## 4 Discussion  
A percentage varying from 1.6% to 20% of subjects undergoing therapy with chloroquine/HCQ for autoimmune diseases, including rheumatoid arthritis, manifest retinal toxicity. This is characterized by damage to the outer retinal layers, associated with reduced visual acuity and visual sensitivity, mainly experienced in the central 10 degrees of the visual field [27; 28; 29]. Direct toxicity to EPR seems to be the most commonly cited pathogenetic mechanism responsible for the final loss of retinal integrity and visual function. More recently, some authors have advanced the hypothesis that the retinal capillary circulation might be involved in the pathogenesis of retinal toxicity. In particular, it has been suggested that chloroquine/HCQ could reduce the VD of the macular retinal capillary network and subsequently lead to a reduction of blood flow. The reduction of the VD of the retinal capillary plexus has been demonstrated by OCTA in subjects with RA undergoing chronic therapy for five to 10 years, in comparison with a healthy population [14]. A greater reduction of VD was detected in the subgroup of patients with early retinal toxicity [16]. However, these assumptions were made in the absence of a clear understanding of the anatomical characteristics of the retinal capillary plexus in subjects with RA. In a previous study, we demonstrated that a reduction in the VD of SCP can be detected early in naive patients with recent onset of symptoms related to RA, compared to a group of healthy controls [25]. This finding may be complementary with the alterations in the retinal macro-circulation already highlighted by [PERSON] et al [24]. In a population study of 113 RA patients, the authors demonstrated a reduction in the caliber of the arterial vessels and a reduction in the arteriovenous ratio, in comparison with a control group. A vascular remodeling of the retinal micro- and macro-circulation, thus, seems to be a characteristic of RA. Primary alterations of the circulation in the large vessels and especially in the peripheral microvessels in patients with RA, including alterations of peripheral  
Figure 1: Optical coherence tomography angiography (OCTA) and capillary perfusion density analysis. Legend: Top row: Left, example of en face OCTA of rheumatoid arthritis patient. The foveal area is identified by a circle 1 mm in diameter centered on the fovea, the parafoveal region is included between the two concentric circles of 1 mm diameter and 3 mm diameter; center, structural optical coherence tomography, showing the complete integrity of the layers and flow signals; right, full retina capillary vessel density analysis. Bottom row: No changes in the retinal architecture and vessel density at one-year follow-up can be seen, compared with baseline images; in particular, the integrity of the retinal inner and outer segments (white arrow) and retinal pigment epithelium (yellow arrow) are well represented; in parallel, no significant change in the vessel density may be observed within 1 and 3 mm circles. capillary circulation of the extremities of the limbs and in the oral and labial mucosa, have been previously described and imply the presence of complex pathogenic mechanisms involving cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation, in addition to endothelial cell activation, and elevated levels of endothelin-1, potentially inducing vascular dysregulation [17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34]. The current study produces evidence of the stability of the VD in the SCP and DCP in patients with RA receiving HCQ over a one-year follow-up. In this cohort of patients, no retinal toxicity was demonstrated on structural OCT and visual field examination. Drugs might need to be administered for a longer period in order to reduce the retinal VD associated with HCQ therapy. Furthermore, the progressive reduction in VD might be affected by the cumulative dose rather than the daily dose.