Aqueous humour interleukin-6 and vision outcomes with anti-vascular endothelial growth factor therapy.

BACKGROUND: This analysis evaluated aqueous humour (AH) interleukin (IL)-6 concentrations and the association between AH IL-6 and visual outcomes in patients with neovascular age-related macular degeneration (nAMD) or diabetic macular oedema (DMO) receiving anti-vascular endothelial growth factor (VEGF) monotherapy. METHODS: Post hoc analysis of the multicentre, double-masked, randomised HARBOR (NCT00891735) and READ-3 (NCT01077401) trials. HARBOR enrolled treatment-naïve nAMD patients. READ-3 enrolled treatment-naïve/previously treated DMO patients. HARBOR patients received ranibizumab 0.5 or 2.0 mg monthly or as needed; AH samples were collected at month 2, after two previous intravitreal injections. READ-3 patients received ranibizumab 0.5 or 2.0 mg as needed; AH samples were collected at baseline and months 3, 6, 9, and 12. MAIN OUTCOME MEASURE: association between AH IL-6 concentrations and month 24 best-corrected visual acuity (BCVA). RESULTS: In both trials (HARBOR, N = 36; READ-3, N = 137), patients with higher AH IL-6 concentrations had worse visual outcomes. HARBOR patients with low AH IL-6 concentrations at month 2 had a mean (95% CI) BCVA change at month 24 of +2.9 (-2.6, 8.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of -9.0 (-22.7, 4.7) letters. READ-3 patients with low AH concentrations at baseline had a mean (95% CI) BCVA change at month 12 of +9.3 (7.4, 11.3) letters, whereas patients with high AH concentrations had a mean (95% CI) BCVA change of +5.6 (2.2, 9.1) letters. CONCLUSIONS: Higher IL-6 AH concentrations may predict suboptimal visual responses to anti-VEGF monotherapy in patients with nAMD/DMO.

Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects.

BACKGROUND: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. METHODS: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. RESULTS: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. CONCLUSIONS: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

Baseline Diabetic Retinopathy Severity and Time to Diabetic Macular Edema Resolution with Ranibizumab Treatment: A Meta-Analysis.

OBJECTIVE: Having a better understanding of how long diabetic macular edema (DME) takes to resolve in patients with diabetic retinopathy (DR) after treatment with ranibizumab, and the factors affecting this outcome, would be of benefit to physicians and patients alike. The objective of this analysis was to evaluate the time to first DME resolution and the impact of baseline DR severity on this outcome in patients treated with ranibizumab in phase III clinical trials. DESIGN: Meta-analysis of data from the phase III trials, RIDE (NCT00473382) and RISE (NCT00473330), and DR Clinical Research Network protocols I (NCT00444600), S (NCT01489189), and T (NCT01627249). PARTICIPANTS: Patients with DME (central subfield thickness [CST] > 250 µm) and DR with Diabetic Retinopathy Severity Scale (DRSS) score between 35 and 85. INTERVENTION: Intravitreal injection of ranibizumab. MAIN OUTCOME MEASURES: The time to first DME resolution (defined as CST ≤ 250 µm) within 24 months was evaluated overall and by baseline DR severity category per the DRSS (35 of 43 [mild or moderate nonproliferative DR], 47-53 [moderately severe or severe nonproliferative DR], 60 [mild proliferative DR], and 61-85 [moderately severe to severe proliferative DR]). RESULTS: There were 777 patients included in the meta-analysis. The overall mean (95% confidence interval) time to first DME resolution, adjusted for baseline CST, was 6.0 (5.6-6.4) months. The mean (95% CI) time to first DME resolution was 7.1 (6.2-7.9), 5.9 (5.2-6.6), 6.0 (4.8-7.2), and 4.5 (3.5-5.5) months for the 35 of 43, 47 to 53, 60, and 61 to 85 baseline DRSS categories, respectively (overall P = 0.002). By month 24, the proportion of eyes with DME resolution was 74.9% (221 of 295), 77.5% (299 of 386), 69.4% (109 of 157), and 78.7% (148 of 188) for the 35 of 43, 47 to 53, 60, and 61 to 85 baseline DRSS categories, respectively (overall P = 0.17). CONCLUSIONS: This meta-analysis of data from patients treated with ranibizumab showed that DME resolution was faster in patients with more severe DR at baseline. However, by month 24, a similar proportion of patients achieved DME resolution, regardless of baseline DR severity. These findings may guide treatment decisions and inform patient expectations in clinical practice. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Effect of less aggressive treatment on diabetic retinopathy severity scale scores: analyses of the RIDE and RISE open-label extension.

