Home-Monitoring Vision Tests to Detect Active Neovascular Age-Related Macular Degeneration.

Importance: Most neovascular age-related macular degeneration (nAMD) treatments involve long-term follow-up of disease activity. Home-monitoring would reduce the burden on patients and their caregivers and release clinic capacity. Objective: To evaluate 3 vision home-monitoring tests for patients to use to detect active nAMD compared with diagnosing active nAMD at hospital follow-up during the after-treatment monitoring phase. Design, Setting, and Participants: This was a diagnostic test accuracy study wherein the reference standard was detection of active nAMD by an ophthalmologist at hospital follow-up. The 3 home-monitoring tests evaluated included the following: (1) the KeepSight Journal (KSJ [International Macular and Retinal Foundation]), which contains paper-based near-vision tests presented as word puzzles, (2) the MyVisionTrack (mVT [Genentech]) vision-monitoring mobile app, viewed on an Apple mobile operating system-based device, and (3) the MultiBit (MBT [Visumetrics]) app, viewed on an Apple mobile operating system-based device. Participants were asked to test weekly; mVT and MBT scores were transmitted automatically, and KSJ scores were returned to the research office every 6 months. Raw scores between hospital follow-ups were summarized as averages. Patients were recruited from 6 UK hospital eye clinics and were 50 years and older with at least 1 eye first treated for active nAMD for at least 6 months or longer to a maximum of 42 months before approach. Participants were stratified by time since starting treatment. Study data were analyzed from May to September 2021. Exposures: The KSJ, mVT, and MBT were compared with the reference standard (in-hospital ophthalmologist examination). Main Outcomes and Measures: Estimated area under receiver operating characteristic curve (AUROC). The study had 90% power to detect a difference of 0.06, or 80% power to detect a difference of 0.05, if the AUROC for 2 tests was 0.75. Results: A total of 297 patients (mean [SD] age, 74.9 [6.6] years; 174 female [58.6%]) were included in the study. At least 1 hospital follow-up was available for 312 study eyes in 259 participants (1549 complete visits). Median (IQR) home-monitoring testing frequency was 3 (1-4) times per month. Estimated AUROC was less than 0.6 for all home-monitoring tests, and only the KSJ summary score was associated with lesion activity (odds ratio, 3.48; 95% CI, 1.09-11.13; P = .04). Conclusions and Relevance: Results suggest that no home-monitoring vision test evaluated provided satisfactory diagnostic accuracy to identify active nAMD diagnosed in hospital eye service follow-up clinics. Implementing any of these evaluated tests, with ophthalmologists only reviewing test positives, would mean most active lesions were missed, risking unnecessary sight loss.

Central serous chorioretinopathy: An evidence-based treatment guideline.

Central serous chorioretinopathy (CSC) is a relatively common disease that causes vision loss due to macular subretinal fluid leakage and it is often associated with reduced vision-related quality of life. In CSC, the leakage of subretinal fluid through defects in the retinal pigment epithelial layer's outer blood-retina barrier appears to occur secondary to choroidal abnormalities and dysfunction. The treatment of CSC is currently the subject of controversy, although recent data obtained from several large randomized controlled trials provide a wealth of new information that can be used to establish a treatment algorithm. Here, we provide a comprehensive overview of our current understanding regarding the pathogenesis of CSC, current therapeutic strategies, and an evidence-based treatment guideline for CSC. In acute CSC, treatment can often be deferred for up to 3-4 months after diagnosis; however, early treatment with either half-dose or half-fluence photodynamic therapy (PDT) with the photosensitive dye verteporfin may be beneficial in selected cases. In chronic CSC, half-dose or half-fluence PDT, which targets the abnormal choroid, should be considered the preferred treatment. If PDT is unavailable, chronic CSC with focal, non-central leakage on angiography may be treated using conventional laser photocoagulation. CSC with concurrent macular neovascularization should be treated with half-dose/half-fluence PDT and/or intravitreal injections of an anti-vascular endothelial growth factor compound. Given the current shortage of verteporfin and the paucity of evidence supporting the efficacy of other treatment options, future studies-ideally, well-designed randomized controlled trials-are needed in order to evaluate new treatment options for CSC.

