Long-term efficacy and safety of brolucizumab in neovascular age-related macular degeneration: A multicentre retrospective real-world study.

PURPOSE: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups. RESULTS: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution. CONCLUSION: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management.

Immunogenicity and Potential for Intraocular Inflammation of Intravitreal Anti-VEGF Drugs.

Background: Concerns of intraocular inflammation associated with intravitreal administration of anti-VEGF drugs have been risen and the exact mechanism is not yet elucidated. Objective: To explore the relationship between immunogenicity and intraocular inflammation in intravitreal anti-VEGF drugs. Methods: This review examines the immunogenicity of individual intravitreal anti-VEGF drugs and their potential link to intraocular inflammation. Results: We suggest that the main cause of intraocular inflammation is the presence of pre-existing and treatment-induced antidrug antibodies, along with considerations related to the molecular structure, which includes the drug's format and size. Conclusions: Researchers and clinicians involved in the advancement of new anti-VEGF drugs should take into consideration the factors related to intraocular inflammation that have been discussed.

Two novel non-coding single nucleotide variants in the DNase1 hypersensitivity site of PRDM13 causing North Carolina macular dystrophy in Korea.

Purpose: Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families. Methods: The regions associated with NCMD were analyzed with genome sequencing, and variants were filtered based on the minor allele frequency (0.5%) and heterozygosity. Non-coding variants were functionally annotated using multiple computational tools. Results: We identified two rare novel variants, chr6:g.99,598,914T>C (hg38; V17) and chr6:g.99,598,926G>A (hg38; V18) upstream of PRDM13 in families A and B, respectively. In Family 1, Grade 2 NCMD and a best-corrected visual acuity of 20/25 and 20/200 in the right and left eyes, respectively, were observed. In Family B, all affected individuals had Grade 1 NCMD with characteristic confluent drusen at the fovea and a best-corrected visual acuity of 20/20 in both eyes. These two variants are 10-22 bp downstream of the reported V10 variant within the DNase1 hypersensitivity site. This site is associated with progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypertrophy and lies in the putative enhancer site of PRDM13. Conclusion: We identified two novel NCMD variants in the Korean population and further validated the regulatory role of the DNase1 hypersensitivity site upstream of PRDM13.

Changes in intraocular pressure following intravitreal dexamethasone implant in patients with history of glaucoma filtration surgery.

PURPOSE: This study aimed to evaluate changes in intraocular pressure following intravitreal dexamethasone implant injection, specifically in patients undergoing glaucoma filtration surgery. METHODS: The degree of increase in intraocular pressure was compared retrospectively among three groups. Group 1 comprised patients who underwent prior glaucoma filtration surgery (54 eyes). Group 2 included patients with or suspected glaucoma without such surgical history (20 eyes). Group 3 included patients without glaucoma (33 eyes). Pressure measurements were taken before the injection and at 1, 2, 3, and 6 months post-injection. A subgroup analysis was performed for pressure > 35 mmHg, > 30 mmHg, > 25 mmHg, and a difference > 10 mmHg between the peak and baseline pressure. RESULTS: Group 1 consistently displayed lower pressures compared with Group 2, with significant difference at both 1- and 6-month post-injections (15.09 mmHg vs. 18.10 mmHg, P = 0.042 and 13.91 mg vs. 17.25 mmHg, P = 0.040). The proportion of patients in Group 1 and Group 3 with pressures > 25 mmHg, > 30 mmHg, and a difference > 10 mmHg did not significantly differ (15.6% vs. 9.5%, P = 0.231; 3.1% vs. 2.3%, P = 0.867; and 17.1% vs. 7.1%, P = 0.231). Notably, Group 2 exhibited a significantly higher proportion within each category (> 25 mmHg, 24.0%; > 30 mmHg, 20.0%; > 10 mmHg difference, 28.0%). CONCLUSION: Intravitreal dexamethasone implant did not increase the risk of elevated intraocular pressure in patients with a history of glaucoma filtration surgery compared with patients with suspected glaucoma; the risk was similar to those without glaucoma.

