loss of biological activity of the variant. Therefore, this study supports the development of a quality control strategy for aflibercept.
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Affiliation(s)
- Meng Li
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Weiyu Li
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Xin Wang
- Fujian Institute for Food and Drug Quality Control, Fuzhou, China
| | - Gang Wu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Jialiang Du
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Gangling Xu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Maoqin Duan
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Xiaojuan Yu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Chunbo Cui
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Chunyu Liu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Zhihao Fu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629
| | - Chuanfei Yu
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629.
| | - Lan Wang
- NHC Key Laboratory of Research On Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, State Key Laboratory of Drug Regulatory Science, National Institutes for Food and Drug Control, Beijing, P.R. China, 102629.
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9
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Chen H, Shi X, Zhang W, Han Q. Aflibercept versus ranibizumab for diabetic macular edema: A meta-analysis. Eur J Ophthalmol 2024; 34:615-623. [PMID: 37226427 PMCID: PMC11067396 DOI: 10.1177/11206721231178658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 05/10/2023] [Indexed: 05/26/2023]
Abstract
OBJECTIVE The purpose of this study was to compare the efficacy and safety of aflibercept (AFL) versus ranibizumab (RAN) for the treatment of diabetic macular edema (DME). METHODS The PubMed, Embase, Cochrane Library, and CNKI databases were searched up to September 2022 to identify prospective randomized controlled trials (RCTs) comparing AFL with RAN for the treatment of DME. Review Manager 5.3 software was used for data analysis. We used the GRADE system to evaluate the quality of the evidence for each outcome. RESULTS A total of 8 RCTs involving 1067 eyes (939 patients) were included; there were 526 eyes in the AFL group and 541 eyes in the RAN group. Meta-analysis revealed that there was no significant difference between RAN and AFL in the best-corrected visual acuity (BCVA) of DME patients at 6 months (WMD: -0.05, 95% CI = -0.12 to 0.01, moderate quality) and 12 months after injection (WMD: -0.02, 95% CI = -0.07 to 0.03, moderate quality). Additionally, there was no significant difference between RAN and AFL in the reduction of central macular thickness (CMT) at 6 months (WMD: -0.36, 95% CI = -24.99 to 24.26, very low quality) and 12 months after injection (WMD: -6.36, 95% CI = -16.30 to 3.59, low quality). Meta-analysis showed that the number of intravitreal injections (IVIs) for AFL was significantly lower than that for RAN (WMD: -0.47, 95% CI = -0.88 to -0.05, very low quality). There were fewer adverse reactions to AFL than to RAN, but the difference was not significant. CONCLUSION This study found that there was no difference in BCVA, CMT or adverse reactions between AFL and RAN at 6 and 12 months of follow-up, but AFL needed fewer IVIs than RAN.
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Affiliation(s)
- Haiyan Chen
- Department of Ophthalmology, the Sixth Hospital of Beijing, Beijing, China
| | - Xuehui Shi
- Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Wang Zhang
- Department of Ophthalmology, the Sixth Hospital of Beijing, Beijing, China
| | - Qianqian Han
- Department of Ophthalmology, the Sixth Hospital of Beijing, Beijing, China
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10
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Cheema AA, Cheema HR. Diabetic Macular Edema Management: A Review of Anti-Vascular Endothelial Growth Factor (VEGF) Therapies. Cureus 2024; 16:e52676. [PMID: 38264181 PMCID: PMC10804209 DOI: 10.7759/cureus.52676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2024] [Indexed: 01/25/2024] Open
Abstract
Diabetic macular edema (DME) is a major cause of vision impairment in diabetic individuals, characterized by fluid accumulation in the macula due to a breakdown of the blood-retinal barrier (BRB). This review article explores the role of anti-vascular endothelial growth factor (anti-VEGF) therapies in the management of DME. Anti-VEGF treatments, including ranibizumab, bevacizumab, and aflibercept, have revolutionized DME management by targeting VEGF, a key mediator in DME pathogenesis. We critically examined the efficacy of these therapies in reducing macular edema and improving visual acuity, assessed their safety and tolerability, and explored the variability in treatment response. The review highlights the latest advancements and future directions in anti-VEGF therapy, including novel drug delivery systems and emerging treatment paradigms. By providing a comprehensive overview of current anti-VEGF therapies, this review seeks to inform clinical practice, guide future research, and contribute to improved patient outcomes in DME management.
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11
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Hein M, Vukmirovic A, Constable IJ, Raja V, Athwal A, Freund KB, Balaratnasingam C. Angiographic biomarkers are significant predictors of treatment response to intravitreal aflibercept in diabetic macular edema. Sci Rep 2023; 13:8128. [PMID: 37208427 DOI: 10.1038/s41598-023-35286-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023] Open
Abstract
This prospective single-center study aims to identify biomarkers that predict improvement in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) at 6 months, in 76 eyes with diabetic macular edema (DME) treated monthly with intravitreal aflibercept. At baseline, all patients underwent standardized imaging with color photography, optical coherence tomography (OCT), fluorescein angiography (FA) and OCT angiography (OCTA). Glycosylated hemoglobin, renal function, dyslipidemia, hypertension, cardiovascular disease and smoking were recorded. Retinal images were graded in a masked fashion. Baseline imaging, systemic and demographic variables were investigated to detect associations to BCVA and CRT change post aflibercept. Predictors of BCVA improvement included greater macular vessel density quantified using OCTA (p = 0.001) and low-density lipoprotein (LDL) ≥ 2.6 mmol/L (p = 0.017). Lower macular vessel density eyes showed a significant reduction in CRT but no BCVA improvement. Predictors of CRT reduction included peripheral non-perfusion seen on ultrawide-field FA (p = 0.005) and LDL ≥ 2.6 mmol/L (p < 0.001). Retinal angiographic biomarkers derived from OCTA and ultrawide-field FA may help predict functional and anatomic response to anti-vascular endothelial growth factor (VEGF) therapy in patients with DME. Elevated LDL is associated with treatment response in DME. These results may be used to better-select patients who will benefit from intravitreal aflibercept for treatment of DME.
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Affiliation(s)
- Martin Hein
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Aleksandar Vukmirovic
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
| | - Ian J Constable
- Lions Eye Institute, Perth, Australia
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia
| | - Vignesh Raja
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia
- Joondalup Eye Clinic, Perth, Australia
| | - Arman Athwal
- School of Engineering Science, Simon Fraser University, Burnaby, BC, Canada
- Department of Medical Physics and Biomedical Engineering, University College London, London, England
| | - K Bailey Freund
- Vitreous Retina Macula Consultants of New York, New York, USA
- Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA
| | - Chandrakumar Balaratnasingam
- Lions Eye Institute, Perth, Australia.
- Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Australia.
- Department of Ophthalmology, Sir Charles Gairdner Hospital, Perth, Australia.
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12
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Fan W, Uji A, Wykoff CC, Brown DM, van Hemert J, Falavarjani KG, Wang K, Sadda SR, Ip M. Baseline retinal vascular bed area on ultra-wide field fluorescein angiography correlates with the anatomical outcome of diabetic macular oedema to ranibizumab therapy: two-year analysis of the DAVE Study. Eye (Lond) 2023; 37:678-683. [PMID: 35332289 PMCID: PMC9998428 DOI: 10.1038/s41433-021-01777-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 11/09/2022] Open
Abstract
PURPOSE To determine the relationship between baseline retinal non-perfusion area (NPA) and retinal vascular bed area (RVBA) on ultra-wide field fluorescein angiography (UWF FA) and long-term response to intravitreal ranibizumab therapy in diabetic macular oedema (DMO). METHODS A post-hoc, 2-year observational case series. Baseline UWF FA images (Optos 200Tx) of 40 eyes from 29 patients with diabetes mellitus and treatment naïve DMO in the DAVE (NCT01552408) study were montaged and stereographically projected at the Doheny Image Reading Center to adjust for peripheral distortion. The retinal vasculature was automatically extracted to calculate RVBA. NPA was manually delineated by two masked certified graders. RVBA and NPA were computed in mm2 automatically by adjusting for peripheral distortion and then correlated with the severity of DMO. RESULTS While global NPA at baseline was not correlated to retinal thickness measurements, baseline NPA in the superior retina was associated with the macular volume (MV) improvement (P = 0.022). Multivariate analysis revealed a smaller RVBA at baseline was correlated with a better MV outcome at two-year follow-up after adjusting for confounding factors (P = 0.049). CONCLUSION Eyes with smaller baseline RVBA appear to have a better long-term anatomic outcome of DMO.
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Affiliation(s)
- Wenying Fan
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Beijing Ophthalmology and Visual Sciences Key Laboratory, Capital Medical University, Beijing, China
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Akihito Uji
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Charles C Wykoff
- Retina Consultants of Houston, Houston, TX, USA
- Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX, USA
| | - David M Brown
- Retina Consultants of Houston, Houston, TX, USA
- Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX, USA
| | | | - Khalil Ghasemi Falavarjani
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kang Wang
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - SriniVas R Sadda
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Michael Ip
- Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, CA, USA.