Systematic review of prognostic factors associated with progression to late age-related macular degeneration: Pinnacle study report 2.

There is a need to identify accurately prognostic factors that determine the progression of intermediate to late-stage age-related macular degeneration (AMD). Currently, clinicians cannot provide individualised prognoses of disease progression. Moreover, enriching clinical trials with rapid progressors may facilitate delivery of shorter intervention trials aimed at delaying or preventing progression to late AMD. Thus, we performed a systematic review to outline and assess the accuracy of reporting prognostic factors for the progression of intermediate to late AMD. A meta-analysis was originally planned. Synonyms of AMD and disease progression were used to search Medline and EMBASE for articles investigating AMD progression published between 1991 and 2021. Initial search results included 3229 articles. Predetermined eligibility criteria were employed to systematically screen papers by two reviewers working independently and in duplicate. Quality appraisal and data extraction were performed by a team of reviewers. Only 6 studies met the eligibility criteria. Based on these articles, exploratory prognostic factors for progression of intermediate to late AMD included phenotypic features (e.g. location and size of drusen), age, smoking status, ocular and systemic co-morbidities, race, and genotype. Overall, study heterogeneity precluded reporting by forest plots and meta-analysis. The most commonly reported prognostic factors were baseline drusen volume/size, which was associated with progression to neovascular AMD, and outer retinal thinning linked to progression to geographic atrophy. In conclusion, poor methodological quality of included studies warrants cautious interpretation of our findings. Rigorous studies are warranted to provide robust evidence in the future.

Associations with Non-Persistence with Intra-Vitreal Therapy for Neovascular Age-Related Macular Degeneration at 24 Months.

AIMS: The aim of the study was to investigate non-persistence with treatment for neovascular age-related macular degeneration (NvAMD) before day 720 (24 months) after initiation, explore associations with baseline characteristics and variation between sites. METHODS: Anonymised demographic and clinical data were extracted from electronic medical records at treating National Health Service (NHS) Trusts for NvAMD eyes starting intra-vitreal therapy from 2017 to 2018. Time to non-persistence with treatment, defined as no recorded attendance for either monitoring or treatment for a period ≥6 months, was visualised with a Kaplan-Meier survival plot. Associations with treatment non-persistence were investigated using a Cox proportional hazards model. RESULTS: Analysis included 7,970 eyes of 7,112 patients treated at 13 NHS trusts. Censoring deaths and those eyes in which treatment was stopped permanently, the Kaplan-Meier analyses demonstrated survival figures of 77.7% for persistence with treatment to day 360 and 71.8% to day 720. Hazard ratios for non-persistence with treatment were reduced at 10 sites, relative to the reference, with first-treated eye status and with baseline acuity worse than or equal to LogMAR 1.0. Hazard ratios increased with younger age, in the presence of other ocular co-morbidities and with baseline acuity better than or equal to LogMAR 0.5. After an episode of non-persistence, visual acuity decreased by at least 0.1 and 0.3 LogMAR in 39% and 18% of eyes, respectively. CONCLUSIONS: Non-persistence with treatment was common, especially in the first year of treatment, and was often associated with a decrease in visual acuity. Treatment site, baseline visual acuity, and age were the strongest predictors of treatment non-persistence before day 720. Understanding and addressing reasons for non-persistence are important to ensure that effective but expensive treatments are used cost-effectively and to maintain acuity. Variation in non-persistence between sites, even after adjustment for other variables, suggests that local factors in treatment provision may be particularly important.

Changes in Retinal Sensitivity Associated With Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa With RPGR Gene Variations.

