The purpose of this study was to determine the pharmacogenetic effects of complement factor H (CFH) Y402H, LOC387715 and high-temperature requirement factor A1 (HTRA1) genotypes on the treatment of exudative age-related macular degeneration (AMD) by intravitreal bevacizumab injection in a Korean population.
Seventy-five patients diagnosed with exudative AMD were treated with intravitreal bevacizumab (2.5 mg) monotherapy. All patients received three initial intravitreal bevacizumab injections every four weeks and were then treated "as needed" based on clinical findings, optical coherence tomography and fluorescein angiography during the 12 month follow-up period after the third injection.
The difference in visual acuity improvement among the three genotypes of LOC387715 were statistically significant at six months post-treatment (logarithm of the minimum angle of resolution; TT, 0.346; GT, 0.264; GG, 0.188; p = 0.037). Among the LOC387715 genotypes, the number of additional injections was lower in patients who had the risk T allele (GG, 2.143; GT, 2.000; TT, 1.575; p = 0.064). There was no significant difference between visual acuity and central macular thickness change in the CFH Y402H polymorphism group during the 12 month follow-up period. However, the TC group of CFH Y402H required more additional bevacizumab injections than the TT group (TT, 1.517; TC, 3.363; p = 0.020).
This study demonstrated that different LOC387715/HTRA1 genotypes resulted in different bevacizumab treatment responses on exudative AMD. Patients with the risk allele had an improved treatment response and less need for additional injections. However, patients with the CFH Y402H risk allele needed more additional injections of bevacizumab in order to improve visual acuity. This study illustrates how pharmacogenetic factors may help determine treatment modality and dosing. This could ultimately provide basic data for 'personalized medicine' in AMD.
Bevacizumab; Complement factor H Y402H; HTRA1; LOC387715; Macular degeneration
To determine whether gene polymorphisms of the major genetic risk factor for age-related macular susceptibility 2 (ARMS2 A69S) and the complement factor H Y402H influence the response to a variable-dosing treatment regimen with ranibizumab for age-related macular degeneration.
This prospective cohort study included 90 patients (90 eyes) with exudative age related macular degeneration (AMD) treated with ranibizumab. Patients underwent a 1-year treatment as in the Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (Mitchell et al.). Injections were administered monthly when a patient lost five letters on the Early Treatment Diabetic Retinopathy Study chart or gained 100 μm in central subfield retinal thickness (CSRT). Genotypes (rs10490924 and rs1061170) were analyzed using gene sequence analysis. Best-corrected visual acuity (BCVA) and CSRT values were compared between ARMS2 and complement factor H genotypes. Multiple regression analysis was used to assess the statistical significance.
Mean increase in visual acuity was 4.44±8.12 letters with a 103.63±94.7 µm decrease in CSRT. BCVA improvement was statistically significant in all genotype groups except in homozygous 69S in the AMRS2 gene. CSRT and BCVA changes were correlated (r=0.2521; 95% CI: 0.04746–0.4364, p=0.0165). Multiple regression analysis revealed a significant impact of 69S (p=0.015) on the change in BCVA.
Visual acuity did not improve during the study in patients homozygous for ARMS2 69S, despite a decrease in CSRT. Further investigation is needed to confirm our findings and understand the mechanisms involved.
To report our experiences in changing from intravitreal bevacizumab to ranibizumab in age-related macular degeneration (AMD).
Retrospective case series.
Participants and methods:
We retrospectively reviewed the records of 34 patients (36 eyes) who were treated with monthly injections of intravitreal bevacizumab for six months and then switched to monthly injections of ranibizumab for 12 months. Best-corrected visual acuity measurements (BCVA), contact lens biomicroscopy, optical coherence tomography (OCT), and fluorescein angiography were performed at the baseline examination and then monthly. Chi-square test was used for statistical analysis.
Following bevacizumab treatment, retinal thickness decreased (P = 0.033) while BCVA improved (P = 0.040). Changing from bevacizumab to ranibizumab resulted in a transient decrease in BCVA (P = 0.045) and an increase in retinal thickness (P = 0.042). In addition, three eyes presented with a large subretinal hemorrhage. However, final retinal thickness was better than the initial thickness and the value following the bevacizumab course. No major ocular or systemic side effects were noted.