OBJECTIVE: To evaluate factors associated with Diabetic Retinopathy Severity Scale (DRSS) changes with less frequent ranibizumab after induction therapy. METHODS AND ANALYSIS: Post hoc analyses of RIDE/RISE and their open-label extension (OLE). Analyses included patients with diabetic retinopathy (DR)/diabetic macular oedema who completed the OLE. Comparisons were made between patients with improved/maintained (≥0 step decrease from OLE baseline (month 36) to month 48) versus worsened (≥1 step increase) DRSS during the OLE. DRSS changes over 12 months were compared between patients randomised to ranibizumab at RIDE/RISE baseline who improved to DRSS score ≤43 at OLE baseline (induced) versus those randomised to sham with DRSS score ≤43 at RIDE/RISE baseline (native). RESULTS: From OLE baseline to month 48, 72% (263/367) of patients improved/maintained DRSS scores. These patients had similar mean best-corrected visual acuity at RIDE/RISE (56.4 letters) and OLE baseline (68.6 letters) versus patients with worsened scores (58.2 and 70.8 letters). Patients who improved/maintained DRSS scores had similar mean central foveal thickness at RIDE/RISE (492 µm) and OLE baseline (196 µm) versus patients with worsened scores (441 and 167 µm). Patients who improved/maintained DRSS scores received a significantly higher (p<0.0001) mean number of pro re nata (PRN) injections (4.4) between OLE baseline and month 48 versus those with worsened scores (2.3). Patients with more severe DR at baseline who achieved mild-to-moderate non-proliferative DR (NPDR) induced by monthly ranibizumab injections were significantly more likely to worsen (p<0.0001) than those with mild-to-moderate NPDR at baseline randomised to sham injections (1.0-step versus 0.1-step worsening). CONCLUSIONS: Most patients improved/maintained DRSS scores with less-than-monthly PRN ranibizumab. Some minimum treatment/monitoring may be necessary to maintain improvements after induction therapy. TRIAL REGISTRATION NUMBERS: NCT00473382/NCT00473330.

Course of Diabetic Retinopathy in Untreated Fellow Eyes in RIDE and RISE: A Post Hoc Analysis.

BACKGROUND AND OBJECTIVE: To characterize diabetic retinopathy (DR) progression without therapy. PATIENTS AND METHODS: This post hoc analysis of the phase 3 RIDE and RISE trials examined the association between baseline DR severity on rates of ≥ 2-step DR progression and improvement in untreated fellow eyes (n = 530) and ranibizumab-treated study eyes (n = 369). Kaplan-Meier analyses estimated progression to proliferative DR (PDR) over 2 years in eyes with nonproliferative DR (NPDR) at baseline. RESULTS: At month 24, 28.8% of untreated fellow eyes with moderately severe to severe NPDR at baseline experienced ≥ 2-step DR progression, versus 10.3% of eyes with absent to moderate NPDR and 0 eyes with mild- to high-risk proliferative DR. Of the untreated fellow eyes with moderately severe to severe NPDR, 18.9% achieved ≥ 2-step DR improvement, compared with 88.4% of ranibizumab-treated eyes. CONCLUSION: Without treatment, patients with moderately severe to severe NPDR are at risk of rapid disease progression and vision loss. [Ophthalmic Surg Lasers Imaging Retina. 2022;53(4):202-207.].

Anti-VEGF-resistant subretinal fluid is associated with better vision and reduced risk of macular atrophy.

