Real-world outcomes after 36 months treatment with ranibizumab 0.5 mg in patients with visual impairment due to diabetic macular edema (BOREAL-DME)
Ophthalmic Res. 2020 Sep 15.
Pascale Massin, Catherine Creuzot-Garcher, Laurent Kodjikian, Jean-François Girmens, Cécile Delcourt, Franck Fajnkuchen, Agnès Glacet-Bernard, Pierre-Jean Guillausseau, Francoise Guthux, Patrick Blin, Angela Grelaud
PMID: 32932257 DOI: 10.1159/000511591
To assess the efficacy, safety and follow-up of 36 months treatment with ranibizumab in patients with diabetic macular edema (DME) in real life setting. Methods This is a prospective phase 4 observational study. Between December 2013 and April 2015, 84 ophthalmologists enrolled a total of 290 adult patients initiating ranibizumab for visual impairment due to diabetic macular edema (DME) and treated them according to their routine practice. The primary outcome (mean change in best-corrected visual acuity [BCVA] after 12 months) was previously reported. Here we present outcomes after 36 months of follow-up for BCVA, change in central subfield thickness (CSFT) and report how participating ophthalmologists treated DME over a 3 year period (number of visits and injections, and evolution of treatment strategy). Results Of the 290 patients enrolled, 187 (64.5%) completed the 36 months of the study (entire cohort). In the entire cohort, 97 patients were treated exclusively with ranibizumab throughout the study and 90 patients switched to other intravitreal treatments. Mean BCVA was 64.2 (20.1) letters, representing a gain of +4.1 (19.9) letters from baseline to Month 36 (M36). CSFT improved over the study, and by M36 had decreased by 127 (138) µm compared to baseline. Over the 36 months of follow-up, patients in the entire cohort paid their ophthalmologists a mean of 30.9 (12.2) visits and had a mean of 7.6 (5.2) any injections Results for quality of life questionnaires NEI-VFQ25 and HUI-3 remained stable throughout the study. Multivariate analysis on the 145 patients with evaluable BCVA data at M36 found that male gender and milder baseline DME characteristics (BCVA ≥59 and CSFT <500 µm) were predictive factors for achieving a BCVA of ≥70 letters at M36. This study did not find any new safety signals, compared to the known profile of ranibizumab. Conclusions Gains in BCVA in this real life study were lower than those observed in randomized clinical trials with ranibizumab, mainly due to under treatment. Safety analysis of ranibizumab did not yield any new safety concerns.
DRUG DEVELOPMENT & PRECLINICAL STUDIES
Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB-VCAM-1 axis
Sci Adv. 2020 Jul 29;6(31):eaaz7815.
Yue Li, Ahmad M N Alhendi, Mei-Chun Yeh, Mina Elahy, Fernando S Santiago, Nandan P Deshpande, Ben Wu, Enoch Chan, Shafqat Inam, Leonel Prado-Lourenco, Jessica Marchand, Rohan D Joyce, Lorna E Wilkinson-White, Mark J Raftery, Meidong Zhu, Samuel J Adamson, François Barnat, Karen Viaud-Quentric, Jim Sockler, Joel P Mackay, Andrew Chang, Paul Mitchell, Sebastian M Marcuccio, Levon M Khachigian
PMID: 32937573 DOI: 10.1126/sciadv.aaz7815
Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.
Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization
Cells. 2020 Sep 9;9(9):E2057.
Franco Aparecido Rossato, Yu Su, Ashley Mackey, Yin Shan Eric Ng
PMID: 32917003 DOI: 10.3390/cells9092057
Many patients with wet age-related macular degeneration do not respond well to anti- vascular endothelial growth factor A (VEGFA) therapy for choroidal neovascularization (CNV), and the efficacy of anti-VEGFA decreases over time. We investigated the hypothesis that fibrotic changes, in particular via endothelial-to-mesenchymal transition (EndoMT), play a role in CNV and alter the therapeutic effects of VEGFA pathway blockage. Induction of EndoMT of primary human retinal endothelial cells led to a significantly reduced response to VEGFA at the level of gene expression, cellular proliferation, migration, and tube formation. Suppression of EndoMT restored cell responsiveness to VEGFA. In a mouse model of spontaneous CNV, fibrotic changes and EndoMT persisted as the CNV lesions became more established over time. VEGFA receptor-2 (VEGFR2) antagonism further induced fibrosis and EndoMT in the CNV. The combination of VEGFR2 antagonism and fibrosis/EndoMT inhibition was more effective than either individual treatment in reducing CNV. Our data indicate that fibrosis and EndoMT are involved in the progression of CNV, are exacerbated by VEGFR2 inhibition, and could provide an explanation for the reduced efficacy of anti-VEGFA treatment over time.