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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13
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Omari A, Su L, Joltikov KA, Rao RC, Jayasundera KT, Gardner TW. Peripheral retinal dysfunction in diabetic macular edema. Acta Ophthalmol 2023; 101:e113-e114. [PMID: 35900071 DOI: 10.1111/aos.15221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/22/2022] [Accepted: 07/19/2022] [Indexed: 01/25/2023]
Affiliation(s)
- Amro Omari
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.,Beaumont Eye Institute, Beaumont Hospital, Royal Oak, Michigan, USA
| | - Lydia Su
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Katherine A Joltikov
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Rajesh C Rao
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.,Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.,Surgery Service, VA Ann Arbor Health System, Ann Arbor, Michigan, USA
| | - Kanishka Thiran Jayasundera
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Thomas W Gardner
- Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA
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Curran K, Lohfeld L, Congdon N, Peto T, Hoang TT, Nguyen HT, Nguyen QN, Nguyen VT, Dardis C, Tran H, Tran HH, Vu AT, Tung MQ. Ophthalmologists' and patients' perspectives on treatments for diabetic retinopathy and maculopathy in Vietnam: a descriptive qualitative study. BMJ Open 2022; 12:e055061. [PMID: 35798521 PMCID: PMC9263907 DOI: 10.1136/bmjopen-2021-055061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION Globally, diabetic retinopathy (DR) is the leading cause of blindness in working-aged adults. Early detection and treatment of DR is essential for preventing sight loss. Services must be available, accessible and acceptable to patients if we are to ensure they seek such care. OBJECTIVES To understand patients' knowledge and attitudes towards laser versus antivascular endothelial growth factor (VEGF) injections to treat DR in Vietnam, and to identify factors Vietnamese ophthalmologists consider when making treatment decisions. METHODS This is a descriptive qualitative study based on semi-structured interviews with 18 patients (12 from Ho Chi Minh City and 6 from Hanoi) plus individual interviews with 24 ophthalmologists working in eye clinics in these cities. Thematic analysis was used to analyse the data. RESULTS In total, 10/24 (41.7%) ophthalmologists were female, and their median age was 41 years (range 29-69 years). The median age of patients was 56.5 years (range 28-72 years), and 7/18 (38.9%) were female. Briefly, factors that influence DR treatment decisions for ophthalmologists are medical considerations (ie, severity of disease, benefits and risks), availability (ie, treatment and resources) and patient-related factors (ie, costs and adherence). Patient's perceived barriers and facilitators to treatments were based on patient and family related factors (ie, treatment and transportation costs) and previous treatment experiences (ie, positive and negative). Recommendations by all participants included ensuring that both laser and anti-VEGF injections are widely available across the country and controlling costs for patients and the healthcare system. CONCLUSIONS Reducing DR treatment costs, optimising treatments options, and expanding the network of clinics offering treatment outside metropolitan areas were the main issues raised by participants. These findings can help inform policy changes in Vietnam and may be generalisable to other low-resource settings.
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Affiliation(s)
- Katie Curran
- Centre of Public Health, Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences, Belfast, UK
| | - Lynne Lohfeld
- Centre of Public Health, Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences, Belfast, UK
- Wenzhou Medical University Eye Hospital, Wenzhou University, Wenzhou, China
| | - Nathan Congdon
- Centre of Public Health, Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences, Belfast, UK
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Tunde Peto
- Centre of Public Health, Queen's University Belfast School of Medicine Dentistry and Biomedical Sciences, Belfast, UK
- Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast, UK
| | - Tung Thanh Hoang
- Department of Ophthalmology, Hanoi Medical University, Hanoi, Vietnam
- Save Sight Institute, The University of Sydney School of Medicine, Sydney, New South Wales, Australia
| | | | - Quan Nhu Nguyen
- Department of Vitreo-Retina, Ho Chi Minh City Eye Hospital, Ho Chi Minh City, Vietnam
| | - Van Thu Nguyen
- Monitoring, Evaluation and Learning, Orbis International, Hanoi, Vietnam
| | - Catherine Dardis
- Department of Ophthalmology, Belfast Health and Social Care Trust, Belfast, UK
| | - Hoang Tran
- Leadership, Orbis International, Hanoi, Vietnam
| | - Hoang Huy Tran
- Department of Community, Ho Chi Minh City Eye Hospital, Ho Chi Minh City, Vietnam
| | - Anh Tuan Vu
- Institute of Ophthalmology, Vietnam National Institute of Ophthalmology, Hanoi, Vietnam
| | - Mai Quoc Tung
- Department of Ophthalmology, Hanoi Medical University, Hanoi, Vietnam
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15
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Al Saad M, Shehadeh A, Hizzani A, Alzibdeh A, Alsubhi AA, Hamdan D, Alkubati E, Meqbil J, Hamadneh L, Ababneh O. Effects of Smoking on Outcomes of Anti-Vascular Endothelial Growth Factor Therapy in Patients with Diabetic Macular Edema: A Retrospective Case-Control Study. Middle East Afr J Ophthalmol 2022; 29:116-121. [PMID: 37408720 PMCID: PMC10319076 DOI: 10.4103/meajo.meajo_135_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 03/15/2023] [Accepted: 04/25/2023] [Indexed: 07/07/2023] Open
Abstract
PURPOSE To determine the effect of smoking on the response to anti-vascular endothelial growth factor (anti-VEGF) therapy treatment in patients with diabetic macular edema (DME). METHODS This is a retrospective case - control study that included 60 eyes with DME. Smoking habits were obtained from hospital records and patient recall. Patients were divided into two groups: the ever-smoker group and the never-smoker group. All patients received Intravitreal ranibizumab with three loading doses followed by PRN protocol and all were followed up for at least 1 year. Outcome measures were best-corrected visual acuity (BCVA), central retinal thickness (CRT) at the fovea, and number of visits. RESULTS Smoking was not associated with worse posttreatment visual acuity and was not found to influence the change in ocular coherence tomography measurement of central macular thickness and the change in BCVA (posttreatment minus pretreatment). There were no statistically significant differences in the duration of treatment or number of visits between two groups of patients the ever-smoker group and the never-smoker group (P > 0.05). CONCLUSION In this study, smoking status did not influence the treatment outcome of anti-VEGFs; however, smoking should be encouraged due to its well-known other systemic unwanted effects.
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Affiliation(s)
- Mouna Al Saad
- Department of Special Surgery / Opthalmology Division, University of Jordan, Amman, Jordan
| | | | - Asem Hizzani
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Abdulla Alzibdeh
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Amani A. Alsubhi
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Dina Hamdan
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Ebtehal Alkubati
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Jehad Meqbil
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Lina Hamadneh
- Doctor of Medicine Department of Special Surgery, Ophthalmology Division University of Jordan
| | - Osama Ababneh
- Department of Special Surgery / Ophthalmology Disvision University of Jordan Amman Jordan
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16
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Impact of the COVID-19 pandemic on visual outcomes of diabetic macular edema patients at a tertiary care veterans affairs center. J Diabetes Metab Disord 2022; 21:759-768. [PMID: 35582648 PMCID: PMC9098215 DOI: 10.1007/s40200-022-01049-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 04/25/2022] [Indexed: 10/27/2022]
Abstract
Purpose There are limited studies on factors that impacted retina clinic patient outcomes during the COVID-19 pandemic. We aimed to evaluate visual and anatomic outcomes in patients with diabetic macular edema (DME) requiring anti-VEGF injections at the veterans' affairs tertiary care eye clinic in Houston, TX. Methods Patient volume from April 2020 was compared to that of April 2019 to determine attendance changes. To evaluate outcomes, we reviewed patients with DME who had scheduled appointments during April 2020. We tracked changes in central foveal thickness (CFT) and Snellen visual acuity (VA) measurements. Patient outcomes were classified as poor (defined as worsening VA or CFT at follow-up) or good (no worsening of either at follow-up). Regression analysis identified characteristics associated with poor outcomes. Results To prevent the spread of COVID-19, patients were called to reschedule clinic appointments. Attendance frequency decreased from 523 patients in April 2019 to 246 patients in April 2020. 134 patients met inclusion criteria (mean age of 64.7 ± 8.8 years). 19/134 of patients were seen on schedule, 89/134 had delayed appointments (average follow-up interval of 115.2 ± 50.0 days), and 26/134 were lost to follow-up. Patients with delayed appointments had higher odds of poor outcome at follow-up compared to patients seen on schedule (OR = 4.03, 95% CI: 1.14-16.92, p = 0.04). Patient's baseline visual acuity, macular thickness, comorbidities, and diabetic retinopathy severity, and demographics did not affect visual outcome at follow-up. Conclusions On average, patients were rescheduled to a visit 2.4 months later than their usual visit. Over half these patients experienced worsening of vision or edema. This demonstrates that lapses in care result in worsening of DME. However, there is no clear association between baseline characteristics and risk of disease progression. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-022-01049-5.
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17
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Cox L, Li Y, Fotuhi M, Vermeirsch S, Yeung I, Hamilton RD, Rajendram R, Lukic M. Treatment of chronic diabetic macular oedema with intravitreal fluocinolone acetonide implant; real-life analysis of outcomes during overall treatment period. Eur J Ophthalmol 2022; 32:3629-3636. [PMID: 35484812 DOI: 10.1177/11206721221097587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE To assess the clinical efficacy of the fluocinolone acetonide (FA) intravitreal implant (Iluvien, Alimera Sciences) over a 12-month period in a population resistant to treatment with first-line anti-VEGF agents. METHODS This study is a retrospective cohort study assessing functional and anatomical outcomes in 13 eyes of 12 patients treated for diabetic macular oedema (DMO) with a single fluocinolone implant (FA) (Iluvien) under real-world conditions. The follow-up period includes the time of first intravitreal treatment (incl anti-VEGF or short-lasting steroids) given until 12 months post FA implant insertion. Primary outcomes were best corrected visual acuity (BCVA), measured using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale, and central foveal thickness (CFT), measured using Topcon 3DOCT-2000 (Topcon Inc) SD-OCT imaging. Mean BCVA and CFT were measured before anti-VEGF treatment, after anti-VEGF treatment, at the time of Iluvien implant insertion, and 6 and 12 months after Iluvien implant insertion. The t-paired sample test was used to ascertain statistical significance of changes in comparison of two samples while the ANOVA analysis was used in comparison of three or more samples. RESULTS The baseline BCVA (SD) of the cohort prior to initiation of anti-VEGF treatment was 47.45 (12.27) ETDRS letters whilst the mean CFT (SD) was 579 (203) microns. Following completion of anti-VEGF therapy, the mean improvement in vision was 8.9 ETDRS letters (p = 0.1) whilst the mean reduction in CFT was 197 microns (p = 0.028). Mean BCVA (SD) at the time of insertion of the FA implant was 55.15 (11.16) ETDRS letters and mean (SD) CFT at time of insertion of the FA was 454.62 μm (109.51). Following the 12-month treatment period with the FA implant, BCVA (SD) was 62.15 (10.25) ETDRS letters (p = 0.0331) and the mean (SD) CFT was 404.36 μm (142.92), a change of -50.26 μm from baseline (p = 0.0369). CONCLUSIONS This study has shown that statistically significant improvements in BCVA and CFT can be achieved over a 12-month period with the Iluvien implant. The implant has been shown to be a safe option in the treatment of DMO and may have a role to play in achieving good functional and anatomical outcomes in DMO while also reducing the frequency of follow-up appointments required to maintain stable vision in the working-age population.
