Ranibizumab Monotherapy in Neovascular Age-Related Macular Degeneration with Pigment Epithelial Detachment

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss among patients over 50 years of age [1,2]. Retinal pigment epithelial detachment (PED) occurs in association with AMD, often leading to decreased central vision due to retinal pigment epithelial (RPE) atrophy and also RPE tear [3]. Angiogenic factors such as vascular endothelial growth factor (VEGF) have been implicated in the development of choroidal neovascularization and have become the major targets in neovascular AMD therapy [4-7]. Currently, bevacizumab and ranibizumab (antiVEGF antibody) are the mainstay of treatment for neovascular AMD. Pivotal clinical trials such as MARINA [6] and ANCHOR [8], as well as PrONTO [9] have all demonstrated the efficacy of ranibizumab in terms of preservation and improvement of visual acuity in patients with neovascular ARMD over photodynamic therapy (PDT).


Introduction
Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss among patients over 50 years of age [1,2]. Retinal pigment epithelial detachment (PED) occurs in association with AMD, often leading to decreased central vision due to retinal pigment epithelial (RPE) atrophy and also RPE tear [3]. Angiogenic factors such as vascular endothelial growth factor (VEGF) have been implicated in the development of choroidal neovascularization and have become the major targets in neovascular AMD therapy [4][5][6][7]. Currently, bevacizumab and ranibizumab (antiVEGF antibody) are the mainstay of treatment for neovascular AMD. Pivotal clinical trials such as MARINA [6] and ANCHOR [8], as well as PrONTO [9] have all demonstrated the efficacy of ranibizumab in terms of preservation and improvement of visual acuity in patients with neovascular ARMD over photodynamic therapy (PDT).
These studies have shown that about one third of patients with ARMD improve in visual acuity by at least 15 letters [6,8], anecdotally we noted that a subset of these patients with pigment epithelial detachment (PED) more often than not, respond poorly to ranibizumab monotherapy. The goal of this study is to report our findings of ranibizumab monotherapy using variable dosing in these patients. neovascularization secondary to age related macular degeneration with pigment epithelial detachment; treated with ranibizumab and the presence of at least one year of follow up data. Exclusion criteria were choroidal neovascularization due to other etiologies such as myopia, presumed ocular histoplasmosis, trauma and concurrent eye disease that may compromise visual acuity such as diabetic retinopathy and advanced glaucoma and previous treatment with subfoveal laser photocoagulation, Photodynamic Therapy (PDT) or pegaptanib (Macugen).

Materials and Methods
All eyes had been treated with intravitreal injections of ranibizumab 0.5mg. Injections were administered at baseline, month 1 and 2 and then on an as-needed basis at the discretion of the treating physician according to a 4 week clinical evaluation and OCT monitoring using the Stratus and Cirrus OCT (Carl Zeiss Meditec, Inc., Dublin, CA). Treatment was administered if there was evidence of any of the following signs: intraretinal fluid, subretinal fluid, worsening pigment epithelial detachment or retinal hemorrhage. Charts were reviewed for baseline demographic data, coexisting diagnoses, number of injections, VA at baseline as well as subsequent visits. Snellen VA was converted to the logarithm of the minimal angle of resolution (logMAR) scale for statistical analyses [10]. Flourescein angiograms were evaluated by a single retinal specialist (DH) All statistical analyses were performed on the Statistical Analyses System 9.1 system (SAS Inc., Cary, NC).

Results
A total of 85 patient charts were reviewed; 14 eyes of 12 patients were included in the study. Demographic characteristics of the patients are summarized in (Table 1).
Baseline fluorescein angiogram showed characteristics of neovascular AMD including the presence of PED. All PEDs were serous with evidence of choriodal neovascularization except one which had a hemorrhagic component. Other clinical findings including visual acuity and central macular thickness readings (CMT) are presented in ( Table 2).
As shown in (Table 2), there was a decline in average visual acuity over the study period where the mean initial logMar was 0.596 (Snellen ~20/80) and mean final logMar was 1.018 (Snellen ~20/200). However, this decline in visual acuity was not statistically significant (p=0.05) despite treatment with ranibizumab. There was also no statistical significance between the mean initial and final CMT values, also indicating no overall improvement with treatment. The mean CMT increased by 19 microns over the duration of the study. (Figures 1 and  2) represent visual acuity and central macular thickness readings of each eye included in the study respectively. There were no significant complications including inflammation, retinal pigment epithelium tears or endophthalmitis associated with intravitreal ranibizumab injection administration To illustrate one of the responses to ranibizumab montotherapy, a case has been described below. A 63 year old female with complaint of acute decreased vision in her right eye, over 2 weeks. She was diagnosed with neovascular AMD with serous PED, given three consecutive monthly ranibizumab injections and subsequently followed monthly with administration of ranibizumab as needed. The PED appeared to resolve periodically only to re-accumulate during a period when no treatment was administered. Figures 3 and 4 show changes on OCT associated with administration of ranibizumab.

Discussion
The findings of this study indicate that ranibizumab monotherapy administered on an as needed basis is of questionable benefit in eyes with     AMD and associated serous PED. This is consistent with the findings demonstrated by Ritter et al. [11] in a small prospective study which showed a decreased volume in the PED initially with ranibizumab activity in the RPE of these patients [19], while another observes the response of persistent PED lesions to high dose ranibizumab [20]. Results from the EXCITE study [21] comparing efficacy of monthly to quarterly ranibizumab treatment suggest that monthly treatments may result in better outcomes for patients with neovascular AMDcould this potentially translate to improvement for patients with PED. Most recently, aflibercept (VEGF Trap) which targets both VEGF-A and Placental Growth Factor (PIGF) has been found to be as effective as ranibizumab [22]; there is a possibility that this new regimen may be more effective in the minimally responsive subset of patients. This remains to be seen as further studies are performed.
There are a few limitations of this study; it is a pilot study with a small sample size and it is retrospective in nature which contributes to selection bias. Though the limitations, this study suggests that ranibizumab alone when administered on an as-needed basis is not effective for the treatment of neovascular AMD with PED. The typical trend in neovascular AMD towards improved vision as well as a decrease in central macular thickness with anti-VEGF therapy was not noted in this study when compared to results from previous studies such as PRONTO, MARINA and ANCHOR. In the future, a prospective study which includes a large sample size would be able to provide additional useful information regarding the management of this subset of patients. monotherapy, however was ineffective in improving visual acuity over one year. The case presented illustrates a response to ranibizumab albeit not a permanent one. There were eyes that had minimal to no response to the injections with worsening of VA and CMT such as in eye #7 (Figures 1 and 2). There are a few theories surrounding the etiology of this particular group of patients that respond poorly to ranibizumab therapy. Limited response to ranibizumab could be attributed to the "wait and observe approach" or as-needed treatment in this study as opposed to the monthly regimen which was utilized in the MARINA and ANCHOR trials. We can also hypothesize that perhaps this is a different lesion such as retinal angiomatous proliferation [12,13], which may require a different mode of therapy or more aggressive therapy such as triple therapy with PDT, intravitreal anti-VEGF therapy and intravitreal steroids [14]. The Verteporfin In Photodynamic Therapy Study (VIP) trial demonstrated that patients with AMD lost less lines of vision when treated with PDT [15], however Axer-Siegel et al. [16] found those patients with serous PED may not benefit at all from PDT. More recent studies have reported success in decreasing the number of required anti-VEGF injections and stabilizing vision with a combination of antiVEGF and PDT including for patients with PED [17,18]. There are currently clinical trials in the pipeline investigating some theories that could result in management of this subset of patients. One such theory, reports that there is an abnormal autoimmunity