BACKGROUND/AIM: To evaluate relationships between subretinal fluid (SRF), macular atrophy (MA) and visual outcomes in ranibizumab-treated neovascular age-related macular degeneration (nAMD). METHODS: This post hoc HARBOR trial (NCT00891735) analysis included ranibizumab-treated (0.5 or 2.0 mg, monthly or as-needed, all treatment arms pooled) eyes with nAMD and baseline (screening, baseline and week 1) SRF. SRF presence, SRF thickness (0, >0-50, >50-100 and >100 µm) and subretinal fluid volume (SRFV) were determined by spectral domain optical coherence tomography (SD-OCT). Best-corrected visual acuity (BCVA) was assessed. MA was identified using fluorescein angiograms and colour fundus photographs, as well as SD-OCT. RESULTS: Seven hundred eighty-five of 1097 eyes met analysis criteria. In eyes without baseline MA, residual versus no SRF at month (M) 3 was associated with lower MA rates at M12 (5.1% vs 22.1%) and M24 (13.3% vs 31.2%) (both p<0.0001); MA percentages at M12/M24 were similar among patients with residual SRF at M6. Higher baseline SRFV was associated with a lower MA rate. Greater mean BCVA was observed with residual SRF of any thickness (>0-50 µm, 71.2 letters; >50-100 µm, 71.3 letters; >100 µm, 69.2 letters) versus no SRF (63.6 letters), but the change in BCVA from baseline to M12 or M24 was the same for eyes with or without treatment-resistant subretinal fluid (TR-SRF) at M3 or M6. CONCLUSION: TR-SRF was not detrimental to vision outcomes over 2 years, regardless of thickness. MA rates were significantly higher without TR-SRF.

Risk of Blindness Among Patients With Diabetes and Newly Diagnosed Diabetic Retinopathy.

OBJECTIVE: To evaluate the association between initial diabetic retinopathy (DR) severity/risk of blindness in patients with newly diagnosed DR/good vision in the U.S. RESEARCH DESIGN AND METHODS: This retrospective cohort study evaluated adult patients with good vision (20/40 or better) and newly diagnosed DR between 1 January 2013 and 31 December 2017 (index date) in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS) Registry. The primary exposure of interest was DR severity at index: mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). The main outcome measure was development of sustained blindness (SB), defined as study eyes with Snellen visual acuity readings of 20/200 or worse at two separate visits ≥3 months apart that did not improve beyond 20/100. RESULTS: Among 53,535 eligible eyes (mean follow-up 662.5 days), 678 (1.3%) eyes developed SB. Eyes with PDR at index represented 10.5% (5,629 of 53,535) of the analysis population but made up 26.5% (180 of 678) of eyes that developed SB. Kaplan-Meier analysis revealed that eyes with moderate NPDR, severe NPDR, and PDR at index were 2.6, 3.6, and 4.0 times more likely, respectively, to develop SB after 2 years of DR diagnosis versus eyes with mild DR at index. In a Cox proportional hazards model adjusted for index characteristics/development of ocular conditions during follow-up, eyes with PDR had an increased risk of developing SB versus eyes with mild NPDR at index (hazard ratio 2.26 [95% CI 2.09-2.45]). CONCLUSIONS: In this longitudinal ophthalmologic registry population involving eyes with good vision, more advanced DR at first diagnosis was a significant risk factor for developing SB.

Ultra-Response to Ranibizumab: Improvement by 4 or More Steps in Diabetic Retinopathy Severity in Diabetic Retinopathy Clinical Research Network Protocol S.

PURPOSE: To quantify and evaluate patients with diabetic retinopathy (DR) who had at least a 4-step improvement on the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) in response to treatment with ranibizumab in the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol S study, and factors predictive of such improvements. DESIGN: Post hoc retrospective analysis of 2-year outcomes in the phase 3 Protocol S study. PARTICIPANTS: Patients randomized to treatment with ranibizumab 0.5 mg with sufficient baseline DRSS severity (≥47) to allow for an at least 4-step improvement (n = 181). METHODS: Study eyes received a ranibizumab 0.5 mg injection at baseline and every 4 weeks for 12 weeks, with subsequent as-needed injections. Fundus photographs graded at baseline and years 1 and 2 using DRSS were used for this analysis. The data source is DRCR.net, but analyses, content, and conclusions of this report are solely the responsibility of the authors. MAIN OUTCOME MEASURES: Proportion of eyes achieving at least a 4-step DRSS improvement (DR ultra-response) at years 1 and 2; treatment course for eyes achieving ultra-response; mean change in best-corrected visual acuity (BCVA) in eyes with and without ultra-response; factors associated with ultra-response (identified by univariate and multivariable analyses). RESULTS: Approximately 30% of ranibizumab-treated eyes achieved DR ultra-response at year 1 (43/148; 29.1%) and year 2 (38/136; 27.9%); 74% of eyes with ultra-response at year 1 maintained their response at year 2. At year 2, patients with DR ultra-response had gained more than 5 additional ETDRS letters compared with those without DR ultra-response. Multivariable analyses identified presence of vitreous hemorrhage at baseline, increasing age, absence of epiretinal membrane, and glycated hemoglobin below 9 as predictive of DR ultra-response. Mean number of injections received was similar for eyes with versus without DR ultra-response to ranibizumab (mean, 7.4 vs. 7.6 in year 1; mean, 4.2 vs. 3.9 in year 2). CONCLUSIONS: Approximately 30% of eyes with a DRSS score of at least 47 receiving ranibizumab 0.5 mg per study protocol experienced at least a 4-step DR severity improvement on the DRSS, accompanied by meaningful improvements in BCVA.

