INCIDENCE AND RISK FACTORS OF INTRAOCULAR INFLAMMATION AFTER BROLUCIZUMAB TREATMENT IN JAPAN: A Multicenter Age-Related Macular Degeneration Study.

PURPOSE: To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration in Japan. METHODS: A total of 1,351 Japanese consecutive patients with neovascular age-related macular degeneration who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors. RESULTS: Intraocular inflammation developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in five patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of three lines or more due to retinal vasculitis and/or retinal occlusion. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. History of IOI (including retinal vasculitis) and/or retinal occlusion (odds ratio [OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset. CONCLUSION: The 1-year cumulative incidence of IOI in Japanese neovascular age-related macular degeneration patients treated with brolucizumab was 12.2%. History of IOI (including retinal vasculitis) and/or retinal occlusion and female sex were significant risk factors.

Genome-Wide Association Study of Age-Related Macular Degeneration Reveals 2 New Loci Implying Shared Genetic Components with Central Serous Chorioretinopathy.

PURPOSE: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. DESIGN: Genome-wide association study (GWAS). PARTICIPANTS: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. METHODS: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. MAIN OUTCOME MEASURES: Associations of genetic variants with AMD. RESULTS: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10-8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10-12 and P = 1.35 × 10-9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10-3 and P = 4.28 × 10-3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = -0.33; P = 0.01; false discovery rate, 0.099). CONCLUSIONS: Our findings imply shared genetic components conferring the risk of both AMD and CSC. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Patient Preferences for Anti-Vascular Endothelial Growth Factor Treatment for Wet Age-Related Macular Degeneration in Japan: A Discrete Choice Experiment.

BACKGROUND: In Japan, intravitreal anti-vascular endothelial growth factor (anti-VEGF) dosing regimens for wet age-related macular degeneration (wAMD) include pro re nata, every 2 months, and treat-and-extend, resulting in different outcomes and patient burden. Although reflecting patient preferences in treatment decision-making is desirable, few studies have examined this in Japan. This study assessed the patients willingness to trade-off between different dosing regimens. PATIENTS AND METHODS: Patients with wAMD were recruited from four Japanese university hospitals to complete a face-to-face cross-sectional survey. In a discrete choice experiment, patients were asked to choose their preferred option from two anti-VEGF treatment profiles shown side-by-side across a series of choice tasks. The profiles varied on four attributes: number of injections in 12 months, number of physician consultations in 12 months, chance of 1-year visual acuity (VA) improvement, and chance of 2-year VA maintenance. Preference weights were estimated using hierarchical Bayes' models. RESULTS: Overall, 120 patients (30 treatment naïve and 90 anti-VEGF experienced) completed the survey. Patients were willing to accept an increase from three to approximately eight injections in 12 months to increase the chance of 1-year VA improvement from 25% to 40%. They would be willing to accept 11 injections in 12 months if the chance of 2-year VA maintenance increased from 80% to 96%. The most valued attributes were increasing the chance of 2-year VA maintenance and reducing the number of injections in 12 months, which were each about twice as important as decreasing physician consultations in 12 months and increasing the chance of 1-year VA improvement (p<0.001). Among the dosing regimens, patients most preferred treat-and-extend because of its higher chance of 2-year VA maintenance. CONCLUSION: Informing patients with wAMD about the likelihood of long-term VA maintenance when selecting treatment may increase the acceptance of an optimal treatment regimen and number of injections.

Genome-wide association study suggests four variants influencing outcomes with ranibizumab therapy in exudative age-related macular degeneration.

To identify factors associated with ranibizumab responses in patients with exudative age-related macular degeneration (AMD), we performed a genome-wide association study (GWAS) and a replication study using a total of 919 exudative AMD patients treated with intravitreal ranibizumab in a Japanese population. In the combined analysis of GWAS and the replication study, no loci reached genome-wide significant level; however, we found four variants showed suggestive level of associations with visual loss at month three (rs17822656, rs76150532, rs17296444, and rs75165563: Pcombined < 1.0 × 10-5). Of the candidate genes within these loci, three were relevant to VEGF-related pathway (KCNMA1, SOCS2, and OTX2). The proportions of patients who worsened visual acuity were 13.7%, 38.8%, 58.0%, and 80.0% in patients with 0, 1, 2, and 3 or more identified risk variants, respectively. Changes in visual acuity decreased linearly as the number of risk variants increased (P = 1.67 × 10-12). The area under the curve using age, baseline visual acuity, and history of previous treatment was 0.607, and improved significantly to 0.713 in combination with identified variants (P < 0.0001). Although further study is needed to confirm their associations, our results offer candidate variants influencing response to ranibizumab therapy.

