Breakdown of the inner endothelial blood-retinal barrier (BRB), as occurs in diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, uveitis and other chronic retinal ...diseases, results in vasogenic edema and neural tissue damage, causing loss of vision. The central mechanism of altered BRB function is a change in the permeability characteristics of retinal endothelial cells caused by elevated levels of growth factors, cytokines, advanced glycation end products, inflammation, hyperglycemia and loss of pericytes. Subsequently, paracellular but also transcellular transport across the retinal vascular wall increases via opening of endothelial intercellular junctions and qualitative and quantitative changes in endothelial caveolar transcellular transport, respectively. Functional changes in pericytes and astrocytes, as well as structural changes in the composition of the endothelial glycocalyx and the basal lamina around BRB endothelium further facilitate BRB leakage. As Starling's rules apply, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular edema. The understanding of the complex cellular and molecular processes involved in BRB leakage has grown rapidly in recent years. Although appropriate animal models for human conditions like diabetic macular edema are lacking, these insights have provided tools for rational design of drugs aimed at restoring the BRB as well as for design of effective transport of drugs across the BRB, to treat the chronic retinal diseases such as diabetic macular edema that affect the quality-of-life of millions of patients.
To evaluate the safety and efficacy of individualized ranibizumab treatment in patients with neovascular age-related macular degeneration.
Twelve-month, phase III, multicenter, open-label, single-arm ...study.
A total of 513 ranibizumab-naïve SUSTAIN patients.
Three initial monthly injections of ranibizumab (0.3 mg) and thereafter pro re nata (PRN) retreatment for 9 months based on prespecified retreatment criteria. Patients switched to 0.5 mg ranibizumab after approval in Europe.
Frequency of adverse events (AEs), monthly change of best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline, the time to first re-treatment, and the number of treatments were assessed.
A total of 249 patients (48.5%) reported ocular AEs, and 8 (1.5%) deaths, 5 (1.2%) patients with ocular serious AEs of the study eye (retinal hemorrhage, cataract, retinal pigment epithelial tear, reduced visual acuity VA, vitreous hemorrhage), and 19 (3.7%) patients with arteriothromboembolic events were observed. Most frequent AEs in the study eye were reduced VA (18.5%), retinal hemorrhage (7.2%), increased intraocular pressure (7.0%), and conjunctival hemorrhage (5.5%). The average number of re-treatments from months 3 to 11 was 2.7. Mean best-corrected visual acuity increased steadily from baseline to month 3 to reach +5.8 letters, decreased slightly from month 3 to 6, and remained stable from month 6 to 12, reaching +3.6 at month 12. Mean change in CRT was -101.1 μm from baseline to month 3 and -91.5 μm from baseline to month 12.
The safety results are comparable to the favorable tolerability profile of ranibizumab observed in previous pivotal clinical studies; individualized treatment with less than monthly re-treatments shows a similar safety profile as observed in previous randomized clinical trials with monthly ranibizumab treatment. Efficacy outcomes were achieved with a low average number of re-treatments. Visual acuity in SUSTAIN patients with individualized re-treatment based on VA/optical coherence tomography assessment reached on average a maximum after the first 3 monthly injections, decreased slightly under PRN during the next 2 to 3 months, and was then sustained throughout the treatment period.
To demonstrate noninferiority of a quarterly treatment regimen to a monthly regimen of ranibizumab in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular ...degeneration (AMD).
A 12-month, multicenter, randomized, double-masked, active-controlled, phase IIIb study.
Patients with primary or recurrent subfoveal CNV secondary to AMD (353 patients), with predominantly classic, minimally classic, or occult (no classic component) lesions.
Patients were randomized (1:1:1) to 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly doses of ranibizumab. Treatment comprised of a loading phase (3 consecutive monthly injections) followed by a 9-month maintenance phase (either monthly or quarterly injection).
Mean change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 12 and the incidence of adverse events (AEs).
In the per-protocol population (293 patients), BCVA, measured by Early Treatment Diabetic Retinopathy Study-like charts, increased from baseline to month 12 by 4.9, 3.8, and 8.3 letters in the 0.3 mg quarterly (104 patients), 0.5 mg quarterly (88 patients), and 0.3 mg monthly (101 patients) dosing groups, respectively. Similar results were observed in the intent-to-treat (ITT) population (353 patients). The mean decrease in CRT from baseline to month 12 in the ITT population was -96.0 μm in 0.3 mg quarterly, -105.6 μm in 0.5 mg quarterly, and -105.3 μm in 0.3 mg monthly group. The most frequent ocular AEs were conjunctival hemorrhage (17.6%, pooled quarterly groups; 10.4%, monthly group) and eye pain (15.1%, pooled quarterly groups; 20.9%, monthly group). There were 9 ocular serious AEs and 3 deaths; 1 death was suspected to be study related (cerebral hemorrhage; 0.5 mg quarterly group). The incidences of key arteriothromboembolic events were low.