Changes in Treatment-Naive Pigment Epithelial Detachments Associated With the Initial Anti-Vascular Endothelial Growth Factor Injection: A Post Hoc Analysis From the HARBOR Trial.

Importance: Pigment epithelial detachment (PED) is a feature commonly associated with neovascular age-related macular degeneration (nAMD) and may be perceived as being difficult to treat. Therefore, this investigation explored changes in PEDs and visual acuity outcomes following an initial anti-vascular endothelial growth factor (VEGF) injection and identified factors associated with positive response. Objective: To describe changes in treatment-naive pigment epithelial detachments associated with the initial anti-VEGF injection. Design, Setting, and Participants: Post hoc analysis of patients from the Phase III, Double-masked, Multicenter, Randomized, Active Treatment-controlled Study of the Efficacy and Safety of 0.5 mg and 2.0 mg Ranibizumab Administered Monthly or on an As-needed Basis in Patients With Subfoveal Neovascular Age-Related Macular Degeneration (HARBOR) trial (NCT00891735) with PED at baseline. The HARBOR trial was a phase 3, randomized, multicenter, double-masked, active treatment-controlled trial. Participants included treatment-naive patients with subfoveal nAMD and PEDs at baseline; intervention arms were pooled for analysis (n = 586). The HARBOR study began in July 2009 and was completed in August 2012, and the post hoc analyses were conducted between October 2016 and May 2018. Interventions: Intravitreal injections of ranibizumab, 0.5 mg and 2.0 mg, administered monthly or on an as-needed basis over 24 months. Main Outcomes and Measures: Post hoc analyses of flattened PED frequency at month 1, univariate and multivariable analysis of patient and ocular characteristics at baseline and PED status at month 1, and total number of ranibizumab injections received stratified by PED status at month 1. Results: A total of 35.5% of patients (208 of 586) with PED at baseline achieved a flattened PED after a single ranibizumab injection. An additional 17.3% subsequently achieved a flattened PED at month 2. Univariate analysis identified an association between older age, lower PED height, and lower subretinal fluid thickness with PED flattening after a single injection. Multivariable analysis identified PED height as a factor associated with this anatomical outcome. Best-corrected visual acuity scores were not superior based on PED flattening at month 1. On average, patients in the as-needed arm who achieved a flattened PED after a single ranibizumab injection required fewer injections by month 24 vs patients whose PED remained present at month 1 (11.0 vs 14.2; difference, 3.3; 95% CI, 1.9-4.6; P < .001). Conclusions and Relevance: In this group of treatment-naive patients with PED from nAMD, after the initial ranibizumab injection approximately one-third and after the second injection approximately one-half had flattened PEDS, although visual outcomes were not superior among those that did vs did not have flattening. The findings suggest flattening may serve as a marker for less intensive as-needed injection frequencies. Trial Registration: ClinicalTrials.gov Identifier: NCT00891735.

Timing of Peak Vision Gains in Patients with Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.

