Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

UNITED KINGDOM DATABASE STUDY OF INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX) FOR MACULAR EDEMA RELATED TO RETINAL VEIN OCCLUSION.

PURPOSE: To study the treatment patterns, visual outcomes and safety profile of intravitreal dexamethasone implant (IDI) used for the treatment of macular edema secondary to retinal vein occlusion. METHODS: Up to 2 years of routinely collected anonymized data within electronic medical record systems were remotely extracted from 16 centers. The outcome measures include visual outcome, number of injections, and safety measures, including the rate of intraocular pressure (IOP) rise, frequency of IOP-lowering medication usage, and cataract surgery rates. RESULTS: The study included 688 eyes (44.4%) with central retinal vein occlusion and 862 eyes (55.6%) with branch retinal vein occlusion; 1,250 eyes (80.6%) were treatment naive and 28% (275/989) had high IOP or were on IOP-lowering medications before IDI use. It was found that 31% (476) of eyes received two injections, and 11.7% (182) and 3.7% (58) of eyes received three and four injections, respectively. The mean baseline Snellen visual acuity improved from 20/125 to 20/40 after the first injection. The probability of cataract surgery was 15% at 24 months. The proportion of eyes with ≥10 mmHg change from baseline was higher in phakic (14.2%) compared with pseudophakic eyes (5.4%, P = 0.004). Three eyes required IOP filtering surgery (0.2%). CONCLUSION: The visual results of IDI in eyes with macular edema secondary to retinal vein occlusion in the real world are comparable to those of clinical trial setting. Increased IOP in eyes with preexisting ocular hypertension or glaucoma can be controlled with additional medical treatment. Intraocular pressure rise with IDI may be more frequent in phakic than in pseudophakic eyes.

Prevalence and phenotype associations of complement factor I mutations in geographic atrophy.

Rare variants in the complement factor I (CFI) gene, associated with low serum factor I (FI) levels, are strong risk factors for developing the advanced stages of age-related macular degeneration (AMD). No studies have been undertaken on the prevalence of disease-causing CFI mutations in patients with geographic atrophy (GA) secondary to AMD. A multicenter, cross-sectional, noninterventional study was undertaken to identify the prevalence of pathogenic rare CFI gene variants in an unselected cohort of patients with GA and low FI levels. A genotype-phenotype study was performed. Four hundred and sixty-eight patients with GA secondary to AMD were recruited to the study, and 19.4% (n = 91) demonstrated a low serum FI concentration (below 15.6 µg/ml). CFI gene sequencing on these patients resulted in the detection of rare CFI variants in 4.7% (n = 22) of recruited patients. The prevalence of CFI variants in patients with low serum FI levels and GA was 25%. Of the total patients recruited, 3.2% (n = 15) expressed a CFI variant classified as pathogenic or likely pathogenic. The presence of reticular pseudodrusen was detected in all patients with pathogenic CFI gene variants. Patients with pathogenic CFI gene variants and low serum FI levels might be suitable for FI supplementation in therapeutic trials.

Diagnostic Accuracy of Monitoring Tests of Fellow Eyes in Patients with Unilateral Neovascular Age-Related Macular Degeneration: Early Detection of Neovascular Age-Related Macular Degeneration Study.