Biosimilars of anti-vascular endothelial growth factor for ophthalmic diseases: A review.

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars.

Nationwide incidence of congenital and infantile cataract requiring surgery in Korea.

Congenital and infantile (CI) cataract is one of the most important and preventable cause of blindness in children, but the incidence has not been studied in Korea. We collected data from the national claims database of the National Health Insurance Service of Korea from 2002 through 2019. We identified children who underwent cataract surgery within the age of 5 years, and cumulative incidence rates were calculated for each of the three age criteria. 989 patients out of 4,221,459 births underwent surgery with CI cataract during the period. The cumulative incidence rates per 10,000 births were 1.60 (0-1 years), 2.38 (0-3 years), and 2.95 (0-5 years), respectively. The incidence peaked in the 2007 birth cohort, which coincides with the start of the national screening program for infants/children. Primary intraocular lens implantation was performed in 439 patients (44%). Strabismus and glaucoma requiring surgery occurred in 291 patients (29.4%) and 32 patients (3.2%), respectively, within 8 years after cataract surgery. The incidence rates of CI cataract in Korea appear to be comparable to previous studies in other regions. The early screening program for infants may reduce delayed diagnosis and increase the proportion of patients undergoing surgery at a critical time for visual development.

Scleral buckling with adjuvant pneumatic retinopexy versus scleral buckling alone for rhegmatogenous retinal detachment.

To compare the efficacy of scleral buckling with adjuvant pneumatic retinopexy (SB with PR) and scleral buckling (SB) alone for primary rhegmatogenous retinal detachment (RRD). This retrospective and comparative study included patients who underwent SB with PR (n = 88) or SB alone (n = 161) for primary RRD. The primary anatomical success rate for SB with PR was 81.8%, whereas that for SB alone was 80.7% (P = 0.836). Among patients who achieved primary anatomical success, those in the SB with PR group showed postoperative epiretinal membrane (ERM) formation more frequently than those in the SB alone group (11 of 72 [15.3%] vs. 6 of 130 [4.6%]) (P = 0.009). The mean time to subretinal fluid absorption was not significantly different between the SB with PR and SB alone groups (11.2 ± 6.2 vs. 11.4 ± 5.8 months, P = 0.881). In the SB with PR group, retinal detachment involving ≥ three quadrants was a significant risk factor for surgical failure (hazard ratio, 3.04; P = 0.041). Adjuvant pneumatic retinopexy does not provide additional benefit in improving the surgical outcomes of SB for primary RRD repair.

ADDITIONAL PNEUMATIC RETINOPEXY IN PATIENTS WITH PERSISTENT RETINAL DETACHMENT AFTER SCLERAL BUCKLING.

PURPOSE: To investigate the efficacy, safety, and indications for additional pneumatic retinopexy (PR) in patients with persistent retinal detachment after scleral buckling. METHODS: This retrospective study included patients who underwent additional PR after scleral buckling for primary rhegmatogenous retinal detachment (n = 78). We defined "inadequate buckle" as retinal detachment persistence because of low buckle height despite accurate buckle placement and "buckle misplacement" as an uncovered tear because of incorrect buckle placement. RESULTS: The anatomical success rate after additional PR was 52.6%. Development of proliferative vitreoretinopathy Grade B (hazard ratio, 5.73; P < 0.001) and inferior retinal tears (hazard ratio, 2.12; P = 0.040) were significant risk factors for anatomical failure. The most common cause of anatomical failure was proliferative vitreoretinopathy (19 of 37; 51.4%), and epiretinal membrane formation was a common complication after additional PR (22 of 78; 28.2%). The anatomical success rate with additional PR was significantly higher in the inadequate buckle group than in the misplacement group (8 of 9 [88.9%] vs. 1228 [42.9%]; P = 0.023). CONCLUSION: Development of proliferative vitreoretinopathy Grade B and inferior retinal tears were significantly associated with anatomical failure after additional PR. Additional PR may benefit patients with superior retinal tears or low buckle height and those without proliferative vitreoretinopathy.