Ranibizumab was clinically effective in the long term but the change of treatment from bevacizumab to a half-size molecule with less half-life in the vitreous such as ranibizumab contributed to a transient “instability” in the eye which may have triggered the large subretinal hemorrhage. There is insufficient experience reported in the literature in switching from one agent to another. A prospective study with controls is necessary to determine whether it is safe to change from one medication to another.
age-related macular degeneration; bevacizumab; ranibizumab; subretinal hemorrhage
To compare the effect of pegaptanib versus ranibizumab on exudative age-related macular degeneration (AMD) with small lesion size.
This is a retrospective study of 81 eyes from 78 patients with exudative AMD treated and followed up over 12 months. Patients with baseline best corrected visual acuity (BCVA) under 20/400 and with a greatest linear dimension of lesion over 4500 μm were excluded from the study. Twenty-six eyes from 25 patients were treated with three consecutive intravitreal injections of pegaptanib (IVP group) and 55 eyes from 54 patients were treated with three consecutive ranibizumab injections (IVR group). Each therapy was repeated as needed. The alteration in BCVA was evaluated in the IVP and IVR groups.
No differences were detected in baseline parameters between the IVP and IVR groups. The mean BCVA (logMAR) at month 1, 3, 6 and 12 after the initial treatment was improved from baseline in the IVP group (−0.095, −0.17, −0.18 and −0.18, respectively) and in the IVR group (−0.077, −0.15, −0.17 and −0.11, respectively), which was statistically significant. There was no difference in the change in mean BCVA between IVP and IVR groups at the same time periods.
The visual outcome of IVP was equivalent with IVR in exudative AMD with small lesion size.
pegaptanib; ranibizumab; age-related macular degeneration; small lesion size
We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10−3, 7.83 × 10−3, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10−3, 2.05 × 10−2, respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.
Age-related macular degeneration; Bevacizumab; Complement factor H; Genetic biomarker; High-temperature requirement A-1; Pigment epithelium-derived factor; Vascular endothelial growth factor
Angiogenesis is a common factor in the pathogenesis of cancer and in exudative age-related macular degeneration (AMD). Therefore, angiogenesis inhibition has been developed as a therapeutic strategy. We report 2 cases of recurrent exudative AMD in which oral sorafenib, a tyrosine kinase inhibitor approved for cancer, was added to intravitreal ranibizumab, an antibody to vascular endothelial growth factor. These 2 patients were followed up by determination of visual acuity, fluorescein angiography, fundoscopy, and optical coherence tomography. The visual acuity of 1 patient improved from 20/70 to 20/60 while he was receiving sorafenib therapy; that of the other did not. Marked improvement was noted in both patients on optical coherence tomography. Additionally, both patients appeared to receive some benefit when low-dose oral sorafenib was used as monotherapy after its initial addition to ranibizumab therapy. Randomized trials of adding sorafenib to standard therapy for patients with neovascular AMD should be considered.
Ranibizumab, a humanized antigen-binding fragment (Fab) that binds all isoforms of VEGF-A, significantly slows down loss of vision and causes significant visual improvement in many patients with choroidal neovascularization (CNV) due to exudative age-related macular degeneration (AMD). These benefits of intravitreal ranibizumab apply to all angiographic subtypes of neovascular AMD and across all lesion sizes when the drug is injected at monthly intervals as shown in two pivotal phase III trials (ANCHOR and MARINA). The results from the PrONTO study suggest that less frequent treatment with ranibizumab through a variable dosing regimen dependent on optical coherence tomography (OCT) findings is a treatment option that results in comparably favorable visual outcomes. Currently, it is unclear whether combination therapy of ranibizumab with photodynamic therapy (PDT) provides any significant advantage over ranibizumab monotherapy (FOCUS trial); however, the combination of PDT and ranibizumab may decrease the need for frequent retreatment. This question will be addressed in the SUMMIT trial. Therapy with ranibizumab is generally very well tolerated with a low rate of seriously adverse ocular events or systemic side-effects. The advent of vascular endothelial growth factor (VEGF) inhibitors has revolutionized the therapy of neovascular AMD. Ranibizumab at the moment appears to be the most effective approved treatment for neovascular AMD.