Importance: X-linked retinitis pigmentosa (XLRP) is a severe cause of early-onset RP in male individuals, characterized by degeneration of photoreceptors, an extinguished electroretinogram, and vision loss. Objective: To assess the duration of improvements in retinal sensitivity associated with a single, subretinal injection of cotoretigene toliparvovec (BIIB112/AAV8-RPGR) gene therapy after vitrectomy surgery in the dosed eye over 12 months in part 1 of the Clinical Trial of Retinal Gene Therapy for X-linked Retinitis Pigmentosa Using BIIB112 (XIRIUS) study, compared with untreated fellow eyes and eyes from the untreated subgroup from the Natural History of the Progression of X-Linked Retinitis Pigmentosa (XOLARIS) study. Design, Setting, and Participants: This was a post hoc analysis of the XIRIUS and XOLARIS studies. Part 1 of the XIRIUS study was a phase 1, dose-escalation study of 18 male participants 18 years or older enrolled between March 8, 2017, and October 16, 2018, with genetically confirmed RPGR-variant XLRP with active disease and best-corrected visual acuity better than or equal to light perception (cohort 1), 34 to 73 letters (20/40 to 20/200 Snellen equivalent; cohorts 2-3), or greater than or equal to 34 letters (better than or equal to 20/200 Snellen equivalent; cohorts 4-6). Participants from the noninterventional, multicenter, global, prospective XOLARIS clinical study who met the inclusion and exclusion criteria of part 1 of XIRIUS were included as a comparator group (n = 103). Safety assessments included all XIRIUS participants; post hoc associations of retinal sensitivity assessments in XIRIUS only included the 12 participants receiving the 4 highest doses of cotoretigene toliparvovec. Data were analyzed on June 30, 2021. Main Outcomes and Measures: Incidence of dose-limiting toxicities (DLTs), treatment-emergent adverse events, changes from baseline in retinal sensitivity (as assessed by macular integrity assessment microperimetry), retinal sensitivity response (achievement of ≥7-dB improvement from baseline at ≥5 of 16 central loci), and low-luminance visual acuity were assessed over 24 months. Results: A total of 18 participants (mean [SD] age, 31.9 [9.4] years; male, 100%) were enrolled and completed the XIRIUS study. A subgroup of 103 participants (mean [SD] age, 30.8 [11.4] years; male, 100%) from the XOLARIS study was included. Administration of the 4 highest doses of cotoretigene toliparvovec (n = 12) among the 18 XIRIUS participants was associated with early improvements in retinal sensitivity. One of 103 untreated participants (1%) in the XOLARIS subgroup achieved improved retinal sensitivity at month 12. No DLTs were noted at any dose, and serious adverse events of reduced visual acuity (n = 2) and noninfective retinitis (n = 1) occurred. Conclusions and Relevance: Results suggest that early and sustained improvements in retinal sensitivity and low-luminance visual acuity in some participants through 12 months support consideration of additional clinical trials. Trial Registration: ClinicalTrials.gov Identifier: XIRIUS: NCT03116113; XOLARIS: NCT04926129.

An Exploratory Study Provides Insights into MMP9 and Aß Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients.

Matrix metalloproteinase-9 (MMP9) and total amyloid-beta (Aß) are prospective biomarkers of ocular ageing and retinopathy. These were quantified by ELISA in the vitreous and blood from controls (n = 55) and in a subset of age-related macular degeneration (AMD) patients (n = 12) for insights and possible additional links between the ocular and systemic compartments. Vitreous MMP9 levels in control and AMD groups were 932.5 ± 240.9 pg/mL and 813.7 ± 157.6 pg/mL, whilst serum levels were 2228 ± 193 pg/mL and 2386.8 ± 449.4 pg/mL, respectively. Vitreous Aß in control and AMD groups were 1173.5 ± 117.1 pg/mL and 1275.6 ± 332.9 pg/mL, whilst plasma Aß were 574.3 ± 104.8 pg/mL and 542.2 ± 139.9 pg/mL, respectively. MMP9 and Aß showed variable levels across the lifecourse, indicating no correlation to each other or with age nor AMD status, though the smaller AMD cohort was a limiting factor. Aß and MMP9 levels in the vitreous and blood were unrelated to mean arterial pressure. Smoking, another modifiable risk, showed no association with vitreous Aß. However, smoking may be linked with vitreous (p = 0.004) and serum (p = 0.005) MMP9 levels in control and AMD groups, though this did not reach our elevated (p = 0.001) significance. A bioinformatics analysis revealed promising MMP9 and APP/Aß partners for further scrutiny, many of which are already linked with retinopathy.

Clinical impact of the worldwide shortage of verteporfin (Visudyne®) on ophthalmic care.

