## 4 Discussion
Only a long, monitored follow-up study can help clarify whether there is a real progressive reduction in VD relative to HCQ dose, cumulative dosage or time of administration. However, any data should be appraised in comparison with a group of RA subjects not undergoing HCQ treatment in order to pinpoint whether the evolution of the VD is spontaneous or is part of a specific pattern of VD changes related to the development of RA. It is equally important to determine the progression of the condition and vascular patterns in subjects presenting HCQ retinal toxicity, in order to identify potential biomarkers indicating subjects at high risk of retinal toxicity. Previous studies analyzing VD reduction during HCQ therapy share a number of limitations. In their investigations, [PERSON] and [PERSON] provided clear evidence of a reduction of VD in patients at high risk of HCQ-induced retinal toxicity (HCQ therapy > five years) [11; 15]. [PERSON]'s study observed a significant reduction of VD in the high-risk group compared with the low-risk group (HCQ therapy < five years); similarly, [PERSON]'s research followed a group of patients receiving HCQ therapy over a period of five years in comparison with a control group, finding a significant reduction of VD in the former. However, neither study categorized the patients according to subtypes of autoimmune diseases, so that data regarding LES, RA and other disorders were pooled. LES is especially important in this context, as it is characterized by primary retinal vascular changes acting as markers of a vaso-occlusive retinopathy, including cotton-wood spot, hard exudates, arteriolar attenuation, vasculitis and arterial occlusion [35]. Moreover, LES-related retinal ischemia may be confused with macula damage due to HCQ [13]. OCTA studies should therefore take into account retinal vascular changes related to the different autoimmune diseases when considering changes involving the VD. The study carried out by [PERSON] and colleagues also fails to include a subclassification of autoimmune diseases, thus compromising a proper evaluation of retinal VD [36]. The authors examined VD and retinal thickness in a cohort of 102 eyes of 102 patients with autoimmune disease, comparing data of 70 patients included in the treatment group with 32 naive patients in the control group. The vascular density values in the control group were matched by those in the treatment group (\(p\) > 0.05), supporting the conclusion that HCQ administered over a mean time of 73 months may not alter the retinal VD. Unfortunately, the data were not categorized by autoimmune disease, and low-risk (HCQ therapy < five years) and high-risk (HCQ therapy > five years) patients were not compared separately with the control group's naive patients. The current study has some clear limitations, the most obvious being the small sample size. However, this is the first study to include naive RA patients and those NB receiving HCQ as first line therapy, monitored with visual field and structural OCT and OCTA in a prospective investigation. Our protocol identifies another limitation, prompted by force of circumstance, namely the absence of multifocal electroretinogram examination (MF-ER) and fundus autofluorescence (FAF) among the inclusion criteria for the early detection of HCQ retinopathy, as recommended by the American Academy of Ophthalmology. Since the current study was carried out during the COVID-19 pandemic, we decided to restrict examinations to those that were quickest and most informative, so as to avoid prolonged stays in the hospital. This ruled out the MF-ERG and FAF. MF-ERG and FAF examinationscould identify specific, early abnormalities and thus categorize some eyes differently, suggesting possible correlations between functional impairment and retinal VD changes. Finally, bearing in mind that HCQ's side effects are usually obvious after five years or more of use, only a long-term follow-up study can confirm the vascular remodeling in RA patients undergoing HCQ therapy and the associated patterns of vascular changes.