Suprachoroidal gene transfer with nonviral nanoparticles
Sci Adv. 2020 Jul 3;6(27):eaba1606.
Jikui Shen, Jayoung Kim, Stephany Y Tzeng, Kun Ding, Zibran Hafiz, Da Long, Jiangxia Wang, Jordan J Green, Peter A Campochiaro
PMID: 32937452 DOI: 10.1126/sciadv.aba1606
Subretinal injections of viral vectors provide great benefits but have limited cargo capacity; they induce innate and adaptive immune responses, which may cause damage and preclude repeated injections; and they pose administration risks. As a new biotechnology, suprachoroidal injections of biodegradable nanoparticles (NPs) containing a reporter plasmid induce reporter expression in rat photoreceptors and RPE throughout the entire eye and maintain expression for at least 8 months. Multiple injections markedly increase expression. Suprachoroidal injection of NPs containing a VEGF expression plasmid caused severe subretinal neovascularization progressing to subretinal fibrosis, similar to what occurs in untreated patients with neovascular age-related macular degeneration, providing a new model and proof of concept for level and duration of expression. Suprachoroidal injection of NPs containing a VEGF-binding protein expression plasmid significantly suppressed VEGF-induced vascular leakage and neovascularization demonstrating therapeutic potential. These data suggest that nonviral NP suprachoroidal gene transfer may provide a noninvasive, repeatable alternative to subretinal injection of viral vectors.
DIAGNOSIS & IMAGING
Non-neovascular age-related macular degeneration with subretinal fluid
Br J Ophthalmol. 2020 Sep 12;bjophthalmol-2020-317326.
Assaf Hilely, Adrian Au, K Bailey Freund, Anat Loewenstein, Eric H Souied, Dinah Zur, Riccardo Sacconi, Enrico Borrelli, Enrico Peiretti, Claudio Iovino, Yoshimi Sugiura, Abdallah A Ellabban, Jordi Monés, Nadia K Waheed, Sengul Ozdek, Duygu Yalinbas, Sarah Thiele, Luísa Salles de Moura Mendonça, Mee Yon Lee, Won Ki Lee, Pierre Turcotte, Vittorio Capuano, Meryem Filali Ansary, Usha Chakravarthy, Albrecht Lommatzsch, Frederic Gunnemann, Daniel Pauleikhoff, Michael S Ip, Giuseppe Querques, Frank G Holz, Richard F Spaide, SriniVas Sadda, David Sarraf
PMID: 32920528 DOI: 10.1136/bjophthalmol-2020-317326
Purpose: To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes.
Methods: This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes.
Results: Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy.
Conclusion: Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.
Multimodal imaging features and clinical relevance of subretinal lipid globules
Am J Ophthalmol. 2020 Sep 9;S0002-9394(20)30493-1.
Pedro Fernández-Avellaneda, K Bailey Freund, Ruikang K Wang, Qinghua He, Qinqin Zhang, Serena Fragiotta, Xiaoyu Xu, Gerardo Ledesma-Gil, Yoshimi Sugiura, Mark P Breazzano, Lawrence A Yannuzzi, Sandra Liakopoulos, David Sarraf, Rosa Dolz-Marco
PMID: 32918902 DOI: 10.1016/j.ajo.2020.09.003
Purpose: To describe the presence of subretinal lipid globules (SLG), analyze the multimodal imaging features inherent in their optical properties and provide a means to distinguish them from other retinal structures and clinical signs.
Design: Retrospective cohort study.