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Affiliation(s)
- Laurence Cox
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Yanda Li
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Majid Fotuhi
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Sandra Vermeirsch
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Ian Yeung
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Robin D Hamilton
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Ranjan Rajendram
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Marko Lukic
- NIHR Biomedical Research Centre, 4960Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
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18
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Wu JH, Viruni N, Chun J, Shanbhag S, Liu TA. Ocular involvement in TEMPI syndrome. Am J Ophthalmol Case Rep 2022; 26:101534. [PMID: 35496764 PMCID: PMC9043672 DOI: 10.1016/j.ajoc.2022.101534] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 03/31/2022] [Accepted: 04/01/2022] [Indexed: 12/21/2022] Open
Abstract
Purpose We report the first case of ocular involvement in TEMPI syndrome, a rare disease characterized by telangiectasias, elevated erythropoietin with erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intra-pulmonary shunting. Observations A 64-year-old Caucasian man with history of TEMPI syndrome presented with subacute bilateral painless vision loss. Ocular examination showed chronic retinal ischemia with microvascular damage, which was likely associated with the chronic systemic hypoxemia, and spontaneous wax and wane of cystoid macular edema, presumedly related to the systemic bortezomib treatment. Conclusions and importance Our case demonstrates that pathologic retinal vascular changes could be seen in association with TEMPI syndrome and suggests that a comprehensive ophthalmological examination may be beneficial for these patients.
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Affiliation(s)
- Jo-Hsuan Wu
- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, University of California, San Diego, CA, 92093, USA
| | - Narine Viruni
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Justin Chun
- Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Satish Shanbhag
- Cancer Specialists of North Florida, Fleming Island, FL, 32003, USA
| | - T.Y. Alvin Liu
- Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, 21287, USA
- Corresponding author. Wilmer Eye Institute, 600 N. Wolfe St., Maumenee 726, Baltimore, MD, 21287, USA.
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19
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Kessler LJ, Auffarth GU, Bagautdinov D, Khoramnia R. Ellipsoid Zone Integrity and Visual Acuity Changes during Diabetic Macular Edema Therapy: A Longitudinal Study. J Diabetes Res 2021; 2021:8117650. [PMID: 34660813 PMCID: PMC8516551 DOI: 10.1155/2021/8117650] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/06/2021] [Indexed: 11/17/2022] Open
Abstract
PURPOSE Ellipsoid zone (EZ) integrity is identified as a potential biomarker for therapy surveillance and outcome prediction of visual acuity (VA). However, only a few studies report long-term results of over 1 year of clinical and anatomical changes in patients with diabetic macular edema (DME). This study is aimed at describing the long-term VA and anatomical outcomes in spectral domain optical coherence tomography (OCT) (relative ellipsoid zone reflectivity ratio, central macular thickness, and volume) in patients with DME treated with antivascular endothelial growth factor (anti-VEGF) therapy. Furthermore, we studied the correlation between EZ integrity and changes in visual acuity. METHODS 71 eyes of 71 patients were included in this retrospective study. Clinical characteristics were reviewed yearly. OCT data were assessed at baseline and after 1, 3, and 5 years. EZ parameters were quantified automatically. OCT parameters and visual outcome were correlated and analyzed in multivariable regression models. RESULTS EZ reflectivity ratio correlated with functional outcome in DME patients from baseline to fifth year at all time points (for all p < 0.05). EZ reflectivity improved the most in the first year of treatment (0.68 to 0.75; p < 0.05) and declined gradually until year 5 of therapy (0.71; compared to baseline p > 0.05). Similarly, best VA was achieved after 1 year (0.40 logarithm of the minimum angle of resolution (logMAR) to 0.28 logMAR; p < 0.001) and declined gradually until year 5. Final VA in year 5 was comparable to baseline (0.45 logMAR, compared to baseline p > 0.05). Together with baseline VA, baseline EZ parameters did predict VA outcome after 1 year (p < 0.05). Concordantly, VA and EZ parameters from year 1 were associated with VA outcome in year 2. CONCLUSION This study described the long-term course of EZ changes during anti-VEGF treatment in DME patients. In addition, our results underlined the potential of EZ parameters as novel OCT biomarkers for prediction of VA outcomes during therapy.
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Affiliation(s)
- Lucy J. Kessler
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
- HEiKA–Heidelberg Karlsruhe Strategic Partnership, Heidelberg University and Karlsruhe Institute of Technology (KIT), Karlsruhe 76131, Germany
| | - Gerd U. Auffarth
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
| | - Dmitrii Bagautdinov
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
| | - Ramin Khoramnia
- Department of Ophthalmology, University of Heidelberg, Heidelberg 69120, Germany
- HEiKA–Heidelberg Karlsruhe Strategic Partnership, Heidelberg University and Karlsruhe Institute of Technology (KIT), Karlsruhe 76131, Germany
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Changes of retinal oxygen saturation during treatment of diabetic macular edema with a pre-defined regimen of aflibercept: a prospective study. Graefes Arch Clin Exp Ophthalmol 2021; 260:451-457. [PMID: 34468834 PMCID: PMC8786788 DOI: 10.1007/s00417-021-05319-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/22/2021] [Accepted: 07/07/2021] [Indexed: 11/08/2022] Open
Abstract
Purpose To study the effect of anti-VEGF therapy for diabetic macular edema (DME) on retinal oxygen saturation (O2S) and its correlation with functional and anatomical changes of retinal tissue. Methods An interventional prospective single group study. Included were 10 eyes of 10 patients with visually significant DME which received a fixed regimen of intravitreal aflibercept every 4 weeks for 5 months, followed by 3 injections every 8 weeks, and were controlled monthly. Visual acuity (VA), central retinal thickness (CRT), arterial (aO2S), venous (vO2S) and arterio-venous difference (AVdO2S) retinal oxygen saturation were noted monthly. Changes after 5th (V6) injection and on last follow-up (V12) were studied. Correlations of different parameters were analyzed. Results The aO2S did not change whereas vO2S decreased (62.2 ± 9.4 pre-op to 57.2 ± 10.5 on V6, p = 0.03). This remained unchanged at 59.4 ± 13.2 on V12 (p = 0.2) and was accompanied by an increase of AVdO2S (40.8 ± 8.3 pre-op to 44.8 ± 10.6, p = 0.03 on V6) which was followed by a non-significant decrease to 41.8 ± 11.3 on V12 (p = 0.06). We found no correlation between BCVA and aO2S. However, mild correlation between BCVA and both vO2S and AVdO2S (r = −0.2 p = 0.035 and r = 0.185 p = 0.05 respectively) was found. No correlation was found between CRT and aO2S, vO2S, or AVdO2S. Conclusions During DME treatment with fixed regimen of intravitreal aflibercept over 11 months, we observed a reduction of vO2S and increase of AVdO2S which correlated with BCVA but not CRT. This could be explained by increasing consumption of O2S in the central retina and, possibly, by re-perfusion process.
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21
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Li X, Lv J, Li J, Ren X. Kir4.1 may represent a novel therapeutic target for diabetic retinopathy (Review). Exp Ther Med 2021; 22:1021. [PMID: 34373707 PMCID: PMC8343704 DOI: 10.3892/etm.2021.10453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 05/28/2021] [Indexed: 12/27/2022] Open
Abstract
As the major cause of irreversible loss of vision in adults, diabetic retinopathy (DR) is one of the most serious complications of diabetes. The imbalance of the retinal microenvironment and destruction of the blood-retinal barrier have a significant role in the progression of DR. Inward rectifying potassium channel 4.1 (Kir4.1) is located on Müller cells and is closely related to potassium homeostasis, water balance and glutamate clearance in the whole retina. The present review discusses the functions of Kir4.1 in regulating the retinal microenvironment and related biological mechanisms in DR. In the future, Kir4.1 may represent a novel alternative therapeutic target for DR through affecting the retinal microenvironment.
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Affiliation(s)
- Xiaoyu Li
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Jiajun Lv
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China.,Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Jiazhi Li
- Department of Radiotherapy Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China
| | - Xiang Ren
- Department of Histology and Embryology, Dalian Medical University, Dalian, Liaoning 116044, P.R. China
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22
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Hyaluronic acid in ocular drug delivery. Carbohydr Polym 2021; 264:118006. [DOI: 10.1016/j.carbpol.2021.118006] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/12/2022]
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Moshfeghi AA, Lanitis T, Kropat G, Kuznik A, Gibson A, Feng H, Prenner J. Social Cost of Blindness Due to AMD and Diabetic Retinopathy in the United States in 2020. Ophthalmic Surg Lasers Imaging Retina 2021; 51:S6-S14. [PMID: 32348529 DOI: 10.3928/23258160-20200401-01] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 08/27/2019] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND OBJECTIVE To estimate the social cost of blindness due to wet age-related macular degeneration (wAMD), diabetic macular edema (DME), and proliferative diabetic retinopathy (PDR) in the United States in 2020. PATIENTS AND METHODS Excess costs that occur because of blindness were estimated as the difference in costs in blind versus non-blind individuals. Per-patient costs were aggregated using the number of cases of blindness due to wAMD, DME, and PDR projected in 2020. RESULTS Associated annual excess direct costs, indirect costs, and quality-adjusted life year loss per blind individual were $4,944, $54,614, and 0.214, respectively. Combining estimates with 246,423 projected cases of blindness due to wAMD, DME, and PDR translated to total societal costs of $20 billion in 2020, estimated to triple by 2050. CONCLUSION Excess social costs associated with blindness in individuals with wAMD, DME, and PDR are substantial, with more than half of the burden attributed to indirect costs. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:S6-S14.].
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Aşikgarip N, Yenerel NM. Comparison of the effects of intravitreal ranibizumab and aflibercept on retinal vessel diameters in patients with diabetic macular edema. Photodiagnosis Photodyn Ther 2021; 34:102282. [PMID: 33813015 DOI: 10.1016/j.pdpdt.2021.102282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To evaluate and compare the effects of intravitreal ranibizumab and aflibercept treatment on retinal vessel diameters in patients with diabetic macular edema (DME). METHODS Thirty initial-treatment naïve patients with DME who received three loading doses at monthly intervals of intravitreal ranibizumab or aflibercept were retrospectively reviewed. The diameters of the central retinal artery and vein sections at a distance of 1500 microns from the optical disc boundary were measured and evaluated at baseline and after the first, second, and third month of the treatment, using infrared images from optical coherence tomography (OCT) (Heidelberg Engineering, Heidelberg, Germany). RESULTS In the superotemporal artery (STA) measurements, the mean basal vessel diameter decreased from 110.00 ± 17.25 μm to 102.60 ± 16.90 μm (p = 0.001) in the third month of the treatment in the ranibizumab group. In the aflibercept group, measurements of the basal STA vessel diameter decreased from 110.20 ± 21.25 μm to 103.93 ± 19.03 μm (p = 0.001) at the third month. The mean basal inferotemporal artery (ITA) vessel diameter was significantly decreased at the third month in both ranibizumab (p = 0.001) and aflibercept groups (p = 0.005). In the superotemporal vein (STV) and inferotemporal vein (ITV) measurements, vessel diameters were found significantly decreased at the end of the third month compared with basal measurements in both the ranibizumab (p = 0.001; p = 0.001, respectively) and aflibercept (p = 0.001; p = 0.004, respectively) treatment groups. The retinal vessel measurements were not found to differ significantly between the two intravitreal treatment agents (p > 0.05). CONCLUSION Both intravitreal ranibizumab and aflibercept agents cause a significant narrowing in the retinal vessel diameters in patients with DME after three loading doses at monthly intervals.
