Efficacy of Faricimab vs Aflibercept in Diabetic Macular Edema in the 20/50 or Worse Vision Subgroup in Phase 3 YOSEMITE/RHINE Trials.

PURPOSE: DRCR.net Protocol T data suggest the response to treatment among patients with diabetic macular edema (DME) may vary depending on baseline best-corrected visual acuity (BCVA). We evaluated the efficacy of faricimab 6 mg versus aflibercept 2 mg over 2 years in patients with DME enrolled in faricimab phase 3 trials with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA ≤20/50. DESIGN: YOSEMITE/RHINE were identically designed, multicenter, randomized, double-masked, active comparator-controlled, noninferiority trials. PARTICIPANTS: Adults aged ≥18 years with center-involving macular edema secondary to type 1 or 2 diabetes. METHODS: Patients were randomized to faricimab every 8 weeks (Q8W), faricimab per a personalized treat-and-extend-based regimen (T&E), or aflibercept Q8W. Post hoc subgroup analyses were conducted using the intent-to-treat population with baseline BCVA ≤20/50 (ETDRS letters <69). MAIN OUTCOME MEASURES: Changes in ETDRS BCVA and central subfield thickness (CST) from baseline to years 1 and 2 were compared between treatment arms using mixed-model repeated measures analyses. RESULTS: In YOSEMITE/RHINE, 220/217 patients in the faricimab Q8W; 220/219, faricimab T&E; and 219/214, aflibercept Q8W arms had baseline BCVA ≤20/50. In both trials, mean change in ETDRS BCVA was comparable between treatments at years 1 and 2. In YOSEMITE, adjusted mean (95% CI) change from baseline in CST (µm) at year 1 was greater with faricimab Q8W (-232.8 [-243.5, -222.1]) and faricimab T&E (-217.4 [-227.9, -206.9]) versus aflibercept Q8W (-190.4 [-200.9, -179.8]; P<0.0001 and P=0.0004, respectively). The pattern was similar in RHINE: faricimab Q8W, -214.2 (-225.3, -203.1); faricimab T&E, -206.6 (-217.4, -195.7); aflibercept Q8W, -186.6 (-197.7, -175.5); P=0.0006 and P=0.0116 for faricimab arms versus aflibercept, respectively. In both trials, change from baseline in CST at year 2 was greater with faricimab Q8W versus aflibercept. Median time to first CST <325 µm and first absence of intraretinal fluid was shorter in the faricimab arms versus aflibercept, with fewer injections on average. CONCLUSIONS: In patients with DME and baseline ETDRS BCVA ≤20/50, faricimab treatment resulted in comparable visual acuity, greater reduction in retinal thickness, and fewer injections compared with aflibercept over 2 years of treatment.

Real-World Safety Outcomes with Brolucizumab in Neovascular Age-Related Macular Degeneration: Findings from the IRIS® Registry.

INTRODUCTION: To assess real-world safety outcomes for adults with neovascular age-related macular degeneration (nAMD) treated with brolucizumab from the US-based IRIS® (Intelligent Research in Sight) Registry. METHODS: In this retrospective study, 18,312 eyes (15,998 patients) treated with ≥ 1 intravitreal brolucizumab injections between 8 October 2019 (US launch date for brolucizumab) and 7 October 2021 were followed up for ≤ 2 years after first injection (index date). The study assessed the predefined incident ocular adverse events of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RO). RESULTS: Overall, 614/18,312 eyes (3.4%) experienced any IOI, RV, and/or RO event. Median (interquartile range [IQR]) time to an event was 84 (42-167) days; 77.4% of events (475/614) occurred within 6 months after index date. Median (IQR) number of brolucizumab injections before an event was 2 (1-4). For eyes with an adverse event and visual acuity (VA) data (n = 406), median (IQR) change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from pre-event VA was 0 (- 7 to + 5) at the 6-month follow-up; 50 eyes (12.3%) had a VA loss of 10 or more ETDRS letters. Risk of an event (hazard ratio [95% confidence interval]) was decreased in eyes from male patients (0.61 [0.53-0.71]), from older patients (0.83 [0.76-0.90]), from treatment-naive patients (0.51 [0.38-0.69]), and from patients who started brolucizumab in the second year after launch (0.68 [0.53-0.86] vs. first year). CONCLUSION: In this large real-world brolucizumab safety study, 3.4% of eyes experienced an IOI, RV, and/or RO event. Among eyes that experienced an adverse event for which VA data were available, median ETDRS vision change was 0 letters (IQR - 7 to + 5).