INTRODUCTION: Since July 2021, a worldwide shortage of verteporfin (Visudyne®) occurred: an essential medicine required for photodynamic therapy (PDT). PDT with verteporfin has a broad range of indications in ophthalmology, including chronic central serous chorioretinopathy, polypoidal choroidal vasculopathy and choroidal haemangioma. For these disorders, PDT is either the first-choice treatment or regarded as a major treatment option. MATERIALS AND METHODS: A questionnaire was sent to key opinion leaders in the field of medical retina throughout the world, to assess the role of PDT in their country and the effects of the shortage of verteporfin. In addition, information on the application of alternative treatments during shortage of verteporfin was obtained, to further assess the impact of the shortage. RESULTS: Our questionnaire indicated that the shortage of verteporfin had a major impact on ophthalmic care worldwide and was regarded to be a serious problem by most of our respondents. However, even though there is ample evidence to support the use of PDT in several chorioretinal diseases, we found notable differences in its use in normal patient care throughout the world. Various alternative management strategies were noted during the verteporfin shortage, including lowering the dose of verteporfin per patient, the use of alternative treatment strategies and the use of a centralized system for allocating the remaining ampoules of verteporfin in some countries. CONCLUSION: The shortage of verteporfin has had a large effect on the care of ophthalmic patients across the world and may have resulted in significant and irreversible vision loss. Mitigation strategies should be developed in consultation with all stakeholders to avoid future medication shortages of verteporfin and other unique ophthalmic medications. These strategies may include mandatory stock keeping, compulsory licensing to an alternative manufacturer or incentivizing the development of competition, for example through novel public-private partnerships.

The Natural History of Leber Congenital Amaurosis and Cone-Rod Dystrophy Associated with Variants in the GUCY2D Gene.

OBJECTIVE: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials. DESIGN: International, multicenter, retrospective cohort study. SUBJECTS: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families. METHODS: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence). MAIN OUTCOMES MEASURES: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging. RESULTS: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD. CONCLUSIONS: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD.

The effect of systemic levels of TNF-alpha and complement pathway activity on outcomes of VEGF inhibition in neovascular AMD.

BACKGROUND/OBJECTIVES: Systemic levels of pro-inflammatory cytokines and activated complement components affect the risk and/or progression of neovascular age-related macular degeneration (AMD). This study investigated the effect of serum pro-inflammatory cytokine levels and complement pathway activity on the clinical response to vascular endothelial growth factor (VEGF) inhibition in neovascular AMD. METHODS: Sixty-five patients with a new diagnosis of neovascular AMD were observed over a six-month period in a single-centre, longitudinal cohort study. At each visit, the visual acuity score (VAS), central macular thickness (CMT), serum levels of CRP, pro-inflammatory cytokines (TNF-α, IL-1ß, IL-2, IL-6 and IL-8), and complement pathway activity were measured. Participant DNA samples were sequenced for six complement pathway single nucleotide polymorphisms (SNPs) associated with AMD. RESULTS: A statistically significant difference in VAS was observed for serum levels of TNF-α only: there was a gain in VAS (from baseline) of 1.37 for participants below the 1st quartile of mean concentration compared to a reduction of 2.71 for those above the 3rd quartile. Statistical significance was maintained after Bonferroni correction (P value set at <0.006). No significant differences in CMT were observed. In addition, statistically significant differences, maintained after Bonferroni correction, were observed in serum complement activity for participants with the following SNPs: CFH region (rs1061170), SERPING1 (rs2511989) and CFB (rs641153). Serum complement pathway components did not significantly affect VAS. CONCLUSIONS: Lower serum TNF-α levels were associated with an increase in visual acuity after anti-VEGF therapy. This suggests that targeting pro-inflammatory cytokines may augment treatment for neovascular AMD.

Treat and extend versus fixed regimen in neovascular age related macular degeneration: A systematic review and meta-analysis.