PURPOSE: To evaluate the diagnostic accuracy of routinely used tests of visual function and retinal morphology compared with fundus fluorescein angiography (FFA) to detect onset of active macular neovascularization in unaffected fellow eyes of patients with unilateral neovascular age-related macular degeneration (nAMD). DESIGN: Prospective diagnostic accuracy cohort study conducted in 24 eye clinics in the United Kingdom over 3 years. PARTICIPANTS: Older adults (>50 years) with recently diagnosed unilateral nAMD with a fellow (study) eye free of nAMD. METHODS: Self-reported vision, Amsler, clinic-measured visual acuity (VA), fundus assessment, and spectral domain OCT. The reference standard is FFA. MAIN OUTCOME MEASURES: Sensitivity and specificity of the 5 index tests. RESULTS: Of 552 participants monitored for up to 3 years, 145 (26.3%) developed active nAMD in the study eye, of whom 120 had an FFA at detection and constituted the primary analysis cohort. Index test positives at nAMD detection in those confirmed by FFA were self-reported vision much worse (5), distortion on Amsler (33), 10-letter decrease in acuity from baseline (36), fundus examination (64), and OCT (110). Percentage index test sensitivities were: self-reported vision 4.2 (95% confidence interval [CI], 1.6-9.8); Amsler 33.7 (95% CI, 25.1-43.5); VA 30.0 (95% CI, 22.5-38.7); fundus examination 53.8 (95% CI, 44.8-62.5); and OCT 91.7 (95% CI, 85.2-95.6). All 5 index test specificities were high at 97.0 (95% CI, 94.6-98.5), 81.4 (95% CI, 76.4-85.5), 66.3 (95% CI, 61.0-71.1), 97.6 (95% CI, 95.3-98.9), and 87.8 (95% CI, 83.8-90.9), respectively. The combination of OCT with one other index test that was a secondary outcome measure increased sensitivity marginally and decreased specificity for all combinations except fundus examination. CONCLUSIONS: Tests of self-reported change in vision, unmasking of new distortion, measurements of acuity, and fundus checks to diagnose active nAMD performed poorly in contrast to OCT. Our findings support a change to guidelines in clinical practice to monitor for onset of nAMD.

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.

Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).

PURPOSE: Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN: Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS: Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS: Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES: The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS: Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS: Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.

Relevance of Retinal Thickness Changes in the OCT Inner and Outer Rings to Predict Progression to Clinical Macular Edema: An Attempt of Composite Grading of Macular Edema.

PURPOSE: To characterize the relevance of macular thickness changes in the inner and outer rings in the progression of macular edema in eyes/patients with diabetes type 2. METHODS: A total of 374 type 2 diabetic patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20-35) were included in a 12-month prospective observational study to identify retinopathy progression. Retinal thickness analyses were performed in 194 eyes/patients using Cirrus SD- OCT and 166 eyes/patients using Spectralis SD-OCT. The DRCR.net classification of subclinical and clinical macular edema was used. A composite grading of macular edema is proposed in this study. RESULTS: A total of 317 eyes/patients completed the study. SD-OCT identified clinical macular edema in 24 eyes/patients (6.7%) and subclinical macular edema in 104 eyes/patients (28.9%) at baseline. Increased thickness of the central subfield is the best predictor for the development of clinical macular edema, with 85.7% sensitivity and 71.9% specificity (OR: 2.57, 95% CI: 0.82-7.99). However, the involvement of the inner and outer rings is a cumulative predictor of progression to clinical macular edema (OR: 8.69, 95% CI: 2.85-26.52). CONCLUSIONS: A composite OCT grading of macular edema taking into account the retinal thickness changes in the inner and outer macular rings offers a simple way to characterize macular edema, with added clinical value.

Retinal layer location of increased retinal thickness in eyes with subclinical and clinical macular edema in diabetes type 2.

PURPOSE: To identify the retinal layer predominantly affected in eyes with subclinical and clinical macular edema in diabetes type 2. METHODS: A cohort of 194 type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (ETDRS levels 20/35) were examined with Cirrus spectral-domain optical coherence tomography (OCT) at the baseline visit (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers of the eyes with subclinical and clinical macular edema was compared with a sample of 31 eyes from diabetic patients with normal OCT and an age-matched control group of 58 healthy eyes. RESULTS: From the 194 eyes in the study, 62 had subclinical macular edema and 12 had clinical macular edema. The highest increases in retinal thickness (RT) were found in the inner nuclear layer (INL; 33.6% in subclinical macular edema and 81.8% in clinical macular edema). Increases were also found in the neighboring layers. Thinning of the retina was registered in the retinal nerve fiber, ganglion cells and inner plexiform layers in the diabetic eyes without macular edema. CONCLUSIONS: The increase in RT occurring in diabetic eyes with macular edema is predominantly located in the INL but extends to neighboring retinal layers indicating that it may be due to extracellular fluid accumulation.