Regional Variation of Infectious Agents Causing Endogenous Endophthalmitis in the United States: A National Database Analysis.

OBJECTIVE: To describe regional variation in microbes causing infectious endogenous endophthalmitis (EE) in the United States. DESIGN: This is a retrospective, national database analysis utilizing the 2002-2014 National Inpatient Sample database. SUBJECTS: Using the International Classification of Disease 9 codes, we identified cases with EE. Cases were stratified regionally into Northeast, South, West, or Midwest. METHODS: Unadjusted chi-square analysis followed by adjusted multivariate logistic regression was performed to evaluate variation in demographic factors, comorbidities using the Elixhauser Comorbidity Index (ECI), microbial variation, mortality, and use of vitrectomy or enucleation by region. MAIN OUTCOME MEASURES: Proportion of microbes, mortality, and vitrectomy by region in addition to factors with significant odds ratios for mortality and for in-hospital vitrectomy. RESULTS: A total of 10 912 patients with infectious EE were identified, with 2063 cases in the Northeast (18.9%), 2145 cases in the Midwest (19.7%), 4134 cases in the South (37.9%), and 2570 cases in the West (23.6%). Chi-square analysis indicated significant regional variation in patient demographics, microbes causing the infection, ECI, mortality, and surgical intervention. The 4 most common microbes for all regions were methicillin-sensitive Staphylococcus aureus (MSSA), Streptococcus, Candida, and methicillin-resistant Staphylococcus aureus. Methicillin-sensitive S. aureus was the most common cause of EE in all regions, although the proportion of MSSA infection did not significantly vary by region (P = 0.03). Further, there was significant regional variation in the proportion of other microbes causing the infection (P < 0.001). Higher rates of vitrectomies were seen in the South and Midwest regions than that in the Northeast and West (P = 0.04). CONCLUSIONS: Regional variation exists in the infectious microbes causing EE. Further studies are needed to elucidate the etiology of these variations. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Recent Progress in Photoreceptor Cell-Based Therapy for Degenerative Retinal Disease.

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of photoreceptors as treatment for these conditions are underway. In this review, we summarize recent progress in the field of photoreceptor transplantation, including some pertinent results regarding photoreceptor manufacture, photoreceptor transplantation, mechanisms of donor-host cell integration such as material transfer and photoreceptor transplant immunology. We conclude by proposing several approaches that may provide a rational basis for selecting a vision restoration strategy (eg, donor-host synapse formation vs donor-host nanotube formation) and improved transplant efficiency.

Recent Progress in Retinal Pigment Epithelium Cell-Based Therapy for Retinal Disease.

Age-related macular degeneration and retinitis pigmentosa are degenerative retinal diseases that cause severe vision loss. Early clinical trials involving transplantation of retinal pigment epithelial cells and/or photoreceptors as a treatment for these conditions are underway. In this review, we summarize recent progress in the field of retinal pigment epithelium transplantation, including some pertinent clinical trial results as well as preclinical studies that address issues of transplant immunology, cell delivery, and cell manufacturing.

Klebsiella Endogenous Endophthalmitis During the COVID-19 Pandemic.

Purpose: To describe the characteristics of Klebsiella pneumoniae endogenous endophthalmitis (KEE) encountered during the COVID-19 pandemic. Methods: This retrospective consecutive case series evaluated eyes that presented with KEE between March 2020 and July 2022. Results: Seven eyes of 5 patients developed KEE. Between January 2020 and July 2022, KEE was observed in 42% of consecutive EE cases compared with 7.8% during the preceding 13 years. COVID-19 was positive in 4 of 5 patients before they developed KEE. Only 1 patient presented with a VA better than hand motions (20/400). All eyes were treated with urgent vitrectomy and intravitreal and systemic antibiotics. No improvement in vision occurred in any patient; VA remained light perception to no light perception in 60% of eyes. Conclusions: The visual prognosis in KEE is extremely poor. The presence of a preceding COVID-19 infection in 80% of patients may signal a new risk factor for KEE. Patients with a hypervirulent Klebsiella syndrome should be routinely screened for EE.

