THE LATEST PUBLISHED RESEARCH

Welcome to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• Progression of Atrophy Between Neovascular & Non-Neovascular AMD
• Macular Atrophy in Eyes with nAMD in the Ladder Trial
• Predicting Treatment Frequency of Ranibizumab Injections in DME
• Six-year Incidence of AMD and Correlation to OCT-derived Drusen Volume Measurements in a Chinese Population
• Visual Outcomes of ForeseeHome Remote Telemonitoring: The ALOFT Study
• Predominantly Persistent Intraretinal Fluid in CATT
• Thiazolidinedione Use & Retinal Fluid in CATT
• Macular Choroidal Thickness and Risk of Referable DR (RDR) in Type 2 Diabetes
• Anti-VEGF Therapy for ME Secondary to HRVO vs. CRVO: SCORE2 Report 18
• Efficacy of Tocilizumab for Non-infectious Uveitis in STOP-Uveitis Study
  
• Noteworthy

Progression of Atrophy Between Neovascular & Non-Neovascular AMD

Researchers compared enlargement rates over five years of follow-up in geographic atrophy vs. macular atrophy associated with macular neovascularization, as part of a retrospective, longitudinal comparative case series.

Participants included a consecutive series of age-related macular degeneration patients with GA or MA with MNV.

Atrophic regions on serial registered fundus autofluorescence (FAF) images were semi-automatically delineated, and area measurements were recorded every 6 ±3 months for the first two years of follow-up and at yearly intervals up to five years.

Main outcome measures were annual raw and square root transformed atrophy growth rates.

A total of 117 eyes of 95 patients were included (61 in the GA and 56 in the MA cohorts); 100 percent and 38.5 percent of eyes completed two and five years of follow-up, respectively. Here are some of the findings:
• Mean baseline lesion size was similar between the two groups (raw: 1.74 vs. 1.53 mm²; p=0.56; square root transformed: 1.17 vs. 1.02 mm; p=0.26).
• Overall enlargement rates were greater for the GA cohort (raw: 1.72 vs. 1.32 mm²/year; p=0.002; square root transformed: 0.41 vs. 0.33 mm/year; p=0.03), as well as the area of atrophy growth at five years (raw: +8.06 vs. +4.55 mm²; p=0.001; square root transformed: +1.93 vs. +1.38 mm, p=0.02).
• The estimated square root transformed area was also significantly greater for the GA cohort at two years (1.84 vs. 1.67 mm; p=0.01).

Researchers determined that presence of MNV was associated with a slower rate of expansion resulting in overall smaller areas of atrophy over time. They added that these findings support the hypothesis that MNV may protect against the progression of atrophy.

SOURCE: Airaldi M, Corvi F, Cozzi M, et al. Differences in long-term progression of atrophy between neovascular and non-neovascular age-related macular degeneration. Ophthalmol Retina 2022; Apr 20. [Epub ahead of print].

Macular Atrophy in Eyes with nAMD in the Ladder Trial

Genentech researchers evaluated whether macular atrophy rates differed in eyes with neovascular age-related macular degeneration treated continuously with the company’s Port Delivery System with ranibizumab (PDS; now approved with the brand name Susvimo) vs. ranibizumab given as a bolus intravitreal injection.

The preplanned exploratory analysis was based on a Phase II, multicenter, randomized, active treatment-controlled, dose-ranging study.

Participants included patients diagnosed with nAMD within nine months of screening who had received at least two previous intravitreal anti-vascular endothelial growth factor injections of any agent and were responsive to treatment.

Eyes were randomized (3:3:3:2) to treatment with the PDS (filled with a customized formulation of ranibizumab 10 mg/ml, 40 mg/ml, or 100 mg/ml and refilled pro re nata) or monthly intravitreal ranibizumab 0.5 mg injections.

Main outcome measures included macular atrophy prevalence, incidence and progression.

