Outcomes of Over 40,000 Eyes Treated for Diabetic Macula Edema in Routine Clinical Practice: A Systematic Review and Meta-analysis

Introduction: We investigated effectiveness and safety outcomes of diabetic macula edema (DME) treatment in routine clinical practice. Methods: A literature search was conducted of peer-reviewed articles published from January 2011 to September 2021. Studies of DME treatment in real-world practice of at least 6 months with at least 50 eyes at baseline were included. Randomized controlled trials (RCTs) were excluded. The primary outcome for this meta-analysis was change in visual acuity (VA) 12 months after starting treatment. Results: Of 3034 initially identified studies, 138 met selection criteria, representing more than 40,000 eyes. The mean 12-month VA gain was 4.6 letters (95% CI 3.7, 5.4; baseline 58.6) for vascular endothelial growth factor inhibitors (anti-VEGF), 4.4 (2.5, 6.3; baseline 54.2) for steroids, and 2.1 (- 1.2, 5.3; baseline 63.6) for macular laser. Australian and New Zealand studies had better baseline VA when initiating treatment compared with Asia, Europe, and North America, translating to better VA at 12 months. Fewer anti-VEGF injections were delivered in real-world practice than registrational RCTs. Neither systemic nor ocular safety was consistently reported. Conclusions: Intravitreal anti-VEGF or steroids for DME generally led to visual gains in real-world practice but these were less impressive than RCTs, with undertreatment and differences in baseline characteristics likely contributing factors. Keywords: Diabetic macula edema; Meta-analysis; Observational; Outcomes; Real-world data; Systematic review; Treatment

Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy

Background: Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight threatening complications of diabetes mellitus and leading causes of adult onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. Methods: Caucasian Australians with type 2 diabetes were evaluated in a genome wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. Results: The top ranked SNP for DME was rs1990145 (p = 4.10 x 10(-6), OR = 2.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p = 3.87 x 10(-6), OR = 0.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p = 0.008) in the DME cohort and rs16999051 in the diabetes gene PCSK.2 (p = 0.007) in the PDR cohort. Conclusion: This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology

Treat-and-extend versus fixed bimonthly treatment regimens for treatment-naive neovascular age-related macular degeneration: real world data from the Fight Retinal Blindness registry

Purpose To compare the outcomes of two different antivascular endothelial growth factor treatment regimens for treatment-naive eyes with neovascular age-related macular degeneration in routine clinical care at 12 and 24 months in Spain. Methods Observational study using the Fight Retinal Blindness (FRB) outcomes registry platform. Eyes were treated with fixed bimonthly (FB) aflibercept group at one center and a treat-and-extend (TAE) regimen using either aflibercept or ranibizumab at the other center. Results We included 192 eyes. Of these, 160 eyes (83%) completed 12 months (86 TAE and 74 FB) and 79 (41%) completed 24 months (46 for TAE and 33 for FB) of follow-up. No statistically significant differences (p > 0.05) were found regarding mean visual acuity (VA, logMAR letters) at baseline (12 month cohort TAE 59.6 vs FB 57.9; 24 month cohort TAE 61.7 vs FB 62.6), final meanVA (12 month cohort TAE 61.1 vs FB 63.0; 24 month cohort TAE 64.8 vs FB 66.4), and median number of injections (12 months TAE 7 vs FB 7; 24 months TAE 11 vs FB 12). However, the distribution of injection frequencies for the TAE group was larger, with 35% of TAE eyes receiving ! 6 injections at 12 months compared with only 19% of FB eyes (p = 0.024). Conclusion Similar VA results were observed with TAE and FB regimens, with no differences in the median number of injections. However, the TAE approach seemed to deliver a wider distribution of injection frequencies due to its individualized approach, which may help reduce the burden of injections in some eyes

Choroidal Structural Changes Correlate With Neovascular Activity in Neovascular Age Related Macular Degeneration.

Purpose To correlate changes in choroidal thickness and vascularity index with disease activity in patients with neovascular age-related macular degeneration (nAMD). Methods Eyes diagnosed with AMD that had two sequential visits within 12 months and that had no choroidal neovascularization (CNV) or had inactive CNV at the first visit were included. Those that had active CNV at follow-up were enrolled as cases. Eyes that did not developed a CNV or that were still inactive at the second visit were enrolled as controls. Disease activity was based on optical coherence tomography (OCT) and fluorescein angiography findings. Subfoveal choroidal thickness (SCT), mean choroidal thickness (MCT), and choroidal vascularity index (CVI) were assessed on enhanced depth imaging OCT and compared between the baseline and follow-up visit. Subgroup analysis accounting for lesion type and previous treatment, if any, were performed. Results Sixty-five eyes from 60 patients (35 females) and 50 age- and sex-matched controls were included. At the active visit, cases had an increase from 164 ± 67 μm to 175 ± 70 μm in mean ± SD SCT and from 144 ± 45 μm to 152 ± 45 μm in MCT (both P < 0.0001). The mean CVI also increased at from 54.5% ± 3.3% to 55.4% ± 3.8% (P = 0.04). Controls did not show significant changes in choroidal measurements between the two visits. Mean SCT, MCT, and CVI values were similar for previously treated and treatment-naive eyes. Conclusions Choroidal thickness and CVI significantly increased with active disease in nAMD eyes. Changes in choroidal thickness may predict CNV development or recurrence before they are otherwise evident clinically

Creation of a neovascular age-related macular degeneration national database using a web-based platform: Fight Retinal Blindness Spain. Report 1: Visual outcomes