Epidemiological Trends of Ocular Injuries in Infants.

Approximately 21,000 consumer product-related ocular injuries occurred in infants in the United States from 2009 to 2019; toys being the most common (12.9%) consumer product in the 1- to 4-month age cohort, detergents in the 5- to 8-month (21.6%) cohort, and chemicals for the 9- to 12-month (34.0%) age cohort. These results identify an important preventable consumer product-related public health problem in infants. [J Pediatr Ophthalmol Strabismus. 2023;60(4):e41-e44.].

Injury to Cone Synapses by Retinal Detachment: Differences from Rod Synapses and Protection by ROCK Inhibition.

Attachment of a detached retina does not always restore vision to pre-injury levels, even if the attachment is anatomically successful. The problem is due in part to long-term damage to photoreceptor synapses. Previously, we reported on damage to rod synapses and synaptic protection using a Rho kinase (ROCK) inhibitor (AR13503) after retinal detachment (RD). This report documents the effects of detachment, reattachment, and protection by ROCK inhibition on cone synapses. Conventional confocal and stimulated emission depletion (STED) microscopy were used for morphological assessment and electroretinograms for functional analysis of an adult pig model of RD. RDs were examined 2 and 4 h after injury or two days later when spontaneous reattachment had occurred. Cone pedicles respond differently than rod spherules. They lose their synaptic ribbons, reduce invaginations, and change their shape. ROCK inhibition protects against these structural abnormalities whether the inhibitor is applied immediately or 2 h after the RD. Functional restoration of the photopic b-wave, indicating cone-bipolar neurotransmission, is also improved with ROCK inhibition. Successful protection of both rod and cone synapses with AR13503 suggests this drug will (1) be a useful adjunct to subretinal administration of gene or stem cell therapies and (2) improve recovery of the injured retina when treatment is delayed.

One-Year Brolucizumab Outcomes in Neovascular Age-Related Macular Degeneration from a Large United States Cohort in the IRIS® Registry.

PURPOSE: To evaluate visual acuity (VA) and injection intervals in patients with neovascular age-related macular degeneration (nAMD) after 12 months of brolucizumab therapy in clinical practice. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who received brolucizumab exclusively for 12 months (2308 eyes of 2079 patients). METHODS: Observational study of eyes with a first injection of brolucizumab (index), followed by 2 or more brolucizumab injections over the following 12 months without switching to another anti-vascular endothelial growth factor (VEGF) agent. MAIN OUTCOME MEASURES: Primary outcomes were change in best recorded VA and, for eyes receiving prior anti-VEGF therapy (treatment-experienced eyes), the difference between the brolucizumab injection interval at 12 months and the anti-VEGF injection interval before switching. The interval before switching was defined as the time between the prior anti-VEGF and index brolucizumab injections; brolucizumab interval was the time between the closest injection to day 365 and the preceding injection. Secondary outcomes included incident adverse events. RESULTS: Overall VA at index was 61.6 ± 18.4 Early Treatment Diabetic Retinopathy Study letters; 83.7% of treatment-naive eyes (184/220) and 86.1% of treatment-experienced eyes (1797/2088) showed stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) VA at 12 months. Among treatment-experienced eyes receiving a prior anti-VEGF injection within 365 days before index, 29.5% (594/2015) showed an interval before switching of 8 weeks or more (mean, 7.6 ± 5.5 weeks), whereas 83.1% (1734/2015) showed a brolucizumab injection interval at 12 months of 8 weeks or more (mean, 10.3 ± 4.0 weeks). In all, 77.1% of treatment-experienced eyes (1554/2015) showed an interval extension of 1 week or more; of these, 55.4% (861/1554) showed an extension of 4 weeks or more. CONCLUSIONS: In this community-based study, at 12 months, brolucizumab treatment prolonged the interval between anti-VEGF injections for most treatment-experienced eyes, particularly those with shorter intervals before switching, while maintaining or improving VA. With careful balancing of the benefits and risks, switching to brolucizumab treatment may offer the advantage of extending the treatment interval for patients with a high anti-VEGF therapy burden. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.