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Affiliation(s)
- Nazife Aşikgarip
- Kırşehir Ahi Evran Training and Research Hospital, Department of Opthalmology, Kırşehir, Turkey.
| | - Nursal Melda Yenerel
- University of Health Sciences, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
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Astaxanthin mediated regulation of VEGF through HIF1α and XBP1 signaling pathway: An insight from ARPE-19 cell and streptozotocin mediated diabetic rat model. Exp Eye Res 2021; 206:108555. [PMID: 33789142 DOI: 10.1016/j.exer.2021.108555] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/08/2021] [Accepted: 03/23/2021] [Indexed: 11/21/2022]
Abstract
Breakdown of outer blood-retina barrier (BRB) has been associated with the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) might play a detrimental role in the pathogenesis of DME, a major clinical manifestation of DR. In the present study, we investigated the inhibitory mechanism of astaxanthin on VEGF and its upstream signaling pathways under in vitro and in vivo conditions. Astaxanthin has been observed to downregulate VEGF expression under hyperglycemic (HG) and CoCl2 induced hypoxic conditions in ARPE-19 cells. There were compelling pieces of evidence for the involvement of transcription factors like HIF1α and XBP1 in the upregulation of VEGF under HG and hypoxic conditions. Thus, we investigated the role of astaxanthin in the expression and nuclear translocation of HIF1α and XBP1. The activation and translocation of HIF1α and XBP1 induced by HG or CoCl2 conditions were hindered by astaxanthin. Additionally, treatment with HIF1α siRNA and IRE1 inhibitor STF-083010 also inhibited the expression of VEGF induced by HG and CoCl2 conditions. These results indicated that the anti-VEGF property of astaxanthin might be associated with the downregulation of HIF1α and XBP1. Furthermore, astaxanthin mitigated the enhanced migration of retinal pigment epithelial (RPE) cells under DR conditions. As well, astaxanthin protected disorganization of zona occludin-1 (ZO-1) tight junction protein in RPE and reduced HG or hypoxic induced permeability of RPE cells. In streptozotocin-induced diabetic rat model, astaxanthin reduced the expression of HIF1α, XBP1, and VEGF as well as protected the abnormalities in the retinal layers induced by diabetes condition. Thus, astaxanthin may be used as a potential nutraceutical to prevent or treat retinal dysfunction in diabetic patients.
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Comparison of the efficacy of aflibercept and ranibizumab after a 3-month loading dose in patients with diabetic macular edema. JOURNAL OF SURGERY AND MEDICINE 2021. [DOI: 10.28982/josam.850861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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27
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Liu B, Zhang B, Hu Y, Cao D, Yang D, Wu Q, Hu Y, Yang J, Peng Q, Huang M, Zhong P, Dong X, Feng S, Li T, Lin H, Cai H, Yang X, Yu H. Automatic prediction of treatment outcomes in patients with diabetic macular edema using ensemble machine learning. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:43. [PMID: 33553336 PMCID: PMC7859823 DOI: 10.21037/atm-20-1431] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background This study aimed to predict the treatment outcomes in patients with diabetic macular edema (DME) after 3 monthly anti-vascular endothelial growth factor (VEGF) injections using machine learning (ML) based on pretreatment optical coherence tomography (OCT) images and clinical variables. Methods An ensemble ML system consisting of four deep learning (DL) models and five classical machine learning (CML) models was developed to predict the posttreatment central foveal thickness (CFT) and the best-corrected visual acuity (BCVA). A total of 363 OCT images and 7,587 clinical data records from 363 eyes were included in the training set (304 eyes) and external validation set (59 eyes). The DL models were trained using the OCT images, and the CML models were trained using the OCT images features and clinical variables. The predictive posttreatment CFT and BCVA values were compared with true outcomes obtained from the medical records. Results For CFT prediction, the mean absolute error (MAE), root mean square error (RMSE), and R2 of the best-performing model in the training set was 66.59, 93.73, and 0.71, respectively, with an area under receiver operating characteristic curve (AUC) of 0.90 for distinguishing the eyes with good anatomical response. The MAE, RMSE, and R2 was 68.08, 97.63, and 0.74, respectively, with an AUC of 0.94 in the external validation set. For BCVA prediction, the MAE, RMSE, and R2 of the best-performing model in the training set was 0.19, 0.29, and 0.60, respectively, with an AUC of 0.80 for distinguishing eyes with a good functional response. The external validation achieved a MAE, RMSE, and R2 of 0.13, 0.20, and 0.68, respectively, with an AUC of 0.81. Conclusions Our ensemble ML system accurately predicted posttreatment CFT and BCVA after anti-VEGF injections in DME patients, and can be used to prospectively assess the efficacy of anti-VEGF therapy in DME patients.
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Affiliation(s)
- Baoyi Liu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Bin Zhang
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Yijun Hu
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Dan Cao
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Dawei Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qiaowei Wu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yu Hu
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Jingwen Yang
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Qingsheng Peng
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Manqing Huang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Pingting Zhong
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xinran Dong
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Songfu Feng
- Department of Ophthalmology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Tao Li
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Haotian Lin
- Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Hongmin Cai
- School of Computer Science and Engineering, South China University of Technology, Guangzhou, China
| | - Xiaohong Yang
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Honghua Yu
- Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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Anti-VEGF Treatment of Diabetic Macular Edema: Two-Year Visual Outcomes in Routine Clinical Practice. J Ophthalmol 2020; 2020:6979758. [PMID: 32280530 PMCID: PMC7125496 DOI: 10.1155/2020/6979758] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 02/05/2020] [Accepted: 02/17/2020] [Indexed: 01/18/2023] Open
Abstract
Purpose The purpose of this study was to evaluate 2-year visual outcomes in patients with diabetic macular edema (DME) treated with anti-VEGF agents in a routine clinical setting. Methods The medical records of patients treated with ranibizumab or aflibercept due to DME at the Eye Hospital, University Medical Centre Ljubljana, Slovenia, between January 2016 and March 2019 were retrospectively reviewed. After applying inclusion and exclusion criteria, 123 patients (123 eyes) were included in the study. Results Baseline visual acuity (VA) was 60.9 ± 15.2 letters (median 63; range 7-85). Baseline central retinal subfield thickness (CRT) was 440.7 ± 132.5 μm (median 430; range 114-1000). No significant change in VA over 2 years was found (mean change +2.1 ± 16.8 letters (median 2; range -53-52)). However, there was a significant change in VA in the subgroup with baseline VA <70 letters (mean change +5.7 ± 17.9 letters (median 5; range -52-52)). VA gains of ≥15 letters were achieved in 25 eyes (20.3%). Changes in CRT were significant over 2 years. Patients received 4.5 ± 2.1 (median 5, range 1-9) and 2.6 ± 2.3 (median 2, range 0-8) injections in the first and second years, respectively. Conclusions The two-year visual outcomes in this retrospective analysis appear to be comparable to previously reported outcomes in routine clinical practice. Our analysis provides some information about the effectiveness of anti-VEGF treatment in routine clinical practice in Slovenia. More intensive treatment should be implemented in the management of patients in order to achieve better visual outcomes.
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Shimura M, Kitano S, Muramatsu D, Fukushima H, Takamura Y, Matsumoto M, Kokado M, Kogo J, Sasaki M, Morizane Y, Utsumi T, Koto T, Sonoda S, Hirano T, Ishikawa H, Mitamura Y, Okamoto F, Kinoshita T, Kimura K, Sugimoto M, Yamashiro K, Suzuki Y, Hikichi T, Washio N, Sato T, Ohkoshi K, Tsujinaka H, Kusuhara S, Kondo M, Takagi H, Murata T, Sakamoto T. Real-world management of treatment-naïve diabetic macular oedema: 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study. Br J Ophthalmol 2020; 104:1755-1761. [PMID: 32169861 PMCID: PMC7785163 DOI: 10.1136/bjophthalmol-2019-315726] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/17/2020] [Accepted: 02/20/2020] [Indexed: 12/19/2022]
Abstract
Background/aims To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). Methods Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. Results Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. Conclusion For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing.