Lucentis; ranibizumab; vascular endothelial growth factor (VEGF); age-related macular degeneration (AMD); neovascular; exudative AMD; treatment
Wet age-related macular degeneration (AMD) causes severe vision loss due to the development of choroidal neovascularization (CNV). The critical role of vascular endothelial growth factor in the pathogenesis of CNV is well understood. Ranibizumab plays an inhibitory role with CNV and reduces vascular permeability by binding to vascular endothelial growth factor. Intravitreal ranibizumab reduces the risk of visual acuity (VA) loss and increases the chance of VA gain compared with no treatment or photodynamic therapy for CNV in AMD. Some high-quality research has shown that the optimal timing for ranibizumab treating wet AMD is the first 3 months. It is recommended that ranibizumab is intravitreally injected monthly in the initiation for at least 3 months. Subsequent managing of regimens should be made dependent on the VA change, fundus examination, and image of optical coherence topography. An individualized strategy or combined method with photodynamic therapy is beneficial to the active lesion in the consecutive treatment of ranibizumab for CNV, and may be a good choice in order to decrease injection times. Regarding the safety profile, ranibizumab has been well tolerated in clinical trials. The principal ocular adverse event detected in clinical trials is a low frequency of ocular inflammation. Key serious ocular adverse events occurred in <5% of ranibizumab-treated patients in large-scale clinical trials. It appears unlikely that treatment with ranibizumab increases the risk of vascular events significantly. Less frequent injections on an as-needed schedule, based on monthly monitoring may have the most optimal risk:benefit ratio.
age-related macular degeneration; choroidal neovascularization; ranibizumab; efficacy; safety
Variants in complement factor H (CFH), the hypothetical LOC387715, and the high-temperature requirement A-1 (HTRA1) genes have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of reported common single-nucleotide polymorphisms (SNPs) in CFH, LOC387715, and HTRA1 with exudative AMD in a northern Chinese population.
A cohort of 121 unrelated patients with exudative AMD and 132 control subjects were enrolled in this study. Genomic DNA was extracted from blood leukocytes. Genotyping for SNPs rs1061170:T>C in CFH (Y402H), rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1 was performed using a polymerase chain reaction (PCR) method followed by allele-specific restriction enzyme digestion and direct sequencing.
The Y402H variant in CFH was not associated with exudative AMD in our study population. Frequencies of Y402H was 10.3% in AMD cases and 8.0% in controls (p=0.353). Significant associations were detected for exudative AMD with SNPs rs10490924:G>T in LOC387715 (A69S), and rs11200638:G>A in the promoter of HTRA1. The risk T-allele frequency of rs10490924 in LOC387715 was 64.9% in cases versus 43.2% in controls (p<0.001). The odds ratio for risk of AMD was 1.56 (95% CI; 0.80–3.03) for the GT genotype and 5.45 (95% CI; 2.59–11.49) for the TT genotype. The A allele frequency of rs11200638 in the HTRA1 promoter was 67.8% in cases versus 42.4% in controls (p<0.001). The odds ratio was 2.75 (95% CI; 1.34–5.64) for the GA genotype and 7.90 (95% CI; 3.61–17.26) for the AA genotype. An odds ratio of 7.94 (95% CI; 3.49–18.04) was obtained for carriers with both TT genotype in LOC387715 and AA genotype in the HTRA1 promoter.
Our data suggest that the LOC387715 and HTRA1 polymorphisms are associated with a higher risk of exudative AMD in northern Chinese. We found no association of CFH Y402H with exudative AMD. The low frequency of CFH Y402H variant was further confirmed in this study population.
Factors influencing the outcome of anti-VEGF treatment in neovascular AMD are still investigated. We analyzed the impact of a loading phase, the significance of an initial response for the long-term and the effect of the CFH polymorphism (p.His402Tyr) on treatment outcome.
Patients treated with ranibizumab for neovascular AMD were analyzed over a period of 24 months by assessing effects of loading phase, initial response and genotype of CFH rs1061170 (c.1204C>T, p.His402Tyr).
