Purpose
To investigate the risk factors for development and progression of retinal pigment epithelial (RPE) atrophy during ranibizumab treatment for neovascular age-related macular degeneration (AMD) in Japanese patients.
Design
Retrospective interventional case series.
Methods
This study included 195 eyes with treatment-naïve subfoveal neovascular AMD. All patients were treated with an as-needed regimen after 3 monthly ranibizumab treatments. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and ARMS2 A69S and CFH I62V polymorphisms were analyzed for their association with development and progression of RPE atrophy.
Results
Ten of 195 eyes (5.1%) had RPE atrophy at baseline; 3 had typical AMD and 7 had polypoidal choroidal vasculopathy (PCV). Among 185 eyes without preexisting RPE atrophy at baseline, 7 (3.8%) developed RPE atrophy at 12 months and 10 (5.4%) during the mean follow-up of 26.7 months. The incidence of newly developed RPE atrophy was lower in PCV than in typical AMD ( P = .036), while the progression of the RPE atrophy area was faster in typical AMD than in PCV (0.57 ± 0.35 and 0.31 ± 0.13 mm/year, respectively; P = .018). The ARMS2 A69S and CFH I62V polymorphisms were significantly associated with the baseline RPE atrophy ( P = .014 and P = .009, respectively).
Conclusions
The RPE atrophy developed in 5.4% of eyes with neovascular AMD during the 26.7 months of ranibizumab treatment. When compared with white individuals, RPE atrophy developed less frequently in Japanese patients, but the progression rate was similar. The subtype of AMD thus affects the development of RPE atrophy.
Age-related macular degeneration (AMD) is a leading cause of blindness for elderly people in both the United States and Japan. Loss of vision in patients with AMD occurs owing to the development of geographic atrophy (GA) and choroidal neovascularization (CNV). The advent of the anti–vascular endothelial growth factor (VEGF) agents has dramatically improved the clinical outcome of patients with neovascular AMD, and these anti-VEGF therapies have become the standard treatment for neovascular AMD.
VEGF plays a critical role in both survival and maintenance of retinal pigment epithelium (RPE) integrity, and RPE-derived VEGF is an essential factor for maintenance of choriocapillaris. Moreover, VEGF is reported to be involved in retinal neuroprotection. The SEVEN-UP study reported that most patients did not attain durable, treatment-free cessation of exudative AMD 7–8 years after initiation of intensive ranibizumab therapy. Thus, most eyes with AMD require anti-VEGF treatment over a long period, and the constant neutralization of VEGF vital for ocular homeostasis may cause unexpected adverse effects. Recently, it was reported that the RPE atrophy and choriocapillary atrophy can be vision-threatening conditions that develop in eyes receiving anti-VEGF treatment. The SEVEN-UP study demonstrated that macular atrophy was present in 98% of study eyes at a mean 7.3 years after initial ranibizumab treatment, and the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) reported that the incidence of GA was 18.3% during 2 years of anti-VEGF treatment. The CATT study also evaluated the growth rate of GA and its associated risk factors in white populations. However, little information is available about Asian patients, who have different subtype distribution of AMD than white patients.
The purpose of this study was to evaluate the prevalence and the progression rate of RPE atrophy in Japanese patients with neovascular AMD undergoing anti-VEGF treatment. We also examined the factors associated with the development and the progression of RPE atrophy.
Since RPE atrophy associated with anti-VEGF treatment for CNV may be indistinguishable from GA, which is a characteristic lesion in dry AMD and is not associated with CNV, we use the term RPE atrophy, not GA, throughout this article.
Methods
We retrospectively studied the medical records of 201 eyes of 201 consecutive patients with subfoveal neovascular AMD. All patients were treated with 3 monthly loading intravitreal injections of ranibizumab (Lucentis; Novartis, Bülach, Switzerland) from January 1 st 2010 through January 31 st 2013, followed by an as-needed regimen of ranibizumab treatment. This study was conducted in accordance with the tenets of the Declaration of Helsinki and approved by the Institutional Review Broad at Kyoto University Graduate School of Medicine. All patients were fully informed of the purpose and procedures of genotyping, and genotyping was performed in each patient whose written consent was obtained.