The analysis population consisted of 220 eyes (58, 62, 59 and 41 eyes in the PDS 10 mg/ml, 40 mg/ml, 100 mg/ml and monthly intravitreal ranibizumab 0.5 mg injection arms, respectively). Here are some of the findings:
• At study baseline, MA was observed in 14.5 percent (PDS, 10 mg/ml), 11.5 percent (PDS, 40 mg/ml), 13.6 percent (PDS, 100 mg/ml) and 7.6 percent (monthly ranibizumab) of eyes.
• At last assessment (mean, 22.1 months), MA prevalence had increased to 38.6 percent (PDS, 10 mg/ml), 40 percent (PDS, 40 mg/ml), 40.4 percent (PDS, 100 mg/ml) and 45.7 percent (monthly ranibizumab).
• In patients without MA at baseline, a higher proportion of eyes in the monthly ranibizumab arm (40.6 percent) developed MA vs. PDS arms (28.6 percent, 32.1 percent and 30.6 percent of eyes in the PDS 10 mg/ml, 40 mg/ml and 100 mg/ml arms, respectively).
• Mean change in MA area from baseline to last assessment for PDS 10 mg/ml, 40 mg/ml, 100 mg/ml and monthly ranibizumab arms was +2.46 mm², +1.61 mm², +1.09 mm² and +1.15 mm², respectively.
• At nine months, for patients without MA at baseline, the difference in incidence of MA between PDS 100 mg/ml and monthly ranibizumab groups (95 percent confidence interval) was -12 percent (-31 percent, 7 percent).

Researchers wrote that, in the Phase II Ladder trial, no evidence of worse MA with the PDS relative to monthly intravitreal ranibizumab 0.5 mg injections was found. They advised that larger trials focusing on MA are needed to confirm this finding.

SOURCE: Jaffe GJ, Cameron B, Kardatzke D, et al. Prevalence and progression of macular atrophy in eyes with neovascular age-related macular degeneration in the Phase 2 Ladder trial of the port delivery system with ranibizumab. Ophthalmol Retina 2022; Apr 12. [Epub ahead of print].

Predicting Treatment Frequency of Ranibizumab Injections in DME

Investigators evaluated the predictors of annual treatment frequency in the second year of pro re nata intravitreal ranibizumab injections for diabetic macular edema, as part of a retrospective study.

They reviewed 65 eyes of 60 patients with center-involved DME that received PRN injections after three monthly loading doses. The central subfield thickness and qualitative findings were assessed on spectral-domain optical coherence tomography images. Investigators then sought to determine whether parameters at baseline or at the 12-month visit were associated with treatment frequency in the second year.

Here are some of the findings:
• The number of ranibizumab injections decreased from six (four to eight) during the first year to two (zero to three) during the second year (p<0.001).
• The injection numbers during the first year (p=0.259; p=0.037) but not second year (p=0.152; p=0.226) were modestly related to the logMAR improvement at 24 months.
• Multivariate analyses revealed that the CST (β=0.336; p=0.005) and hyperreflective walls in the foveal cystoid spaces (β=0.273; p=0.020) at baseline were associated with the number of IVR injections during the second year.
• Treatment frequency during the second year was related to CST (β=0.266, p=0.012), hyperreflective walls (β=0.394, p=0.002) and cumulative doses of ranibizumab injections (β=0.294; p=0.006) at the 12-month visit.

Investigators found that cumulative doses of ranibizumab injections, central subfield thickness and hyperreflective walls in the foveal cystoid spaces at 12-month visits were predictors of the frequency of ranibizumab injections during the second year of treatment for DME.

SOURCE: Nishikawa K, Murakami T, Ishihara K, et al. Factors predicting the treatment frequency of ranibizumab injections during the second year in diabetic macular edema. Jpn J Ophthalmol 2022; Apr 19. [Epub ahead of print].

Six-year Incidence of AMD and Correlation to OCT-derived Drusen Volume Measurements in a Chinese Population

Investigators reported the six-year incidence of optical coherence tomography-derived age-related changes in drusen volume and related systemic and ocular associations.

Chinese adults ages 40 years and older were assessed at baseline and six years with color fundus photography (CFP) and spectral-domain OCT. CFPs were graded for age-related macular degeneration features, and drusen volume was generated using commercially available automated software.

A total of 4,172 eyes of 2,580 participants (mean age 58.12 ±9.03 years; 51.12 percent women) had baseline and six-year follow-up CFP for grading; of them, 2,130 eyes of 1,305 participants had gradable SD-OCT images, available for analysis. Here are some of the findings:

• Based on CFP grading, 136 (3.39 percent) participants developed incident early AMD and 10 (0.25 percent) developed late AMD.
• Concurrently, retinal pigment epithelial-Bruch's membrane (RPE-BrC) volumes decreased, remained stable and increased in 6.8, 78.5 and 14.7 percent, respectively, over six years.
• In eyes where RPE-BrC volumes were >0 mm³ at baseline, this was associated with two-fold higher prevalence rate of any AMD at baseline (p<0.001).
• Multivariable analysis showed that when compared with eyes where RPE-BrC volume was unchanged, volume decrease was significantly associated with older age (OR=1.30; p<0.001), smoking (OR=2.21; p=0.001) and chronic kidney disease (OR=3.4, p=0.008), while increase was associated with older age (OR=1.36; p<0.001) and hypertension (OR=1.43; p=0.016).

