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Research Update 581


The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study – 6 month results.

Eye (London, England). 2023 May 12.

Khanani AM, Aziz AA, Khan H, Gupta A, Mojumder O, Saulebayeva A, Abbey AM, Almeida DRP, Avery RL, Banda HK, Barakat MR, Bhandari R, Chang EY, Haug SJ, London NJS, Mein L, Sheth VS, Wolfe JD, Singer MA, Danzig CJ.

Background/Objective: Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD).

Subjects/Methods: Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid.

Results: After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 μM (p < 0.001), a - 25.3 μM (p < 0.001) and a - 84.5 μM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 μM (p < 0.001), a - 38.1 μM (p < 0.001) and a - 80.1 μM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved.

Conclusions: Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD.

DOI: 10.1038/s41433-023-02553-5


Anti-vascular endothelial growth factor dosing frequency and visual outcomes in macular oedema following branch retinal vein occlusion.

Eye (London, England). 2023 May 8.

Modi YS, Goduni L, Moini H, Gibson A, Boucher N, Lucas G, Dhoot DS.

Objectives: To determine the relationship between treatment frequency with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents and visual acuity (VA) outcomes in eyes with macular oedema (MO) secondary to branch retinal vein occlusion (BRVO) in US clinical practice.

Methods: Study eyes that initiated anti-VEGF injections between January 2012 and May 2016 were followed for ≥1 year in a retrospective analysis of medical records (Vestrum Health database). Eyes were analysed in 2 cohorts by treatment duration (years 1 and 2) and then in 2 subcohorts by injection frequency (≤6 or ≥7 injections/year).

Results: Among 3099 eyes with MO secondary to BRVO, 1197 (38.6%) received ≤6 injections (mean injections, 4.6; baseline mean VA, 53 letters) and 1902 (61.4%) received ≥7 injections through 1 year (mean injections, 8.8; baseline mean VA, 52 letters). At year 1, mean VA gain from baseline was 10.4 versus 13.9 letters in eyes receiving ≤6 versus ≥7 injections (p < 0.001). At year 2, mean VA in eyes receiving ≤6 (n = 42) versus ≥7 injections (n = 227) was 64 versus 68 letters, respectively (p = 0.19). Mean VA change between the start and end of year 2 in eyes receiving ≥7 injections in year 1 and ≤6 in year 2 differed significantly from that of eyes receiving ≥7 injections in both years (-3.0 vs 0.7 letters, respectively; p < 0.001).

Conclusions: In routine clinical practice, more frequent dosing with anti-VEGF agents was associated with greater visual benefits in eyes with MO secondary to BRVO.

DOI: 10.1038/s41433-023-02527-7


Progression dynamics of early versus later-stage atrophic lesions in non-neovascular AMD using quantitative OCT biomarker segmentation.

Ophthalmology, Retina. 2023 May 9:

Coulibaly LM, Reiter GS, Fuchs P, Lachinov D, Leingang O, Vogl WD, Bogunovic H, Schmidt-Erfurth U.

Purpose: To investigate the progression of geographic atrophy (GA) secondary to non-neovascular age-related macular degeneration (AMD) in early and later stage lesions using AI-based precision tools.

Design: Retrospective analysis of an observational cohort study.

Subjects: Seventy-four eyes of forty-nine patients with at least one complete retinal pigment epithelial and outer retinal atrophy (cRORA) lesion secondary to AMD were included. Patients were divided between recently developed cRORA and lesions with advanced disease status.

Methods: Patients were prospectively imaged by spectral domain optical coherence tomography (SD-OCT) volume scans. The study period encompassed 18 months with scheduled visits every 6 months. Growth rates of recently to cRORA converted lesions were compared with lesions in an advanced disease status using mixed effect models.

Main Outcome Measures: The progression of retinal pigment epithelial loss (RPEL) was considered the primary endpoint. Secondary endpoints consisted of external limiting membrane disruption (ELMD) and ellipsoid zone loss (EZL). These pathognomonic imaging biomarkers were quantified using validated deep learning algorithms. Further the EZ/RPE-Loss ratio was analysed in both study cohorts.

Results: Mean [95%CI] square root progression of recently converted lesions was 79.676[-77.140 – 236.493], 68.219[-101.210 – 237.648) and 84.825[-124.816 – 294.467] mm/half year for RPEL, ELML and EZL respectively. Mean square root progression of advanced lesions was 131.737[-22.574 – 286.047], 129.964[-36.666 – 296.594] and 116.837[-90.556 – 324.301] mm/half year for RPEL, ELML and EZL respectively. RPEL (p=0.038) and ELMD (p=0.026) progression showed significant differences between the two study cohorts. Further recent converters had significantly (p<0.001) higher EZ/RPE-Loss ratios in all time points compared to patients in an advanced disease status (1.716 [1.135 – 2.296] versus 1.153 [0.576 – 1.729]).