PURPOSE: To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26, 2021. METHODS: Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. MAIN OUTCOME MEASURES: Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. RESULTS: Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. CONCLUSIONS: Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Work-related ocular trauma in the United States: a National Trauma Databank study.

PURPOSE: This study aims to investigate trends and risk factors associated with work-related ocular injuries occurring in adults aged 19-64 using the National Trauma Databank (NTDB). METHODS: In this retrospective, cross-sectional study, the NTDB was used to collect all patients with an ICD-9 code of work-related ocular trauma from 2007 to 2014. Demographic data and risk factors collected included age, gender, race, setting, machinery, and mechanism. Descriptive statistics, univariate, and logistic regression multivariate analyses were conducted. RESULTS: Between 2007 and 2014, 234,983 cases of work-related trauma were identified, of which 11,097 (5.7%) cases involved ocular trauma. The mean age of patients was 40.7 years (SD = 12.2), and the majority of patients (93.7%) were male. Most injuries occurred in an industrial facility, and the most common injuries were orbital floor fractures (OFFs), ocular contusions, open wounds to the adnexa, and open globe injuries (OGIs). OFFs most commonly involved a concurrent fracture of another facial or skull bone. Male gender (RR = 1.22; CI 1.09-1.38), accidental falls (RR = 1.50; CI 1.41-1.60), trauma from falling objects (RR = 1.34; CI 1.21-1.48), involvement in an unarmed fight (RR = 1.63; CI 1.39-1.91), assault by a blunt object (RR = 1.59; CI 1.31-1.91), and injury caused by animals (RR = 1.63; CI 1.30-2.02) were risk factors for OFFs. Patients with OFFs were less likely to have a concurrent OGI (RR = 0.27; CI 0.23-0.32). On the other hand, injuries occurring in industrial facilities (RR = 1.29; CI 1.11-1.51) and injuries with a loose foreign body striking the eye or adnexa (RR = 1.54; CI 1.28-1.84) were risk factors for OGI. The most common causes of work-related ocular trauma were accidental falls, motor vehicle accidents, and accidentally being struck in the eye. The mean length of hospital stay was 6.56 days (SD = 10.82); 36.7% of patients required ICU admission, and the overall in-hospital mortality rate was 2.8%. CONCLUSION: The majority of work-related ocular trauma occurred in men, most commonly in industrial locations. Accidental falls were the most common identified cause of trauma. OFF was the most common ocular injury; 80% of OFF cases involved additional facial and skull fractures. Patients with OFFs were less likely to have a concurrent OGI compared with patients without OFFs.

Trends in Endogenous Endophthalmitis in Rural and Urban Settings in the United States.

PURPOSE: The objective of this study is to explore and compare trends in urban and rural cases of endogenous endophthalmitis (EE) in the United States. METHODS: This study utilizes data from the 2002-2014 National Inpatient Sample (NIS) Database. Disease diagnoses and procedures were identified using codes from the International Classification of Diseases, Ninth Revision (ICD-9). Cases of EE were defined as cases of endophthalmitis in the setting of bacteremia or candidemia without a recent history of ocular trauma. The NIS Database defines urban and rural hospitals based on the hospital county's population statistics. Statistical analysis was performed using IBM SPSS 23. RESULTS: We identified 8255 cases of EE. Of these cases, 523 (6.3%) occurred in rural areas; 7733 (93.7%) occurred in urban areas. Of the cases of EE, 7692 (93.2%) were bacterial EE, 412 (5.0%) were candida EE, and 151 (1.8%) were mixed EE. Candida EE was observed in 1.7% of rural cases and 5.2% of urban cases (p < .001). Pars plana vitrectomies were performed more often in urban hospitals than in rural hospitals (11.5% vs. 2.9%; p < .001). CONCLUSION: Endogenous endophthalmitis remains a rare but devastating ocular infection. In this study, we have demonstrated that there are important differences in cases of EE that present to urban and rural hospitals. Future investigations into these differences in patient demographics, source/systemic infections, and hospital courses may allow clinicians and hospitals to develop a more targeted approach to treating EE based on the type of community from which the patient presents.

Epidemiology of United States tennis-related ocular injuries from 2000 to 2019.