Scientists found that AMD incidence detected at six years on CFP and correlated OCT-derived drusen volume measurement change was low. They added that older age and some systemic risk factors were associated with drusen volume change, and that their findings offer new insights into relationships between systemic risk factors and outer retinal morphology in Asian eyes.

SOURCE: Tan AC, Chee ML, Fenner BJ, et al. Six-year incidence of age-related macular degeneration and correlation to OCT-derived drusen volume measurements in a Chinese population. Br J Ophthalmol 2021; Oct 4. [Epub ahead of print].

Visual Outcomes of ForeseeHome Remote Telemonitoring: The ALOFT Study

Researchers evaluated long-term visual acuity and performance of a monitoring strategy with a self-operated artificial intelligence enabled home monitoring system in conjunction with standard care for early detection of neovascular age related macular degeneration. The retrospective review was sponsored and funded by Notal Vision.

The study included patients with dry AMD from five referral clinics. Researchers reviewed clinical data of patients monitored with the ForeseeHome (FSH) device from August 2010 to July 2020.

Main outcome measures included:

• visual acuity at baseline;
• VA at diagnosis of nAMD for eyes that converted while monitored and VA from the final study follow-up;
• weekly frequency of use;
• duration of monitoring;
• modality of conversion diagnosis (system alert vs. detection by other standard care means); and
• duration and number of treatments since conversion to final study follow-up was collected.

A total of 3,334 eyes of 2,123 patients were reviewed (mean age: 74 ±8 years) were monitored for a mean duration of 3.1 ±2.4 years, with a total of 1,706,433 tests in 10,474 eye-monitoring years. Here are some of the findings:

• The mean weekly use per patient was 5.2 ±3.4, which continued over the usage period.
• A total of 285 eyes converted while monitored at an annual rate of 2.72 percent; they were treated with mean 17.3 ±16.5 injections over a mean of 2.7 ±2 years, with 6.4 ±3.1 injections per year for eyes treated for greater than one year.
• The median VA at baseline and final follow-up for eyes that didn’t convert were 20/27 and 20/34 with a median change of zero letters.
• The median VA at baseline, conversion and final follow-up for eyes that converted during the monitoring period were 20/30, 20/39 and 20/32 with a median change from baseline to conversion, baseline to recent and conversion to recent of -4, -4 and 0 letters, respectively.
• Fifty-two percent of conversions detected had a system alert prior to conversion.
• Forty-eight percent of patients were detected by symptoms or routine visit.
• Patients experienced a non-nAMD alert on average every 4.6 years.
• At conversion and at final follow-up the proportion of eyes that maintained ≥20/40 was 84 percent (CI, 78 to 88 percent) and 82 percent (76 to 86 percent), respectively.

Researchers concluded that patients in the FSH monitoring program showed excellent long-term VA years after conversion to nAMD.

SOURCE: Mathai M, Reddy S, Elman MJ, et al. Analysis of the Long-term visual Outcomes of ForeseeHome Remote Telemonitoring - The ALOFT study. Ophthalmol Retina 2022; April 25. [Epub ahead of print].

Predominantly Persistent Intraretinal Fluid in CATT

Investigators described predominantly persistent intraretinal fluid (PP-IRF) and its association with visual acuity, along with retinal anatomic findings at long-term follow-up in eyes treated with pro re nata ranibizumab or bevacizumab for neovascular age-related macular degeneration.

The study involved a cohort within the Participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) assigned to PRN treatment.

Investigators assessed IRF presence on optical coherence tomography scans at baseline and monthly follow-up visits by the Duke OCT Reading Center. PP-IRF through week 12, year 1 and year 2 were defined as IRF presence at baseline and ≥80 percent of follow-up visits. Among eyes with baseline IRF, mean VA scores (letters) and change from baseline were compared between eyes with and without PP-IRF. Adjusted mean VA scores and change from baseline were also calculated using linear regression analysis to account for baseline patient features identified as predictors of VA in previous CATT studies. Outcomes were also adjusted by concomitant predominantly persistent subretinal fluid.