PURPOSE: To compare efficacy of treat and extend (T&E) versus fixed regimen treatment protocols in neovascular age-related macular degeneration (nAMD). METHODS: Randomized clinical trials (RCTs) comparing T&E versus fixed regimen protocols for nAMD were systematically searched. Primary outcome was to compare the mean best corrected visual acuity (BCVA) change in T&E regimen versus fixed regimen. Secondary outcomes were change in the mean optical coherence tomography (OCT) central retinal thickness (CRT) and mean number of injections. Standardized mean difference (SMD) along with 95% confidence intervals (CIs) were calculated. Random-effect models were used for meta-analyses. RESULTS: Four RCTs were included, with a total of 649 and 621 eyes in the T&E and fixed regimen cohort at 12 months, and 267 and 249 eyes at 24 months. Pooled analysis of mean BCVA change included all four RCTs at 12 months and two RCTs at 24 months, showing no difference between the two groups (12-month: SMD = 0.08, 95% CI: -0.20 to 0.35, p = 0.55; 24-month: SMD = 0.04, 95% CI: -0.13 to 0.21, p = 0.64). Pooled analysis of OCT CRT change at 12 months included three studies, showing no difference between the two groups (SMD = 0.03, 95% CI: -0.46 to 0.51, p = 0.91). Pooled analysis of mean injection number included all four RCTs at 12 months and two RCTs at 24 months, showing significant difference between the two groups (12-month: SMD = -1.11, 95% CI: -1.67 to -0.56, p < 0.001; 24-month: SMD = -1.34, 95% CI: -1.54 to -1.15, p < 0.001). CONCLUSION: A T&E regimen proved as effective as a fixed dosage regimen throughout a 24-month follow-up and with a lower number of injections.

Adaptive optics: principles and applications in ophthalmology.

This is a comprehensive review of the principles and applications of adaptive optics (AO) in ophthalmology. It has been combined with flood illumination ophthalmoscopy, scanning laser ophthalmoscopy, as well as optical coherence tomography to image photoreceptors, retinal pigment epithelium (RPE), retinal ganglion cells, lamina cribrosa and the retinal vasculature. In this review, we highlight the clinical studies that have utilised AO to understand disease mechanisms. However, there are some limitations to using AO in a clinical setting including the cost of running an AO imaging service, the time needed to scan patients, the lack of normative databases and the very small size of area imaged. However, it is undoubtedly an exceptional research tool that enables visualisation of the retina at a cellular level.

3D-Reconstructed Retinal Pigment Epithelial Cells Provide Insights into the Anatomy of the Outer Retina.

The retinal pigment epithelium (RPE) is located between the neuroretina and the choroid, and plays a critical role in vision. RPE cells internalise outer segments (OS) from overlying photoreceptors in the daily photoreceptor renewal. Changes to RPE structure are linked with age and retinopathy, which has been described in the past by conventional 2D electron microscopy. We used serial block face scanning electron microscopy (SBF-SEM) to reconstruct RPE cells from the central mouse retina. Three-dimensional-reconstructed OS revealed the RPE to support large numbers of photoreceptors (90-216 per RPE cell). Larger bi-nucleate RPE maintained more photoreceptors, although their cytoplasmic volume was comparable to smaller mono-nucleate RPE supporting fewer photoreceptors. Scrutiny of RPE microvilli and interdigitating OS revealed the angle and surface area of contact between RPE and photoreceptors. Bi-nucleate RPE contained more mitochondria compared to mono-nucleate RPE. Furthermore, bi-nucleate cells contained larger sub-RPE spaces, supporting a likely association with disease. Use of perfusion-fixed tissues ensured the highest possible standard of preservation, providing novel insights into the 3D RPE architecture and changes linked with retinopathy. This study serves as a benchmark for comparing retinal tissues from donor eyes with age-related macular degeneration (AMD) and other retinopathies.

Rare Genetic Variants in Complement Factor I Lead to Low FI Plasma Levels Resulting in Increased Risk of Age-Related Macular Degeneration.