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Affiliation(s)
- Masahiko Shimura
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Shigehiko Kitano
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Daisuke Muramatsu
- Department of Ophthalmology, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan
| | - Harumi Fukushima
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | | | - Makiko Matsumoto
- Department of Ophthalmology, Nagasaki University School of Medicine Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masahide Kokado
- Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
| | - Jiro Kogo
- Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Mariko Sasaki
- Department of Ophthalmology, Tachikawa Hospital, Tachikawa, Japan.,Department of Ophthalmology, National Hospital Organisation Tokyo Medical Center, Meguro-ku, Tokyo, Japan
| | - Yuki Morizane
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takuya Utsumi
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo, Japan
| | - Takashi Koto
- Kyorin Eye Center, Kyorin University School of Medicine, Mitaka, Tokyo, Japan
| | - Shozo Sonoda
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takao Hirano
- Deparment of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Hiroto Ishikawa
- Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Yoshinori Mitamura
- Department of Ophthalmology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Tokushima, Japan
| | - Fumiki Okamoto
- Department of Ophthalmology, University of Tsukuba Faculty of Medicine, Tsukuba, Ibaraki, Japan
| | - Takamasa Kinoshita
- Department of Ophthalmology, Sapporo City General Hospital, Sapporo, Japan
| | - Kazuhiro Kimura
- Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Masahiko Sugimoto
- Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Kenji Yamashiro
- Department of Ophthalmology, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | - Yukihiko Suzuki
- Department of Ophthalmology, Hirosaki University School of Medicine Graduate School of Medicine, Hirosaki, Aomori, Japan
| | | | - Noriaki Washio
- Department of Ophthalmology, Showa General Hospital, Kodaira, Tokyo, Japan
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
| | - Kishiko Ohkoshi
- Department of Ophthalmology, St. Luke's International Hospital, Tokyo, Japan
| | - Hiroki Tsujinaka
- Department of Ophthalmology, Nara Medical University, Kashihara, Nara, Japan
| | - Sentaro Kusuhara
- Department of Surgery Related, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mineo Kondo
- Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Hitoshi Takagi
- Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Toshinori Murata
- Deparment of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Kurra P, Brazionis L, Gale J, Chen K, Lake S, Robledo KP, Henderson T. Visual Outcomes in the Management of Diabetic Maculopathy in Central Australia. Ophthalmic Epidemiol 2020; 27:265-271. [PMID: 32070176 DOI: 10.1080/09286586.2020.1730909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE In major urban centres and high-resource settings, treatment of diabetic maculopathy with anti-Vascular Endothelial Growth Factor (VEGF) injections has largely displaced laser treatment. However, intravitreal therapy alone requires frequent follow-up, a barrier to adherence in remote Australia. We report vision outcomes of phased diabetic maculopathy treatment in remote Central Australia for maculopathy using laser and, in a subset, supplementary injection treatment. METHODS We audited clinical records of patients undergoing laser treatment for diabetic maculopathy between 2001 and 2013 at an ophthalmology service based at Alice Springs Hospital, a regional hub in remote Australia. All patients receiving macular laser treatment were included, and some required supplementary injection(s). The primary outcome measure was change in best-corrected visual acuity [BCVA] from baseline treatment. RESULTS Of 338 maculopathy-treated patients, 88% were indigenous and 39% were male. Of 554 maculopathy laser-treated eyes, 118 (21%) received supplementary injection/s. In the laser treatment phase, median BCVA was 78 letters at baseline (interquartile range 62-80) and decreased by a median of two letters at final visit. In the subset who underwent subsequentinjection treatment, BCVA was 60 letters at first injection, with a median five-letter increase by final visit. Overall outcomes were similar in Indigenous and non-Indigenous Australians. Predictors of reduction in BCVA in the macular laser treatment phase were better baseline BCVA, older age, and PRP treatment (all p < .005). CONCLUSION Laser treatment for diabetic maculopathy preserved vision in Central Australia, where barriers to follow-up can preclude regular injections. Supplementary injections stabilized vision in the laser-resistant subset.
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Affiliation(s)
- Pavani Kurra
- Department of Ophthalmology, Alice Springs Hospital , Alice Springs, Australia
| | - Laima Brazionis
- NHMRC Clinical Trials Centre, The University of Sydney , Sydney, Australia.,Department of Medicine, The University of Melbourne , Melbourne, Australia
| | - Jesse Gale
- Department of Ophthalmology, Alice Springs Hospital , Alice Springs, Australia.,Surgery and Anaesthesia, University of Otago , Wellington, New Zealand
| | - Katie Chen
- Department of Ophthalmology, Alice Springs Hospital , Alice Springs, Australia
| | - Stewart Lake
- Department of Ophthalmology, Alice Springs Hospital , Alice Springs, Australia.,Department of Medicine, The University of Melbourne , Melbourne, Australia
| | - Kristy P Robledo
- NHMRC Clinical Trials Centre, The University of Sydney , Sydney, Australia
| | - Tim Henderson
- Department of Ophthalmology, Alice Springs Hospital , Alice Springs, Australia.,Department of Ophthalmology, Flinders Medical Centre , Adelaide, Australia
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Shimura M, Kitano S, Muramatsu D, Fukushima H, Takamura Y, Matsumoto M, Kokado M, Kogo J, Sasaki M, Morizane Y, Kotake O, Koto T, Sonoda S, Hirano T, Ishikawa H, Mitamura Y, Okamoto F, Kinoshita T, Kimura K, Sugimoto M, Yamashiro K, Suzuki Y, Hikichi T, Washio N, Sato T, Ohkoshi K, Tsujinaka H, Kusuhara S, Kondo M, Takagi H, Murata T, Sakamoto T. Real-world management of treatment-naïve diabetic macular oedema in Japan: two-year visual outcomes with and without anti-VEGF therapy in the STREAT-DME study. Br J Ophthalmol 2019; 104:1209-1215. [PMID: 31784500 PMCID: PMC7577088 DOI: 10.1136/bjophthalmol-2019-315199] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/12/2019] [Accepted: 11/16/2019] [Indexed: 12/04/2022]
Abstract
Background/Aims To investigate real-world outcomes for best-corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve, centr-involving diabetic macular oedema (DME). Methods Retrospective analysis of longitudinal medical records obtained from 27 institutions specialising in retinal diseases in Japan. A total of 2049 eyes with treatment-naïve DME commencing intervention between 2010 and 2015 who were followed for 2 years were eligible. Interventions for DME included anti-vascular endothelial growth factor (VEGF) therapy, local corticosteroid therapy, macular photocoagulation and vitrectomy. Baseline and final BCVA (logMAR) were assessed. Eyes were classified by the treatment pattern, depending on whether anti-VEGF therapy was used, into an anti-VEGF monotherapy group (group A), a combination therapy group (group B) and a group without anti-VEGF therapy (group C). Results The mean 2-year improvement of BCVA was −0.04±0.40 and final BCVA of >20/40 was obtained in 46.3% of eyes. Based on the treatment pattern, there were 427 eyes (20.9%) in group A, 807 eyes (39.4%) in group B and 815 eyes (39.8%) in group C. Mean improvement of BCVA was −0.09±0.39, –0.02±0.40 and −0.05±0.39, and the percentage of eyes with final BCVA of >20/40 was 49.4%, 38.9%, and 52.0%, respectively. Conclusion Following 2-year real-world management of treatment-naïve DME in Japan, BCVA improved by 2 letters. Eyes treated by anti-VEGF monotherapy showed a better visual prognosis than eyes receiving combination therapy. Despite treatment for DME being selected by specialists in consideration of medical and social factors, a satisfactory visual prognosis was not obtained, but final BCVA remained >20/40 in half of all eyes.
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Affiliation(s)
- Masahiko Shimura
- Department of Ophthalmology, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan
| | - Shigehiko Kitano
- Department of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | | | - Harumi Fukushima
- Department of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoshihiro Takamura
- Department of Ophthalmology, School of Medical Sciences, University of Fukui, Yoshida, Japan
| | - Makiko Matsumoto
- Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Masahide Kokado
- Department of Ophthalmology, Wakayama Medical University, Wakayama, Japan
| | - Jiro Kogo
- Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Mariko Sasaki
- Department of Ophthalmology, Tachikawa Hospital, Tachikawa, Japan
| | - Yuki Morizane
- Department of Ophthalmology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Osamu Kotake
- Department of Ophthalmology, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan
| | - Takashi Koto
- Kyorin Eye Center, Kyorin University School of Medicine, Mitaka, Japan
| | - Shozo Sonoda
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Takao Hirano
- Deparment of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hiroto Ishikawa
- Department of Ophthalmology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yoshinori Mitamura
- Department of Ophthalmology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
| | - Fumiki Okamoto
- Department of Ophthalmology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takamasa Kinoshita
- Department of Ophthalmology, Sapporo City General Hospital, Sapporo, Japan
| | - Kazuhiro Kimura
- Departmet of Ophthalmology, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masahiko Sugimoto
- Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Kenji Yamashiro
- Department of Ophthalmology, Japanese Red Cross Otsu Hospital, Otsu, Japan
| | - Yukihiko Suzuki
- Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | | | - Noriaki Washio
- Department of Ophthalmology, Showa General Hospital, Kodaira, Japan
| | - Tomohito Sato
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan
| | - Kishiko Ohkoshi
- Department of Ophthalmology, St. Luke's International Hospital, Tokyo, Japan
| | - Hiroki Tsujinaka
- Department of Ophthalmology, Nara Medical University Graduate School of Medicine, Kashihara, Japan
| | - Sentaro Kusuhara
- Department of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mineo Kondo
- Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hitoshi Takagi
- Department of Ophthalmology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshinori Murata
- Deparment of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
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Mechanisms of extracellular vesicle uptake in stressed retinal pigment epithelial cell monolayers. Biochim Biophys Acta Mol Basis Dis 2019; 1866:165608. [PMID: 31740401 DOI: 10.1016/j.bbadis.2019.165608] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 10/24/2019] [Accepted: 11/05/2019] [Indexed: 12/16/2022]
Abstract
PURPOSE Extracellular vesicles (EVs) can mediate long-distance communication in polarized RPE monolayers. Specifically, EVs from oxidatively stressed donor cells (stress EVs) rapidly reduced barrier function (transepithelial resistance, TER) in naïve recipient monolayers, when compared to control EVs. This effect on TER was dependent on dynamin-mediated EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Here, we further determined molecular mechanisms involved in uptake of EVs by naïve RPE cells. METHODS RPE cells were grown as monolayers in media supplemented with 1% FBS followed by transfer to FBS-free media. Cultures were used to collect control or stress EVs upon treatment with H2O2, others served as naïve recipient cells. In recipient monolayers, TER was used to monitor EV-uptake-based activity, live-cell imaging confirmed uptake. EV surface proteins were quantified by protein chemistry. RESULTS Clathrin-independent, lipid raft-mediated internalization was excluded as an uptake mechanism. Known ligand-receptor interactions involved in clathrin-dependent endocytosis include integrins and proteoglycans. Desialylated glycans and integrin-receptors on recipient cells were necessary for EV uptake and subsequent reduction of TER in recipient cells. Protein quantifications confirmed elevated levels of ligands and neuraminidase on stress EVs. However, control EVs could confer activity in the TER assay if exogenous neuraminidase or additional ligand was provided. CONCLUSIONS In summary, while EVs from both stressed cells and control contain cargo to communicate stress messages to naive RPE cells, stress EVs contain surface ligands that confer rapid uptake by recipient cells. We propose that EVs potentially contribute to RPE dysfunction in aging and disease.