Primary outcome measures included:
• predominantly persistent intraretinal fluid through week 12, year 1 and year 2;
• VA score and VA change; and
• scar development at year 2.

Here are some of the findings:
• Among 363 eyes with baseline IRF, 108 (29.8 percent) had PP-IRF through year one and 95 (26.1 percent) did through year two.
• Comparing eyes with and without PP-IRF through year one, mean one-year VA score was 62.4 vs. 68.5 (p=0.002) and was 65 vs. 67.4 after adjustment (p=0.13).
• PP-IRF through year two was associated with worse adjusted one-year mean VA score (64.8 vs. 69.2; p=0.006) and change (4.3 vs. 8.1; p=0.01), and two-year mean VA score (63 vs. 68.3; p=0.004) and change (2.4 vs. 7.1; p=0.009).
• PP-IRF through year two was associated with higher two-year risk of scar development (adjusted HR=1.49; p=0.03).

Investigators wrote that approximately one-quarter of eyes had PP-IRF through year two. PP-IRF through year one was associated with worse long-term VA, but the relationship disappeared after adjustment for baseline predictors of VA, although PP-IRF through year two was independently associated with worse long-term VA and scar development, investigators added.

SOURCE: Core JQ, Pistilli M, Hua P, et al; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Predominantly persistent intraretinal fluid in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmol Retina 2022; Apr 8. [Epub ahead of print].

Thiazolidinedione Use & Retinal Fluid in CATT

Thiazolidinediones, commonly used antidiabetic medications, have been associated with an increased risk of development of diabetic macular edema and increased vascular endothelial cell permeability. Macular neovascularization in age-related macular degeneration and associated fluid leakage may be influenced by thiazolidinediones. This study aimed to determine the association between thiazolidinedione usage and retinal morphological outcomes or visual acuity in patients treated with bevacizumab or ranibizumab for neovascular AMD.

The secondary analysis of data from the Comparison of Age-related Macular Degeneration Treatments Trials included participant self-reported diabetes status and thiazolidinedione usage at baseline. Visual acuity; intraretinal, subretinal and subretinal pigment epithelium fluid; and foveal thickness of retinal layers were evaluated at baseline and during two-year follow-up. Comparisons of outcomes between thiazolidinedione usage groups were adjusted by macular neovascularization lesion type in multivariable regression models.

Patients taking thiazolidinedione (n=30) had lower adjusted mean VA score at baseline (difference -6.2 letters; p=0.02), increased intraretinal fluid at year two (75 vs. 50 percent, adjusted OR 2.8; p=0.04), greater mean decrease in subretinal tissue complex thickness from baseline at year one (difference -75.1 um; p=0.02) and greater mean decrease in subretinal thickness at year one (difference -41.9 um; p=0.001) and year two (difference -43.3 um; p=0.001).

In this exploratory analysis, diabetic patients taking thiazolidinediones who were treated with bevacizumab or ranibizumab for nAMD had worse baseline mean VA, greater reductions in subretinal and subretinal tissue complex thickness from baseline, and increased IRF compared to patients not taking thiazolidinediones.

SOURCE: Core JQ, Hua P, Daniel E, et al; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Thiazolidinedione use and retinal fluid in the comparison of age-related macular degeneration treatments trials. Br J Ophthalmol 2022; Apr 15. [Epub ahead of print].

Macular Choroidal Thickness and Risk of Referable DR in Type 2 Diabetes

Researchers looked at the associations between choroidal thickness and two-year incidence of referable diabetic retinopathy, as part of a prospective cohort study.

Patients with type 2 diabetes in Guangzhou, China, ages 30 to 80 years, underwent comprehensive exams, including standard 7-field fundus photography. Macular CT was measured using a commercial swept-source optical coherence tomography device (DRI OCT Triton, Topcon). The relative risk (RR) with 95% confidence intervals helped quantify the association between CT and new-onset RDR. The prognostic value of CT was assessed using the area under the ROC curve, net reclassification improvement (NRI) and integrated discrimination improvement (IDI).