204 eyes were included. A change of +5.0 [−1;+11] letters and +1.5 [−5.5;+9.5] was observed with a median of 4 ;  and 10 ;  ranibizumab injections during 12 and 24 months, respectively. Loading phase was no significant predictor for treatment as VA outcome in eyes with and without loading phase was similar (p = 0.846 and p = 0.729) at 12 and 24 months. In contrast, initial response was a significant predictor for improving vision of 5 or more letters at 12 (p = 0.001; OR = 6.75) and 24 months (p = 0.01; OR = 4.66). Furthermore, the CT genotype at CFH rs1061170 was identified as a significant predictor for a favorable VA outcome at 12 and 24 months (OR = 6.75, p = 0.001 and OR = 4.66, p = 0.01).
Our data suggest that clinical decisions regarding treatment may be guided by observing patients’ initial response as well as their genotype of SNP rs1061170, while the criterion of loading phase may not bear the customary value.
To present a rare case of retinal pigment epithelium (RPE) rupture following YAG laser posterior capsulotomy (YAG PC) in a patient with exudative age-related macular degeneration (AMD).
Materials and Methods
An 85-year-old pseudophakic male patient on ranibizumab 0.5 mg/0.05 ml treatment due to exudative AMD received YAG PC for dense posterior capsule opacification (PCO) in his right eye. The patient had received his last intravitreal ranibizumab injection 3 months before YAG PC; his macula appeared stable on fundoscopy and optical coherence tomography scans at repeated visits, but his vision deteriorated to counting fingers due to PCO.
Following left eye posterior YAG PC, his best-corrected visual acuity (BCVA) improved to 6/12 (Snellen chart). Despite satisfactory visual results, the patient developed a parafoveal inferotemporal RPE rupture. A decision for further treatment with ranibizumab (0.5 mg/0.05 ml) intravitreal injections was made. After a total of 7 injections, the patient was clinically stable and his BCVA was 6/18 (Snellen chart).
RPE rupture is a well-known, serious complication in patients with exudative AMD, which often has devastating results on patients’ vision. Offering YAG PC to those patients could lead to a rupture of the RPE even in cases which appear to be stable and well controlled. Clinicians should be aware of this complication and inform the patients accordingly.
Retinal pigment epithelium tear; YAG Laser; Age-related macular degeneration; Pigment epithelial detachment rupture; Ranibizumab
The purpose of this study was to evaluate the safety of intravitreal ranibizumab injection in patients with age-related macular degeneration.
Materials and methods
We examined retinal ganglion cell function using the photopic negative response of the electroretinogram (ERG) in patients with age-related macular degeneration (AMD) treated with intravitreal injections of ranibizumab. We studied 32 eyes of 32 patients with AMD and aged 50–84 years with a mean of 71 years. An intravitreal ranibizumab injection was given three times at monthly intervals. Additional injections were given according to an optical coherence tomography-guided variable dosing regimen. ERG recordings were made before treatment (baseline) and at 3, 6, 9, and 12 months postoperatively. Full-field cone ERGs were elicited by red stimuli on a blue background. The focal macular ERGs were elicited by a 15 degree white stimulus spot centered on the macular region. We measured the amplitudes of the a and b waves, oscillatory potentials, and the photopic negative response of the full-field cone and focal macular ERGs.
Visual acuity was significantly better than the baseline acuity, and macular thickness was significantly reduced after the intravitreal injections of ranibizumab. The amplitudes and implicit times of each wave of the full-field cone ERGs were not significantly changed after intravitreal ranibizumab injections. However, the amplitudes of each wave of the focal macular ERGs were increased after the injections. The implicit times of the a and b waves of the focal macular ERGs were significantly shortened after intravitreal injections of ranibizumab. The ratio of the full-field and focal photopic negative response/b-wave amplitude was not significantly changed after the injections.
The amplitudes of the focal macular ERGs, including the photopic negative response improved after repeated intravitreal ranibizumab injections, accompanied by a recovery of visual acuity and macular structure. The results of the full-field cone ERGs indicate that retinal ganglion cell function was not altered by repeated intravitreal ranibizumab injection.
age-related macular degeneration; retinal ganglion cell; photopic negative response; electroretinogram; ranibizumab
We compared the efficacy of intravitreal ranibizumab and bevacizumab for treating neovascular age-related macular degeneration using an on-demand regimen.