Methods: The clinical data and multimodal imaging features of 39 patients (49 eyes) showing SLG were evaluated. Patients underwent color fundus photography, near-infrared reflectance (NIR), spectral-domain (SD) and swept-source (SS) optical coherence tomography (OCT) and OCT angiography. In vitro phantom models were used to model OCT optical properties of water, mineral oil, and intralipid droplets and to investigate the optical mechanisms producing hypertransmission tails beneath SLG.
Results: The SLG were not visible in color fundus photographs or NIR images. With both SD- and SS-OCT B-scans, SLG appeared as 31-157 micron round hyporeflective structures demonstrating a characteristic hypertransmission tail previously described with lipid globules found in the choroid and in neovascular membranes. Similarly, with en face OCT, SLG appeared as small round hyporeflective structures. SLG were encountered most often in eyes with neovascular age-related macular degeneration (AMD) that had type 1 macular neovascularization (MNV) (91.8%). Of these eyes, 93.3% were receiving intravitreal anti-vascular endothelial growth factor (VEGF) therapy (median of 15 injections) with a mean follow-up of 52.6 months. The number of prior injections positively correlated with the number of SLG. The detection of MNV preceded the presence of SLG in 66.7% of cases. En face OCT showed that in many eyes (49%) SLG appeared in clusters of >10. In 38.8% of eyes, SLG were found overlying type 1 MNV and in 44.9% of eyes, often those with more numerous SLG, the SLG were located near the lesion border. In 2 eyes with AMD followed for nonexudative type 1 MNV, SLG were detected prior to the detection of other imaging signs of exudation. SLG were observed in several other exudative macular diseases. Phantom models demonstrated that the hypertransmission tail beneath SLG is related to a lensing effect produced by these hyporeflective spherical structures.
Conclusions: SLG are a newly recognized OCT feature frequently seen in eyes receiving intravitreal anti-VEGF therapy for type 1 MNV due to AMD. OCT B-scans show SLG as small, round, hyporeflective structures with a characteristic hypertransmission tail. This OCT signature is influenced by the OCT focal plane and it relates to reduced signal attenuation through oil and a lensing effect created by a higher refractive index compared to surrounding tissue.
A Pilot Study on MicroRNA Profile in Tear Fluid to Predict Response to Anti-VEGF Treatments for Diabetic Macular Edema
J Clin Med. 2020 Sep 10;9(9):E2920.
Hwei Wuen Chan, Binxia Yang, Wendy Wong, Paul Blakeley, Ivan Seah, Queenie Shu Woon Tan, Haofei Wang, Mayuri Bhargava, Hazel Anne Lin, Charmaine Hc Chai, Erlangga Ariadarma Mangunkusumo, Naing Thet, Yew Sen Yuen, Raman Sethi, Si Wang, Walter Hunziker, Gopal Lingam, Xinyi Su
PMID: 32927780 DOI: 10.3390/jcm9092920
(1) Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) is an established treatment for center-involving diabetic macular edema (ci-DME). However, the clinical response is heterogeneous. This study investigated miRNAs as a biomarker to predict treatment response to anti-VEGF in DME.
(2) Methods: Tear fluid, aqueous, and blood were collected from patients with treatment-naïve DME for miRNA expression profiling with quantitative polymerase chain reaction. Differentially expressed miRNAs between good and poor responders were identified from tear fluid. Bioinformatics analysis with the miEAA tool, miRTarBase Annotations, Gene Ontology categories, KEGG, and miRWalk pathways identified interactions between enriched miRNAs and biological pathways.
(3) Results: Of 24 participants, 28 eyes received bevacizumab (15 eyes) or aflibercept (13 eyes). Tear fluid had the most detectable miRNA species (N = 315), followed by serum (N = 309), then aqueous humor (N = 134). MiRNAs that correlated with change in macular thickness were miR-214-3p, miR-320d, and hsa-miR-874-3p in good responders; and miR-98-5p, miR-196b-5p, and miR-454-3p in poor responders. VEGF-related pathways and the angiogenin-PRI complex were enriched in good responders, while transforming growth factor-β and insulin-like growth factor pathways were enriched in poor responders.
(4) Conclusions: We reported a panel of novel miRNAs that provide insight into biological pathways in DME. Validation in larger independent cohorts is needed to determine the predictive performance of these miRNA candidate biomarkers.