LONG-TERM OUTCOMES OF RANIBIZUMAB TREATMENT OF MYOPIC CHOROIDAL NEOVASCULARIZATION IN EAST-ASIAN PATIENTS FROM THE RADIANCE STUDY.

PURPOSE: To evaluate long-term efficacy and safety of ranibizumab for treatment of myopic choroidal neovascularization (mCNV) in clinical practice. METHODS: Noninterventional, retrospective cohort study of East-Asian patients previously treated with ranibizumab during the RADIANCE trial. Forty-one patients who completed the RADIANCE trial were followed-up for up to 48 months (post-RADIANCE observation period). Outcome measures were best-corrected visual acuity changes from baseline (assessed at RADIANCE trial initiation), mCNV recurrences, and ocular adverse events. RESULTS: Mean visual gain from baseline best-corrected visual acuity (56.5 ± 12.1 letters) (20/80) was significant at 12 months (+14.3 ± 11.4 letters, n = 40, P < 0.0001), 24 months (+10.4 ± 22.3 letters, n = 31, P = 0.0143), 30 months (+11.0 ± 22.4 letters, n = 29, P = 0.0134), 42 months (+12.9 ± 20.9 letters, n = 25, P = 0.0051), and 48 months (+16.3 ± 18.7, n = 16, P = 0.0034). Of the 16 patients who completed 48 months of follow-up, 63% gained ≥10 letters and 13% lost ≥10 letters. Over the post-RADIANCE observation period, 83% of patients required no further treatment for mCNV, 10% experienced mCNV recurrences, and 12% experienced a nonserious ocular adverse event. Patients who required additional treatment for mCNV received a mean of 5.0 (SD 5.9, range 1.0-18.0) ranibizumab injections. CONCLUSION: Best-corrected visual acuity gained at the end of the RADIANCE trial was sustained over additional 36 months of follow-up. Few patients required further treatment and no new safety concerns were observed.

A prospective multicenter study on genome wide associations to ranibizumab treatment outcome for age-related macular degeneration.

We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.

A modified treat-and-extend regimen of aflibercept for treatment-naïve patients with neovascular age-related macular degeneration.

PURPOSE: To evaluate a modified treat-and-extend (TAE) regimen of intravitreal aflibercept injection (IAI) for treatment-naïve patients with neovascular age-related macular degeneration (AMD). METHODS: Thirty-six eyes (36 patients) treated with the modified TAE regimen were evaluated at 12 months retrospectively. The modified TAE regimen consisted of three steps: 1) an induction phase, during which patients were treated with ≥ 3-monthly IAIs until exudative activity disappeared, 2) an observation phase, during which patients were monitored until exudative activity appeared, and 3) a TAE phase, for which the initial treatment interval was determined based on the disease recurrence interval, followed by treatment intervals changing by 2 weeks. RESULTS: Mean logMAR BCVA improved significantly from 0.48 ± 0.51 at baseline to 0.40 ± 0.53 at 12 months (P < 0.01), and was maintained (losing <0.3 logMAR units) in 35 eyes (97.2 %). Mean central retinal thickness and central choroidal thickness decreased significantly after 12 months. In the TAE phase, the distribution of treatment intervals was ≥8 weeks in 64.7 % (11 eyes) at 12 months. The mean number of injections was 4.53. CONCLUSION: A modified TAE regimen of IAI for neovascular AMD produced good functional outcomes over 12 months with the small number of injections.

Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD).

BACKGROUND: Patients with exudative age-related macular degeneration (AMD) who did not respond to ranibizumab at the induction phase were assessed and referred to as initial non-responders. METHODS: We retrospectively reviewed the medical records of 215 patients (218 eyes) with exudative AMD. For the initial treatments, patients received three intravitreal injections of ranibizumab (IVR) every 4 weeks. Minimum follow-up period was 12 months. We defined patients with no improvement of best corrected logMAR visual acuity (BCVA), and with no decrease of central retinal thickness (CRT) at the end of the initial treatment, as initial non-responders. Patients who had previous treatment history prior to this investigation were included, but patients who had photodynamic therapy (PDT) with IVR were excluded. RESULTS: Twenty-two eyes (10.1%) were identified as initial non-responders. The mean BCVA of initial non-responders before IVR and after induction phase were 0.39 and 0.36, respectively. There was no significant difference between these values, however the mean BCVA decreased significantly to 0.55 at 12 months after the beginning of the induction phase (P = 0.021). The mean greatest linear dimension (GLD) of the lesion before IVR of initial non-responders was 4,121 µm. We found 16 eyes with typical AMD, and six eyes with polypoidal choroidal vasculopathy. One eye had predominantly classic choroidal neovascularization (CNV), and others had occult CNV of typical AMD. As additional treatments, twelve eyes received PDT, and in three of the eyes exudation remained after PDT. CONCLUSION: Initial non-responders were more prevalent in patients with occult CNV than in patients with other CNV types. Some of the initial non-responders did not respond to PDT. This study suggested possible involvement of other factors, in addition to vascular endothelial growth factor, in the occurrence of CNV in initial non-responder patients.