Rationale and protocol paper for the Asia Pacific Network for inherited eye diseases.

PURPOSE: There are major gaps in our knowledge of hereditary ocular conditions in the Asia-Pacific population, which comprises approximately 60% of the world's population. Therefore, a concerted regional effort is urgently needed to close this critical knowledge gap and apply precision medicine technology to improve the quality of lives of these patients in the Asia-Pacific region. DESIGN: Multi-national, multi-center collaborative network. METHODS: The Research Standing Committee of the Asia-Pacific Academy of Ophthalmology and the Asia-Pacific Society of Eye Genetics fostered this research collaboration, which brings together renowned institutions and experts for inherited eye diseases in the Asia-Pacific region. The immediate priority of the network will be inherited retinal diseases (IRDs), where there is a lack of detailed characterization of these conditions and in the number of established registries. RESULTS: The network comprises 55 members from 35 centers, spanning 12 countries and regions, including Australia, China, India, Indonesia, Japan, South Korea, Malaysia, Nepal, Philippines, Singapore, Taiwan, and Thailand. The steering committee comprises ophthalmologists with experience in consortia for eye diseases in the Asia-Pacific region, leading ophthalmologists and vision scientists in the field of IRDs internationally, and ophthalmic geneticists. CONCLUSIONS: The Asia Pacific Inherited Eye Disease (APIED) network aims to (1) improve genotyping capabilities and expertise to increase early and accurate genetic diagnosis of IRDs, (2) harmonise deep phenotyping practices and utilization of ontological terms, and (3) establish high-quality, multi-user, federated disease registries that will facilitate patient care, genetic counseling, and research of IRDs regionally and internationally.

Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4.

Purpose: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD). Methods: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.R45W, and group B, missense variants located between amino acids (aa) 1196 and 1201. The clinical parameters of the two genotypes were compared, and deep learning based on spectral-domain optical coherence tomographic (SD-OCT) images was used to distinguish the morphologic differences. Results: Groups A and B included 29 and 22 patients, respectively. The median age of onset in groups A and B was 14.0 and 40.0 years, respectively. The median logMAR visual acuity of groups A and B was 0.70 and 0.51, respectively, and the survival curve analysis revealed a 15-year difference in vision loss (logMAR 0.22). A statistically significant difference was observed in the visual field classification, but no significant difference was found in the multifocal electroretinographic classification. High accuracy (75.4%) was achieved in classifying genotype groups based on SD-OCT images using machine learning. Conclusions: Distinct clinical severities and morphologic phenotypes supported by artificial intelligence-based classification were derived from the two investigated RP1L1 hotspots: a more severe phenotype (p.R45W) and a milder phenotype (1196-1201 aa). This newly identified genotype-phenotype association will be valuable for medical care and the design of therapeutic trials.

Efficacy and Safety of Switching from Adalimumab Originator to SB5, Adalimumab Biosimilar for Noninfectious Uveitis.

PURPOSE: To evaluate the efficacy and safety of switching from adalimumab originator (Humira, AbbVie) to SB5, adalimumab biosimilar (Adalloce, Samsung Bioepis) in patients with noninfectious uveitis (NIU). METHODS: Fifteen patients (29 eyes) with NIU who were switched from adalimumab originator to SB5 and followed up for 6 months or longer were retrospectively included. Data consisted of best-corrected visual acuity (BCVA, logMAR), intraocular pressure (IOP, mmHg), anterior chamber (AC) cell grade, anterior vitreous (AV) cell grade, vitreous haze grade, central macular thickness (CMT, µm), and macular volume (MV, mm3) at pre-switching, 2, 4, and 6 months post-switching. RESULTS: There were no significant differences in BCVA, AC and AV cell grades, and vitreous haze grades at 2, 4, and 6 months post- compared with pre-switching, and no significant differences in CMT and MV at 2 and 6 months post-switching. CMT and MV decreased from 260.55 ± 67.44 µm and 8.37 ± 1.14 mm3 at pre-switching to 244.14 ± 60.31 µm (p = 0.032) and 8.11 ± 1.20 mm3 (p = 0.027) at 4 months post-switching, respectively. There was no recurrence of uveitis, as defined by AC cell grade, vitreous haze, or BCVA. Four patients (27%) were switched back to adalimumab originator after a mean of 9 weeks, due to discomfort during the injection (three patients) and technical difficulty with the new injection device (one patient). No other adverse events occurred after switching to SB5. CONCLUSION: Switching from adalimumab originator to SB5 for NIU does not result in clinically significant differences in treatment efficacy and safety.