PURPOSE: To investigate whether time to peak best-corrected visual acuity (BCVA) was predictive of magnitude of BCVA changes at study end in patients with neovascular age-related macular degeneration (nAMD) who received ranibizumab and assess whether patient baseline characteristics and on-study events were predictive of time to peak BCVA. DESIGN: Exploratory analysis of data from HARBOR (ClinicalTrials.gov identifier, NCT00891735). PARTICIPANTS: Treatment-naïve patients 50 years of age or older with subfoveal nAMD. METHODS: Data by ranibizumab dose were pooled; data by dosing schedule (pro re nata [PRN] and monthly) were evaluated separately. Time to peak BCVA was the monthly evaluation at which the patient's greatest gain in Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline was achieved. Early peakers achieved peak BCVA between day 7 and month 6; late peakers achieved peak BCVA between months 7 and 12, months 13 and 18, and months 19 and 24. Variables evaluated for effect of time to peak BCVA included baseline demographic and clinical characteristics, presence of persistent subretinal fluid (SRF) or intraretinal fluid (IRF), and on-study events (atrophy status, fibrosis, retinal pigment epithelium tears). MAIN OUTCOME MEASURES: Time to peak BCVA and its predictive value for magnitude of BCVA changes and BCVA at month 24 (study end). RESULTS: Most patients reached peak BCVA after more than 6 months of treatment: 64% in the PRN group (301/474) and 70% in the monthly groups (327/469). Thirty-six percent and 30% of patients, respectively, peaked early, and 64% and 70%, respectively, peaked late. At month 24, early peakers on average lost vision (PRN, -1.6 ETDRS letters; monthly, -1.9 ETDRS letters). By contrast, late peakers achieved significantly better vision gains from baseline (PRN, 8.5-17.7 ETDRS letters; monthly, 10.1-18.7 ETDRS letters). No differences were found in patient characteristics, persistent SRF or IRF, or on-study events to account for the observed different outcomes between early and late peakers. CONCLUSIONS: In most treatment-naïve patients with nAMD, vision gains were achieved at a slower rate (>6 months), and a slower response was associated with better vision outcomes after 24 months of ranibizumab. These findings suggest that continued treatment may result in greater vision improvements when consistent anti-vascular endothelial growth factor therapy is maintained over a longer period.

The Value of Prior Response to Anti-Vascular Endothelial Growth Factor for Age-Related Macular Degeneration: A HARBOR Subanalysis.

PURPOSE: To evaluate disease activity-free intervals of patients with neovascular age-related macular degeneration (nAMD) in the pHase III, double-masked, multicenter, randomized, Active treatment-controlled study of the efficacy and safety of 0.5 mg and 2.0 mg Ranibizumab administered monthly or on an as-needed Basis (PRN) in patients with subfoveal neOvasculaR age-related macular degeneration (HARBOR) to determine whether duration of response to previous treatment with ranibizumab informs future disease activity and need for subsequent injections. DESIGN: Retrospective subgroup analysis of the phase 3 HARBOR study (clinicaltrials.gov identifier, NCT00891735). PARTICIPANTS: Patients from the ranibizumab 0.5 mg pro re nata arm of the phase 3 HARBOR clinical trial who received all 3 loading injections and missed no more than 1 study visit (N = 217). METHODS: A disease activity-free interval was defined as a consecutive period in months when treatment was not required because the patient did not meet protocol retreatment criteria. Percentage of disease activity-free eyes at the next 1 and 2 months after a first disease activity-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was evaluated. Additionally, duration that eyes remained untreated after disease activity-free intervals was evaluated by Kaplan-Meier estimates. MAIN OUTCOME MEASURES: Key outcome measures included duration of the first treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months achieved by each patient; mean number of additional months patients remained treatment free after a treatment-free interval; and percentage of eyes requiring treatment within 2 months after each treatment-free interval. RESULTS: Percentage of eyes requiring retreatment the month after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 60% (90/151), 33% (33/100), 26% (20/77), 36% (24/66), and 19% (9/48), respectively. Percentage of eyes requiring retreatment within 2 months after a treatment-free interval of ≥2, ≥3, ≥4, ≥5, and ≥6 months was 73% (109/149), 53% (53/100), 53% (40/75), 47% (30/64), and 43% (20/46), respectively. After treatment-free intervals of ≥2, ≥3, ≥4, ≥5, and ≥6 months, mean (standard error of the mean) additional time treatment free was 1.3 months (0.17 month), 2.4 months (0.33 month), 2.9 months (0.44 month), 3.2 months (0.50 month), and 4.0 months (0.60 month), respectively. CONCLUSIONS: Longer treatment-free intervals may indicate longer future disease-free intervals; however, this association varies. Thus, although longer intervals suggest greater likelihood of not needing retreatment within 1 to 2 months, regular assessment is warranted owing to the unpredictability of nAMD disease activity.

Advances in the treatment of diabetic retinopathy.