Two-year visual results for older Asian women treated with photodynamic therapy or bevacizumab for myopic choroidal neovascularization.

PURPOSE: To compare the long-term visual and anatomic outcome of treatment with photodynamic therapy (PDT) or intravitreal bevacizumab (IVB; Avastin; Genentech Inc, South San Francisco, California, USA) for choroidal neovascularization attributable to pathologic myopia (mCNV). DESIGN: An open-label, interventional case series. SETTING: Multi-institutional. PATIENTS: Thirty-one eyes of Japanese women who received either PDT or IVB for mCNV. Inclusion criteria were age 50 years or older, greatest linear dimension (GLD) 1200 to 3000 microm, and baseline best-corrected visual acuity (BCVA) 20/200 to 20/40. INTERVENTION PROCEDURES: Patients received either PDT or IVB (1 mg/40 microL) throughout the study, with re-treatment when necessary. MAIN OUTCOME MEASURES: BCVA and visual gain/loss at 3, 6, 12, 18, and 24 months after the initial treatment. RESULTS: Age, BCVA, location of CNV, refractive error, and symptom duration at baseline did not differ significantly between groups. BCVA was significantly improved at 3 to 12 months (P < .05); however, the significance was lost at 18 and 24 months in the IVB group. The PDT group showed no significant improvement within the first year, and vision slowly worsened after 12 months, becoming significantly worse at 18 and 24 months compared to baseline (P< .01). BCVA was significantly higher in the IVB group at 6 months (P< .05), and 12 months or further (P < .01). Visual gain was significantly greater in the IVB group at 6, 12, 18, and 24 months (P < .05 for 6, 18, and 24 months and P < .01 for 12 months). CONCLUSIONS: These findings indicate that the effects of PDT and IVB have a different time course, and that IVB provides a significantly better BCVA than PDT for mCNV over the long-term.

[Evaluation of cases of polypoidal choroidal vasculopathy showing classic choroidal neovascularization in their natural course].

BACKGROUND: Some cases of polypoidal choroidal vasculopathy (PCV) in their natural course develop into classic choroidal neovascularization(CNV) as shown by fluorescein angiography (FA) findings. SUBJECTS AND METHOD: We evaluated 8 eyes of 8 PCV patients showing classic CNV by FA findings, using indocyanine green angiography (IA) and optical coherence tomography(OCT). RESULT: All patients showed subretinal grayish exudates, which were considered fibrinous. Five cases were recognized as true subretinal CNV according to IA and OCT findings. The other 3 patients showed polypoidal dilatation with vascular networks by IA, and a moderately reflective mass considered fibrinous over the polypoidal elevation of retinal pigment epithelium (RPE) by OCT. CONCLUSION: Both true CNV and PCV with fibrin are present in PCV patients showing classic CNV. It requires care to determine proper treatment.

Polypoidal choroidal vasculopathy: incidence, demographic features, and clinical characteristics.

OBJECTIVE: To clarify the incidence, demographic features, and clinical characteristics of polypoidal choroidal vasculopathy (PCV) in Japanese patients. METHODS: Consecutive patients with presumed neovascular age-related macular degeneration (AMD) who met the eligibility criteria were examined between January 1, 1999, and October 31, 2001. All patients underwent complete ophthalmologic examination and fluorescein and indocyanine green angiography. RESULTS: Among 471 eyes of 418 patients who met the criteria, 110 eyes (23%) of 100 patients were diagnosed as having PCV and 361 eyes (77%) of 318 patients as having neovascular AMD. Mean age of patients with PCV was 68.4 years, with a male preponderance (63% of patients); involvement was mostly unilateral (90% of patients), and polypoidal vascular lesions were located mainly in the macula (85% of eyes). Retinal manifestations of PCV were characterized by serous macular detachment (52% of eyes), submacular hemorrhage (30% of eyes), and retinal pigment epithelium degeneration (10% of eyes). There were few subretinal fibrovascular proliferations (7% of eyes). Mean visual acuity was 0.31 in eyes with PCV and 0.18 in eyes with AMD. The incidence of severe visual loss (0.2 or worse) was 35% in PCV and 53% in AMD. CONCLUSIONS: The incidence of PCV in Japanese patients is high, and the incidence and demographic features vary in different ethnic groups. The clinical manifestations of PCV and AMD resemble each other; however, PCV is characterized by low incidence of subretinal fibrovascular proliferation, slow progression of vascular abnormality, and minimal association with conventional choroidal neovascularization. These factors seem to lead to a more favorable visual outcome in PCV compared with neovascular AMD.

Genome and virulence determinants of high virulence community-acquired MRSA.

BACKGROUND: A new type of meticillin-resistant Staphylococcus aureus (MRSA), designated community-acquired MRSA, is becoming increasingly noticeable in the community, some strains of which cause fatal infections in otherwise healthy individuals. By contrast with hospital-acquired MRSA, community-acquired MRSA is more susceptible to non b-lactam antibiotics. We investigated the high virulence potential of certain strains of this bacterium. METHODS: We ascertained the whole genome sequence of MW2, a strain of community-acquired MRSA, by shotgun cloning and sequencing. MW2 caused fatal septicaemia and septic arthritis in a 16-month-old girl in North Dakota, USA, in 1998. The genome of this strain was compared with those of hospital-acquired MRSA strains, including N315 and Mu50. FINDINGS: Meticillin resistance gene (mecA) in MW2 was carried by a novel allelic form (type IVa) of staphylococcal cassette chromosome mec (SCCmec), by contrast with type II in N315 and Mu50. Type IVa SCCmec did not carry any of the multiple antibiotic resistance genes reported in type II SCCmec. By contrast, 19 additional virulence genes were recorded in the MW2 genome. All but two of these virulence genes were noted in four of the seven genomic islands of MW2. INTERPRETATION: MW2 carried a range of virulence and resistance genes that was distinct from those displayed on the chromosomes of extant S aureus strains. Most genes were carried by specific allelic forms of genomic islands in the MW2 chromosome. The combination of allelic forms of genomic islands is the genetic basis that determines the pathogenicity of medically important phenotypes of S aureus, including those of community-acquired MRSA strains.

Polypoidal choroidal vasculopathy: natural history.

PURPOSE: The present study was performed to clarify the long-term natural history of polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective, consecutive observational case series. METHODS: Fourteen eyes of 12 consecutive patients with PCV were prospectively followed in our clinic for at least 2 years without any treatment after a first visit to the clinic between February 1996 and November 1998. All patients underwent complete ophthalmologic examination, color fundus photography, and fluorescein and indocyanine green (ICG) angiography at regular intervals. Inclusion criteria were as follows: eyes had serous and/or hemorrhagic pigment epithelium detachment (PED) and retinal detachment in the posterior pole, and ICG angiography revealed a branching vascular network with polypoidal dilations at the terminals of the network. Exclusion criteria were as follows: other diseases such as exudative age-related macular degeneration, high myopia, angioid streaks, and presumed ocular histoplasmosis syndrome, and patients who previously underwent any ocular surgery. RESULTS: Patients were followed for mean of 39.9 months (range, 24-54 months). PCV was present in 10 (83%) men and two women and in the elderly (mean age 68.1 years), usually unilateral (83%) with vascular lesions located at the macula (93%). The PCV manifested in two patterns, exudative and hemorrhagic. In the exudative pattern, serous PED and retinal detachment were predominant at the macula. The hemorrhagic pattern was characterized by hemorrhagic PED and subretinal hemorrhage at the macula. ICG angiography revealed polypoidal choroidal neovascularization that was changeable in appearance and repeatedly grew and spontaneously regressed, but the vascular network persisted. In some eyes, a collection of small aneurysmal dilations of vessels resembling a cluster of grapes appeared and all of them had marked bleeding and leakage and worse outcome. CONCLUSION: Polypoidal choroidal vasculopathy is a long persistent chronic disease and the patients had a variable course. Fifty percent of the patients had a favorable course. In the remaining half of the patients, the disorder persisted for a long time with occasional repeated bleeding and leakage, resulting in macular degeneration and visual loss. Eyes with a cluster of grapes-like polypoidal dilatations of the vessels had a high risk for severe visual loss.