Comment on “Assessment of the long-term visual and anatomical outcomes of ranibizumab to treat neovascular age-related macular degeneration”

Dear Editor,

The study by Kucuk et al^[1] evaluated the long-term visual and anatomical outcomes in patients who underwent intravitreal ranibizumab (Lucentis, Novartis Pharma AG, Basel, Switzerland) monotherapy to treat neovascular age-related macular degeneration (AMD) and followed-up for at least 2y. The authors concluded that ranibizumab monotherapy can stabilize visual acuity for a mean period of 4y in patients with neovascular AMD.

We would like to address several challenges that have arisen from this study, which can be specifically summarized below.

1) The study was retrospectively conducted with a great number of patients (75.67%) that were lost from the assessment up to the end of the follow-up period. 2) Of the 6 angiographic types of choroidal neovascularization (CNV) existing in neovascular AMD patients, the study revealed only 3 of them, namely, the occult, the predominantly, and the minimally classic CNVs. The other 3 angiographic types [e.g. the mixed CNV, the retinal angiomatous proliferation (a distinct form of occult CNV associated with proliferation of intraretinal capillaries^[2]), and the polypoidal choroidal vasculopathy (PCV)] were not screened and investigated in the study populations. The indocyanine green angiography (ICGA) should have been used to highlight patients with the 2 angiographic subtypes of PCV^[3], namely, subtype 1, PCV sharing a common pathogenic background with neovascular AMD, and subtype 2, idiopathic PCV. Importantly, there is a difference in early treatment response with anti-vascular endothelial growth factor (VEGF) agent between the 2 subtypes of PCV^[4]. The treatment would have had to be individualized according to the existing angiographic type. The ICGA should be a standard investigation for all patients with newly diagnosed neovascular AMD, especially those with occult neovascular AMD, to avoid missing this relevant subset. 3) The following pertinent data are missing from the study: the mean time duration of neovascular AMD from diagnosis to the initiation of the treatment; the forms of neovascular lesions that may arise secondary to neovascular AMD [e.g. the type 1 located under the retinal pigment epithelium (RPE), the type 2 located in the subretinal space, or the type 3 intraretinal]; the serous and/or hemorrhagic detachment of the neurosensory retina or RPE; the retinal hard exudates; the location of the intraretinal cystoid fluid if it existed in some cases (e.g. inner/outer nuclear layers or ganglion cell layer); the qualitative status of the ganglion cell complex, the external limiting membrane (ELM) band, the ellipsoid zone, and the interdigitation zone; the qualitative status of the RPE band-Bruch's membrane complex (e.g. pigment migration within the neurosensory retina, RPE porosity, micro-rips or blowouts in the RPE, focal RPE atrophy, and RPE thickening); the quantification of the subretinal hyperreflective material; the prevalence of vitreoretinal interface abnormalities (e.g. vitreomacular adhesion/traction and epiretinal membranes); the fluorescein angiographic findings including hyperfluorescence resembling occult CNV lesions in early or mid-phase of angiogram having lacy/stippled appearance, late hyperfluorescence only, and progressive leakage; the prevalence of the outer retinal tubulation; the subfoveal choroidal thickness; and the time to absence of retinal fluid (dryness) as well as the retinal fluid status at the end of the study [e.g. presence (wetness) or absence (dryness) of retinal fluid]. The effectiveness of the intravitreal ranibizumab monotherapy in routine clinical practice cannot be evaluated without considering these items. 4) The authors ascertained that the ranibizumab therapy can stabilize the visual acuity score for a mean follow-up time of 3.9y in patients with neovascular AMD. Of note, the mean central macular thickness (CMT) values before treatment (303 µm) and at the end of the study (251 µm) were under the cutoff (315.2 µm^[5]) of the upper level of normal CMT plus 2 standard deviations. However, the final visual and anatomical outcomes of this study were unsatisfactory. Specifically, there was a loss of 2.4 letters in visual acuity, the fibrotic scars developed in 63.5% of the eyes, and the geographic atrophy (GA) was evident in 8.1% of the eyes. Nothing was stated related to the locations of the fibrotic scars (subfoveal/subretinal fibrosis) as well as the GA (foveal/extrafoveal; contiguous with or clearly outside of the area of total CNV lesion). Potential reasons for these suboptimal outcomes include multiple factors. Most likely, there was a permanent VEGF receptor 2-mediated breakdown of the inner blood-retinal barrier and a permanent VEGF receptor 1-mediated rupture of the RPF junctions induced by long-term VEGF overexpression. This permanent chronic retinal capillaropathy caused by persistent subretinal and intraretinal fluid was temporarily relieved by reduction of the edematous component with ranibizumab therapy. However, the pathology was incurable because of irreversible ischemic changes to the macular ganglion cell complex, close to the foveola, with macular edema being a minor factor^[6].

Altogether, regardless of the anti-vascular endothelial growth factor agents used and regardless of the treatment dosing paradigms chosen (e.g. treat-and-extend, pro re nata, fixed-interval, or escalated algorithm), the efficacy of therapy depends primarily on the promptness of the therapy after the onset of neovascular AMD^[6]–^[11].