As the diabetes epidemic in the United States continues to worsen, so too does the prevalence of diabetic retinopathy (DR). DR is divided broadly into nonproliferative and proliferative stages, with or without vision-threatening macular edema. Progression to proliferative DR is associated with vision loss that is often irreparable, and a rapid decline in health-related quality of life. Vascular endothelial growth factor (VEGF)-A is upregulated in the diabetic eye, and has been identified as a key driver of DR pathogenesis. With this perspective, we review the published phase III clinical trial data of anti-VEGF therapies approved for the treatment of DR in the United States. Using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale, in which an improvement of ≥2 steps is considered clinically significant, approximately one-third of patients with DR and macular edema experience this level of improvement after 1 year of treatment with either ranibizumab or aflibercept. The rates of clinically significant DR improvement with ranibizumab could be twice that in the subgroup of patients with moderately severe or severe nonproliferative DR and macular edema. These clinical trial data indicate that intraocular inhibition of VEGF is a rational approach for the management of DR.

Simulating an Anti-Vascular Endothelial Growth Factor Switch in Neovascular Age-Related Macular Degeneration: A HARBOR Subanalysis.

PURPOSE: A simulated switching study assessed the effects of continuing the same anti-vascular endothelial growth factor (VEGF) treatment among patients who typically are considered for a therapy switch. Post hoc analysis of data from HARBOR was undertaken. Patients with neovascular age-related macular degeneration who demonstrated a suboptimal response after 3 or 6 months of ranibizumab treatment were identified as switching candidates. Rather than switching, however, patients continued on ranibizumab treatment, and visual and anatomic outcomes from the point of the hypothetical switch were examined. DESIGN: Post hoc analysis of the phase 3 HARBOR clinical trial. PARTICIPANTS: Patients were included in 3- and 6-month switcher analyses if they received 3 of 3 initial monthly ranibizumab doses and 5 of 6 initial monthly ranibizumab doses, respectively, and met all the following: 5-letter or fewer gain from baseline, best-corrected visual acuity (BCVA) 20/40 or worse, and intraretinal or subretinal fluid with central foveal thickness (CFT) equal to or greater than central subfield thickness. METHODS: Patient data were examined at months 3 and 6 to identify those who met predetermined switching criteria. Best-corrected visual acuity and CFT were examined from the point at which switching criteria were met through months 6, 12, 18, and 24 of HARBOR and compared with those who did not meet the criteria. MAIN OUTCOME MEASURES: Outcome measures included mean BCVA and CFT change over time from the point (month 3 or 6) at which switching criteria were met. RESULTS: By months 3 and 6, only 44 of 1059 patients (4.2%) and 37 of 769 patients (4.8%), respectively, met the inclusion criteria for hypothetical switching. Patients who met switching criteria at month 3 gained, on average, 5.3 letters from months 3 to 12 and 2.7 letters from months 3 to 24. Month 6 switchers gained, on average, 1.6 letters from months 6 to 12 and 1.8 letters from months 6 to 24. Both groups experienced significant CFT reductions over 24 months. CONCLUSIONS: Month 3 hypothetical switchers achieved vision and anatomic improvement while continuing their original ranibizumab treatment. Month 6 switcher outcomes replicated those commonly reported in published anti-VEGF switching studies: stable vision or nominal improvements in vision with continued substantial anatomic improvement.

The Impact of Systemic Factors on Clinical Response to Ranibizumab for Diabetic Macular Edema.

PURPOSE: To evaluate the effect of systemic factors on best-corrected visual acuity (BCVA) achieved with ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) for treatment of diabetic macular edema (DME) in the RIDE and RISE phase 3 studies. DESIGN: Exploratory, post hoc analysis of 2 randomized, double-masked, sham-injection controlled studies. PARTICIPANTS: Adults with DME, BCVA of 20/40 to 20/320 Snellen equivalent, and central foveal thickness of 275 µm or more. METHODS: Analysis of RIDE (clinicaltrials.gov identifier, NCT00473382) and RISE (clinicaltrials.gov identifier, NCT00473330) pooled ranibizumab data through month 24. Change in BCVA was assessed for association with the following covariates: age, body mass index (BMI), blood pressure, serum glucose, glycosylated hemoglobin (HbA1c), blood urea nitrogen, serum creatinine, estimated glomerular filtration rate, and blood chemistry variables. Change in BCVA at month 24 was assessed according to the following categories of diabetes medication use history: insulin only (n = 193), insulin plus other medications (n = 221), or other noninsulin medications (n = 331). MAIN OUTCOME MEASURES: Change in BCVA from baseline assessed by randomized treatment group in pooled 0.3- and 0.5-mg monthly ranibizumab groups. RESULTS: In patients with DME, vision improvement with ranibizumab was not influenced by systemic factors such as diabetes medication history, serum glucose, HbA1c, renal function, BMI, and blood pressure. Patients taking insulin with or without other medications at baseline had longer diabetes disease duration (mean, 17.4 and 20.9 years, respectively) compared with those taking other noninsulin medications (mean, 11.9 years). At month 24, among ranibizumab-treated patients, the mean BCVA change from baseline (Early Treatment Diabetic Retinopathy Study letters ± standard deviation) was not different between patients taking only insulin (12.6±11.2 letters), insulin plus other medications (12.2±12.4 letters), or other noninsulin medications (14.0±13.7 letters). Mean BCVA change also was comparable among patients taking thiazolidinediones (12.9±9.7 letters) and those not taking thiazolidinediones (13.2±13.3 letters). CONCLUSIONS: There were no associations between systemic factors (baseline values or change from baseline) and mean change of BCVA at month 24. These results suggest that visual response to ranibizumab therapy in DME was not influenced by nonocular factors related to systemic management of diabetes in the RIDE and RISE studies.