Phenotypic and Genetic Alterations in Adult-Onset Cone and Cone-Rod Dystrophy.

INTRODUCTION: The objective of this study was to investigate the clinical characteristics and genetic spectrum of adult-onset cone/cone-rod dystrophy (AOCD/AOCRD) in Korean individuals. METHODS: This is a single-center, retrospective cross-sectional study. We analyzed 22 individuals with genetically confirmed cone dystrophy, with symptoms beginning after 30 years of age. All patients underwent comprehensive ophthalmic and electrophysiological examinations. Exome sequencing of 296 genes associated with inherited retinal disease was performed. The clinical features of patients with AOCD/AOCRD and the causative genes and variants detected by exome sequencing were analyzed. RESULTS: The median age at the first visit was 52 years (range, 31-76 years), and the most common initial symptom was reduced visual acuity. In most cases, fundus photography showed a bull's eye pattern with foveal sparing, consistent with perifoveal photoreceptor loss on optical coherence tomography. We identified disease-causing variants in six genes: RP1, CRX, CDHR1, PROM1, CRB1, and GUCY2D. Pathogenic variants in RP1, CRX, and CDHR1 were identified in 77% of the AOCD/AOCRD cases, including p.Cys1399LeufsTer5, p.Arg1933Ter, and p.Ile2061SerfsTer12 in RP1; p.Ter300GlnextTer118 in CRX; and p.Glu201Lys in CDHR1. No characteristic imaging differences were observed for any of the causative genes. Most of the RP1-related AOCD/AOCRD cases showed a decreased amplitude only in the photopic electroretinogram (ERG), whereas CRX-related AOCD/AOCRD cases showed a slightly decreased amplitude in both the scotopic and photopic ERGs. CONCLUSION: In case of visual impairment with bull's eye pattern of RPE atrophy recognized after the middle age, a comprehensive ophthalmic examination and genetic test should be considered, with the possibility of AOCD/AOCRD in East Asians.

Whole genome sequencing for inherited retinal diseases in the Korean National Project of Bio Big Data.

PURPOSE: This study aimed to analyze the genetic results of inherited retinal diseases (IRDs) and evaluate the diagnostic usefulness of whole genome sequencing (WGS) in the Korean National Project of Bio Big Data. METHODS: As part of the Korean National Project of Bio Big Data, WGS was performed on 32 individuals with IRDs with no identified pathogenic variants through whole or targeted exome sequencing. RESULTS: Individuals with retinitis pigmentosa (n = 23), cone dystrophy (n = 2), cone-rod dystrophy (n = 2), familial exudative vitreoretinopathy (n = 2), pigmented paravenous chorioretinal atrophy (n = 1), North Carolina macular dystrophy (n = 1), and bull's-eye macular dystrophy (n = 1) were included. WGS revealed genetic mutations in the IQCB1, PRPF31, USH2A, and GUCY2D genes in five cases (15.6%). Two large structural variations and an intronic variant were newly detected in three cases. Two individuals had biallelic missense mutations that were not identified in previous exome sequencing. CONCLUSION: With WGS, the causative variants in 15.6% of unsolved IRDs from the Korean National Project of Bio Big Data were identified. Further research with a larger cohort might unveil the diagnostic usefulness of WGS in IRDs and other diseases.

Comparison of posterior capsule rupture rates during phacoemulsification using 3D heads-up visualization system and traditional microscopes.

