Macular Disease Foundation Australia logo

    Research update: 519

    The latest research highlights for 8 November 2021.


    Three-Year Outcomes of Neovascular Age-Related Macular Degeneration in Eyes That Do Not Develop Macular Atrophy or Subretinal Fibrosis 

    Transl Vis Sci Technol.2021 Nov 1;10(13):5. 

    Pierre-Henry Gabrielle, Vuong Nguyen, Jennifer J Arnold, Sanjeeb Bhandari, Francesco Viola, Odette A M Tigchelaar-Besling, Gonzaga Garay-Aramburu, Louise O’Toole, Chui Ming Gemmy Cheung, Daniel Barthelmes, Catherine Creuzot-Garcher. Mark Gillies

    Purpose: To report the 36-month treatment outcomes of eyes with neovascular age-related macular degeneration (nAMD) receiving vascular endothelial growth factor (VEGF) inhibitors in daily practice who did not develop either subretinal fibrosis (SRFi) or macular atrophy (MA). 

    Methods: This is a retrospective analysis of data from the Fight Retinal Blindness registry. Treatment-naïve eyes starting intravitreal injection of VEGF inhibitors for nAMD from January 1, 2010, to September 1, 2017, and did not have SRFI and MA at baseline were tracked. 

    Results: We identified 2478 eligible eyes, of which 1712 eyes did not develop SRFi or MA, 291 developed extrafoveal SRFI or MA, and 475 developed subfoveal SRFi or MA over 36 months. The estimated visual acuity stabilized from 6 months to 36 months in eyes that did not develop SRFI or MA with a mean (95% confidence interval [CI]) change in VA of -1 (-2, 0) letters, whereas eyes that developed extrafoveal (-3 [-5, -2] letters) or subfoveal (-10 [-11, -8] letters) SRFi or MA declined in vision in the same period. Eyes with no or extrafoveal SRFi or MA over 36 months were more likely to maintain their visual improvement from six months to 36 months (odds ratio [OR; 95% CI] = 2.3 [1.5, 3.3] for absence vs. subfoveal SRFi or MA, P ≤ 0.01 and OR = 2.0 [1.2, 3.4] for extrafoveal vs. subfoveal MA or SRFi, P = 0.01). 

    Conclusions: Treatment-naïve nAMD eyes receiving VEGF inhibitors maintain their initial six-month visual improvement over three years if they do not develop SRFI or MA. 

    Translational relevance: The nAMD is still a major cause of blindness despite antiangiogenic treatments. We found that eyes that did not develop subretinal fibrosis or macular atrophy maintained their initial vision improvement for at least three years, suggesting that identifying treatments for these complications is the final barrier to achieving excellent outcomes in nAMD. 

    DOI: 10.1167/tvst.10.13.5 


    Importance of Treatment Duration: Unmasking Barriers and Discovering the Reasons for Undertreatment of Anti-VEGF Agents in Neovascular Age-Related Macular Degeneration 

    Clin Ophthalmol.2021 Oct 27;15:4317-4326.

    Bianka Sobolewska, Muhammed Sabsabi, Focke Ziemssen

    Purpose: Since non-adherence (NA) to intravitreal therapy with VEGF drugs is one of the most important modifiable factors compromising treatment outcome of nAMD, the purpose of this study was to investigate the contributing factors and barriers during long-term nAMD treatment. 

    Methods: Barriers and potential reasons for NA were prospectively measured using the Adherence Barriers Questionnaire Intravitreal Therapy (ABQ-IVT). A random sample of patients receiving intravitreal therapy was drawn based on data for different treatment periods. Three age-sex matched groups included the treatment periods of ≤30 months (group 1), between >30 months and ≤60 months (group 2), and >60 months (group 3). The occurrence of gaps between treatments and/or OCT visits was evaluated. 

    Results: NA with gaps of >56 days after the scheduled appointment was detected in 39%, 89%, and 100% of patients in group 1, 2, and 3, respectively (groups 1 and 2 vs group 3, p < 0.001). Two or more of such gaps were observed in 6%, 72%, and 94% of patients in group 1, 2, and 3, respectively. The overall ABQ-IVT score showed corresponding differences between the groups: 25.89 ± 7.68 (group 1, 95% CI 22.07-29.71), 34.72 ± 10.32 (group 2, 95% CI: 29.59-38.86), and 33.28 ± 9.04 (group 3, 95% CI 28.78-37.77). Accordingly, the score was inversely correlated with the number of regular follow-up visits in groups 2 and 3 (Pearson correlation coefficient r = -0.65 (p = 0.003) and r = -0.5 (p = 0.034), respectively). Within the groups of longer treatment duration, univariate logistic regression analysis showed higher odds of time commitment and challenge accompanying person to be relevant barriers. 

