In this week’s issue

• High-dose aflibercept holds strong at 2 years for CI-DME with significantly fewer injections.
• Retinal disease burden in the US is vast and unevenly distributed.
• Retinal imaging may serve as a noninvasive window into microvascular kidney disease.
• Keratoconus may be underrecognized in older adults.

Ophthalmology

Fewer injections, same gains: can high-dose aflibercept hold up at two years? 

For patients with diabetic macular edema (DME), less is more. Central DME is the leading cause of diabetes-related vision loss and often requires frequent anti-vascular endothelial growth factor (anti-VEGF) injections, imposing a significant treatment burden. Aflibercept 8 mg was developed to extend the dosing interval beyond the standard 8-week interval seen with the 2 mg formulation, with previously published data supporting noninferiority. This study evaluated whether the noninferiority could be maintained over 2 years of treatment. Six hundred fifty-eight patients with central DME were randomized to aflibercept 2 mg dosed every 8 weeks (2q8), aflibercept 8 mg dosed every 12 weeks (8q12), or aflibercept 8 mg dosed every 16 weeks (8q16). Visual acuity improvements and reduction in central retinal thickness were comparable across all three groups at 96 weeks, with patients in the 8q groups receiving fewer injections. Additionally, 88% and 83% of patients in the 8q12 and 8q16 groups were able to extend their treatment intervals, with approximately half qualifying for intervals of 20 weeks or longer. Overall, high-dose aflibercept provides durable visual and anatomic outcomes while substantially reducing injection burden through 96 weeks of treatment in patients with central DME.

JAMA Ophthalmology 

How identity shapes retinal disease risk

Retina care is not just about treating disease, but also about addressing disparities. Age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), and retinal vein occlusion (RVO) are major causes of vision loss in the United States. As treatment options for these diseases expand, understanding their epidemiologic risk factors has become increasingly important. This cross-sectional meta-analysis combined numerous population-based datasets from 2022 to estimate the prevalence of these retinal diseases across sexual, racial, ethnic, and geographic groups in the US. The study found that, in 2022, 21.9 million Americans were living with AMD (prevalence 13.6%), 10 million with DR (3.0%), 1.1 million with DME (0.3%), and 0.9 million with RVO (0.3%), with significant racial, ethnic, and geographic disparities in both disease burden and access to retina specialists. Caucasians demonstrated a higher prevalence of AMD and RVO, while Black and Hispanic populations displayed a higher prevalence of DR and DME. Wyoming had the poorest access to retinal specialists, highlighting significant disparities in access. These findings indicate that retinal disease burden in the US is not evenly distributed and that understanding these disparities may guide future screening programs, workforce planning, and resource allocation for retina care.

American Journal of Ophthalmology 

Can the retina serve as a biomarker of kidney disease?

Retinal imaging continues to serve as a window to systemic health. Diabetic nephropathy is a leading cause of chronic kidney disease (CKD) worldwide. Yet, current screening methods rely primarily on serologic and urine tests that may miss early microvascular damage. In this cross-sectional study, swept-source optical coherence tomography angiography (SS-OCTA) metrics were assessed as indirect biomarkers of diabetic nephropathy severity. The study analyzed 375 eyes from 234 patients using wide-field angiograms centered on the fovea. Metrics included nonperfusion area (NPA), foveal avascular zone (FAZ) area, vessel density (VD), and vessel skeletonized density (VSD), which were correlated to albuminuria, CKD staging, and Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. There was a significant positive association between retinal NPA and albuminuria, CKD presence, worsening CKD severity, and higher KDIGO risk categories. In patients with no or mild diabetic retinopathy, more circular FAZ morphology and higher retinal VSD were inversely associated with albuminuria. These findings suggest that SS-OCTA metrics, particularly retinal NPA, may serve as promising noninvasive biomarkers for diabetic nephropathy severity and systemic microvascular risk.