One-year progression of diabetic subclinical macular edema in eyes with mild nonproliferative diabetic retinopathy: location of the increase in retinal thickness.

PURPOSE: To characterize the 1-year progression of retinal thickness (RT) increase occurring in eyes with subclinical macular edema in type 2 diabetes. METHODS: Forty-eight type 2 diabetic eyes/patients with mild nonproliferative diabetic retinopathy (NPDR; levels 20 and 35 in the Early Treatment Diabetic Retinopathy Study) classified as presenting subclinical macular edema at baseline completed the 1-year follow-up period, from a sample of 194 followed in a 12-month observational and prospective study (ClinicalTrials.gov identifier: NCT01145599). Automated segmentation of the retinal layers in these eyes was performed, followed by verification and correction by a human grader. RESULTS: The highest increase in RT over the 1-year follow-up period for the 48 eyes/patients with subclinical macular edema was found in the inner nuclear layer (INL). Progression to clinical macular edema was also associated with increased thickening of other retinal layers aside from the INL. The microvascular disease activity shown by microaneurysm (MA) turnover ≥6 was associated with progression from subclinical to clinical macular edema. CONCLUSIONS: Increases in RT occurring over a period of 1 year in diabetic eyes with mild NPDR and subclinical macular edema occur mainly in the INL. The development of clinical macular edema appears to be associated with increased thickening of other retinal layers and microvascular disease activity.

Impact of treat and extend criteria on proportions that can be extended after loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration: PRECISE Report 5.

OBJECTIVE: To study the impact of definitions of various treatment extension criteria on the proportion of patients who could be extended at their first visit after the loading phase of 2 mg aflibercept therapy for neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on the loading phase of three intravitreal doses of 2 mg aflibercept in routine clinical practice were recruited from December 2019 to August 2021. The response to the loading phase was assessed at approximately 8 weeks post-loading (up to 140 days from first injection) based on different definitions of response. The proportion of patients that qualify for interval extension based on different clinical trial criteria was also evaluated. RESULTS: A total of 722 patients with visual acuity (VA) and optical coherence tomography (OCT) scans done at all 4 visits were included. Of these 32.4% of eyes responded with complete macular fluid resolution after the first injection with no recurrence through the loading phase (super-responders) while 26.9% had persistent macular fluid in all 4 visits (true non-responders). The rest were considered suboptimal responders. Change in VA showed marked variations within each of these categories of fluid resolution. For extension of next treatment interval, if presence of any macular fluid at the post-loading visit is the only criteria considered, about 50% could be extended to 8 weeks. If both VA worsening by ≥5 letters and a > 25 µm increase in central sub-field thickness (CST) are considered, 90% will be eligible for interval extension. CONCLUSION: Clinical trial designs and pre-defined treatment extension/shortening criteria determine the proportion of patients requiring treatment in the post-loading visit. The short and long-term impact of interval extension immediate post-loading on visual outcome in clinical practice is unknown.

Associations of presenting visual acuity with morphological changes on OCT in neovascular age-related macular degeneration: PRECISE Study Report 2.

PURPOSE: To study associations of optical coherence tomography (OCT) features with presenting visual acuity (VA) in treatment naive neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on aflibercept therapy were recruited from December 2019 to August 2021. Demographic and OCT (Spectralis, Heidelberg Engineering) features associated with good VA (VA ≥ 68 ETDRS letters, Snellen ≥ 6/12) and poor VA (VA < 54 letters, Snellen < 6/18) were analysed using Generalised Estimating Equations to account for inter-eye correlation. RESULTS: Of 2274 eyes of 2128 patients enrolled, 2039 eyes of 1901 patients with complete data were analysed. Mean age was 79.4 (SD 7.8) years, female:male 3:2 and mean VA 58.0 (SD 14.5) letters. On multivariable analysis VA < 54 letters was associated with increased central subfield thickness (CST) (OR 1.40 per 100 µm; P < 0.001), foveal intraretinal fluid (OR 2.14; P < 0.001), polypoidal vasculopathy (PCV) relative to Type 1 macular neovascularisation (MNV) (OR 1.66; P = 0.049), presence of foveal subretinal hyperreflective material (SHRM) (OR 1.73; P = 0.002), foveal fibrosis (OR 3.85; P < 0.001), foveal atrophy (OR 5.54; P < 0.001), loss of integrity of the foveal ellipsoid zone (EZ) or external limiting membrane (ELM) relative to their preservation (OR 3.83; P < 0.001) and absence of subretinal drusenoid deposits (SDD) (presence vs absence; OR 0.75; P = 0.04). These features were associated with reduced odds of VA ≥ 68 letters except MNV subtypes and SDD. CONCLUSION: Presence of baseline fovea-involving atrophy, fibrosis, intraretinal fluid, SHRM, PCV EZ/ELM loss and increased CST determine poor presenting VA. This highlights the need for early detection and treatment prior to structural changes that worsen baseline VA.