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Liu S, Wang D, Chen F, Zhang X. Hyperreflective foci in OCT image as a biomarker of poor prognosis in diabetic macular edema patients treating with Conbercept in China. BMC Ophthalmol 2019; 19:157. [PMID: 31337360 PMCID: PMC6651859 DOI: 10.1186/s12886-019-1168-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 07/18/2019] [Indexed: 11/20/2022] Open
Abstract
Purpose To investigate the dynamic changes of hyperreflective foci (HF) in diabetic macular edema (DME) patients during the intravitreal Conbercept treatment in China. Methods DME Patients receiving intravitreal Conbercept (IVC) injections during the year 2016–2017 were retrospectively investigated. Thirteen patients (26 eyes) were recruited in this study. They received IVC once a month for 3 consecutive months. The number and location of HFs, the best-corrected visual acuity (BCVA) and central macular thickness (CMT) at each visit were analyzed and compared. Results After the first injection, BCVA (LogMAR) was increased from 0.75 ± 0.48 to 0.43 ± 0.24 (p < 0.05), CMT improved from 575.9 ± 191.9 to 388.2 ± 198.5 μm (p = 0.014). However, the BCVA and CMT had no statistical difference after the second and third injection as compared with those after the first injection respectively. The baseline number of HFs was 5.39 ± 4.24, 5.15 ± 5.17 and 0.88 ± 1.90 in the inner retinal, outer retinal and subretinal layer respectively. The number of HFs in these three retinal layers decreased significantly after the first injection (p = 0.0045, p < 0.0001 and p = 0.0045, respectively). However, after the second injection, only the number of HFs in the inner retinal layer experienced a further decrease. After the third injection, no statistically significant HFs changes was observed in each retinal layers. Correlation analysis showed that there was a positive significant correlation between the baseline number of HFs in the inner retina, outer retina, subretina and final BCVA (r = 0.571, p = 0.002; r = 0.464, p = 0.017; r = 0.405, p = 0.04 respectively). There was also a significant positive correlation between outer retinal HFs reduction, total retinal HFs reduction and increase of BCVA (r = 0.40, p = 0.043 and r = 0.393, p = 0.04 respectively). There were no severe ocular adverse reactions or systemic adverse events. Conclusions Conbercept is effective and safe in the treatment of DME. HFs can act as a biomarker of poor final visual outcome.
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Affiliation(s)
- Shulin Liu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, 1 You Yi Road, Yu Zhong District, Chongqing, 400016, People's Republic of China
| | - Desai Wang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, 1 You Yi Road, Yu Zhong District, Chongqing, 400016, People's Republic of China
| | - Fei Chen
- Ophthalmology Department, The people's Hospital of BiShan District of Chongqing City, Chongqing, People's Republic of China
| | - Xuedong Zhang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, 1 You Yi Road, Yu Zhong District, Chongqing, 400016, People's Republic of China.
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Chung YR, Kim YH, Lee SY, Byeon HE, Lee K. Insights into the pathogenesis of cystoid macular edema: leukostasis and related cytokines. Int J Ophthalmol 2019; 12:1202-1208. [PMID: 31341814 DOI: 10.18240/ijo.2019.07.23] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 01/02/2019] [Indexed: 12/29/2022] Open
Abstract
Cystoid macular edema (CME) is the abnormal collection of intraretinal fluid in the macular region, especially in the inner nuclear and outer plexiform layers. CME leads to severe visual impairment in patients with various retinal diseases, such as diabetic retinopathy, retinal vascular occlusion, choroidal neovascularization, and uveitis. Although various retinal conditions lead to CME, a shared pathogenesis of CME is involved in these diseases. Accordingly, the pathogenesis of CME based on vasogenic mechanisms is first discussed in this review, including vascular hyperpermeability, leukostasis, and inflammation. We then describe cytotoxic mechanisms based on retinal Müller cell dysfunction. This comprehensive review will provide an understanding of the pathogenesis of CME for potential therapeutic strategies.
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Affiliation(s)
- Yoo-Ri Chung
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Young Ho Kim
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Seung Yeop Lee
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Korea
| | - Hye-Eun Byeon
- Institute of Medical Science, Ajou University School of Medicine, Suwon 16499, Korea
| | - Kihwang Lee
- Department of Ophthalmology, Ajou University School of Medicine, Suwon 16499, Korea
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Namba R, Kaneko H, Suzumura A, Shimizu H, Kataoka K, Takayama K, Yamada K, Funahashi Y, Ito S, Nonobe N, Terasaki H. In Vitro Epiretinal Membrane Model and Antibody Permeability: Relationship With Anti-VEGF Resistance in Diabetic Macular Edema. ACTA ACUST UNITED AC 2019; 60:2942-2949. [DOI: 10.1167/iovs.19-26788] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
- Rina Namba
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Kaneko
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ayana Suzumura
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideyuki Shimizu
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keiko Kataoka
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kei Takayama
- Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan
| | - Kazuhisa Yamada
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhito Funahashi
- Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seina Ito
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Norie Nonobe
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroko Terasaki
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Hu XY, Liu H, Wang LN, Ding YZ, Luan J. Efficacy and safety of vitrectomy with internal limiting membrane peeling for diabetic macular edema: a Meta-analysis. Int J Ophthalmol 2018; 11:1848-1855. [PMID: 30450318 DOI: 10.18240/ijo.2018.11.18] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 05/25/2018] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate the efficacy and safety of vitrectomy with internal limiting membrane (ILM) peeling for diabetic macular edema (DME). METHODS The PubMed, Embase, Web of Science, Cochrane, SionMed, ClinicalTrials.gov, CNKI databases and Wanfang databases, published until Oct. 2017, were searched to identify studies comparing the clinical outcomes following vitrectomy with and without ILM peeling, for treating DME. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for vitrectomy with and without ILM peeling with regard to best corrected visual acuity (BCVA), central macular thickness (CMT), and complication incidents. RESULTS A total of 14 studies involving 857 eyes were included of which three studies were Chinese and the rests were English literatures. Meta-analysis indicated that compared with vitrectomy alone, vitrectomy with ILM peeling could improve BCVA more obviously (OR=1.66, 95%CI: 1.12-2.46, P=0.01) and had higher rate of CMT reduction (OR=3.89, 95%CI: 1.37-11.11, P=0.01). There were significant statistical differences between the two surgical methods for both BCVA and CMT (P<0.05). For the incidence of intraoperative and postoperative complications, the incidence of epiretinal membrane (ERM) was slightly lower in the ILM peeling group than the group without ILM peeling (OR=0.38, 95%CI: 0.07-2.00, P=0.25), although insignificant statistically. Other incidences of overall complications, iatrogenic peripheral retinal break and increased intraocular pressure indicated no significant difference between two groups (OR=1.19, 95%CI: 0.82-1.73, P=0.36; OR=1.21, 95%CI: 0.66-2.21, P=0.53; OR=1.34, 95%CI: 0.75-2.40, P=0.32). CONCLUSION Vitrectomy is effective for DME and the effect can be improved by additional ILM peeling, especially for anatomical efficacy, without increasing the incidence of intraoperative and postoperative complications. However, it is imperative to gain more evaluation in the future due to the paucity of prospective randomized study.
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Affiliation(s)
- Xin-Ying Hu
- Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Huan Liu
- Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Li-Na Wang
- Department of Epidemiology & Biostatistics, School of Public Health, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Zhi Ding
- Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Jie Luan
- Department of Ophthalmology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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Shah N, Ishii M, Brandon C, Ablonczy Z, Cai J, Liu Y, Chou CJ, Rohrer B. Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers. Biochim Biophys Acta Mol Basis Dis 2018; 1864:2610-2622. [PMID: 29684588 DOI: 10.1016/j.bbadis.2018.04.016] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 04/03/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023]
Abstract
Retinal pigment epithelium (RPE) alterations in age-related macular degeneration occur in patches, potentially involving long-distance communication between damaged and healthy areas. Communication along the epithelium might be mediated by extracellular vesicles (EVs). To test this hypothesis, EVs were collected from supernatants of polarized ARPE-19 and primary porcine RPE monolayers for functional and biochemical assays. EVs from oxidatively stressed donor cells reduced barrier function in recipient RPE monolayers when compared to control EVs. The effect on barrier function was dependent on EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Mass spectrometry-based proteomic analysis of EVs identified HDAC6, which is known to reduce tight junction stability. Activity assays confirmed the presence of HDAC6 in EVs, and EV transfer assays using HDAC6 inhibitors confirmed its effect in monolayers. These findings demonstrate that EVs can communicate stress messages to healthy RPE cells, potentially contributing to RPE dysfunction.
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Affiliation(s)
- Navjot Shah
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States; Ralph H. Johnson VA Medical Center, Charleston, SC 29401, United States
| | - Masakii Ishii
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States; Ralph H. Johnson VA Medical Center, Charleston, SC 29401, United States
| | - Carlene Brandon
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Zsolt Ablonczy
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Jingwen Cai
- Cellular Biology & Anatomy, Augusta University, Augusta, GA 30912, United States
| | - Yutao Liu
- Cellular Biology & Anatomy, Augusta University, Augusta, GA 30912, United States
| | - C James Chou
- Department of Drug Discovery, Medical University of South Carolina, Charleston, SC 29425, United States
| | - Bärbel Rohrer
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, United States; Ralph H. Johnson VA Medical Center, Charleston, SC 29401, United States; Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, United States.
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EFFICACY AND SAFETY OUTCOMES OF INTRAVITREAL AFLIBERCEPT FOCUSING ON PATIENTS WITH DIABETIC MACULAR EDEMA FROM JAPAN. Retina 2018; 39:938-947. [PMID: 29470308 PMCID: PMC6510325 DOI: 10.1097/iae.0000000000002100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE To evaluate the efficacy and safety of intravitreal aflibercept injection (IAI) in Japanese patients with diabetic macular edema (DME). METHODS VIVID-DME was a Phase 3 study comprising patients with DME randomized 1:1:1 to IAI 2 mg every 4 weeks (2q4), IAI 2 mg every 4 weeks until Week 16 then 8-week dosing (2q8), and laser. A total of 403 patients (76 Japanese) were included in this study. VIVID-Japan (72; all Japanese patients) was a nonrandomized, open-label study comprising Japanese patients with DME receiving IAI 2q4 until Week 16, then 2q8. Primary efficacy endpoint (Week 52) of VIVID-DME was mean change from baseline in best-corrected visual acuity; VIVID-Japan evaluated safety and tolerability. RESULTS Mean change in best-corrected visual acuity (letters) for 2q4, 2q8, and laser groups was +10.6, +10.9, and +1.2 and +9.8, +9.5, and +1.1 in the non-Japanese and Japanese populations of VIVID-DME, respectively. In VIVID-Japan, it was +9.3 for IAI 2q8. Intravitreal aflibercept injection also provided consistently greater benefits for anatomical outcomes versus laser. Adverse events were consistent with the known safety profile of IAI. CONCLUSION In Japanese patients with DME, IAI treatment was superior to laser for visual and anatomical outcomes and resulted in efficacy and safety outcomes similar to those in a non-Japanese patient population.