Investigative Ophthalmology and Visual Science  

A new target for putting the brakes on subretinal fibrosis
Too much fibrosis with M2 macrophages. Subretinal fibrosis is a major driver of permanent vision loss in neovascular age-related macular degeneration. While anti-VEGFs are the first-line therapy for choroidal neovascularization (CNV), no drugs are available that specifically prevent subretinal fibrosis. This preclinical study explored whether tumor necrosis factor alpha–induced protein 3 (TNFAIP3), an anti-inflammatory regulator in macrophages, could abrogate CNV-associated fibrosis. Using a laser-induced in vivo murine model of CNV, the authors found that TNFAIP3 expression in M2 macrophages initially rises but later declines with the progression of subretinal fibrosis. Mechanistically, TNFAIP3 suppresses M2 macrophage polarization through the NF-κB/Spi1/C/EBPβ pathway and reduces TGF-β1/Smad-driven epithelial–mesenchymal transition in RPE cells, thereby reducing fibrosis. In TNFAIP3-overexpressing mice, M2 macrophages reduce CNV area by more than 80% and fibrosis area by approximately 40% compared to controls. Overall, TNFAIP3 may serve as a future cell-targeted strategy for the management of CNV and subretinal fibrosis.

Cornea

Keratoconus beyond midlife: A blind spot in ophthalmology?

Traditional assumptions about keratoconus and age may warrant closer scrutiny. Research suggests that keratoconus (KCN) is most commonly diagnosed in individuals in their third or fourth decade of life, with disease progression stabilizing by the early 50s. However, keratoconus prevalence rates vary across studies and much of the existing literature emphasizes young adults. In this population-based cross-sectional study, adults aged ≥60 years were recruited to undergo a comprehensive ophthalmologic evaluation. Among 3,191 participants, the prevalence of KCN was 5.36%, with prevalence increasing with age from 4.6% in individuals aged 60–64 years to 6.92% in those aged ≥80 years. Interestingly, illiteracy had a significant positive association with KCN, and the most common corneal pattern observed was asymmetric bowtie with inferior steepening. These findings challenge traditional assumptions about the unimodal distribution of KCN and suggest it may be underrecognized in older adults, suggesting a need for routine corneal topographic studies in elderly patients, especially in those undergoing cataract surgery, as KCN can significantly impact lens selection and refractive outcomes.

The Lancet Digital Health

Can AI predict who will benefit from anti-VEGF for wet AMD?

Treatment response in neovascular age-related macular degeneration (nAMD) can be difficult to predict, even though repeated injections carry major financial and procedural burden. In this prospective multicenter study across 18 tertiary hospitals in China, investigators developed the KongMing Model, a lesion-aware transformer-based deep learning system trained on pretreatment optical coherence tomography (OCT) images to predict both functional and anatomic response to anti-vascular endothelial growth factor (anti-VEGF) therapy under a 3+PRN regimen. The model generated three clinically relevant forecasts: response after a single injection, after the initial three loading injections, and at 1 year. KongMing showed excellent performance for predicting best-corrected visual acuity (BCVA) change, with AUCs of 0.948, 0.972, and 0.989 in the internal test set and 0.941, 0.964, and 0.979 in the external test set across those same timepoints, while also outperforming ophthalmologists in head-to-head comparison. The model also predicted post-treatment BCVA values with low mean absolute error (~0.05) and generated post-treatment OCT images that closely resembled true scans. Overall, this study suggests AI may help personalize anti-VEGF counseling and treatment planning in nAMD by forecasting both visual and structural outcomes before therapy begins. 

Atropine for the Treatment of Childhood Myopia (ATOM2) - 2012

How low can you go… with the dose of atropine in myopic children? Following the first ATOM1 study, which showed that 1% atropine could slow myopia progression, the 2012 ATOM2 study sought to determine what dosage provided the most benefit without the cost. In this study, 400 myopic children were randomized to treatment with atropine 0.01% (n=84), atropine 0.1% (n=155), or atropine 0.5% (n=161).

Key Points:

• There was no clinically significant (although there was statistically significant) difference in the progression of myopia among patients treated with the 3 doses of atropine.
• Patients treated with atropine 0.01% experienced less visual side effects and minimal atropine-associated adverse events as compared to the 0.1% and 0.5% groups.

Overall, the ATOM2 study is a landmark study because it showed that atropine 0.01% was a safe and efficacious dose in children to decrease the progression of myopia while minimizing the visual side effects seen with higher doses.