Baseline characteristics of eyes with early residual fluid post loading phase of aflibercept therapy in neovascular AMD: PRECISE study report 3.

PURPOSE: To compare the baseline characteristics in patients with and without early residual fluid (ERF) after aflibercept loading phase (LP) in patients with treatment naïve neovascular age related macular degeneration (nAMD). METHODS: Patients with nAMD initiated on LP of three intravitreal aflibercept doses were recruited from December 2019 to August 2021. Baseline demographic and OCT features associated with any ERF were analysed using Generalised Estimating Equations to account for inter-eye correlation. Receiver operating characteristic (ROC) curve was performed for selection of CST threshold. RESULTS: Of 2128 patients enrolled, 1999 eyes of 1862 patients with complete data were included. After LP, ERF was present in 1000 (50.0%), eSRF in 746(37.3%) and eIRF in 428 (21.4%) eyes. In multivariable analysis of baseline features, eyes with increased central subfield thickness (CST) (OR 1.31 per 100 microns increase [95% CI 1.22 to 1.41]; P < 0.001), eyes with IRF and SRF at baseline (1.62 [95% CI 1.17 to 2.22]; P = 0.003), and those with SRF only (OR 2.26 [95% CI 1.59 to 3.20]; P < 0.001) relative to IRF only were determinants of ERF. CST ≥ 418 microns had 57% sensitivity and 58% specificity to distinguish ERF from no ERF at visit 4. CONCLUSION: On average, 50% of eyes have ERF after aflibercept LP. Clinically relevant baseline determinants of ERF include CST ≥ 418 µ and presence of only SRF. These eyes may require further monthly treatment before extending treatment intervals.

Subretinal transient hyporeflectivity in neovascular age-related macular degeneration and its response to a loading phase of aflibercept: PRECISE report 4.

PURPOSE: To describe the prevalence of subretinal transient hyporeflectivity (STHR) in exudative neovascular age-related macular degeneration (nAMD) and its response to a loading phase of aflibercept. METHODS: Optical coherence tomography (OCT) scans of treatment-naïve nAMD patients captured at baseline and after a loading phase of aflibercept were graded for presence of STHR, defined as a small, well-defined, round, subretinal, hyporeflective area, delimited between the ellipsoid zone (EZ) and the retinal pigmented epithelium/Bruch membrane complex. OCT parameters recorded were macular neovascularisation (MNV) subtypes, location of retinal fluids (subretinal fluid, SRF and intraretinal fluid, IRF), central retinal and choroidal thickness. Response was defined as absence of IRF and SRF. Factors associated with completely resolved STHR versus persistent STHR post-loading phase were compared. RESULTS: 2039 eyes of 1901 patients were analysed. STHR was observed in 79 eyes of 78 patients, with an estimated prevalence of 3.87% (95% CI 3.08-4.81%). STHR were seen in 44 type 1 MNV (56%), 27 with type 2 (34%), and 8 with type 3 (10%). At baseline, a total of 303 STHR were present, ranging between 1-22 per eye. The total number of STHR reduced significantly after the loading phase to 173 (p = 0.002). Complete disappearance of STHR was seen in 44 eyes (56%) and persistent STHR in the rest (44%). CONCLUSIONS: STHR may represent a marker of low-grade exudation in nAMD eyes with good response to a loading phase of aflibercept. However, its potential role as an independent nAMD activity biomarker is limited as most resolve after the loading phase.