    Conclusion: NA is an arising problem with increasing duration of intravitreal therapy. Treatment barriers, detected by the ABQ-IVT, might change or increase during the course of the treatment. 

    DOI: 10.2147/OPTH.S325763 

    Changes in Systemic Levels of Vascular Endothelial Growth Factor After Intravitreal Injection of Aflibercept or Brolucizumab for Neovascular Age-Related Macular Degeneration 

    Retina.2021 Nov 1. 

    Reinhard Angermann, Anna Lena Huber, Yvonne Nowosielski, Stefan Salcher, Thomas Gasser, Christof Seifarth, Martina T Kralinger, Claus Zehetner

    Purpose: To analyze and compare the effects of intravitreal brolucizumab vs. aflibercept on systemic vascular endothelial growth factor (VEGF)-A levels in patients with neovascular age-related macular degeneration. 

    Methods: In this prospective interventional case series study, brolucizumab (6.0 mg/50 µL) or aflibercept (2.0 mg/50 µL) was injected intravitreally in 30 patients each. Blood samples were drawn at baseline and 7 and 28 days after the first injection. Systemic VEGF-A levels were measured using enzyme-linked immunosorbent assay. Thirty healthy individuals served as controls. 

    Results: The median baseline systemic VEGF-A levels in the brolucizumab, aflibercept, and control groups were 10.8 (8.0-13.2), 12.0 (8.0-18.5), and 10.0 (8.0-15.1) pg/ml, respectively (p=0.315). In the brolucizumab group, VEGF-A levels significantly decreased to 8.0 (8.0-11.5) pg/ml on day 7 (p=0.0254) and to 8.0 (8.0-8.0) pg/ml on day 28 (p<0.001). In the aflibercept group, VEGF-A levels significantly decreased to 8.0 (8.0-8.0) pg/ml on day 7 (p<0.001) but returned to baseline level, 12.5 (8.5-14.6) pg/ml, on day 28 (p=0.120). VEGF-A levels were significantly different between the treatment groups after 28 days (p<0.001). 

    Conclusion: Intravitreal brolucizumab resulted in a sustained reduction of systemic VEGF-A levels until 28 days post-treatment, which raises concerns regarding its safety and long-term effects. 

    DOI: 10.1097/IAE.0000000000003344 

    Comparison Between Ranibizumab Biosimilar, Innovator Ranibizumab and Bevacizumab in a Real-World Situation 

    Ophthalmol Ther.2021 Nov 5.

    Dhanashree Ratra, Krishnakanta Roy, Sneha Giridhar, Sushant Madaan, Sankara Nethralaya Vitreoretinal Study Group


    Introduction: To analyze the efficacy of biosimilar ranibizumab compared to innovator ranibizumab and bevacizumab. 

    Methods: We retrospectively analyzed consecutive patients treated with biosimilar ranibizumab for wet age-related macular degeneration (AMD) and macular edema (ME) (due to diabetes and vein occlusion) and compared them with ranibizumab- and bevacizumab-treated patients. 

    Results: Of 202 patients, 67 (33.2%) received biosimilar ranibizumab (BSR), 69 (34.2%) ranibizumab (RBZ) and 66 (32.7%) bevacizumab (BEV). All patients received three consecutive injections followed by pro re nata dosing. The follow-up ranged from 3 to 24 months. The mean numbers of injections were 6.68 for RBZ, 6.4 for BEV and 4.7 for BSR. At 3 months, nAMD (n = 115, 56.9%) and ME (n = 87, 43.1%) groups showed significant improvement in vision and central foveal thickness (CFT) across all three agents. After ≥ 6 months, the effects were maintained in the AMD group but not in the ME group. Maximum effect was seen at 1 month. At no point in time was a significant difference noted among the three anti-vascular endothelial growth factor (anti-VEGF) agents. No major safety concerns were noted. 

    Conclusions: Biosimilar ranibizumab is comparable to innovator ranibizumab and bevacizumab in efficacy and safety. 

    DOI: 10.1007/s40123-021-00416-4 


    Morphological and Anatomical Features of Type 1 Macular Neovascularization Trunks in Age-Related Macular Degeneration using Optical Coherence Tomography Angiography 

    Retina.2021 Oct 23. 

    Kwang-Eon Choi, Seong-Woo Kim, Cheolmin Yun, Jaeryung Oh

    Purpose: To evaluate the morphological features of macular neovascularization (MNV) trunks at different layers using optical coherence tomography angiography (OCTA). 

    Methods: Type 1 MNV trunks in age-related macular degeneration were retrospectively evaluated at the sub-retinal pigment epithelium (subRPE) and sub-Bruch’s membrane (subBM) layers. The detectability and location of the trunks were compared. MNV trunks at the subBM layer on OCTA b-scans were evaluated using a flow overlay. The correlations of the MNV trunk with OCTA and OCT parameters were evaluated. 

    Results: Among the 63 included eyes, 27 showed core vessels at the subRPE layer and 52 showed MNV trunks at the subBM layer, which were connected with the MNV at the subRPE layer. The locations of the MNV trunks in each layer were different. MNV trunk types at the subBM layer were related to disease duration, distance from the large choroidal vessels, and MNV vessel density. The large choroidal vessel diameter was correlated with the MNV trunk diameter at the subBM layer. 

    Conclusion: MNV trunks at the subBM layer were detected more frequently than distal MNV trunks at the subRPE layer. MNV trunk features at the subBM layer may be related to disease duration and a large choroidal vessel. 

    DOI: 10.1097/IAE.0000000000003331 


    Association of Smoking, Alcohol Consumption, Blood Pressure, Body Mass Index, and Glycemic Risk Factors With Age-Related Macular Degeneration: A Mendelian Randomization Study 

    JAMA Ophthalmol.2021 Nov 4.

    Valerie Kuan, Alasdair Warwick, Aroon Hingorani, Adnan Tufail, Valentina Cipriani, Stephen Burgess, Reecha Sofat, International AMD Genomics Consortium (IAMDGC)

    Importance: Advanced age-related macular degeneration (AMD) is a leading cause of blindness in Western countries. Causal, modifiable risk factors need to be identified to develop preventive measures for advanced AMD. 

    Objective: To assess whether smoking, alcohol consumption, blood pressure, body mass index, and glycemic traits are associated with increased risk of advanced AMD. 

    Design, setting, participants: This study used 2-sample mendelian randomization. Genetic instruments composed of variants associated with risk factors at genome-wide significance (P < 5 × 10-8) were obtained from published genome-wide association studies. Summary-level statistics for these instruments were obtained for advanced AMD from the International AMD Genomics Consortium 2016 data set, which consisted of 16 144 individuals with AMD and 17 832 control individuals. Data were analyzed from July 2020 to September 2021. 

    Exposures: Smoking initiation, smoking cessation, lifetime smoking, age at smoking initiation, alcoholic drinks per week, body mass index, systolic and diastolic blood pressure, type 2 diabetes, glycated hemoglobin, fasting glucose, and fasting insulin. 

    Main outcomes and measures: Advanced AMD and its subtypes, geographic atrophy (GA), and neovascular AMD. 

    Results: A 1-SD increase in logodds of genetically predicted smoking initiation was associated with higher risk of advanced AMD (odds ratio [OR], 1.26; 95% CI, 1.13-1.40; P < .001), while a 1-SD increase in logodds of genetically predicted smoking cessation (former vs current smoking) was associated with lower risk of advanced AMD (OR, 0.66; 95% CI, 0.50-0.87; P = .003). Genetically predicted increased lifetime smoking was associated with increased risk of advanced AMD (OR per 1-SD increase in lifetime smoking behavior, 1.32; 95% CI, 1.09-1.59; P = .004). Genetically predicted alcohol consumption was associated with higher risk of GA (OR per 1-SD increase of log-transformed alcoholic drinks per week, 2.70; 95% CI, 1.48-4.94; P = .001). There was insufficient evidence to suggest that genetically predicted blood pressure, body mass index, and glycemic traits were associated with advanced AMD. 

    Conclusions and relevance: This study provides genetic evidence that increased alcohol intake may be a causal risk factor for GA. As there are currently no known treatments for GA, this finding has important public health implications. These results also support previous observational studies associating smoking behavior with risk of advanced AMD, thus reinforcing existing public health messages regarding the risk of blindness associated with smoking. 

    DOI: 10.1001/jamaophthalmol.2021.4601 


    Emerging Treatment Modalities for Neovascular Age-Related Macular Degeneration: A Systematic Overview 

    Adv Ther.2021 Nov 1. 

    Dionysis D Balatsoukas, Konstantinos T Tsaousis, Konstadinos G Boboridis, Anastasios G Konstas, Fotis Topouzis

    Introduction: Neovascular age-related macular degeneration (nAMD) represents a leading cause of irreversible visual loss affecting the quality of life of millions of elderly patients worldwide. Although the introduction of intravitreal injections with anti-vascular endothelial growth factors (anti-VEGF) agents has revolutionized the management of nAMD, their effectiveness and ultimate success are limited by several therapeutic challenges. Consequently, real-world efficacy appears significantly inferior to that reported by randomized controlled trials. Therefore, further innovative, long-term treatment options are essential to improve the prognosis and outcome of nAMD therapy. 

    Methods: Emerging pharmacological therapies for nAMD and those currently in clinical trials are reviewed and their mechanism of action, safety, and efficacy are discussed. The evidence presented herein has been collected from online databases PubMed, Cochrane library, and the site. 

    Results: A number of promising technologies and novel anti-VEGF therapies are currently being tested and some have already reached phase III trials. Anti-VEGF agents with enhanced durability and possibly efficacy, gene therapy, angiogenic targets, alternative drug delivery routes such as sustained delivery implants, drug carriers, and encapsulated cell technology are currently being explored. We briefly discuss the potential value of these options. 

    Conclusion: Several options may optimize future nAMD management. On the basis of current, albeit limited evidence, the most promising technology to reach clinical practice soon appears to be the sustained drug delivery options, which may improve visual outcome and reduce the socioeconomic burden of nAMD. 

    DOI: 10.1007/s12325-021-01949-7 


    Vitreous Noise on Optical Coherence Tomography as an Early Finding of Brolucizumab-Related Intraocular Inflammation 

    Case Rep Ophthalmol.2021 Sep 21;12(3):797-803. 

    Yuji Yoshikawa, Tomoyuki Kumagai, Kei Shinoda


    We describe a case of brolucizumab-related intraocular inflammation (IOI) detected using vitreous haze on optical coherence tomography (OCT) at an early stage before the patient was aware of any symptom. A 69-year-old female presented with decreased right vision. The patient was diagnosed with pachychoroidal neovasculopathy and started intravitreal aflibercept (IVA) with a 3+ treat-and-extend strategy (TAE). Although the serous retinal detachment (SRD) disappeared after IVA treatment, the patient was managed with treatment every 4 weeks without extending the treatment interval To shorten the treatment interval, intravitreal brolucizumab (IVBr) was started 44 weeks after starting IVA treatment. After initiating IVBr treatment, the SRD completely disappeared. However, 16 weeks after starting IVBr, OCT showed noise in the vitreous cavity, which had not been seen before, and infrared images showed a black smoke-like shadow over the macula. Despite these findings, the patient had no subjective symptoms, and so IVBr was re-administered with an 8-week TAE interval. Five days after IVBr treatment, vitreous inflammatory cells were observed, and the noise in the vitreous cavity and the smoke-like shadow in the infrared image were further enhanced. We diagnosed the patient with brolucizumab-related IOI, and anti-inflammatory treatment was initiated. After extensive treatment, the vitreous opacity gradually disappeared, and the vitreous noise on OCT and the black smoke-like shadow on infrared images disappeared. IOI may have already been present 16 weeks after starting IVBr treatment, when we judged that there was no inflammation and IVBr was re-administered. When following patients receiving IVBr, IOI may be detected by OCT at an earlier stage by evaluating vitreous haze. 

    DOI: 10.1159/000518809 


    Caffeine Inhibits Choroidal Neovascularization Through Mitigation of Inflammatory and Angiogenesis Activities 

    Front Cell Dev Biol.2021 Oct 14;9:737426. 

    Christine M Sorenson, Yong-Seok Song, Ismail S Zaitoun, Shoujian Wang, Barbara A Hanna, Soesiawati R Darjatmoko, Zafer Gurel, Debra L Fisk, Colleen M McDowell, Ryan M McAdams, Nader Sheibani


    Adenosine receptors (AR) are widely expressed in a variety of tissues including the retina and brain. They are involved in adenosine-mediated immune responses underlying the onset and progression of neurodegenerative diseases. The expression of AR has been previously demonstrated in some retinal cells including endothelial cells and retinal pigment epithelial cells, but their expression in the choroid and choroidal cells remains unknown. Caffeine is a widely consumed AR antagonist that can influence inflammation and vascular cell function. It has established roles in the treatment of neonatal sleep apnea, acute migraine, and post lumbar puncture headache as well as the neurodegenerative diseases such as Parkinson and Alzheimer. More recently, AR antagonism with caffeine has been shown to protect preterm infants from ischemic retinopathy and retinal neovascularization. However, whether caffeine impacts the development and progression of ocular age-related diseases including neovascular age-related macular degermation remains unknown. Here, we examined the expression of AR in retinal and choroidal tissues and cells. We showed that antagonism of AR with caffeine or istradefylline decreased sprouting of thoracic aorta and choroid/retinal pigment epithelium explants in ex vivo cultures, consistent with caffeine’s ability to inhibit endothelial cell migration in culture. In vivo studies also demonstrated the efficacy of caffeine in inhibition of choroidal neovascularization and mononuclear phagocyte recruitment to the laser lesion sites. Istradefylline, a specific AR 2A antagonist, also decreased choroidal neovascularization. Collectively, our studies demonstrate an important role for expression of AR in the choroid whose antagonism mitigate choroidal inflammatory and angiogenesis activities. 

    DOI: 10.3389/fcell.2021.737426