Associations of the intestinal microbiome with the complement system in neovascular age-related macular degeneration
NPJ Genom Med. 2020 Sep 1;5:34.
Denise C Zysset-Burri, Irene Keller, Lieselotte E Berger, Carlo R Largiadèr, Matthias Wittwer, Sebastian Wolf, Martin S Zinkernagel
PMID: 32922859 PMCID: PMC7463023 DOI: 10.1038/s41525-020-00141-0
Age-related macular degeneration (AMD) is a leading cause of severe vision loss in the aged population. The etiology of AMD is multifactorial including nutritional factors, genetic variants mainly in the complement pathway, environmental risk factors and alterations in the intestinal microbiome. However, it remains unexplored whether there is an interdependency of these factors leading to the development of AMD. To investigate this issue, a shotgun metagenomics analysis of 57 neovascular AMD and 58 healthy controls as well as of 16 complement C3-deficient mice and 16 wildtypes was performed. Whereas the class Negativicutes was more abundant in patients, the genus Oscillibacter and species Bacteroides had a significantly higher prevalence in persons without AMD. Similar taxonomic features were identified that distinguished wildtype mice from C3-deficient mice. Moreover, several purine signaling pathways were associated with both, neovascular AMD and C3 deficiency. While SNPs within the complement factor B gene were more abundant in controls, SNPs within the high temperature requirement A serine peptidase 1 and complement factor H (CFH) genes were associated with neovascular AMD. Using a classification model, Negativicutes was identified as a potential biomarker for AMD and furthermore, it positively correlated with CFH. This study suggests an association between the intestinal microbiome and the complement system in neovascular AMD.
Systemic Levels of C-Reactive Protein in Patients with Age-Related Macular Degeneration: A Systematic Review with Meta-Analyses
Mech Ageing Dev. 2020 Sep 13;111353.
Chen Feng, Marie Krogh Nielsen, Torben Lykke Sørensen, Yousif Subhi
PMID: 32937187 DOI: 10.1016/j.mad.2020.111353
Ageing of the retina is associated with the gradual accumulation of basal deposits and the formation of drusen. However, in some individuals this process is exacerbated and causes development of age-related macular degeneration. Late features of age-related macular degeneration include geographic atrophy of the neuroretina or choroidal neovascularization. Such changes lead to blurred vision, metamorphopsia, and scotoma, and is the leading cause of vision loss in developed countries. Chronic low-grade inflammation has been investigated because of its relationship to ageing and its role in the gap between chronological and biological ageing. Here, we systematically reviewed studies investigating systemic C-reactive protein in patients with age-related macular degeneration. We identified 53 studies with 60,598 participants (10,392 patients and 38,901 controls). Our meta-analyses revealed that early age-related macular degeneration was not associated to systemic C-reactive protein (Cohen's d = 0.03 [-0.04 to 0.10]; OR = 1.06 [0.93 to 1.20]; P = 0.39) whereas late age-related macular degeneration (Cohen's d = 0.38 [0.24 to 0.51]; OR = 1.99 [1.55 to 2.52]; P < 0.0001), and neovascular age-related macular degeneration (Cohen's d = 0.40 [0.24 to 0.56]; OR = 2.07 [1.55 to 2.76]; P < 0.0001) was associated with a small-to-moderate increase in systemic C-reactive protein. Our review provides an overview of this extensively studied field, provide summary estimates that provide insight into when and to what extent systemic C-reactive protein is associated with age-related macular degeneration, and help in distinguishing the potentially reversible disease processes from that of irreversible retinal ageing.
Biomarkers for central serous chorioretinopathy
Ther Adv Ophthalmol. 2020 Aug 24;12:2515841420950846.