Age-related macular degeneration and modification of systemic complement factor H production through liver transplantation.

PURPOSE: To investigate whether modification of liver complement factor H (CFH) production, by alteration of liver CFH Y402H genotype through liver transplantation (LT), influences the development of age-related macular degeneration (AMD). DESIGN: Multicenter, cross-sectional study. PARTICIPANTS: We recruited 223 Western European patients ≥ 55 years old who had undergone LT ≥ 5 years previously. METHODS: We determined AMD status using a standard grading system. Recipient CFH Y402H genotype was obtained from DNA extracted from recipient blood samples. Donor CFH Y402H genotype was inferred from recipient plasma CFH Y402H protein allotype, measured using enzyme-linked immunosorbent assays. This approach was verified by genotyping donor tissue from a subgroup of patients. Systemic complement activity was ascertained by measuring levels of plasma complement proteins using an enzyme-linked immunosorbent assay, including substrates (C3, C4), activation products (C3a, C4a, and terminal complement complex), and regulators (total CFH, C1 inhibitor). MAIN OUTCOME MEASURES: We evaluated AMD status and recipient and donor CFH Y402H genotype. RESULTS: In LT patients, AMD was associated with recipient CFH Y402H genotype (P = 0.036; odds ratio [OR], 1.6; 95% confidence interval [CI], 1.0-2.4) but not with donor CFH Y402H genotype (P = 0.626), after controlling for age, sex, smoking status, and body mass index. Recipient plasma CFH Y402H protein allotype predicted donor CFH Y402H genotype with 100% accuracy (n = 49). Plasma complement protein or activation product levels were similar in LT patients with and without AMD. Compared with previously reported prevalence figures (Rotterdam Study), LT patients demonstrated a high prevalence of both AMD (64.6% vs 37.1%; OR, 3.09; P<0.001) and the CFH Y402H sequence variation (41.9% vs 36.2%; OR, 1.27; P = 0.014). CONCLUSIONS: Presence of AMD is not associated with modification of hepatic CFH production. In addition, AMD is not associated with systemic complement activity in LT patients. These findings suggest that local intraocular complement activity is of greater importance in AMD pathogenesis. The high AMD prevalence observed in LT patients may be associated with the increased frequency of the CFH Y402H sequence variation. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

A Multi-Modal AI-Driven Cohort Selection Tool to Predict Suboptimal Non-Responders to Aflibercept Loading-Phase for Neovascular Age-Related Macular Degeneration: PRECISE Study Report 1.

Patients diagnosed with exudative neovascular age-related macular degeneration are commonly treated with anti-vascular endothelial growth factor (anti-VEGF) agents. However, response to treatment is heterogeneous, without a clinical explanation. Predicting suboptimal response at baseline will enable more efficient clinical trial designs for novel, future interventions and facilitate individualised therapies. In this multicentre study, we trained a multi-modal artificial intelligence (AI) system to identify suboptimal responders to the loading-phase of the anti-VEGF agent aflibercept from baseline characteristics. We collected clinical features and optical coherence tomography scans from 1720 eyes of 1612 patients between 2019 and 2021. We evaluated our AI system as a patient selection method by emulating hypothetical clinical trials of different sizes based on our test set. Our method detected up to 57.6% more suboptimal responders than random selection, and up to 24.2% more than any alternative selection criteria tested. Applying this method to the entry process of candidates into randomised controlled trials may contribute to the success of such trials and further inform personalised care.

Genome-wide association study of primary open angle glaucoma risk and quantitative traits.