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Terasaki H, Ogura Y, Kitano S, Sakamoto T, Murata T, Hirakata A, Ishibashi T. Management of diabetic macular edema in Japan: a review and expert opinion. Jpn J Ophthalmol 2018; 62:1-23. [PMID: 29210010 DOI: 10.1007/s10384-017-0537-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 08/29/2017] [Indexed: 12/14/2022]
Abstract
Diabetic retinopathy is a frequent cause of visual impairment in working-age adults (≥ 30 years) and in Japan is most commonly observed in those aged 50-69 years. Diabetic macular edema (DME) is one of the main causes of vision disturbance in diabetic retinopathy, which is a clinically significant microvascular complication of diabetes. Anti-vascular endothelial growth factor (VEGF) therapy is becoming the mainstay of treatment for DME. However, to achieve sustained long-term improvement in visual acuity, conventional laser photocoagulation, vitrectomy and steroid therapy are also expected to play a role in the treatment of DME. This review summarizes the epidemiology and pathology of diabetic retinopathy and DME, evaluates the findings regarding the diagnosis and treatment of DME, and underscores the importance of systemic management of the disease in the context of the current health care situation in Japan. Finally, the unmet needs of patients with DME and prospects for research are discussed. The weight of evidence suggests that it is important to establish a multipronged treatment strategy centered on anti-VEGF therapy.
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Affiliation(s)
- Hiroko Terasaki
- Department of Ophthalmology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Yuichiro Ogura
- Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigehiko Kitano
- Department of Diabetic Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Taiji Sakamoto
- Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Toshinori Murata
- Department of Ophthalmology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akito Hirakata
- Department of Ophthalmology, Kyorin University School of Medicine, Tokyo, Japan
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An Analysis of Medicare Reimbursement to Ophthalmologists: Years 2012 to 2013. Am J Ophthalmol 2017; 182:133-140. [PMID: 28784553 DOI: 10.1016/j.ajo.2017.07.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 07/26/2017] [Accepted: 07/26/2017] [Indexed: 11/23/2022]
Abstract
PURPOSE To analyze trends in utilization and payment of ophthalmic services in the Medicare population for years 2012 and 2013. DESIGN Retrospective, cross-sectional study. METHODS A retrospective cross-sectional observational analysis was performed using publicly available Medicare Physician and Other Supplier aggregate file and the Physician and Other Supplier Public Use File. Variables analyzed included aggregate beneficiary demographics, Medicare payments to ophthalmologists, ophthalmic medical services provided, and the most common Medicare-reimbursed ophthalmic services. RESULTS In 2013, total Medicare Part B reimbursement for ophthalmology was $5.8 billion, an increase of 3.6% from the previous year. From 2012 to 2013, the total number of ophthalmology services rendered increased by 2.2%, while average dollar amount reimbursed per ophthalmic service decreased by 5.4%. The top 5 highest reimbursed services accounted for 85% of total ophthalmic Medicare payments in 2013, an 11% increase from 2012. During 2013, drug reimbursement represented 32.8% of the total Medicare payments to ophthalmologists. Ranibizumab and aflibercept alone accounted for 95% of the entire $1.9 billion in drug reimbursements ophthalmologists in 2013. CONCLUSION Medicare Part B reimbursement for ophthalmologists was primarily driven by use of anti-vascular endothelial growth factor (anti-VEGF) injections from 2012 to 2013. Of the total drug payments to ophthalmologists, biologic anti-VEGF agents ranibizumab and aflibercept accounted for 95% of all drug reimbursement. This is in contrast to other specialties, in which drug reimbursement represented only a small portion of Medicare reimbursement.
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Desjardins DM, Yates PW, Dahrouj M, Liu Y, Crosson CE, Ablonczy Z. Progressive Early Breakdown of Retinal Pigment Epithelium Function in Hyperglycemic Rats. Invest Ophthalmol Vis Sci 2017; 57:2706-13. [PMID: 27191823 PMCID: PMC4874474 DOI: 10.1167/iovs.15-18397] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Diabetic macular edema (DME), an accumulation of fluid in the subretinal space, is a significant cause of vision loss. The impact of diabetes on the breakdown of the inner blood-retina barrier (BRB) is an established event that leads to DME. However, the role of the outer BRB in ocular diabetes has received limited attention. We present evidence that the breakdown of normal RPE function in hyperglycemia facilitates conditions conducive to DME pathogenesis. METHODS Brown Norway rats (130-150 g) were injected intraperitoneally with streptozotocin (STZ; 60 mg/kg) to induce hyperglycemia. After 4 weeks, Evans blue (EB) dye was injected intravenously to determine whether there was leakage of albumin into the retina. Subretinal saline blebs (0.5-1 μL) were placed 4 and 9 weeks after STZ injection, and time-lapse optical coherence tomography tracked the resorption rate. In a subset of rats, intravitreal bevacizumab, a humanized monoclonal antibody targeted to VEGF, was given at 5 weeks and resorption was measured at 9 weeks. RESULTS The ability of the RPE to transport fluid was reduced significantly after 4 and 9 weeks of hyperglycemia with a reduction of over 67% at 9 weeks. No EB dye leakage from inner retinal vessels was measured in hyperglycemic animals compared to control. The intravitreal administration of bevacizumab at week 5 significantly increased the rate of fluid transport in rats subjected to hyperglycemia for 9 weeks. CONCLUSIONS These results demonstrate that chronic hyperglycemia altered RPE fluid transport, in part dependent on the actions of VEGF. These results support the idea that RPE dysfunction is an early event associated with hyperglycemia that contributes to fluid accumulation in DME.
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Klein KA, Cleary TS, Reichel E. Effect of intravitreal aflibercept on recalcitrant diabetic macular edema. Int J Retina Vitreous 2017; 3:16. [PMID: 28373914 PMCID: PMC5376679 DOI: 10.1186/s40942-017-0064-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 02/22/2017] [Indexed: 01/09/2023] Open
Abstract
Background Despite anti-VEGF therapy, some patients develop chronic diabetic macular edema. The objective of this study was to evaluate anatomic and visual outcomes of switching patients with chronic DME from intravitreal bevacizumab or ranibizumab to intravitreal aflibercept injection. Methods In this retrospective observational case series, 11 eyes with recalcitrant diabetic macular edema (DME) were evaluated 6 months prior to and 6 months following initial intravitreal aflibercept injection (IAI). Recalcitrant DME was defined as having a thickened retina (≥350 μm) on spectral domain optical coherence tomography (SD-OCT) with persistent cystic changes (less than a 15% reduction in central retinal thickness) over 6 months prior to intravitreal aflibercept switch despite aggressive treatment for DME during this time. Results One hundred and forty-seven patients in total were treated with IAI during this time, and of these, 31 patients were treated with IAI for DME. 18 eyes had less than 4 treatments within the 6 months prior to switch to IAI, 6 patients had a central retinal thickness (CRT) on SD-OCT of less than 350 μm at time of switch to IAI, and 2 patients had a greater than 15% decline in CRT on SD-OCT over the 6 months prior to switch to IAI. A total of 11 patients were included in the study. Over the 6 months prior to switch, the mean change in central retinal thickness was +18.6% and over the 6 months following switch to aflibercept the mean change in central retinal thickness was −27.1%. Switching to a regimen of at least 3 intravitreal aflibercept injections over 6 months resulted in some anatomic improvement and improvement or stabilization of Snellen visual acuity in all eligible patients. Conclusions In patients with recalcitrant diabetic macular edema, switching to intravitreal aflibercept resulted in improved a 25% or more decrease in central retinal thickness in 81% (9/11) patients at 6-month follow-up. Sixty-three percent (7/11) had improvement in Snellen visual acuity after switching to intravitreal aflibercept injection, suggesting some reversibility of functional damage.
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Affiliation(s)
- Kendra A Klein
- New England Eye Center and Tufts Medical Center, Tufts University, 260 Tremont Street, Biewend Building, 9 - 11th Floor, Boston, MA 02111 USA
| | - Tina S Cleary
- Ophthalmic Consultants of Boston, 50 Staniford Street, #600, Boston, MA 02114 USA
| | - Elias Reichel
- New England Eye Center and Tufts Medical Center, Tufts University, 260 Tremont Street, Biewend Building, 9 - 11th Floor, Boston, MA 02111 USA
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Mynampati BK, Sambhav K, Grover S, Chalam KV. Inhibition of proliferation of retinal vascular endothelial cells more effectively than choroidal vascular endothelial cell proliferation by bevacizumab. Int J Ophthalmol 2017; 10:15-22. [PMID: 28149771 DOI: 10.18240/ijo.2017.01.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Accepted: 09/28/2016] [Indexed: 11/23/2022] Open
Abstract
AIM To evaluate the differential inhibitory effects of bevacizumab on cell proliferation of vascular endothelial growth factor (VEGF)-stimulated choroidal vascular endothelial cells (CVECs) and retinal vascular endothelial cells (RVECs) in vitro. METHODS VEGF (400 ng/mL) enriched CVECs and RVECs were treated with escalating doses of bevacizumab (0.1, 0.5, 1, 1.5 and 2 mg/mL). Cell proliferation changes were analyzed with WST-1 assay and trypan blue exclusion assay at 48, 72h and 1wk. Morphological changes were recorded with bright field microscopy. RESULTS VEGF enriched RVECs showed significantly more decline of cell viability than CVECs after bevacizumab treatment. One week after treatment, RVEC cell proliferation decreased by 29.7%, 37.5%, 52.8%, 35.9% and 45.6% at 0.1, 0.5, 1.0, 1.5 and 2 mg/mL bevacizumab respectively compared to CVEC proliferation decrease of 4.1%, 7.7%, 2.4%, 4.1% and 17.7% (P<0.05) by WST-1 assay. Trypan blue exclusion assay also revealed similar decrease in RVEC proliferation of 20%, 60%, 73.3%, 80% and 93.3% compared to CVEC proliferation decrease of 4%, 12%, 22.9%, 16.7% and 22.2% respectively (P<0.05). The maximum differential effect between the two cell types was observed at bevacizumab doses of 1.0 and 1.5 mg/mL at all time points. RVECs were 22 fold more sensitive (P<0.01) compared to CVECs (52.8% vs 2.4%) at concentration of 1.0 mg/mL, and 8.7 fold more at 1.5 mg/mL (35.9% vs 4.1%) 1wk after treatment (P<0.05 respectively). CONCLUSION VEGF-enriched RVECs are more susceptible to bevacizumab inhibition than CVECs at clinically used dosage of 1.25 mg and this differential sensitivity between two cell types should be taken into consideration in dosage selection.