Purpose: Rare genetic variants in complement factor I (CFI) that cause low systemic levels of the protein (FI) have been reported as a strong risk factor for advanced age-related macular degeneration (AMD). This study set out to replicate these findings. Methods: FI levels were measured by sandwich ELISA in an independent cohort of 276 patients with AMD and 205 elderly controls. Single-nucleotide polymorphism genotyping and Sanger sequencing were used to assess genetic variability. Results: The median FI level was significantly lower in those individuals with AMD and a rare CFI variant (28.3 µg/mL) compared to those with AMD without a rare CFI variant (38.8 µg/mL, P = 0.004) or the control population with (41.7 µg/mL, P = 0.0085) or without (41.5 µg/mL, P < 0.0001) a rare CFI variant. Thirty-six percent of patients with AMD with a rare CFI variant had levels below the fifth percentile, compared to 6% in controls with CFI variants. Multiple regression analyses revealed a decreased FI level associated with a rare CFI variant was a risk factor for AMD (early or late AMD: odds ratio [OR] 12.05, P = 0.03; early AMD: OR 30.3, P = 0.02; late AMD: OR 10.64, P < 0.01). Additionally, measurement of FI in aqueous humor revealed a large FI concentration gradient between systemic circulation and the eye (∼286-fold). Conclusions: Rare genetic variants in CFI causing low systemic FI levels are strongly associated with AMD. The impermeability of the Bruch's membrane to FI will have implications for therapeutic replacement of FI in individuals with CFI variants and low FI levels at risk of AMD.

Ambient Air Pollution Associations with Retinal Morphology in the UK Biobank.

Purpose: Because air pollution has been linked to glaucoma and AMD, we characterized the relationship between pollution and retinal structure. Methods: We examined data from 51,710 UK Biobank participants aged 40 to 69 years old. Ambient air pollution measures included particulates and nitrogen oxides. SD-OCT imaging measured seven retinal layers: retinal nerve fiber layer, ganglion cell-inner plexiform layer, inner nuclear layer, outer plexiform layer + outer nuclear layer, photoreceptor inner segments, photoreceptor outer segments, and RPE. Multivariable regression was used to evaluate associations between pollutants (per interquartile range increase) and retinal thickness, adjusting for age, sex, race, Townsend deprivation index, body mass index, smoking status, and refractive error. Results: Participants exposed to greater particulate matter with an aerodynamic diameter of <2.5 µm (PM2.5) and higher nitrogen oxides were more likely to have thicker retinal nerve fiber layer (ß = 0.28 µm; 95% CI, 0.22-0.34; P = 3.3 × 10-20 and ß = 0.09 µm; 95% CI, 0.04-0.14; P = 2.4 × 10-4, respectively), and thinner ganglion cell-inner plexiform layer, inner nuclear layer, and outer plexiform layer + outer nuclear layer thicknesses (P < 0.001). Participants resident in areas of higher levels of PM2.5 absorbance were more likely to have thinner retinal nerve fiber layer, inner nuclear layer, and outer plexiform layer + outer nuclear layers (ß = -0.16 [95% CI, -0.22 to -0.10; P = 5.7 × 10-8]; ß = -0.09 [95% CI, -0.12 to -0.06; P = 2.2 × 10-12]; and ß = -0.12 [95% CI, -0.19 to -0.05; P = 8.3 × 10-4], respectively). Conclusions: Greater exposure to PM2.5, PM2.5 absorbance, and nitrogen oxides were all associated with apparently adverse retinal structural features.

Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR.

Retinal gene therapy has shown great promise in treating retinitis pigmentosa (RP), a primary photoreceptor degeneration that leads to severe sight loss in young people. In the present study, we report the first-in-human phase 1/2, dose-escalation clinical trial for X-linked RP caused by mutations in the RP GTPase regulator (RPGR) gene in 18 patients over up to 6 months of follow-up (https://clinicaltrials.gov/: NCT03116113). The primary outcome of the study was safety, and secondary outcomes included visual acuity, microperimetry and central retinal thickness. Apart from steroid-responsive subretinal inflammation in patients at the higher doses, there were no notable safety concerns after subretinal delivery of an adeno-associated viral vector encoding codon-optimized human RPGR (AAV8-coRPGR), meeting the pre-specified primary endpoint. Visual field improvements beginning at 1 month and maintained to the last point of follow-up were observed in six patients.

An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.

BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity. METHODS: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed. RESULTS: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified. CONCLUSION: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.