Predictors of Diabetic Macular Edema Treatment Frequency with Ranibizumab During the Open-Label Extension of the RIDE and RISE Trials.

PURPOSE: To investigate the role of baseline demographics, disease characteristics, and treatment responses to ranibizumab during RIDE/RISE in predicting long-term treatment frequency with a criteria-based pro re nata (PRN) regimen during the open-label extension (OLE). DESIGN: Pooled, retrospective, post hoc analysis from the phase III, randomized RIDE/RISE studies and subsequent OLE. PARTICIPANTS: Five hundred patients enrolled in the OLE after completion of the 36-month RIDE/RISE studies. METHODS: Summary statistics of RIDE/RISE baseline characteristics and treatment responses were generated by PRN ranibizumab 0.5 mg annualized injection frequency in the OLE (0 and >7 annualized injections). Univariable regression and analysis of variance, and multivariable analysis of covariance were performed on the annualized number of ranibizumab injections administered during the OLE versus baseline characteristics and response to treatment during the RIDE/RISE studies. MAIN OUTCOME MEASURES: Association of patient characteristics and responses to treatment during RIDE/RISE with the observed ranibizumab treatment burden during the OLE. RESULTS: During the OLE, 121 patients required no treatment, 132 required >0 to ≤3 annualized injections, 159 required >3 to ≤7 annualized injections, and 88 required >7 annualized injections. Parameters identified in the multivariable analysis as related to the annualized number of injections included the total number of rescue focal macular lasers received during the core studies (P = 0.0203), central foveal thickness at baseline (P = 0.0002) and month 36 (P < 0.0001), fluorescein leakage area at month 36 (P = 0.0137), and glycated hemoglobin (HbA1c) levels at month 36 (P = 0.0054). Patients receiving 0 versus >7 annualized injections during the OLE had, on average, a shorter duration of diabetes and diabetic macular edema (DME) at baseline, were less likely to have proliferative diabetic retinopathy at baseline, received fewer rescue focal macular laser treatments, and were more likely to experience diabetic retinopathy severity scale improvement of ≥2 steps. CONCLUSIONS: Patients who received less frequent injections during the RIDE/RISE OLE tended to have less advanced disease at baseline and responded better to initial ranibizumab treatment, suggesting that earlier anti-vascular endothelial growth factor treatment of center-involving DME with visual acuity loss may decrease long-term treatment burden.

Predicting vision gains with anti-VEGF therapy in neovascular age-related macular degeneration patients by using low-luminance vision.

BACKGROUND/AIMS: To evaluate baseline low-luminance visual acuity (LLVA) as a predictor of visual acuity improvement in patients with neovascular (wet) age-related macular degeneration (wAMD) receiving antivascular endothelial growth factor A (anti-VEGF) therapy. METHODS: In the HARBOR trial, 1084 treatment-naïve patients ≥50 years of age with subfoveal wAMD received intravitreal ranibizumab 0.5 or 2.0 mg monthly or as needed. To measure LLVA, patients read a normally illuminated ETDRS (Early Treatment Diabetic Retinopathy Study) chart with a neutral density filter placed in front of the study eye. Patients were assigned into quartiles based on the magnitude of the difference between best-corrected visual acuity under optimal luminance (BCVA) and LLVA (BCVA-LLVA gap). The association between mean change in BCVA from baseline and BCVA-LLVA gap at baseline was analysed using a general linear model. RESULTS: A smaller baseline BCVA-LLVA gap predicted significantly higher BCVA gains over 24 months (p<0.0001 at each month; Pearson correlation), even after controlling for baseline BCVA or stratifying by treatment arm. Patients in the smallest baseline BCVA-LLVA gap quartile gained an average of +13.4 letters compared with +2.4 letters for patients in the widest baseline BCVA-LLVA gap quartile. At months 12 and 24, the smallest baseline BCVA-LLVA gap quartile had the highest proportion of ≥15-≥30-letter gain, and the widest baseline BCVA-LLVA gap quartile had the highest proportion of ≥15-/≥30-letter loss (p<0.0001; Fisher's exact test). CONCLUSIONS: The baseline BCVA-LLVA gap is a significant predictor of visual acuity response to anti-VEGF treatment in patients with wAMD. TRIAL REGISTRATION NUMBER: NCT00891735; Post-results.