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Affiliation(s)
- Bharani Krishna Mynampati
- Department of Ophthalmology, University of Florida, College of Medicine, Jacksonville, FL 32209, USA
| | - Kumar Sambhav
- Department of Ophthalmology, University of Florida, College of Medicine, Jacksonville, FL 32209, USA
| | - Sandeep Grover
- Department of Ophthalmology, University of Florida, College of Medicine, Jacksonville, FL 32209, USA
| | - Kakarla V Chalam
- Department of Ophthalmology, University of Florida, College of Medicine, Jacksonville, FL 32209, USA
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Granström T, Forsman H, Lindholm Olinder A, Gkretsis D, Eriksson JW, Granstam E, Leksell J. Patient-reported outcomes and visual acuity after 12months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting. Diabetes Res Clin Pract 2016; 121:157-165. [PMID: 27718374 DOI: 10.1016/j.diabres.2016.09.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 08/29/2016] [Accepted: 09/01/2016] [Indexed: 01/18/2023]
Abstract
AIMS To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12months in a real world setting. METHODS In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used. RESULTS The total patient group had significantly improved visual acuity and reduced retinal thickness at 4months and remains at 12months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity. CONCLUSIONS Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12months after treatment start.
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Affiliation(s)
- Therese Granström
- School of Education, Health and Social Studies, Dalarna University, Falun, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
| | - Henrietta Forsman
- School of Education, Health and Social Studies, Dalarna University, Falun, Sweden.
| | - Anna Lindholm Olinder
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Sachs Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden; Department of Clinical Research and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
| | | | - Jan W Eriksson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
| | - Elisabet Granstam
- Center for Clinical Research Västmanland County Hospital, Uppsala University/County Council of Västmanland, Västerås, Sweden; Department of Ophthalmology, Västmanland County Hospital, Västerås, Sweden.
| | - Janeth Leksell
- School of Education, Health and Social Studies, Dalarna University, Falun, Sweden; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
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Recommendations for the Appropriate Management of Diabetic Macular Edema: Light on DME Survey and Consensus Document by an Expert Panel. Eur J Ophthalmol 2016; 26:252-61. [DOI: 10.5301/ejo.5000736] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2015] [Indexed: 11/20/2022]
Abstract
Purpose The Light on DME survey was designed to address several issues concerning the management of diabetic macular edema (DME) with the objective of producing practical recommendations for the appropriate treatment of this condition. Methods The recommendations considered aspects of DME treatment that are controversial and insufficiently supported by the evidence and were based on a consensus reached by an expert panel. Consensus was achieved by means of the Delphi method. Thirty-one Italian retinologists were asked to rate the appropriateness of a comprehensive set of scenarios typically encountered in the management of DME in clinical practice. The results of the appropriateness evaluation were analyzed by the study panel and a second assessment round was conducted for those scenarios on which no consensus was reached. Results Consensus was reached on several relevant aspects of current DME management, namely the initiation and course of treatment with anti-vascular endothelial growth factor (VEGF) therapy, assessment of the outcomes of anti-VEGF therapy based on both functional and morphologic outcomes, combination of anti-VEGF with laser therapy, and management of nonresponders to anti-VEGFs. A few issues, including the definition of DME based on novel diagnostic tools, the need for stable metabolic parameters before initiating anti-VEGF therapy, and the use of a second anti-VEFG after failure of the first anti-VEGF, proved controversial. Conclusions A clear consensus among DME experts was reached on several relevant aspects of DME management. Based on this consensus, detailed and practical recommendations to guide ophthalmologists in the use of novel approaches to DME could be developed.
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Clinical practice pattern in management of diabetic macular edema in Japan: survey results of Japanese retinal specialists. Jpn J Ophthalmol 2016; 61:43-50. [PMID: 27722786 DOI: 10.1007/s10384-016-0481-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 09/15/2016] [Indexed: 10/20/2022]
Abstract
PURPOSE To elucidate the current clinical practice patterns of diabetic macular edema (DME) management by retinal specialists in Japan in the era of anti-vascular endothelial growth factor (VEGF) therapy. METHODS Forty-six retinal specialists were administered a survey regarding the pathology and clinical practice of DME. RESULTS Nearly, half of the specialists (45.2 %) think that the main biochemical factor involved in DME development is the vascular permeability-potentiating action of VEGF-A. Most specialists (70.6 %) use three modalities for detecting DME: optical coherence tomography, fluorescein angiography, and fundus examination. For focal macular edema, focal laser is used as first-line therapy by 70.3 % of specialists, whereas 21.6 % use medical treatment in combination with focal/grid laser. For diffuse macular edema, anti-VEGF therapy is the first choice (72.5 %), irrespective of visual acuity, whereas 17.5 % select off-label sub-Tenon's steroid injections. Vitrectomy is often performed for vitreomacular traction (86.5 %) or when anti-VEGF agent/laser therapy is ineffective (73.2 %). For persistent DME after vitrectomy, anti-VEGF agents (46.3 %) or steroids (intravitreal injections, 14.6 %; sub-Tenon's injections, 36.6 %) are selected. When applying anti-VEGF treatment regimen, most specialists continue loading injections until central retinal thickness stabilized (51.4 %) or both visual acuity and central retinal thickness stabilized (24.3 %). In the maintenance phase, many specialists provide injections with pro re nata (76.3 %), whereas 50.0 % responded that the treat-and-extend regimen is ideal. CONCLUSIONS Our survey presents the current views about the DME management and practice patterns of anti-VEGF therapy by one part of the retinal specialists in Japan, and highlights the differences or gaps between evidence and actual clinical practice.
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Desjardins D, Liu Y, Crosson CE, Ablonczy Z. Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia. PLoS One 2016; 11:e0162596. [PMID: 27617745 PMCID: PMC5019386 DOI: 10.1371/journal.pone.0162596] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/25/2016] [Indexed: 12/15/2022] Open
Abstract
In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE) is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE). Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb) or vascular endothelial growth factor (VEGF), increased histone deacetylase (HDAC) activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA), suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro) and fluid transport (in vivo). Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina.
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Affiliation(s)
- Danielle Desjardins
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America
| | - Yueying Liu
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America
| | - Craig E. Crosson
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America
| | - Zsolt Ablonczy
- Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, United States of America
- * E-mail:
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Capitão M, Soares R. Angiogenesis and Inflammation Crosstalk in Diabetic Retinopathy. J Cell Biochem 2016; 117:2443-53. [PMID: 27128219 DOI: 10.1002/jcb.25575] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 04/27/2016] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes and one of the most frequent causes of blindness in active age. Etiopathogenesis behind this important complication is related to several biochemical, hemodynamic and endocrine mechanisms with a preponderant initial role assumed by polyol pathways, increment of growth factors, accumulation of advanced glycation end products (AGE), activation of protein kinase C (PKC), activation of the renin-angiotensin-aldosterone system (RAAS), and leukostasis. Chronic and sustained hyperglycemia works as a trigger to the early alterations that culminate in vascular dysfunction. Hypoxia also plays an essential role in disease progression with promotion of neovascularization and vascular dystrophies with vitreous hemorrhages induction. Thus, the accumulation of fluids and protein exudates in ocular cavities leads to an opacity augmentation of the cornea that associated to neurodegeneration results in vision loss, being this a devastating characteristic of the disease final stage. During disease progression, inflammatory molecules are produced and angiogenesis occur. Furthermore, VEGF is overexpressed by the maintained hyperglycemic environment and up-regulated by tissue hypoxia. Also pro-inflammatory mediators regulated by cytokines, such as tumor necrosis factor (TNF-α) and interleukin-1 beta (IL-1β), and growth factors leads to the progression of these processes, culminating in vasopermeability (diabetes macular edema) and/or pathological angiogenesis (proliferative diabetic retinopathy). It was found a mutual contribution between inflammation and angiogenesis along the process. J. Cell. Biochem. 117: 2443-2453, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Margarida Capitão
- Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal
| | - Raquel Soares
- Department of Biochemistry, Faculty of Medicine, University of Porto, Portugal. .,i3S, Instituto de Investigação e Inovação em Saúde, University of Porto, Portugal.
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Tolentino MS, Tolentino AJ, Tolentino MJ. Current and investigational drugs for the treatment of diabetic retinopathy. Expert Opin Investig Drugs 2016; 25:1011-22. [DOI: 10.1080/13543784.2016.1201062] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Chatziralli IP, Sharma PK, Sivaprasad S. Treatment Modalities for Idiopathic Macular Telangiectasia: An Evidence-Based Systematic Review of the Literature. Semin Ophthalmol 2016; 32:384-394. [PMID: 27077639 DOI: 10.3109/08820538.2015.1096399] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 09/10/2015] [Indexed: 11/13/2022]
Abstract
PURPOSE The purpose of this systematic review was to stratify the literature on the therapeutic approaches for macular telangiectasia (Mactel type 1 and 2) to provide evidenced-based practical guidelines for the optimal standard care of these conditions. METHODS A comprehensive search of PubMed was performed using a specific search algorithm. All articles retrieved were carefully screened and their references were manually reviewed for additional relevant data. Level of evidence was provided for each treatment modality, graded as level I, II, III, IV, and V, and indicative of very strong, strong, substantial, relatively weak, and weak evidence, respectively. RESULTS 1445 abstracts were checked and 123 were found to be relevant. Out of them, 102 were eligible for the purpose of our review and 86 were focused on treatment of macular telangiectasia. Most publications combined cases of Mactel type 1 and type 2, despite their distinct pathophysiology. In Mactel type 1, laser photocoagulation of the telangiectasia remains the mainstay in controlling macular edema, while anti-vascular endothelial growth factor (anti-VEGF) agents provide short-term benefits. In Mactel type 2, current treatment options are not effective in the management of the non-proliferative stage, while anti-VEGF agents seem to be effective in the treatment of choroidal neovascularization complicating the disease. CONCLUSION It is important to differentiate the type of macular telangiectasia to plan appropriate treatment.
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Affiliation(s)
| | | | - Sobha Sivaprasad
- a Laser and Retinal Research Unit, King's College Hospital , London , UK
- c NIHR Moorfields Biomedical Research Centre , London , UK
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