The inclusion criteria were as follows: (1) symptomatic subfoveal AMD, (2) age >50 years, (3) 3 consecutive monthly ranibizumab injections, (4) follow-up by an as-needed regimen with ranibizumab monotherapy, and (5) a minimum follow-up of 12 months after the initial injection of loading treatment. The exclusion criteria included (1) other concomitant ocular diseases (ie, diabetic retinopathy, glaucoma, retinal vein occlusion, or epiretinal membrane); (2) other macular abnormalities (ie, retinal angiomatous proliferation, myopic choroidal neovascularization, angioid streaks, or other secondary choroidal neovascularization); and (3) a history of laser photocoagulation, photodynamic therapy, anti-VEGF treatment other than ranibizumab, or vitrectomy. There were no exclusion criteria for baseline best-corrected visual acuity (BCVA) and a history of cataract surgery. If a patient had neovascular AMD in both eyes, the right eye was selected for this study.
Before loading treatment, each patient underwent a comprehensive ophthalmologic examination, including measurement of BCVA and intraocular pressure; indirect ophthalmoscopy; slit-lamp biomicroscopy with a contact lens; color fundus photography (TRC-NW8F; Topcon Corp, Tokyo, Japan); spectral-domain optical coherence tomography (OCT) (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany); fundus autofluorescence; and fluorescein and indocyanine green angiography (HRA-2; Heidelberg Engineering).
The subtypes of neovascular AMD included in this study were typical AMD and polypoidal choroidal vasculopathy (PCV). We excluded retinal angiomatous proliferation (RAP) owing to the fact that it represents a rare (4.5%) subtype of neovascular AMD in Japanese populations, as well as exhibiting particular features that differentiate it from typical AMD and PCV (ie, female prevalence, bilaterality, rich drusen, and poor prognosis). Typical AMD involved classic CNV, occult CNV, or a combination of both. The diagnosis of PCV was based on indocyanine green angiography, which showed a branching vascular network that terminated in polypoidal lesions.
The greatest linear dimension was determined based on indocyanine green angiography. Choroidal vascular hyperpermeability was evaluated in either mid- or late-phase indocyanine green angiography, and was defined as multifocal areas of hyperfluorescence with blurred margins within the choroid. Subfoveal choroidal thickness was defined as the distance between the line corresponding to the Bruch membrane and the chorioscleral interface. Using an enhanced depth imaging technique, subfoveal choroidal thickness was manually measured with a built-in caliper tool (Spectralis HRA+OCT).
Genotyping was performed in 173 patients. Genomic DNA was prepared from leukocytes of peripheral blood with a DNA extraction kit (QuickGene-610L; Fujifilm, Tokyo, Japan). We genotyped the major AMD-associated single nucleotide polymorphisms (SNPs): ARMS2 A69S rs10490924 and CFH I62V rs800292. The SNPs were genotyped using TaqMan SNP assays with the ABI PRISM 7700 system (Applied Biosystems Inc, Foster City, California, USA).
After 3 consecutive monthly loading injections, patients were monitored monthly, and retreatment of each patient was performed based on any decreased vision relative to the previous visit, with the development of new macular hemorrhage or the presence of fluid accumulation determined by OCT. Dry macula was defined as resolution of intraretinal and/or subretinal fluid detected by OCT at 1 month after loading treatment. Wet macula was defined as existence of any retinal fluid detected by OCT at 1 month after loading treatment. The persistence of pigment epithelial detachment was not considered to be wet macula.