Conclusion: Early cRORA lesions have a slower growth rate in comparison to atrophic lesions in advanced disease stages. Differences in growth dynamics may play a crucial role in understanding the pathophysiology of non-neovascular AMD and for the interpretation of clinical trials in GA. Individual disease monitoring using AI-based quantification paves the way towards optimized GA management.

DOI: 10.1016/j.oret.2023.05.004

Evaluation of the inclusion of spectral-domain optical coherence tomography in a telemedicine diabetic retinopathy screening program: a real clinical practice.

Retina (Philadelphia, PA.) 2023 May 4.

Arruabarrena C, Rodríguez-Miguel A, Allendes G, Vera C, Son B, Teus MA.

Purpose: To evaluate whether combining spectral-domain optical coherence tomography (SD-OCT) with monoscopic fundus photography using a non-mydriatic camera (MFP-NMC) improves the accuracy of diabetic macular edema (DME) referrals in a teleophthalmology diabetic retinopathy screening program.

Methods: We conducted a cross-sectional study with all diabetic patients aged ≥18 years who attended screening from September 2016 to December 2017. We assessed DME according to the three MFP-NMC and the four SD-OCT criteria. The sensitivity and specificity obtained for each criterion were estimated by comparing them with the ground truth of DME.

Results: This study included 3918 eyes (1925 patients; median age, 66 years; interquartile range, 58-73; females, 40.7%; once-screened, 68.1%). The prevalence of DME ranged from 1.22% to 1.83% and 1.54% to 8.77% on MFP-NMC and SD-OCT, respectively. Sensitivity barely reached 50% in MFP-NMC and less for the quantitative criteria of SD-OCT. When macular thickening and anatomical signs of DME were considered, sensitivity increased to 88.3%, and the false DMEs and non-gradable images were reduced.

Conclusions: Macular thickening and anatomical signs showed the highest suitability for screening, with a sensitivity of 88.3% and a specificity of 99.8%. Notably, MFP-NMC alone missed half of the true DMEs that lacked indirect signs.

DOI: 10.1097/IAE.0000000000003832


Association of autoantibody levels with different stages of age-related macular degeneration (AMD): Results from the population-based Gutenberg Health Study (GHS).

Graefe’s archive for clinical and experimental ophthalmology. 2023 May 9.

Korb CA, Lackner KJ, Wolters D, Schuster AK, Nickels S, Beutgen VM, Münzel T, Wild PS, Beutel ME, Schmidtmann I, Pfeiffer N, Grus FH.

Purpose: Anti-retinal autoantibodies are assumed to be associated with age-related macular degeneration (AMD). To our knowledge, this is the first evaluation of autoantibodies in human sera of participants with different stages of AMD in a large population-based, observational cohort study in Germany.

Methods: The Gutenberg Health Study (GHS) is a population-based, observational cohort study in Germany, including 15,010 participants aged between 35 and 74. Amongst others, non-mydriatic fundus photography (Visucam PRO NM™, Carl Zeiss Meditec AG, Jena, Germany) was performed. Fundus images of the first 5000 participants were graded based on the Rotterdam Eye Study classification. Sera of participants with AMD (n=541) and sera of age-matched participants without AMD (n=490) were analyzed by antigen-microarrays. Besides descriptive statistics, autoantibody-levels were compared by Mann-Whitney-U test and the associations of level of autoantibodies with AMD were calculated by logistic regression analysis. Likewise, possible associations of the autoantibodies and both clinical and laboratory parameters on AMD subjects were analyzed.

Results: Autoantibodies against transferrin (p<0.001) were significantly downregulated in participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only compared to Controls. Mitogen-activated protein kinase 3 (p=0.041), glutathione peroxidase 4 (p=0.048), clusterin (p=0.045), lysozyme (p=0.19), protein kinase C substrate 80K-H (p=0.02), heat shock 70 kDa protein 1A (p=0.04) and insulin (p=0.018) show a trend between Control and participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only. CONCLUSIONS: This study contributes to a growing knowledge of autoantibodies in association with different AMD stages compared to controls in the context of a large population-based study in Germany. Especially autoantibodies against inflammatory proteins were downregulated in participants with early AMD and soft, distinct drusen (≥63 μm) or pigmentary abnormalities only.

DOI: 10.1007/s00417-023-06085-2

The Emerging Role of Gut Microbiota in Age-related Macular Degeneration.

The American journal of pathology. 2023 May 6:

Xiao J, Zhang JY, Luo W, He PC, Skondra D.