Altered leukotriene B4 metabolism in CYP4F18-deficient mice does not impact inflammation following renal ischemia.

Inflammatory responses to infection and injury must be restrained and negatively regulated to minimize damage to host tissue. One proposed mechanism involves enzymatic inactivation of the pro-inflammatory mediator leukotriene B4, but it is difficult to dissect the roles of various metabolic enzymes and pathways. A primary candidate for a regulatory pathway is omega oxidation of leukotriene B4 in neutrophils, presumptively by CYP4F3A in humans and CYP4F18 in mice. This pathway generates ω, ω-1, and ω-2 hydroxylated products of leukotriene B4, depending on species. We created mouse models targeting exons 8 and 9 of the Cyp4f18 allele that allows both conventional and conditional knockouts of Cyp4f18. Neutrophils from wild-type mice convert leukotriene B4 to 19-hydroxy leukotriene B4, and to a lesser extent 18-hydroxy leukotriene B4, whereas these products were not detected in neutrophils from conventional Cyp4f18 knockouts. A mouse model of renal ischemia-reperfusion injury was used to investigate the consequences of loss of CYP4F18 in vivo. There were no significant changes in infiltration of neutrophils and other leukocytes into kidney tissue as determined by flow cytometry and immunohistochemistry, or renal injury as assessed by histological scoring and measurement of blood urea nitrogen. It is concluded that CYP4F18 is necessary for omega oxidation of leukotriene B4 in neutrophils, and is not compensated by other CYP enzymes, but loss of this metabolic pathway is not sufficient to impact inflammation and injury following renal ischemia-reperfusion in mice.

Embryonic expression of the optineurin (glaucoma) gene in different stages of mouse development.

PURPOSE: To analyze optineurin (Optn) gene expression in various embryonic stages of mouse development by whole mount in situ hybridization. METHODS: FVB/NcrlBR mouse embryos (10.5 and 13.5 dpc) were collected by timed breeding experiments. A 712 bp Optn cDNA fragment was amplified by PCR and cloned into a transcription vector pCRII-TOPO. Digoxigenin labeled sense and antisense RNA probes were generated by in vitro transcription. The labeled RNA probe was localized using an anti-digoxigenin antibody conjugated with alkaline phosphatase. Colorimetric detection was performed with substrate solution containing, 4-nitro-blue tetrazolium chloride (NBT) and 5-bromo-4-chloro-3-indolyl phosphate (BCIP). RESULTS: This study revealed that the developing eye represents a major expression site for Optn. At both 10.5 and 13.5 dpc a strong specific expression was detected in the outer layer of the optic cup (future pigment layer of the retina). This is in contrast to the expression of another glaucoma gene, Cyp1b1, the expression of which at this state is only limited to the inner (neural) layer of the optic cup (future nervous layer of the retina). Inspection of sections from the cephalic region of whole mounts also revealed limited Optn staining in the lens as well as in the optic nerve. A second Optn expression domain was detected at the base of the developing forelimb. The biological significance of this observation is not clear and remains to be determined. CONCLUSIONS: Eye and forelimb were identified as two major sites for expression of the Optn gene. These findings suggest that Optn expression is triggered during early stages of eye development. Expression of the Optn gene in ocular tissues during mouse embryogenesis correlates with the presence and distribution of the optineurin protein, as previously reported in adult ocular tissues. These findings are also in agreement with the predicted function of Optn protein in the eye and the role of its ortholog in human glaucoma. Further investigations are required to determine the molecular mechanisms of Optn in the developing murine forelimb.