Here are some of the findings:
• A total of 1,345 patients with diabetes were included in the study, and 120 (8.92 percent) had newly developed RDR at the two-year follow-up.
• After adjusting for other factors, the increased RDR risk was associated with:
   o greater HbA1c (RR=1.35; CI, 1.17 to 1.55, p<0.001);
   o higher systolic blood pressure (SBP; RR=1.02, CI, 1.01 to 1.03; p=0.005);
   o lower triglyceride (TG) level (RR=0.81; CI, 0.69 to 0.96, p=0.015);
   o presence of diabetic retinopathy (DR; RR=8.16, CI, 4.47 to 14.89; p<0.001); and
   o thinner average CT (RR=0.903; CI, 0.871 to 0.935; p<0.001).
• The addition of average CT improved NRI (0.464 ±0.096; p<0.001) and IDI (0.0321 ±0.0068, p<0.001) for risk of RDR.
• The addition of average CT also improved the AUC from 0.708 (CI, 0.659 to 0.757) to 0.761 (CI, 0.719 to 0.804).

Researchers determined that CT thinning, measured by SS-OCT, was an early imaging biomarker for the development of RDR, suggesting that alterations in CT play an essential role in DR occurrence.

SOURCE: Wang W, Li L, Wang J, et al. Macular choroidal thickness and the risk of referable diabetic retinopathy in type 2 diabetes: A 2-year longitudinal study. Invest Ophthalmol Vis Sci 2022; Apr 1;63(4):9.

Anti-VEGF Therapy for ME Secondary to HRVO vs. CRVO: SCORE2 Report 18

Intravitreal anti-vascular endothelial growth factor injections are commonly used to treat eyes with macular edema secondary to hemiretinal vein occlusion or central retinal vein occlusion. Information on whether differences exist in outcomes after anti-VEGF therapy can help guide treatment for the different disease types.

Investigators compared baseline characteristics, treatment burden and outcomes of macular edema treatment in participants with HRVO with those of participants with CRVO.

This post hoc outcome analysis from the Study of Comparative Treatments for Retinal Vein Occlusion 2 randomized clinical trial included 362 participants with macular edema caused by HRVO or CRVO, treated at 66 U.S. sites. Randomization began in September 2014, and the last month 24 follow-up visit occurred in February 2018. Data were analyzed from April 2020 to May 2021.

Eyes were initially randomized to six monthly intravitreal injections of aflibercept or bevacizumab, and were treated according to protocol between months six and 12 depending on six-month outcome. After month 12, patients were treated per investigator discretion and observed through month 60.

The main outcome was mean visual acuity letter score (VALS).

Of 362 included patients, 157 (43.4 percent) were female, and the mean age was 68.9 ±12 years. Outcome data were analyzed up to month 24 owing to substantial missing data at later visits. Here are some of the findings:
• A significantly greater proportion of participants with HRVO than those with CRVO were Black (37 vs. 11 percent).
• Treatment rates between months 12 to 23 were 0.36 (CI, 0.32 to 0.40) injections per month for patients with CRVO and 0.28 (CI, 0.19 to 0.36) for patients with HRVO (p=0.11).
• The mean VALS from months one to 24 of an HRVO study eye exceeded that of a CRVO study eye by 5.5 (CI, 1.5 to 9.5; p=0.01), consistent with the magnitude of the VALS difference between eyes with CRVO and HRVO at baseline.
• Eyes with CRVO presented at baseline with more macular edema than eyes with HRVO (difference in central subfield thickness [CST], 86 μm; CI, 48 to 124; p<0.001), with no difference in CST between the groups throughout months one to 24.

Investigators found Black race was more prevalent among participants with HRVO than CRVO and that no differences were observed in the frequency of treatments for macular edema between eyes with CRVO and HRVO, although eyes with CRVO presented with worse visual acuity and more macular edema on average than eyes with HRVO. The magnitude of VALS improvement, central retinal thickness in response to anti-VEGF therapy and treatment burden were similar between the groups, investigators added.

SOURCE: Scott IU, Oden NL, VanVeldhuisen PC, et al.; SCORE2 Study Investigator Group. Baseline characteristics and outcomes after anti-vascular endothelial growth factor therapy for macular edema in participants with hemiretinal vein occlusion compared with participants with central retinal vein occlusion: Study of comparative treatments for retinal vein occlusion 2 (SCORE2) Report 18. JAMA Ophthalmol 2022; Mar 24. [Epub ahead of print].