Age-related macular degeneration (AMD) is a progressive, degenerative retinal disease that is a leading cause of blindness globally. While multiple risk factors have been identified regarding disease incidence and progression, including smoking, genetics, and diet, the understanding of AMD pathogenesis remains unclear. As such, primary prevention is lacking, and current treatments have limited efficacy. More recently, the gut microbiome has emerged as an influential player in various ocular pathologies. As mediators of metabolism and immune regulation, perturbations in gut microbiota may impart significant effects distally on the neuroretina and its adjacent tissues, termed the “gut-retina” axis. In this review, key studies over the past several decades are summarized, both in humans and in animal models, which shed insight on the relationships between the gut microbiome and retinal biology and their implications for AMD. The literature linking gut dysbiosis with AMD are examined, along with preclinical animal models and techniques apt for studying the role of gut microbiota in AMD pathogenesis, which include interactions with systemic inflammation, immune regulation, chorioretinal gene expression, and diet. As understanding of the gut-retina axis continues to advance, so too will the possibility for more accessible and effective prevention and therapy of this vision-threatening condition.

DOI: 10.1016/j.ajpath.2023.04.006


Point-to-point associations of drusen and hyperreflective foci volumes with retinal sensitivity in non-exudative age-related macular degeneration.

Eye (London, England). 2023 May 11.

Reiter GS, Bogunovic H, Schlanitz F, Vogl WD, Seeböck P, Ramazanova D, Schmidt-Erfurth U.

Objectives: To evaluate the quantitative impact of drusen and hyperreflective foci (HRF) volumes on mesopic retinal sensitivity in non-exudative age-related macular degeneration (AMD).

Methods: In a standardized follow-up scheme of every three months, retinal sensitivity of patients with early or intermediate AMD was assessed by microperimetry using a custom pattern of 45 stimuli (Nidek MP-3, Gamagori, Japan). Eyes were consecutively scanned using Spectralis SD-OCT (20° × 20°, 1024 × 97 × 496). Fundus photographs obtained by the MP-3 allowed to map the stimuli locations onto the corresponding OCT scans. The volume and mean thickness of drusen and HRF within a circle of 240 µm centred at each stimulus point was determined using automated AI-based image segmentation algorithms.

Results: 8055 individual stimuli from 179 visits from 51 eyes of 35 consecutive patients were matched with the respective OCT images in a point-to-point manner. The patients mean age was 76.85 ± 6.6 years. Mean retinal sensitivity at baseline was 25.7 dB. 73.47% of all MP-spots covered drusen area and 2.02% of MP-spots covered HRF. A negative association between retinal sensitivity and the volume of underlying drusen (p < 0.001, Estimate -0.991 db/µm3) and HRF volume (p = 0.002, Estimate -5.230 db/µm3) was found. During observation time, no eye showed conversion to advanced AMD.

Conclusion: A direct correlation between drusen and lower sensitivity of the overlying photoreceptors can be observed. For HRF, a small but significant correlation was shown, which is compromised by their small size. Biomarker quantification using AI-methods allows to determine the impact of sub-clinical features in the progression of AMD.

DOI: 10.1038/s41433-023-02554-4


Exploring patient acceptability of emerging intravitreal therapies for geographic atrophy: A mixed-methods study.

Eye (London). 2023 May 11.

Enoch J, Ghulakhszian A, Sekhon M, Crabb DP, Taylor DJ, Dinah C.

Background/Objectives: The acceptability of emerging intravitreal therapies for patients with Geographic Atrophy (GA) is currently unknown. This study therefore aimed to investigate the extent to which regular intravitreal injections may be acceptable to GA patients.

Subjects/Methods: Thirty UK-based individuals with GA secondary to age-related macular degeneration (AMD), recruited from two London-based hospitals, were interviewed in April-October 2021 regarding acceptability of new GA treatments. Participants responded to a structured questionnaire, as well as open-ended questions in a semi-structured interview. The Theoretical Framework of Acceptability (TFA) informed framework analysis of the qualitative data.

Results: Twenty participants (67%) were female, and median (interquartile range (IQR)) age was 83 (78, 87) years. 37% of participants had foveal centre-involving GA, and better eye median (IQR) logMAR visual acuity was 0.30 (0.17, 0.58). Data suggested that 18 participants (60% (95% CI: 41-79%)) would accept the treatment, despite awareness of potential drawbacks. Eight participants (27% (95% CI: 10-43%) were ambivalent or undecided about treatment, and four (13%) (95% CI: 0-26%) would be unlikely to accept treatment. Reducing the frequency of injections from monthly to every other month increased the proportion of participants who considered the treatments acceptable. Conversely, factors limiting acceptability clustered around: the limited magnitude of treatment efficacy; concerns about side effects or the increased risk of neovascular AMD; and the logistical burden of regular clinic visits for intravitreal injections. Misunderstandings of potential benefits indicate the need for appropriately-designed patient education tools to support decision-making.

Conclusions: Our study suggests a majority of participants would be positive about intravitreal treatment for GA, in spite of potential burdens.

DOI: 10.1038/s41433-023-02571-3