A total of 186 wet age-related macular degeneration eyes of 186 treatment-naïve patients were compared retrospectively (67 eyes treated with ranibizumab with 91 treated with bevacizumab). At baseline, mean age, best corrected visual acuity, and angiographic lesion types were similar in both groups. Best corrected visual acuity and ocular coherence tomography were evaluated.
Sixty eyes treated with ranibizumab and 85 eyes treated with bevacizumab completed a 12-month evaluation. At 12 months, mean best corrected visual acuity increased by +6.65 letters with ranibizumab treatment and by +5.59 with bevacizumab treatment (P = 0.64). Visual acuity improved by ≥15 letters in 15 eyes treated with ranibizumab and in 21 eyes treated with bevacizumab (P = 0.75). An overall reduction in ocular coherence tomography central thickness occurred for all time points. The mean number of injections per eye was 5.97 with ranibizumab and 5.92 with bevacizumab (P = 0.90).
Intravitreal therapies with ranibizumab or bevacizumab have similar visual and anatomical results. These results confirm those of comparison of Age-Related Macular Degeneration Treatment Trials in as-needed cohorts in clinical practice. Randomized long-term clinical trials are necessary to examine the systemic safety of these treatments.
AMD; anti-VEGF therapy; bevacizumab; choroidal neovascularization; ranibizumab; wet AMD
To compare visual acuity (VA) outcomes between intravitreal injection of bevacizumab and ranibizumab in the treatment of neovascular age-related macular degeneration (AMD).
We conducted a consecutive, retrospective case series study in patients with newly diagnosed all type choroidal neovascularization (CNV) secondary to AMD who received an intravitreal injection of bevacizumab (1.25mg) or ranibizumab (0.3mg) at Lions Eye Institute, Western Australia from Mar. 2006 to May 2008. All patients received injection at baseline with additional monthly injections given at the discretion of the treating physician. Main outcome measures were changes in VA.
There were 371 consecutive patients received injection at least in one eye with at least 6 months of follow up (median of 12.0 months). Bevacizumab treatment prevented 221 out of 278 (79.5%) patients from losing < 15 letters in VA compared with 79 out of 93 (84.9%) of ranibizumab treated patients (P=0.25). While 68 (24.5%) of bevacizumab treated patients gained ≥15 letters of VA compared with 24 (25.8%) of ranibizumab treated patients (P=0.79). 75.3% and 66.2% patients benefited from ranibizumab and bevacizumab respectively with final VA better than 6/60 (P=0.10). Multivariate analysis showed that pre-treatment VA was negatively associated with benefit outcome. Assignment of injection was not associated with VA outcome of benefit after adjusting the covariate (P=0.857).
There are no difference in treatment efficacy in terms of VA between bevacizumab and ranibizumab in routine clinical condition.
age-related macular degeneration; anti-VEGF; bevacizumab; ranibizumab; choroidal neovascularization
Purpose. To evaluate the effects of photodynamic therapy (PDT) combined with intravitreal injection of ranibizumab (IVR) for exudative age-related macular degeneration (AMD). Methods. Retrospective case series. Thirty eight eyes of 38 patients with exudative AMD underwent combined therapy consisting first of IVR, followed by PDT within a week and the second IVR at 1 month. All patients were followed up for more than 12 months. The best corrected visual acuity (BCVA) and central macular thickness (CMT) were examined. Results. The mean number of IVR and PDT sessions were 2.9 ± 1.3 and 1.1 ± 0.3, respectively. The mean BCVA and CMT were significantly improved to 0.38 logMAR units (P < 0.01) and 240 μm (P < 0.01) at 12 months, respectively. Thirty-six of 38 eyes (94.8%) improved or maintained BCVA at 12 months. Conclusion. PDT combined with IVR for exudative AMD was effective at improving visual acuity and CMT with a low recurrence rate for 12 months.
Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data.
In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a non-inferiority limit of 5 letters on the eye chart.
Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.
At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.)
To define factors that determine the location and stability of fixation in patients with neovascular age-related macular degeneration (NV-AMD) treated with intravitreal ranibizumab injections.
The location and stability of fixation using microperimetry were determined in 77 eyes treated with ranibizumab for NV-AMD for at least 12 months. All patients were treated with three injections of ranibizumab 0.5 mg, 1 month apart and retreated according to predefined criteria. The fixation parameters were correlated to the visual acuity, and quantitative measures on OCT.