Color fundus photography, fluorescein and indocyanine green angiography, fundus autofluorescence, and the OCT were used to assess RPE atrophy at baseline. Progression and development of RPE atrophy were judged based mainly on both color fundus photography and OCT, as well as fundus autofluorescence when available at the 12-month and at the final visit. The diagnosis of GA was made using the similar criteria as in previous studies. Retinal pigment epithelial atrophy was defined as follows: (1) its presence within the macular vascular arcade; (2) a roughly round or oval area of partial or complete depigmentation of the RPE, with thinning of the overlying neurosensory retina; (3) ≥250 μm in the longest linear dimension; (4) atrophic changes of RPE and photoreceptor cell with increased choroidal signal beneath them on OCT; and (5) at least 1 of the additional characteristics: sharp demarcated borders, visibility of underlying choroidal vessels, or uniform reduced autofluorescence signal bounded by sharp borders on fundus autofluorescence. We analyzed RPE atrophy detected at baseline as preexisting RPE atrophy, and considered RPE atrophy that was not detected at baseline but was present at follow-up visit as newly developed RPE atrophy. The presence of RPE atrophy was assessed by the readers who were masked to clinical findings and number of ranibizumab injections.
The area of RPE atrophy on a selected color fundus photography was measured using the public domain software ImageJ (National Institutes of Health, Bethesda, Maryland, USA). We manually demarcated the outline of RPE atrophy. The scaling factor for this image was determined from the distance between the origin and the first branch of an arbitrary vessel at the optic disc. This distance was measured on the fluorescein angiography image using a built-in caliper tool, and the pixel value in ImageJ was converted into millimeters. The square root transformation strategy was used to investigate progression in the RPE atrophy area. The square root transformation of the atrophy area decreased the dependence of growth rates on baseline lesion measurements.
All values are presented as either the mean ± standard deviation or the number. The visual acuity, measured with a Landolt chart, was converted to the logarithm of the minimal angle of resolution (logMAR) for statistical analyses. Counting fingers and hand motion were converted to 2.00 and 3.00 in logMAR units, respectively. The number of risk alleles for each genotype was counted as 0, 1, or 2, when the associations of genotype with outcomes were evaluated using tests of linear regression models for continuous outcomes. Mann-Whitney U tests were used to compare patient age, greatest linear dimension, visual acuity, visual acuity improvement, number of injections, and subfoveal choroidal thickness between eyes with RPE atrophy at baseline and those without, and between eyes with RPE atrophy development at each follow-up visit and those without. Fisher exact tests were used to compare sex ratio and the rates of subtype of neovascular AMD, smoking history, choroidal vascular hyperpermeability, and dry/wet macula status between eyes with RPE atrophy at baseline and those without, and between eyes with RPE atrophy development at each follow-up visit and those without. χ 2 trend tests were used to compare the genotype distribution. Risk factors with P < .20 in the univariate analysis were included in a multivariate analysis, in order to assess the independent effect of each predictor on the development of RPE atrophy. We evaluated the association of baseline characteristics to the growth rate of RPE atrophy using univariate analysis. Multiple regression analysis was performed including baseline factors with P < .20 in the univariate analysis as the variables to evaluate the independent influence of each factor on the growth rate of RPE atrophy. Statistical significance was defined at P < .05.
Results
We enrolled 201 consecutive patients (1 eye per patient, n = 201 eyes) with AMD who were treated with 3 monthly loading injections of ranibizumab in this study. All patients were Japanese. Five eyes of 5 patients developed retinal pigment epithelial tear, and 1 eye developed massive vitreous hemorrhage that necessitated vitrectomy. These 6 eyes of 6 patients were excluded from the analysis. The characteristics of the participants are summarized in Table 1 . The mean age of the 195 patients was 73.3 ± 7.9 years, and 132 (67.7%) were men. Of the 195 eyes, 99 eyes (50.8%) had typical AMD, and 96 (49.2%) had PCV. The mean follow-up period was 26.7 ± 10.5 months (range, 12–58 months). The number of injections was 7.7 ± 3.9 times during the study period. A total of 111 patients (56.9%) had a history of smoking; 3 patients’ smoking histories were unknown. Fundus autofluorescence images were available for determining the presence of RPE atrophy in 17 eyes at 12 months and 24 eyes at last visit.