PURPOSE: To characterize trends in ocular tennis injuries over the last 20 years. METHODS: The National Electronic Injury Surveillance System was utilized to characterize tennis-related eye injuries in a nationally representative sample of emergency department visits. Data were divided into 5 age groups, and various demographic information was obtained. RESULTS: Approximately 16,000 tennis-related ocular injuries were identified with males being affected nearly 2:1 compared to females. The youngest age group (0-20) had the greatest proportion of injuries, with most injuries in boys 11-15 years old. Injuries occurred most often during the spring season. Most patients were treated and released from the ED. Of those patients who were hospitalized, one-third had an open globe injury. CONCLUSIONS: The overall number of injuries trended downward during the timespan of the study. Although most patients did not experience serious visual consequences, the greatest proportion of ocular tennis injuries occurred in the pediatric age group in whom the risk of amblyopia is high. Primary care providers and tennis regulatory bodies should consider recommending eye safety sports goggles in children to mitigate the potential for significant visual morbidity.

Risk factors for ischemic cerebral stroke in patients with acute amaurosis fugax.

OBJECTIVE: The National Stroke Association and the American Heart Association consider retinal ischemia, as in the case of amaurosis fugax (AF), to be a stroke event. The purpose of this study was to evaluate the risk factors for ischemic cerebral stroke in patients hospitalized for acute AF. METHODS: The National Inpatient Sample Database from 2002 to 2014 was used to identify patients 21 years of age and older with a primary admission diagnosis of AF with the ICD-9 code 362.34. Comorbidity measures and in-hospital events were extracted using relevant ICD-9 codes. Statistical analyses were performed using IBM SPSS 25 and R package. RESULTS: A weighted total of 12,142 patients was identified. The most common comorbidities in this cohort with AF included hypertension, dyslipidemia, tobacco use, coronary artery disease (CAD), and diabetes mellitus. Multivariable regression analysis showed comorbidities of hypercoagulable state, systemic vasculitis, CAD, and atherosclerosis to be independent risk factors for ischemic stroke in patients with AF. In contrast, dyslipidemia was associated with a decreased risk. Asian/Pacific Islander race conferred a 5-fold increased risk compared with Whites. CONCLUSION: Ischemic stroke and myocardial infarction were diagnosed in 0.3%-0.9% of hospitalized acute AF cases. Presence of hypercoagulable state, systemic vasculitis, CAD, and atherosclerosis each individually increased the risk of ischemic stroke by more than 3-fold; patients with these risk factors and acute AF should be closely monitored for developing acute systemic thrombotic events.

Epidemiology of ocular injuries associated with landscaping tools.

The purpose of this retrospective, cross-sectional study was to determine and analyze the trends in ocular injuries related to landscaping activities and equipment from 2010 to 2019. A total of 168,845 ocular injuries were associated with landscaping activities with the majority of cases occurring in men (80.4%) between the ages of 41-60 during the summer months of June, July, and August. The majority of ocular injuries did not require admission (97.8%) but of those that were admitted 42% had an open globe injury (n = 399). The results of this investigation provide useful information for emergency room physicians and ophthalmologists in understanding the prevalence of these landscaping-associated ocular injuries and further draw suspicion for the incidence of open globe injuries in this population.

New Prospects for Retinal Pigment Epithelium Transplantation.

ABSTRACT: Retinal pigment epithelium (RPE) transplants rescue photoreceptors in selected animal models of retinal degenerative disease. Early clinical studies of RPE transplants as treatment for age-related macular degeneration (AMD) included autologous and allogeneic transplants of RPE suspensions and RPE sheets for atrophic and neovascular complications of AMD. Subsequent studies explored autologous RPE-Bruch membrane-choroid transplants in patients with neovascular AMD with occasional marked visual benefit, which establishes a rationale for RPE transplants in late-stage AMD. More recent work has involved transplantation of autologous and allogeneic stem cell-derived RPE for patients with AMD and those with Stargardt disease. These early-stage clinical trials have employed RPE suspensions and RPE monolayers on biocompatible scaffolds. Safety has been well documented, but evidence of efficacy is variable. Current research involves development of better scaffolds, improved modulation of immune surveillance, and modification of the extracellular milieu to improve RPE survival and integration with host retina.