The location of fixation was predominantly central in 52.6%, poor central fixation in 9.2%, and predominantly eccentric fixation in 38.2%. The fixation was stable in 65%, relatively unstable in 25%, and unstable in 10%. Visual acuity was the only factor that determined the stability and location of fixation. The characteristics of fixation were not related to the macular thickness or volume as measured by OCT.
Better visual outcome ensures central and stable fixation. Quantitative measures of OCT parameters do not determine fixation. Further studies on morphological features of the macula may provide some insight into the determinants of fixation.
fixation stability; antiVEGF; neovascular age-related macular degeneration; microperimetry
To investigate the association between polymorphism rs1061170 (T1277C, Y402H) in age-related macular degeneration (AMD) susceptibility gene Complement Factor H (CFH) and treatment response of neovascular AMD.
We performed a literature-based meta-analysis including 10 published association studies involving 1,510 patients. Treatments included anti-VEGF (bevacizumab and ranibizumab) or photodynamic therapy. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed- and random-effects models. Q-statistic test was used to assess heterogeneity.
Polymorphism rs1061170 showed a significant summary OR of 1.68 (95% CI, 1.09 to 2.60; P = 0.020; CC versus TT; random-effects) for treatment response of neovascular AMD with heterogeneity of 0.09. In subgroup analysis, rs1061170 was more likely to be a predictor of response to anti-VEGF therapy (P = 0.011). However, heterozygous TC genotype was not associated with altered treatment response (OR = 1.18, 95% CI, 0.95 to 1.47; P = 0.145; fixed-effects). Influence analysis indicated the robustness of our findings.
rs1061170 might be associated with treatment response of neovascular AMD, especially for the anti-VEGF agents. It might be the first meta-analytically confirmed genetic marker predictive for AMD treatment response though a further validation in larger studies is needed.
To determine whether the complement factor H (CFH) Y402H variant is associated with specific age-related macular degeneration (AMD) clinical phenotypes.
Retrospective, case-control study.
188 Caucasian subjects with AMD and 189 control subjects were genotyped for the T-to-C polymorphism in exon-9 of the CFH gene by restriction-fragment length analysis and DNA sequencing using genomic DNA from mouthwash samples. AMD phenotypes were characterized by clinical examination, fundus photography, and fluorescein angiography.
Heterozygosity for the at-risk genotype (TC) increased the likelihood for AMD 2.1-fold (95% CI 1.3–3.3) while homozygosity for the genotype (CC) increased the likelihood for AMD 6.5-fold (95% CI 3.4–12.5) in our population. The C allele was significantly associated with predominantly classic choroidal neovascularization (OR 2.01, 95% CI 1.34–3.30). Neovascular lesion size was similar among the three genotypes (p=0.67).
The Y402H CFH variant carried a significantly increased risk for developing AMD in our population. Genotype/phenotype correlations regarding choroidal neovascular lesion type were observed
Age-related macular degeneration (AMD) has a complex etiology arising from genetic and environmental influences. This past decade have seen several genes associated with the disease. Variants in five genes have been confirmed to play a major role. The objective of this study was to evaluate whether genes influence treatment response to ranibizumab for neovascular AMD. The hypothesis was that an individual’s genetic variation will determine treatment response.
The study was a two-site prospective open-label observational study of patients newly diagnosed with exudative (neovascular) AMD receiving intravitreal ranibizumab therapy. Treatment-naïve patients were enrolled at presentation and received monthly “as needed” therapy. Clinical data was collected monthly and DNA extracted. Genotyping was performed using the Illumina (San Diego, California) 660-Quad single-nucleotide polymorphism (SNP) chip. Regression analyses were performed to identify SNPs associated with treatment-response end points.
Sixty-five patients were enrolled. No serious adverse events were recorded. The primary outcome measure was change in ETDRS visual acuity at 12 months. A SNP in the CFH gene was found to be associated with less improvement in visual acuity while receiving ranibizumab therapy. The C3 gene, among others, was associated with reduced thickening and improved retinal architecture. VEGFA, FLT1, and CFH were associated with requiring fewer ranibizumab injections over the 12-month study.