After 3 initial monthly ranibizumab injections, both monthly (0.3 mg) and quarterly (0.3 mg/0.5 mg) ranibizumab treatments maintained BCVA in patients with CNV secondary to AMD. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens. The noninferiority of a quarterly regimen was not achieved with reference to 5.0 letters. The safety profile was similar to that reported in prior ranibizumab studies.
Central serous chorioretinopathy (CSC) is a common cause of central vision loss, primarily affecting men 20–60 years of age. To date, no consensus has been reached regarding the classification of ...CSC, and a wide variety of interventions have been proposed, reflecting the controversy associated with treating this disease. The recent publication of appropriately powered randomised controlled trials such as the PLACE trial, as well as large retrospective, non-randomised treatment studies regarding the treatment of CSC suggest the feasibility of a more evidence-based approach when considering treatment options. The aim of this review is to provide a comprehensive overview of the current rationale and evidence with respect to the variety of interventions available for treating CSC, including pharmacology, laser treatment, and photodynamic therapy. In addition, we describe the complexity of CSC, the challenges associated with treating CSC, and currently ongoing studies. Many treatment strategies such as photodynamic therapy using verteporfin, oral mineralocorticoid antagonists, and micropulse laser treatment have been reported as being effective. Currently, however, the available evidence suggests that half-dose (or half-fluence) photodynamic therapy should be the treatment of choice in chronic CSC, whereas observation may be the preferred approach in acute CSC. Nevertheless, exceptions can be considered based upon patient-specific characteristics.
•The treatment of central serous chorioretinopathy (CSC) is controversial.•In chronic CSC, the most effective treatment appears to be half-dose (or half-fluence) photodynamic therapy (PDT).•In acute CSC, observation or early half-dose (or half-fluence) PDT can be considered.•Future studies will shed light on the efficacy of new treatment strategies.
Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family. Upon binding to VEGF- and neuropilin-receptor sub-types, PlGF modulates a range of neural, glial ...and vascular cell responses that are distinct from VEGF-A. As PlGF expression is selectively associated with pathological angiogenesis and inflammation, its blockade does not affect the healthy vasculature. PlGF actions have been extensively described in tumor biology but more recently there has been accumulating preclinical evidence that indicates that this growth factor could have an important role in retinal diseases. High levels of PlGF have been found in aqueous humor, vitreous and/or retina of patients exhibiting retinopathies, especially those with diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD). Expression of this growth factor seems to correlate closely with many of the key pathogenic features of early and late retinopathy in preclinical models. For example, studies using genetic modification and/or pharmacological treatment to block PlGF in the laser-induced choroidal neovascularization (CNV) model, oxygen-induced retinopathy model, as well as various murine diabetic models, have shown that PlGF deletion or inhibition can reduce neovascularization, retinal leakage, inflammation and gliosis, without affecting vascular development or inducing neuronal degeneration. Moreover, an inhibitory effect of PlGF blockade on retinal scarring in the mouse CNV model has also been recently demonstrated and was found to be unique for PlGF inhibition, as compared to various VEGF inhibition strategies. Together, these preclinical results suggest that anti-PlGF therapy might have advantages over anti-VEGF treatment, and that it may have clinical applications as a standalone treatment or in combination with anti-VEGF. Additional clinical studies are clearly needed to further elucidate the role of PlGF and its potential as a therapeutic target in ocular diseases.
•PlGF might be an important player in a range of retinal diseases, based on preclinical findings.•PlGF shows distinct actions versus VEGF, due to differential receptor activation.•PlGF inhibition shows a pleiotropic working mechanism, defined in preclinical studies.
To compare the efficacy and safety between half-dose photodynamic therapy (PDT) and eplerenone therapy for treating chronic central serous chorioretinopathy (cCSC).
This was a multicenter, ...open-label, randomized controlled trial.
This investigator-initiated trial was conducted in 3 academic medical centers in the Netherlands. Eligible patients were randomized at a 1:1 ratio to receive either indocyanine green angiography-guided half-dose PDT or oral eplerenone for 12 weeks. Both anatomical and functional outcomes were evaluated at 3 months after the start of treatment.