Gideon Nkrumah, Manuel Paez-Escamilla, Sumit Randhir Singh, Mohammed Abdul Rasheed, Dmitri Maltsev, Abhilash Guduru, Jay Chhablani
PMID: 32923941 PMCID: PMC7448152 DOI: 10.1177/2515841420950846
Central serous chorioretinopathy (CSCR) is a common chorioretinal disease characterized by serous retinal detachment that most commonly involves the macular region. Although the natural history of the acute form shows a self-limiting course, a significant number of patients suffer from recurrent episodes leading to chronic disease, often leaving patients with residual visual impairment. Visual morbidity is often worsened by a delay in the diagnosis due to the incorrect understanding of the particular biomarkers of the disease. The aim of this review is to provide clinical understanding of the biomarkers of CSCR with an emphasis on the most recent findings in patient demographics, risk factors, clinical imaging findings, and management options. Patients with these biomarkers, age 30-44 years, male gender, increased stress levels, hypercortisolism (endogenous and exogenous exposures), sleep disturbance, pregnancy, and genetic predisposition have increased susceptibility to CSCR. Also, biomarkers on optical coherence tomography (OCT) such as choroidal thickness (CT) and choroidal vascularity index (CVI) showed good diagnostic and prognostic significance in the management of CSCR. There are nonspecific features of CSCR on OCT and OCT angiography such as choroidal neovascularization, photoreceptor alteration/cone density loss, and flat irregular pigment epithelium detachment. We described rare complications of CSCR such as cystoid macular edema (CME) and cystoid macular degeneration (CMD). Patients with CME recovered some vision when treated with anti-vascular endothelial growth factors (anti-VEGFs). Patients with CMD had irreversible macular damage even after treatment with anti-VEGFs.
Treatment of radiation maculopathy and radiation-induced macular edema: a systematic review
Surv Ophthalmol. 2020 Sep 9;S0039-6257(20)30130-2.
Matteo Fallico, Argyrios Chronopoulos, James S Schutz, Michele Reibaldi
PMID: 32918934 DOI: 10.1016/j.survophthal.2020.08.007
Radiation maculopathy and radiation-induced macular edema are common sight-threatening complications following radiotherapy, especially that used for uveal melanoma. While many treatment and preventive strategies have been proposed, management of these conditions is still challenging. Initially, treatments were based on the use of retinal laser, but the outcomes were poor. Subsequently, management has shifted towards injection of intravitreal anti-vascular endothelial growth factor (anti-VEGF) or corticosteroids. We review current clinical evidence, which mostly relies on small sample-sized and retrospective studies, for the management of radiation maculopathy and, in particular, radiation-induced macular edema. At present, the first line approach is usually intravitreal anti-VEGF. Intravitreal dexamethasone implant may be an option for those with suboptimal response or contraindications to anti-VEGF agents. Possible preventive treatments that require future study are intravitreal bevacizumab and ranibizumab, peripheral laser photocoagulation, and subtenon triamcinolone acetonide.
A case of anti-VEGF therapy application in Takayasu arteries with retinopathy
Am J Ophthalmol Case Rep. 2020 Apr 29;19:100706.
Qiaoyun Gong, Tianwei Qian, Feng'e Chen, Xun Xu, Weijun Wang
PMID: 32923739 PMCID: PMC7474339 DOI: 10.1016/j.ajoc.2020.100706
Purpose: Takayasu arteritis (TA) is a systemic granulomatous large vessel vasculitis that involves mainly the aorta and its primary branches, and occurs most commonly in young females. Ocular manifestations of TA include small vessels dilation, microaneurysm, arteriovenous anastomosis, retinal ischemia and retinopathy. However, no specific and effective treatments for Takayasu retinopathy is applied. This case aimed to demonstrate the role of anti-VEGF (vascular endothelial growth factor) therapy in treating Takayasu retinopathy.
Observations: We herein reported an 18-year-old Asian woman who presented with typical wreath-like arteriovenous anastomosis around the disc in the right eye and vitreous hemorrhage in the left eye. The stenosis and occlusion of bilateral subclavian arteries, carotid arteries and other proximal arteries on angiography confirmed the diagnosis of TA. Meanwhile, elevated ESR and CRP revealed that TA was in the active stage. We applied anti-VEGF therapy in treating Takayasu retinopathy specially to inhibit neovascularization. Additionally, vitreous extraction was conducted in the left eye after the treatment of anti-VEGF therapy.
Conclusions and importance: This is the first report of effective application of anti-VEGF therapy in inhibiting wreath-like arteriovenous anastomosis and improving vitrectomy in TA.