This study is one of the first prospective pharmacogenetic study of intravitreal ranibizumab. Although preliminary, the results identify a number of putative genetic variants, which will be further examined by replication and functional studies to elucidate the complete pharmacogenetic architecture of therapy for AMD.
To describe a patient with a giant pigment epithelial detachment (PED) secondary to exudative age-related macular degeneration (ARMD) successfully treated with a single intravitreal ranibizumab (Lucentis) injection (0.5 mg/0.05 ml).
An 89-year-old woman presented with a six-day history of reduced vision and distortion in the left eye. Best-corrected visual acuity in that eye was 6/15. Fundoscopy revealed a giant PED and exudates temporally to the fovea. Optical coherence tomography showed a PED associated with subretinal and intraretinal fluid. Fluorescein angiography confirmed the diagnosis of an occult choroidal neovascularization. Treatment with intravitreal injections of ranibizumab (Lucentis) was recommended, although the increased risk of retinal pigment epithelium (RPE) rip was mentioned.
Four weeks after the first intravitreal Lucentis injection, the visual acuity in the left eye improved to 6/7.5, with a significant improvement of the distortion and a complete anatomical resolution of the PED confirmed by optical coherence tomography.
Giant PED secondary to exudative ARMD can be successfully treated with intravitreal ranibizumab, despite the increased risk of RPE rip. To our knowledge, this is the first case presenting with complete resolution of PED after a single ranibizumab injection.
Age-related macular degeneration; Anti-VEGF; Pigment epithelial detachment; Ranibizumab (Lucentis); Retinal pigment epithelium rip
Combination verteporfin photodynamic therapy (vPDT) and antivascular endothelial growth factor (anti-VEGF) therapy may decrease the need for injections while maintaining visual acuity in exudative age-related macular degeneration. This pilot study was designed to determine the threshold fluence dose of vPDT (the dose required to demonstrate an effect on choroidal perfusion) combined with ranibizumab.
Seven patients were randomized to sham vPDT (two patients), 20% fluence vPDT (two patients), or 40% fluence vPDT (three patients) in combination with three-monthly intravitreal 0.5 mg ranibizumab injections. Intravitreal ranibizumab was reinjected if disease activity was seen on fluorescein angiography, optical coherence tomography, or clinical examination. Indocyanine green-determined choroidal hypoperfusion was graded in a masked fashion.
Patients with 20% vPDT had mild hypoperfusion defects at seven days that resolved by week 4 (threshold dose); patients with 40% fluence vPDT had marked hypoperfusion at seven days that persisted as long as 12 months. Recruitment was stopped after limited efficacy was observed. One patient with 20% fluence vPDT lost 19 letters at one year; no other patient lost or gained >10 letters. Central retinal thickness decreased in six of seven patients, but ranibizumab injections did not decrease.
This pilot study shows that the threshold fluence dose of vPDT (when combined with ranibizumab) is approximately 20% standard fluence, and that mild and transient choroidal hypoperfusion can occur. Forty percent fluence vPDT causes a more prolonged and striking hypoperfusion. Despite hypoperfusion, no decrease in visual acuity or injections required was noted, suggesting that even higher fluence levels of vPDT may be necessary to decrease the number of anti-VEGF injections.
neovascular age-related macular degeneration; choroidal hypoperfusion; threshold dose; verteporfin photodynamic therapy
The purpose of this study was to evaluate the visual outcome and self-reported vision-targeted health status in patients treated with intravitreal ranibizumab for wet age-related macular degeneration (AMD).
A total of 51 eyes from 50 patients aged 76 ± 7 years, with wet AMD not previously treated, were included in this prospective study. Best corrected visual acuity was examined using Early Treatment Diabetic Research Study charts and near vision reading. All patients underwent an ophthalmological examination, including fluorescein and indocyanine green angiography (occult cases) and optical coherence tomography. The Visual Function Questionnaire test was completed before and 37 ± 7 months after the start of intravitreal injections.
