Since early detection of HCQ-induced retinopathy is important, it is of great interest to find a modality that helps diagnose early-stage of retinopathy. In 2016, the AAO guideline proposed various modalities, including SD-OCT, AVF, FAF, and mfERG, for screening of HCQ-induced retinopathy, but none are gold standard.(15)The mfERG is more sensitive for diagnosis of HCQ-induced retinopathy in the early stages than the combination of AVF and SD-OCT tests.(25, 29) For this reason, in this study, based on mfERG changes, we divided patients into two groups : patients with Abnormal mfERG (Case group) and patients with Normal mfERG (Control group) and evaluated them with OCTA imaging. Patients with RA and SLE were also evaluated in separate subgroups. Because HCQ use for more than 5 years is a high risk for HCQ-induced retinopathy (15), we enrolled patients with at least 7 years of HCQ use.
Based on our findings, the mean Vessel Density (VD) in the SCP layer was not significantly different between the Abnormal mfERG and Normal mfERG groups, although in the RA subgroup, VD in Whole Image, ParaFovea and PeriFovea of the SCP layer in the Abnormal mfERG group decreased compared to the normal group. But it was not observed in SLE patients. The mean VD in the DCP layer (Whole Image, PeriFovea,) in the Abnormal mfERG group was lower than the normal group. This difference was also present in the RA subgroup but was not observed in the SLE subgroup. The mean VD in the Fovea area did not differ between the two groups. Also, FAZ Area and Flow Area (outer retina, choriocapillaris) were not different in the two groups and only Choriocapillaris Flow Area was lower in RA patients with Abnormal mfERG compared to RA patients with Normal mfERG.
To the best of our knowledge, limited studies have been conducted on the use of OCTA in the evaluation of HCQ-induced retinopathy, the results of which are also controversial. Some studies have evaluated OCTA changes between healthy individuals and patients with a history of HCQ use, and some studies have evaluated OCTA changes between High Risk (HCQ users over 5 years) and Low Risk (HCQ users less than 5 years).(22, 23, 28, 30-32) A review of studies in this field shows confusing results. To our knowledge, no study has been performed to evaluate changes in OCTA among patients with HCQ-induced retinopathy based on mfERG and those without retinopathy.
In the study of Tarakcioglu et al, which was performed among 102 patients ,No significant difference was observed between the HCQ treatment group and the control group in the parameters of FAZ, Flow Area, vascular density, SCP and DCP.(28) Based on our results, the patients in both groups were similar in the parameters of FAZ, Flow Area and SCP vascular density. In Bulut et al study, the mean of vascular density(both SCP and DCP layers) in the group with HCQ use< 5 years was higher than the group with HCQ use >5years and also the FAZ Area in the group with HCQ use >5 years was wider;(22)While in our study, vascular density in DCP was significantly different between the two groups, Their study was performed in patients with RA , Sjogren , SLE and Connective tissue disease ,While our study was performed in SLE and RA patients; The duration of treatment and the cumulative dose of HCQ were also lower than in our study. In Goker et al, The mean VD of the HCQ group was lower than group of healthy individuals, and the FAZ Area was higher in the HCQ group than in healthy individuals.(30) In this study, patients were compared with healthy people. Since rheumatologic diseases, especially SLE, affect retinal vascularity(33), the results may not be related to HCQ .While we compared OCTA parameters in two groups of patients that can eliminate vascular changes caused by the disease itself.
In the Forte et al study, was reported that with increasing cumulative dose and duration of HCQ use, VD in SCP and DCP decreased and also FAZ Area increased with Swept-source optical coherence tomography (SS-OCT)and separately, the vascular density in the areas of Fovea, PeriFovea, ParaFovea was not determined and the number of patients was 10.(23) Based on our results with RTVue XR-OCTA, VD, especially in the PeriFovea area, is inversely related to the cumulative dose and duration of HCQ.
In our study, changes in vascular density, especially in the DCP layer in RA patients, differed between the two groups of Abnormal mfERG and Normal mfERG. The Telek et al study also found that HCQ-induced retinopathy changes were more common in RA patients than in SLE patients. This may be due to longer use of HCQ or older patients.(34) Ozek et al evaluated changes in OCTA in RA patients. VD in the DCP layer (Deep Temporal, Deep Hemi inferior) was lower in RA patients with a history of HCQ of more than 5 years compared to healthy individuals and also compared to individuals with a history of HCQ of less than 5 years.(31)
In our study, we concluded that VD in the SCP layer (Whole Image, PeriFovea) was inversely related to the cumulative dose of the drug and the duration of drug administration. Also, VD in the DCP layer (Whole Image, PeriFovea) is inversely proportional to the duration of HCQ consumption. However, no relationship was observed between FAZ Area and Flow Area with drug duration and cumulative dose of HCQ. The mechanism of HCQ-induced retinal toxicity is not well understood. According to some studies, the accumulation of HCQ in RPE cells interferes with the clearance of intracellular toxic substances. That the inner layers and outer layers of the retina are damaged and some studies have suggested that the inner layer of the retina is not involved.(6) One study found that ganglion cell-inner plexiform layer (GC-IPL) thinning occurs in patients with a history of HCQ before changes in AVF and RPE changes.(35) In our study, DCP changes were greater than SCP, although these changes were not observed in SLE patients. In the study of De Sisternes et al, it was stated that HCQ retinopathy first begins in the photoreceptors and the paraFovea region, and that the Fovea is involved in more advanced stages.(5) In our study, FAZ Area and VD in Fovea Area in the two groups were not significantly different, which could be due to the fact that Fovea area is not involved in the early and subclinical stages of HCQ retinopathy. Flow area in Choriocapillaris was lower in RA patients with abnormal mfERG than in the other group, which may indicate that Choriocapillaris is involved in early HCQ retinopathy, but this difference was not observed in the SLE group, so further studies are needed.
The patients we evaluated all had normal AVF, FAF, SD-OCT, but some had evidence of early stage of HCQ-induced retinopathy at mfERG.
The strength of our study compared to other studies is that we performed OCTA in patients with a history of HCQ in two groups: Abnormal mfERG (with subclinical or early stage of HCQ Retinopathy) and Normal mfERG (without HCQ Retinopathy). To evaluate whether OCTA can help as a sensitive test to diagnose subclinical or early-stage retinopathy. Another feature of our study is that we separately evaluated RA and SLE patients who may have different immunological mechanisms. The limitations of our study are that it is cross-sectional and retrospective and the sample size is small, so doing a prospective study with more patients will help to get more accurate results. Also, the study of OCTA parameters in patients who have proven retinopathy due to HCQ in all three tests SD-OCT, mfERG, AVF can provide us with more useful information. But usually, the number of these patients is small.
In conclusion, we found that the density of retinal vessels in the Perifovea area decreased with increasing cumulative dose of and duration of treatment, but the FAZ Area did not change significantly. In RA patients with Abnormal mfERG (early stage of HCQ Retinopathy) mean VD of PeriFovea, ParaFovea area of DCP layer was reduced compared to RA patients with Normal mfERG (without HCQ Retinopathy) but FAZ Area and VD of Fovea did not change significantly in early retinopathy. OCTA may be used as a non-invasive modality to diagnose early stages of HCQ retinopathy but our knowledge in this area is still limited and more studies are needed.