| Age (y) | 73.3 ± 7.9 |
| Sex (m) | 132 (67.7%) |
| PCV | 96 (49.2%) |
| Baseline BCVA | 0.34 ± 0.33 |
| GLD (μm) | 3419 ± 1381 |
| Subfoveal choroidal thickness (μm) | 245.1 ± 92.7 |
| CVH (+) | 48 (24.6%) |
| Smoking history (+) | 111 (56.9%) |
| Follow-up period (mo) | 26.7 ± 10.5 |
Ten eyes (5.1%) of 10 patients showed RPE atrophy at baseline ( Figure 1 ). Of the 10 eyes, 8 had extrafoveal RPE atrophy, 1 had juxtafoveal atrophy, and 1 had subfoveal atrophy. The eyes with RPE atrophy at baseline showed a higher prevalence of PCV (70.0%) compared with the eyes without RPE atrophy at baseline (48.1%), but the difference was not statistically significant ( Table 2 ). In 6 of 7 PCV eyes with RPE atrophy at baseline, preexisting RPE atrophy was observed over the network vessels of PCV. In 3 typical AMD eyes with RPE atrophy at baseline, preexisting RPE atrophy was observed within or adjacent to the CNV area. The lesion size was significantly larger in eyes with RPE atrophy, and smoking was negatively associated with the atrophy ( P = .018 and P = .007, respectively). The G allele of ARMS2 A69S and the A allele of CFH I62V were risk alleles for atrophy ( P = .014 and P = .009, respectively).
| Atrophy (+) at Baseline (n = 10) | Atrophy (−) at Baseline (n = 185) | P Value (Univariate) | P Value (Multivariate) | |
|---|---|---|---|---|
| Sex (m/f) | 7/3 | 125/60 | .588 | – |
| Age (y) | 73.7 ± 6.7 | 73.2 ± 8.0 | .982 | – |
| Subtype (tAMD/PCV) | 3/7 | 96/89 | .153 | .320 |
| VA at baseline | 0.35 ± 0.32 | 0.34 ± 0.34 | .926 | – |
| CVH (+/−) | 2/8 | 46/139 | .536 | – |
| GLD | 4634 ± 1638 | 3352 ± 1340 | .012 | .018 |
| Subfoveal choroidal thickenss (μm) | 254.0 ± 116.3 | 244.6 ± 91.6 | .847 | – |
| Smoking history (+/−) | 2/8 | 109/73 | .015 | .007 |
| ARMS2 A69S (GG/GT/TT) | 3/3/2 | 27/63/61 | .190 | .014 |
| CFH I62V (AA/AG/GG) | 5/5/0 | 33/69/61 | .006 | .009 |
Among 185 eyes of 185 participants who had no RPE atrophy at baseline, 7 eyes (3.8%) of 7 patients developed RPE atrophy at 12 months, and 10 eyes (5.4%) of 10 patients had developed RPE atrophy by the last visit ( Figure 2 ). All of the RPE atrophy developed within or adjacent to the CNV area. Table 3 shows the comparison of clinical characteristics between RPE atrophy (+) and RPE atrophy (−) at 12 months among the 185 eyes without preexisting RPE atrophy at baseline. In contrast to the baseline RPE atrophy, only 1 eye (1.1%) with PCV developed RPE atrophy, while 6 eyes (6.3%) with typical AMD developed RPE atrophy, but this difference was not statistically significant. The number of injections was less frequent, and visual acuity at baseline was worse in the RPE atrophy (+) group than in the RPE atrophy (−) group ( P = .022 and P = .017, respectively). In multivariate analysis, the significant risk factors for the development of RPE atrophy were female sex ( P = .041), less frequent injections ( P = .022), worse visual acuity at 12 months ( P = .20), and the presence of the A allele of CFH I62V ( P = .020).