PURPOSE: Primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss. Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved. We analyzed carefully characterized POAG cases in a genome-wide association study (GWAS). METHODS: We performed a GWAS in 387 POAG cases using public control data (WTCCC2). We also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP). Promising single nucleotide polymorphisms (SNPs), based on various prioritisation criteria, were genotyped in a cohort of 294 further POAG cases and controls. RESULTS: We found 2 GWAS significant results in the discovery stage for association, one of which which had multiple evidence in the gene 'neural precursor cell expressed, developmentally down-regulated 9' (NEDD9; rs11961171, p=8.55E-13) and the second on chromosome 16 with no supporting evidence. Taking into account all the evidence from risk and quantitative trait ocular phenotypes we chose 86 SNPs for replication in an independent sample. Our most significant SNP was not replicated (p=0.59). We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing. Two of these, for phenotypes CDR (rs4385494, discovery p=4.51x10-5, replication p=0.029) and CCT (rs17128941, discovery p=5.52x10-6, replication=0.027), show the consistent direction of effects between the discovery and replication data. We also assess evidence for previously associated known genes and find evidence for the genes 'transmembrane and coiled-coil domains 1' (TMCO1) and 'cyclin-dependent kinase inhibitor 2B' (CDKN2B). CONCLUSIONS: Although we were unable to replicate any novel results for POAG risk, we did replicate two SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing. There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits. We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study. Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.

Extended real-world experience with the ILUVIEN® (fluocinolone acetonide) implant in the United Kingdom: 3-year results from the Medisoft® audit study.

BACKGROUND: This study aimed to assess the long-term effectiveness of the 0.2 µg/day fluocinolone acetonide (FAc) implant over ≥3 years for patients with diabetic macular oedema. METHODS: A retrospective audit of pseudo-anonymised data from patients with chronic diabetic macular oedema (cDMO) and treated with the FAc implant across 14 UK clinical sites. Safety and clinical effectiveness were measured. RESULTS: Two-hundred and fifty-six eyes had ≥3 years of follow-up (mean 4.28 years), during which a mean of 1.14 FAc implants were used per eye. Mean best-recorded visual acuity (BRVA) increased from 52.6 to 56.7 letters at month 3 and remained stable thereafter; this trend was also seen in pseudophakic eyes. The proportion of patients attaining a BRVA ≥6/12 increased from 17% at baseline to 27% 1 month after FAc implant and remained stable above 30% from month 12 onwards. Eyes with no prior history of intraocular pressure (IOP)-related events required significantly less treatment-emergent IOP-lowering medication than those with a prior history of IOP events (17.9% vs. 50.0% of eyes; p < 0.001). The incidence of an IOP increase of ≥10 mmHg, use of IOP-lowering medication, laser trabeculoplasty and IOP-lowering surgery was 28.9%, 29.7%, 0.8% and 2.7%, respectively, for the whole cohort. There were significant reductions in mean central foveal thickness and macular volume (p < 0.001). CONCLUSIONS: The FAc implant was well tolerated, with predictable and manageable IOP-related events while delivering a continuous microdose of corticosteroid to eyes with cDMO, providing prolonged vision preservation and a reduced number of treatments.

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.

The changing landscape for the management of patients with neovascular AMD: brolucizumab in clinical practice.

Untreated neovascular age-related macular degeneration (nAMD) can lead to severe and permanent visual impairment. The chronic nature of the disease can have a significant impact on patients' quality of life and an economic and time burden on medical retina (MR) services, with the care need outweighing the growth of resources that clinical services can access. The introduction of a new treatment into clinical services can be challenging, especially for services that are already under capacity constraints. Guidance for practical implementation is therefore helpful. Roundtable meetings, facilitated by Novartis UK, between a working group of MR experts with experience of leading and managing NHS retinal services in the intravitreal era were conducted between 2020 and 2021. These meetings explored various aspects and challenges of introducing a new anti-vascular endothelial growth factor (VEGF) therapy to the UK medical retina services. Provision of clear expert recommendations and practical guidance nationally, that can be adapted locally as required to support clinicians and healthcare professionals (HCPs), is valuable in supporting the introduction of a new anti-VEGF therapy within the NHS environment. The experts provide ophthalmologic HCPs with a collation of insights and recommendations to support the introduction and delivery of brolucizumab in their local service in the face of current and projected growth in demand for retina care.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.