A total of 107 patients were randomly assigned to receive either half-dose PDT (n = 53) or eplerenone treatment (n = 54). Thirteen patients (3 in the PDT group and 10 in the eplerenone group) did not adhere to the study protocol. At the 3-month evaluation visit, 78% of patients in the PDT group had complete resolution of subretinal fluid accumulation compared to only 17% of patients in the eplerenone group (P < .001). Mean best-corrected visual acuity in Early Treatment of Diabetic Retinopathy Study letters at the 3-month evaluation visit was 83.7 ± 10.8 and 82.8 ± 9.0 in the PDT and eplerenone groups, respectively (P = .555). In addition, mean retinal sensitivity on microperimetry was 25.4 ± 3.4 dB and 23.9 ± 4.0 dB in the PDT and eplerenone groups, respectively (P = .041). Finally, mean vision-related quality of life scores were 87.2 ± 8.5 and 83.8 ± 12.1 in the PDT and eplerenone groups, respectively (P = .094). Three patients (6%) in the PDT group experienced adverse events during the study compared to 18 patients (33%) in the eplerenone group.
Half-dose PDT is superior to oral eplerenone for cCSC with respect to both short-term safety and efficacy outcomes.
To demonstrate superiority of ranibizumab 0.5 mg monotherapy or combined with laser over laser alone based on mean average change in best-corrected visual acuity (BCVA) over 12 months in diabetic ...macular edema (DME).
A 12-month, randomized, double-masked, multicenter, laser-controlled phase III study.
We included 345 patients aged ≥18 years, with type 1 or 2 diabetes mellitus and visual impairment due to DME.
Patients were randomized to ranibizumab + sham laser (n = 116), ranibizumab + laser (n = 118), or sham injections + laser (n = 111). Ranibizumab/sham was given for 3 months then pro re nata (PRN); laser/sham laser was given at baseline then PRN (patients had scheduled monthly visits).
Mean average change in BCVA from baseline to month 1 through 12 and safety.
Ranibizumab alone and combined with laser were superior to laser monotherapy in improving mean average change in BCVA letter score from baseline to month 1 through 12 (+6.1 and +5.9 vs +0.8; both P<0.0001). At month 12, a significantly greater proportion of patients had a BCVA letter score ≥15 and BCVA letter score level >73 (20/40 Snellen equivalent) with ranibizumab (22.6% and 53%, respectively) and ranibizumab + laser (22.9% and 44.9%) versus laser (8.2% and 23.6%). The mean central retinal thickness was significantly reduced from baseline with ranibizumab (-118.7 μm) and ranibizumab + laser (-128.3 μm) versus laser (-61.3 μm; both P<0.001). Health-related quality of life, assessed through National Eye Institute Visual Function Questionnaire (NEI VFQ-25), improved significantly from baseline with ranibizumab alone and combined with laser (P<0.05 for composite score and vision-related subscales) versus laser. Patients received ∼7 (mean) ranibizumab/sham injections over 12 months. No endophthalmitis cases occurred. Increased intraocular pressure was reported for 1 patient each in the ranibizumab arms. Ranibizumab monotherapy or combined with laser was not associated with an increased risk of cardiovascular or cerebrovascular events in this study.
Ranibizumab monotherapy and combined with laser provided superior visual acuity gain over standard laser in patients with visual impairment due to DME. Visual acuity gains were associated with significant gains in VFQ-25 scores. At 1 year, no differences were detected between the ranibizumab and ranibizumab + laser arms. Ranibizumab monotherapy and combined with laser had a safety profile in DME similar to that in age-related macular degeneration.
The pachychoroid disease spectrum (PDS) includes several chorioretinal diseases that share specific choroidal abnormalities. Although their pathophysiological basis is poorly understood, diseases ...that are part of the PDS have been hypothesized to be the result of venous congestion. Within the PDS, central serous chorioretinopathy is the most common condition associated with vision loss, due to an accumulation of subretinal fluid in the macula. Central serous chorioretinopathy is characterized by distinct risk factors, most notably a high prevalence in males and exposure to corticosteroids. Interestingly, sex differences and corticosteroids are also strongly associated with specific types of arteriovenous anastomoses in the human body, including dural arteriovenous fistula and surgically created arteriovenous shunts. In this manuscript, we assess the potential of such arteriovenous anastomoses in the choroid as a causal mechanism of the PDS. We propose how this may provide a novel unifying concept on the pathophysiological basis of the PDS, and present cases in which this mechanism may play a role.
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