PURPOSE: To compare the posterior capsule rupture (PCR) rates of cataract surgery using a traditional ophthalmic surgical microscope (OSM) and a 3D heads-up visualization system (HUVS). SETTING: Single tertiary referral center. DESIGN: Retrospective study. METHODS: This study included 10 101 eyes that underwent phacoemulsification cataract surgery. Surgeries were performed using either 3D HUVS (1964 eyes, performed by 2 surgeons, HUVS group) or traditional OSM (8137 eyes, performed by 6 surgeons, OSM group) from February 2018 to June 2022. Data were collected based on the diagnosis-related group system, and the rate of PCR requiring vitrectomy and the surgical time were evaluated. RESULTS: The PCR rates were not significantly different between the OSM (n = 63; 0.7%) and HUVS (n = 19; 0.9%, P = .392) groups. The mean surgical time was significantly longer in the HUVS group (14.7 ± 10.6 minutes) than in the OSM group (12.9 ± 9.9 minutes, P < .001). In the 3D HUVS group, there were no PCR cases among the initial 100 patients. In both groups, no significant difference was observed in the PCR rates over time. Although the difference was not statistically significant, the PCR rate decreased over time in the HUVS group. CONCLUSIONS: The results indicate that 3D HUVS-based cataract surgery performed by experienced cataract surgeons had a PCR rate similar to that of traditional OSM-based surgery during the 4-year study period. Although the surgical time was slightly longer with 3D HUVS, cataract surgery using 3D HUVS can be performed safely by experienced surgeons.

Patient-Centered Economic Burden of Exudative Age-Related Macular Degeneration: Retrospective Cohort Study.

BACKGROUND: Exudative age-related macular degeneration (AMD), one of the leading causes of blindness, requires expensive drugs such as anti-vascular endothelial growth factor (VEGF) agents. The long-term regular use of effective but expensive drugs causes an economic burden for patients with exudative AMD. However, there are no studies on the long-term patient-centered economic burden of exudative AMD after reimbursement of anti-VEGFs. OBJECTIVE: This study aimed to evaluate the patient-centered economic burden of exudative AMD for 2 years, including nonreimbursement and out-of-pocket costs, compared with nonexudative AMD using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). METHODS: This retrospective cohort study was conducted using the OMOP CDM, which included 2,006,478 patients who visited Seoul National University Bundang Hospital from June 2003 to July 2019. We defined the exudative AMD group as patients aged >50 years with a diagnosis of exudative AMD and a prescription for anti-VEGFs or verteporfin. The control group was defined as patients aged >50 years without a diagnosis of exudative AMD or a prescription for anti-VEGFs or verteporfin. To adjust for selection bias, controls were matched by propensity scores using regularized logistic regression with a Laplace prior. We measured any medical cost occurring in the hospital as the economic burden of exudative AMD during a 2-year follow-up period using 4 categories: total medical cost, reimbursement cost, nonreimbursement cost, and out-of-pocket cost. To estimate the average cost by adjusting the confounding variable and overcoming the positive skewness of costs, we used an exponential conditional model with a generalized linear model. RESULTS: We identified 931 patients with exudative AMD and matched 783 (84.1%) with 2918 patients with nonexudative AMD. In the exponential conditional model, the total medical, reimbursement, nonreimbursement, and out-of-pocket incremental costs were estimated at US $3426, US $3130, US $366, and US $561, respectively, in the first year and US $1829, US $1461, US $373, and US $507, respectively, in the second year. All incremental costs in the exudative AMD group were 1.89 to 4.25 and 3.50 to 5.09 times higher in the first and second year, respectively, than those in the control group (P<.001 in all cases). CONCLUSIONS: Exudative AMD had a significantly greater economic impact (P<.001) for 2 years on reimbursement, nonreimbursement, and out-of-pocket costs than nonexudative AMD after adjusting for baseline demographic and clinical characteristics using the OMOP CDM. Although economic policies could relieve the economic burden of patients with exudative AMD over time, the out-of-pocket cost of exudative AMD was still higher than that of nonexudative AMD for 2 years. Our findings support the need for expanding reimbursement strategies for patients with exudative AMD given the significant economic burden faced by patients with incurable and fatal diseases both in South Korea and worldwide.

Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial.

BACKGROUND/AIMS: To evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD). DESIGN: Prospective, double-masked, randomised, phase 3 trial. METHODS: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity. RESULTS: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups. CONCLUSIONS: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants.

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5.

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns.

Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

Bilateral macular hole in a patient with CAPN5-related neovascular inflammatory vitreoretinopathy.

PURPOSE: To characterize the genotype and phenotype of a patient with CAPN5-related neovascular inflammatory vitreoretinopathy (NIV) who have undergone surgery for macular holes. METHODS: We observed a patient presenting with retinitis pigmentosa and posterior uveitis who later developed vitreoretinal macular traction and a macular hole. Genetic testing was performed using a targeted gene panel. Fundus photography and spectral-domain optical coherence tomography were also performed. RESULTS: In a targeted gene panel, a monoallelic pathogenic variant, c.750G > T, p.Lys250Asn, in the CAPN5 gene was identified, and CAPN5-NIV was diagnosed. At the first visit, peripheral retinal degeneration and mild posterior uveitis were observed. At that time, neovascularization, epiretinal or fibrous membranes were not observed. After 5 years, vitreomacular traction developed and progressed to a full-thickness macular hole in both eyes. After pars plana vitrectomy, the macular hole was successfully closed without aggravation of uveitis. CONCLUSION: In this case, a pathogenic variant of CAPN5 lead to a distinct phenotype of retinitis pigmentosa, posterior uveitis, vitreomacular traction, and macular hole without typical inflammatory neovascularization or tractional membranes. Therefore, the clinical variability of CAPN5-NIV and genetic diagnosis should be considered in cases of atypical retinitis pigmentosa with bilateral macular hole.

Clinical and genetic features of Koreans with retinitis pigmentosa associated with mutations in rhodopsin.

Purpose: To investigate the clinical features, natural course, and genetic characteristics of Koreans with rhodopsin-associated retinitis pigmentosa (RHO-associated RP). Design: We conducted a retrospective, multicenter, observational cohort study. Participants: We reviewed the medical records of 42 patients with RHO-associated RP of 36 families who visited 4 hospitals in Korea. Methods: Patients with molecular confirmation of pathogenic variants of the RHO gene were included. The patients were divided into two subgroups: the generalized and sector RP groups. A central visual field of the better-seeing eye of <10° or a best-corrected visual acuity of the better-seeing eye <20/40 indicated the progression to late-stage RP. Results: The mean age at which symptoms first appeared was 26.3 ± 17.9 years (range: 8-78 years), and the mean follow-up period was 80.9 ± 68.7 months (range: 6-268 months). At the last follow-up visit, the generalized RP group showed a significantly higher rate of visual field impairment progression to late-stage RP than that of the sector RP group (22 of 35 [62.9%] vs. 0 of 7 [0.0%], p = 0.003). No cases in the sector RP group progressed to generalized RP. Best-corrected visual acuity deterioration to late-stage RP was observed only in the generalized RP group (13 of 35 patients; 37.1%), whereas no deterioration was observed in the sector RP group. We identified 16 known and three novel RHO mutations, including two missense mutations (p.T108P and p.G121R) and one deletion mutation (p.P347_A348del). The pathogenic variants were most frequently detected in exon 1 (14 of 36 [38.9%]). The most common pathogenic variants were p.P347L and T17M (5 of 36 [13.9%] families). Among 42 patients of 36 families, 35 patients of 29 families (80.6%) presented with the generalized RP phenotype, and seven patients of seven families (19.4%) presented with the sector RP phenotype. Three variants (p.T17M, p.G101E, and p.E181K) presented with both the generalized and sector RP phenotypes. Conclusion: This multicenter cohort study provided information on the clinical and genetic features of RHO-associated RP in Koreans. It is clinically important to expand the genetic spectrum and understand genotype-phenotype correlations to ultimately facilitate the development of gene therapy.