| Atrophy (+) (n = 7) | Atrophy (−) (n = 178) | P Value (Univariate) | P Value (Multivariate) | |
|---|---|---|---|---|
| Sex (m/f) | 3/4 | 122/56 | .155 | .041 |
| Age (y) | 73.9 ± 8.0 | 73.2 ± 8.0 | .760 | – |
| Subtype (tAMD/PCV) | 6/1 | 90/88 | .072 | .124 |
| Number of injections | 3.7 ± 1.3 | 5.5 ± 2.2 | .022 | .022 |
| VA at baseline | 0.58 ± 0.28 | 0.33 ± 0.33 | .017 | .725 |
| CVH (+/−) | 2/5 | 44/134 | .555 | – |
| GLD | 3256 ± 472 | 3357 ± 1364 | .846 | – |
| Subfoveal choroidal thickness (μm) | 228.6 ± 104.4 | 245.2 ± 91.4 | .760 | – |
| Smoking history (+/−) | 3/4 | 106/69 | .289 | – |
| VA at 12 months | 0.53 ± 0.42 | 0.24 ± 0.34 | .085 | .020 |
| Visual improvement | −0.047 ± 0.33 | −0.082 ± 0.31 | .328 | — |
| Dry macula / wet macula at 3 months | 7/0 | 127/51 | .100 | .994 |
| ARMS2 A69S (GG/GT/TT) | 2/2/2 | 25/61/59 | .440 | – |
| CFH I62V (AA/AG/GG) | 4/1/2 | 29/68/59 | .094 | .020 |
We also evaluated RPE atrophy at the last follow-up visit ( Table 4 ). Three eyes further developed RPE atrophy; all of these eyes had typical AMD. Polypoidal choroidal vasculopathy was significantly less prevalent among patients with RPE atrophy at the last visit ( P = .013). Patients who had developed RPE atrophy until the last visit showed a better response to initial loading treatment with ranibizumab ( P = .036) and received less frequent ranibizumab injections ( P = .029). In multivariate analysis, the subtype of neovascular AMD was the sole significant risk factor for the development of RPE atrophy ( P = .036).
| Atrophy (+) (n = 10) | Atrophy (−) (n = 175) | P Value (Univariate) | P Value (Multivariate) | |
|---|---|---|---|---|
| Sex (m/f) | 5/5 | 120/55 | .189 | .090 |
| Age (y) | 75.1 ± 7.4 | 73.1 ± 8.0 | .367 | – |
| Subtype (tAMD/PCV) | 9/1 | 87/88 | .013 | .036 |
| Numbers of injections | 5.6 ± 3.7 | 7.9 ± 3.9 | .029 | .148 |
| VA at baseline | 0.44 ± 0.32 | 0.33 ± 0.34 | .184 | .565 |
| CVH (+/-) | 2/8 | 44/131 | .528 | – |
| GLD | 3111 ± 484.1 | 3367 ± 1373 | .761 | – |
| Subfoveal choroidal thickenss (μm) | 218.6 ± 93.3 | 246.0 ± 91.6 | .430 | – |
| Smoking history (+/-) | 4/6 | 105/67 | .162 | .262 |
| VA at last visit | 0.45 ± 0.51 | 0.26 ± 0.36 | .264 | – |
| Visual improvement | 0.009 ± 0.39 | −0.065 ± 0.35 | .469 | – |
| Dry macula / wet macula at 3 months | 10/0 | 124/51 | .036 | .994 |
| ARMS2 A69S (GG/GT/TT) | 2/3/4 | 25/60/57 | .990 | – |
| CFH I62V (AA/AG/GG) | 4/2/4 | 29/67/57 | .449 | – |
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