The patients received a mean number of 7.8 ± 5.0 (range 2–22) injections. One month after the third intravitreal injection, significant improvement was seen in both visual acuity (53 ± 14 to 61 ± 14 letter, P = 0.001) and near vision (17 ± 9 to 11 ± 8 points, P = 0.001). During follow-up, mean visual acuity decreased from 53 ± 14 to 44 ± 24 letters (P = 0.011), and near vision decreased from 17 ± 9 to 20 ± 11 points (P = 0.048). Despite visual impairment, the quality of life test revealed no significant decrease in mental health (P = 0.529) or ability to read a newspaper (P = 0.21), but a decrease in distance activities (reading street signs, steps, going to the theater) from 57 ± 27 to 46 ± 31 points (P = 0.007) was documented.
Decreased visual acuity was related to a decrease in self-reported visual function for distance activities, while mental health items, such as worrying, were not influenced.
visual outcome; quality of life; age-related macular degeneration
Two biologically related factors, complement factor H (CFH) and C-reactive protein (CRP) have been associated with age-related macular degeneration (AMD). The Y402H variant of CFH is located within the binding site of CFH for CRP. Although plasma CRP levels have been related to AMD, and plasma CRP levels are partly determined by genetic variation, there is no information on whether genetic variants in CRP are associated with AMD.
We performed a prospective analysis among 111 men who eventually developed AMD and 401 men who remained free of AMD, all participants in the Physicians’ Health Study. We determined genotypes for the common T>C single nucleotide polymorphism (SNP) in exon 9 of CFH (rs1061170; protein Y402H) as well as seven previously described CRP SNPs (rs3093059, rs2794521, rs3091244, rs1417938, rs1800947, rs1130864, rs1205). We used logistic regression analysis to evaluate individual SNPs as well as six CRP haplotypes for association with AMD.
The high-risk C allele of CFH was present in 45% of cases and 34% of controls. We observed an odds ratio for AMD of 1.46 (95% CI=1.05-2.04) for TC heterozygotes and 2.13 (95% CI=1.10-4.16) for CC homozygotes assuming a multiplicative (log-additive) model, and calculated an attributable fraction of 25% (95% CI=1% to 44%). For CRP, single-marker or haplotype-based analysis failed to reveal any significant associations with risk of AMD.
These prospective data confirm an association between the Y402H variant of CFH and risk of AMD. In contrast, although biologically plausible, genetic variation in CRP does not appear to be associated with risk of AMD. Further prospective study of larger numbers of subjects is needed to substantiate available information on the genetic epidemiology of AMD.
To evaluate intraretinal anatomy in patients with exudative age-related macular degeneration (AMD) using high-speed ultrahigh resolution optical coherence tomography (hsUHR-OCT) before and 1 month after intravitreal injection of ranibizumab.
Retrospective case series.
Twelve eyes of 12 patients.
A broad bandwidth superluminescent diode laser light source and spectral/Fourier domain signal detection were used to create a prototype hsUHR-OCT instrument with 3.5 μm axial image resolution and approximately 25,000 lines/second acquisition speed. Twelve eyes of 12 patients with exudative AMD were imaged with hsUHR-OCT before and 1 month after intravitreal ranibizumab injection. High pixel density and raster-scanned 3-dimensional (3D) OCT data sets were generated. Three-dimensional imaging software was used to calculate subretinal/retinal pigment epithelium fluid volume and volume of the fibrovascular lesion.
Main Outcome Measures
Qualitative and quantitative analysis of hsUHR-OCT images and 3D data sets.
All eyes had some degree of normalization of macular contour after intravitreal ranibizumab. The inner/outer photoreceptor segment junction visualized on hsUHR-OCT was discontinuous, overlying the fibrovascular lesion in all 12 of 12 eyes both before and after treatment; 9 of 12 eyes had focal areas of thinning of the outer nuclear layer, which remained after treatment. Volumetric measurements were possible in 8 of 12 eyes with 3D-rendering software. Fibrovascular lesion volume did not change significantly after treatment.
hsUHR-OCT is capable of unprecedented imaging speed and resolution, making it a valuable instrument in measuring in vivo intraretinal pathology. All 12 eyes had some normalization of macular contour. Fibrovascular lesion volume did not change significantly 1 month after treatment, suggesting that ranibizumab does not cause much initial regression of preexisting neovascular tissue. Photoreceptor abnormalities remained in all patients after treatment of wet AMD, suggesting that although ranibizumab improves overall retinal architecture, some photoreceptor damage may be irreversible.
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