Background: To study the visual outcomes of neovascular AMD (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs at national level. Methods: Multicenter national database of nAMD eyes treated with anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat-and-extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web-based tool (Fight Retinal Blindness!). Results: 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p = 0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/-3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p = 0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p = 0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). Conclusion: Independent, large-scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real-world international cohorts. Keywords: aflibercept; age-related macular degeneration; audit; benchmark standard; bevacizumab; national database; national dataset; neovascular AMD; ranibizumab

Vascular endothelial growth factor inhibitors for predominantly Caucasian myopic choroidal neovascularization: 2-year treatment outcomes in clinical practice: data from the Fight Retinal Blindness! Registry

Purpose: To report the 24-month outcomes of vascular endothelial growth factor (VEGF) inhibitors for myopic choroidal neovascularization (mCNV) in predominantly Caucasian eyes in routine clinical practice. Methods: Retrospective analysis of treatment-na¿ıve eyes starting intravitreal injection of VEGF inhibitors of either bevacizumab (1.25 mg) or ranibizumab (0.5 mg) for mCNV from 1 January 2006 to 31 May 2018 that were tracked in the Fight Retinal Blindness! registry. Results: We identified 203 eyes (bevacizumab-85 and ranibizumab-118) of 189 patients. The estimated mean (95% CI) change in VA over 24 months for all eyes using longitudinal models was +8 (5, 11) letters with a median (Q1, Q3) of 3 (2, 5) injections given mostly during the first year. The estimated mean change in VA at 24 months was similar between bevacizumab and ranibizumab [+9 (5, 13) letters for bevacizumab versus +9 (6, 13) letters for ranibizumab; p = 0.37]. Both agents were also similar in the mCNV activity outcomes, treatment frequency and visit frequency. Conclusions: The 24-month treatment outcomes of VEGF inhibitors for mCNV were favourable in this largest series yet reported of predominantly Caucasian eyes in routine clinical practice,with approximately two lines of visual gain and amedian of three injections given mostly during the first year. These outcomes are similar to those reported for predominantly Asian eyes.Bevacizumab appeared to be as safeandeffective as ranibizumab. Key words: anti-VEGF therapy - Caucasian - high myopia - myopia - myopic choroidal neovascularization - optical coherence tomography - pathologic myopia - VEGF inhibitor

Conditional müller cell ablation causes independent neuronal and vascular pathologies in a novel transgenic model

Müller cells are the major glia of the retina that serve numerous functions essential to retinal homeostasis, yet the contribution of Müller glial dysfunction to retinal diseases remains largely unknown. We have developed a transgenic model using a portion of the regulatory region of the retinaldehyde binding protein 1 gene for conditional Müller cell ablation and the consequences of primary Müller cell dysfunction have been studied in adult mice. We found that selective ablation of Müller cells led to photoreceptor apoptosis, vascular telangiectasis, blood-retinal barrier breakdown and, later, intraretinal neovascularization. These changes were accompanied by impaired retinal function and an imbalance between vascular endothelial growth factor-A (VEGF-A) and pigment epithelium-derived factor. Intravitreal injection of ciliary neurotrophic factor inhibited photoreceptor injury but had no effect on the vasculopathy. Conversely, inhibition of VEGF-A activity attenuated vascular leak but did not protect photoreceptors. Our findings show that Müller glial deficiency may be an important upstream cause of retinal neuronal and vascular pathologies in retinal diseases. Combined neuropro-tective and anti-angiogenic therapies may be required to treat Müller cell deficiency in retinal diseases and in other parts of the CNS associated with glial dysfunction

Hemiretinal vein occlusion 12-month outcomes are unique with vascular endothelial growth factor inhibitors: data from the Fight Retinal Blindness! Registry

BACKGROUND/AIMS To describe baseline characteristics and 12-month outcomes with vascular endothelial growth factor (VEGF) inhibitors of treatment-naïve hemiretinal vein occlusion (HRVO) compared with branch (BRVO) and central (CRVO) variants in routine clinical care. METHODS A database observational study recruited 79 HRVO eyes, 590 BRVO eyes and 344 CRVO eyes that initiated therapy over 10 years. The primary outcome was mean change in visual acuity (VA-letters read on a logarithm of minimal angle of resolution chart) at 12 months. Secondary outcomes included mean change in central subfield thickness (CST), injections and visits. RESULTS At baseline, mean VA in HRVO (53.8) was similar to CRVO (51.9; p=0.40) but lower than BRVO (59.4; p=0.009). HRVO eyes improved to match BRVO eyes from soon after treatment started through 12 months. Mean change in VA was greater in HRVO (+16.4) than both BRVO (+11.4; p=0.006) and CRVO (+8.5; p<0.001). Mean change in CST in HRVO (-231 µm) was similar to CRVO (-259 µm; p=0.33) but greater than BRVO eyes (-151 µm; p=0.003). The groups had similar median burdens of eight injections and nine visits. CONCLUSIONS HRVO generally experienced the greatest mean change in VA of the three types of RVO when treated with VEGF inhibitors, ending with similar 12-month VA and CST to BRVO despite starting closer to CRVO. Inclusion of HRVO in BRVO or CRVO cohorts of clinical trials would be expected to proportionally inflate and skew the visual and anatomic outcomes

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

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

Analysis of candidate genes for macular telangiectasia type 2

Purpose: To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach.Methods: Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they cosegregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts.Results: We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism.Conclusions: We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel