Hydroxychloroquine Retinal Toxicity Research Articles

Inter-eye asymmetry of microvascular density in patients on hydroxychloroquine therapy by optical coherence tomography angiography

AimsTo explore the inter-eye retinal microvascular density asymmetry of patients on hydroxychloroquine (HCQ) therapy through optical coherence tomography angiography (OCTA). Methods40 subjects were enrolled in this cross-sectional study, including 20 systemic lupus erythematasus patients currently treated with HCQ (40 eyes) and 20 age- and sex-matched normal controls (NCs, 40 eyes). OCTA images were obtained to measure macular and peripapillary mircrovasculatures and microstructures, including vessel density, retinal nerver fiber layer thickness, and peripapillary ganglion cell-inner plexiform layer thickness. The absolute values of the difference between right and left eyes were taken as a measure of inter-eye asymmetry. ResultsMacular whole image vessel density (wiVD-M) and perifoveal vessel density (pfVD) of superficial capillary plexus (SCP) were notably reduced in both the right and left eyes of the HCQ treatment group compared with NCs. Specifically, SLE patients treated with HCQ have higher inter-eye asymmetry of wiVD-M of SCP (2.28 ± 1.03 vs 1.27 ± 0.79, p < 0.01) and pfVD of SCP (2.55 ± 1.26 vs 1.78 ± 1.06, p = 0.04) compared with NCs. There were no significant differences in inter-eye asymmetry of structure parameters. Inter-eye asymmetry of wiVD-M of SCP (AUC = 0.80, p < 0.01) and pfVD of SCP (AUC = 0.71, p = 0.02) exhibited greater discrimination power. ConclusionSLE Patients treated with HCQ exhibited a notably higher inter-eye vessel density asymmetry compared to that of NCs. Thus, inter-eye vessel density asymmetry could be used to screen for HCQ retinal toxicity.

Dermatologists' and Rheumatologists' Adherence to the Latest Recommendations for Screening of Hydroxychloroquine Retinopathy in Saudi Arabia: A Cross-Sectional Study.

Hydroxychloroquine (HCQ) is used to manage the symptoms of inflammatory rheumatic and dermatologic disorders. However, HCQ retinopathy is aserious side effect becauseeven after the drug is discontinued, irreversible vision loss may occur and may continue to progress.According to the American Academy of Ophthalmology (AAO),the recent recommendation for HCQ dosing is ≤5 mg/kg of real body weight, with baseline ophthalmologic screening during the first year of HCQ treatment and yearly screening after five years of continuous use of HCQ medication, unless the patient is at high risk or symptoms have developed.Nonetheless, this study aims to assess dermatologists' and rheumatologists' adherence in Saudi Arabia to the 2016 AAO HCQ retinal toxicity guidelines. A questionnaire-based cross-sectional study was conducted on dermatologists and rheumatologists in Saudi Arabia. It was conducted between August and September 2022 and questionnaires were sent to dermatologists and rheumatologists via their professional emails or accounts. The collected sample consisted of 635 participants; males and females represented 54% and 46%, respectively; 47.6% were consultants; 50.1% were rheumatologists; and 49.9% were dermatologists. Approximately 28.2% of the participants reported treating one to three patients with HCQ in the previous year. Only 45.4% of the respondents stated that the ideal recommended HCQ dose for reducing the risk of retinopathy is "≤ 5 mg/kg of the real body weight." More than 50% of the respondents stated that systemic lupus erythematosus was the most common disease for which they used HCQ. Additionally, 36.5% of the physicians screened patients during the first year of HCQ treatment. We found significant associations between practice levels and specialty practice-related questions with a p-value of less than 0.05, except for the specialty practice-related question, "What is the most common disease for which you use HCQ?" with a p-value of 0.074. Also, we found significant associations between all demographic variables and screening-related variables with a p-value of less than 0.05, with two exceptions: no significant associations were found between specialty area and the screening-related question, "Do you recommend screening tests for all patients starting treatment with HCQ?" at p = 0.270, and gender and the screening-related question, "When would you recommend screening tests for a patient without risk?" at p = 0.142. Dermatologists and rheumatologists in Saudi Arabia have shown poor adherence to the most recent AAO recommendations. Educating physicians and patients about the AAO guidelines is needed for HCQ to be used in a way that is both effective and safe.

Retinopatia chlorochinowa w dobie pandemii COVID-19

Hydroxychloroquine (HCQ, Plaquenil) is used in treatment of a variety of autoimmune disorders, in dermatology, rheumatology and oncology. Hydroxychloroquine and chloroquine (CQ) have been associated with irreversible visual loss due to retinal toxicity. Hydroxychloroquine retinal toxicity is far more common than previously considered; an overall prevalence of 7.5% was identified in patients taking HCQ for greater than 5 years, rising to almost 20% after 20 years of treatment. SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is causing the COVID-19 pandemic. There is no current standard of care. Clinicians need to be mindful of the toxicity of a wide variety of possibly unfamiliar substances being tested or repurposed to treat COVID-19.

Changes in visual function associated with hydroxychloroquine retinal toxicity

AbstractIntroduction: Non‐infectious inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, antiphospholipid antibody syndrome and others cause significant morbidity and are treated with immunosuppression. Hydroxychloroquine (HCQ) sulfate is used as a second line immunosuppressant and has many advantages over other agents. These include increased life expectancy, reduced risk of neoplasia, reduced risk of diabetes and hypercholesterolaemia. HCQ is safe in pregnancy. After more than 5 years of treatment, HCQ can cause a degenerative maculopathy characterized by loss of parafoveal photoreceptors and RPE cells, leading to a ring‐like visual field defect. Current detection of early retinal toxicity relies on central visual field testing, optical coherence tomography (OCT) scan and fundus autofluorescence. The reason for the parafoveal predilection for retinopathy is not understood. HCQ is concentrated in melanin‐containing cells, and there is increased melanin concentration in the macular RPE cells. A hypothesis is that HCQ concentrated in the macular RPE cells leads to toxicity, with macular pigment protecting the fovea but leaving a ring of potentially vulnerable tissue in the parafoveal region. We were interested to investigate parafoveal function in patients with mild HCQ maculopathy and report the results of detailed macular function assessment of red/green (RG) and yellow / blue (YB) colour vision and rod‐ and cone‐mediated rapid flicker sensitivity.Methods: Two patients with confirmed early hydroxychloroquine maculopathy participated in the study. RG and YB colour thresholds were measured with the Colour Assessment and Diagnosis (CAD) test. Cone and rod‐mediated rapid flicker sensitivity was also measured in both central and paracentral vision using the Flicker‐Plus test. Both patients had taken HCQ for more than 15 years and had paracentral scotomas on 10–2 field test and loss of the parafoveal outer nuclear layer and ellipsoid layer, confirming the presence of maculopathy. To test the hypothesis of parafoveal toxicity risk, 20 short wavelength (BAF) and infrared wavelength (IRAF) autofluorescence images were reviewed. The BAF images are surrogate markers of the macular pigment and the IRAF the melanin concentration. Normalized maps of the difference between BAF and IRAF were calculated to investigate the possibility of a ring of vulnerable tissue.Results: Both patients had normal RG, but abnormal YB colour thresholds. One subject had normal cone flicker thresholds, but the rod flicker thresholds were raised in all quadrants in both eyes. The second subject had significantly elevated rod thresholds and elevated cone flicker thresholds in both eyes. Of note is that the degree of retinopathy in the second patient was greater than in the first. The areas of greatest threshold elevation correlated with the areas of greatest field loss and anatomical disruption on OCT.Conclusion: These new findings show that hydroxychloroquine retinopathy affects preferentially both YB colour vision and rod‐mediated flicker sensitivity. The cone‐mediated flicker sensitivity is also affected in more advanced disease. A model for the anatomical location of the toxicity will be presented, based on the hypothesis outlined above.

INTRAVITREAL DEXAMETHASONE FOR THE TREATMENT OF MACULAR EDEMA SECONDARY TO HYDROXYCHLOROQUINE TOXICITY.

Cystoid macular edema is a vision-threatening complication infrequently associated with hydroxychloroquine retinal toxicity. There are limited data on the best treatment for this pathology. A retrospective case series is presented. In this series, we present three cases of cystoid macular edema in patients with diagnosed hydroxychloroquine maculopathy successfully treated with intravitreal dexamethasone implantation. Minimal literature has been published regarding the best management of cystoid macular edema related to hydroxychloroquine toxicity. Our case series suggests a possible new agent in the treatment of this rare occurrence.

Machine Learning–Based Automated Detection of Hydroxychloroquine Toxicity and Prediction of Future Toxicity Using Higher-Order OCT Biomarkers

Despite guidelines for hydroxychloroquine (HCQ) toxicity screening, there are clear challenges to accurate detection and interpretation. In the current report, the feasibility of automated machine learning (ML)-based detection of HCQ retinopathy and prediction of progression to toxicity in eyes without preexisting toxicity has been described. Retrospective, longitudinal cohort study. Subjects on HCQ therapy. This was an institutional review board-approved, retrospective, longitudinal image analysis of 388 subjects on HCQ. Multilayer, compartmental, retinal segmentation with ellipsoid zone (EZ) mapping was used to harvest quantitative spectral-domain (SD)-OCT biomarkers. Using a combination of clinical features (i.e., cumulative HCQ dose and the duration of therapy) and quantitative imaging biomarkers (e.g., volumetric EZ integrity and compartmental measurements), ML models were created to detect toxicity and predict progression based on ground-truth OCT-based toxicity readings by 2 masked retina specialists. Furthermore, 10-fold cross-validation was performed. The model performance was visualized using receiver operator curves and calculating the area under the curve (AUC). The corresponding sensitivity and specificity values were evaluated for the feasibility of HCQ toxicity screening and prediction. The prevalence of HCQ toxicity in this cohort of 388 patients was 9.8% (n= 38). Twenty-one eyes progressed to toxicity during follow-up. OCT-based features (i.e., partial EZ attenuation, EZ volume, outer nuclear layer volume, and compartmental thicknesses) and clinical features (i.e., HCQ daily dose, HCQ cumulative dose, and duration of therapy) showed significant differences between the toxic and nontoxic groups. Percentage area with partial EZ attenuation (i.e., percentage of the macula with an EZ-retinal pigment epithelium thickness of ≤ 20 μm) was the most discriminating single feature (toxic, 35.7 ± 46.5%; nontoxic, 1.8 ± 4.4%; P < 0.0001). Using a random forest model, high-performance, automated toxicity detection was achieved, with a mean AUC of 0.97, sensitivity of 95%, and specificity of 91%. Furthermore, the toxicity progression prediction model had a mean AUC of 0.89, with a sensitivity and specificity of 90% and 80%, respectively. This report described the feasibility of high-performance automated classification models that used a combination of clinical and quantitative SD-OCT biomarkers to detect HCQ retinal toxicity and predict progression to toxicity in cases without toxicity. Future work is needed to validate these findings in an independent dataset.

Quantitative autofluorescence findings in patients undergoing hydroxychloroquine treatment.

BackgroundTo measure quantitative autofluorescence (qAF) in patients under treatment with hydroxychloroquine (HCQ) and at risk of retinal toxicity but with no apparent signs of retinal toxicity and to compare it with that of untreated subjects.MethodsConsecutive patients at risk for the development of HCQ retinal toxicity (duration of treatment >5 years or daily HCQ dose >5 mg/kg of actual body weight [ABW]) but no alterations on spectral domain—optical coherence tomography, short‐wavelength autofluorescence and 10–2 visual field examination were recruited. Healthy subjects matched by age and sex were also enrolled in the study. All subjects underwent qAF measurements in one eye. Images were analysed using the conventional qAF grid by Delori calculating the qAF of eight sectors of the intermediate ring and the mean of those values (qAF8).ResultsThirty‐nine patients treated with HCQ (38 females, mean age 52.1 ± 8.6 years) and 39 untreated subjects (38 females, mean age 51.2 ± 8.6 years) were included. In both HCQ patients and untreated subjects, qAF8 was positively correlated with age (p = 0.004). Although HCQ patients showed a higher mean qAF8 compared with untreated subjects (294.7 ± 65.3 vs. 268.9 ± 57.5), the difference was not significant (p = 0.068). HCQ patients showed significantly higher mean qAF values in the inferior‐temporal, inferior and inferior‐nasal sectors of the intermediate ring of qAF grid compared with untreated subjects (all p < 0.05).ConclusionsThese results suggest a possible preclinical increase of qAF values in inferior parafoveal sectors probably induced by HCQ exposure.

Rapid Macular Thinning Is an Early Indicator of Hydroxychloroquine Retinal Toxicity

To demonstrate rapid macular thinning as an early and objective sign of hydroxychloroquine retinopathy. Retrospective case cohort. Cohort of 301 patients receiving long-term hydroxychloroquine therapy at Kaiser Permanente Northern California who underwent a minimum of 4 OCT studies that included Early Treatment Diabetic Retinopathy Study (ETDRS) retinal thickness values over a minimum of 4 years. Creation of sequential retinal thickness plots to show the rate of change in macular thickness within ETDRS regions. Identification of rapid macular thinning, comparison of patients with rapid thinning to those with stable macular thickness, and comparison of rapid thinning patients with and without conventional OCT or 10-2 visual field signs of hydroxychloroquine toxicity. Retina thinning in 219 stable patients receiving long-term hydroxychloroquine therapy averaged (mean ± standard deviation) 0.62 ± 0.45 μm/year, whereas 82 patients showed a period of relatively linear rapid thinning with a loss of 3.75 ± 1.34 μm/year. Of the patients with rapid thinning, 38 eventually demonstrated conventional OCT or 10-2 visual field signs of hydroxychloroquine retinal toxicity. The cumulative retinal thinning in these patients was 25.1 ± 6.2 μm compared with 15.7 ± 4.0 μm in those without conventional toxicity (P<0.01). Retinal thickness remains stable for many years in most patients receiving long-term hydroxychloroquine therapy, but after a critical point, the retina may begin to thin rapidly. Sequential plots of inner and outer ETDRS ring macular thickness provide objective evidence of this early structural change several years before conventional signs appear. This approach can alert patients and prescribing physicians to potential retinal damage and uses readily available OCT measurements that could be automated by manufacturers for use in comprehensive eye care settings.

Hydroxychloroquine Causes Early Inner Retinal Toxicity and Affects Autophagosome-Lysosomal Pathway and Sphingolipid Metabolism in the Retina.

Hydroxychloroquine (HCQ) is an anti-malarial drug but also widely used to treat autoimmune diseases like arthritis and lupus. Although there have been multiple reports of the adverse effect of prolonged HCQ usage on the outer retina, leading to bull's-eye maculopathy, the effect of HCQ toxicity on the inner retina as well as on overall visual functions has not been explored in detail. Furthermore, lack of an established animal model of HCQ toxicity hinders our understanding of the underlying molecular mechanisms. Here, using a small clinical study, we confirmed the effect of HCQ toxicity on the inner retina, in particular the reduction in central inner retinal thickness, and established a mouse model of chronic HCQ toxicity that recapitulates the effects observed in human retina. Using the mouse model, we demonstrated that chronic HCQ toxicity results in loss of inner retinal neurons and retinal ganglion cells (RGC) and compromises visual functions. We further established that HCQ treatment prevents autophagosome-lysosome fusion and alters the sphingolipid homeostasis in mouse retina. Our results affirm the notion that HCQ treatment causes early damage to the inner retina and affects visual functions before leading to characteristic toxicity in the macular region of the outer retina, 'bull's-eye maculopathy.' We also provide insights into the underlying molecular mechanisms of HCQ retinal toxicity that may involve autophagy-lysosomal defects and alterations in sphingolipid metabolism.

New insights in pathogenic mechanism of hydroxychloroquine retinal toxicity through optical coherence tomography angiography analysis.

There is only a unique report with a small sample size studying hydroxychloroquine (HCQ) retinal toxicity with swept-source (SS) optical coherence tomography angiography (OCTA). The aim of this study was to quantify OCTA quantitative parameters in patients who underwent HCQ therapy. We conducted a retrospective study. The study included 43 eyes of 22 patients taking HCQ for more than 5 years (high-risk group), 57 eyes of 29 patients taking HCQ for 5 years or less (low-risk group) and 25 eyes of 50 age-matched healthy controls. OCTA quantitative parameters (vessel density (VD) and foveal avascular zone (FAZ) area in superficial capillary plexus (SCP), middle capillary plexus (MCP), deep capillary plexus (DCP), total capillary plexus (TCP), and choriocapillaris (CC)) were recorded. In the low-risk group, VD in the SCP and MCP was increased compared to control group (p value <.05). In the high-risk group, VD in the SCP, MCP and TCP was increased (p value <.05). The subgroup analysis revealed an increased VD at SCP in systemic lupus erythematosus (SLE) high-risk patients, an increased VD at TCP and CC in rheumatoid arthritis (RA) high-risk subjects, and a decreased VD at CC level in the high-risk group patients with Sjögren's syndrome (SS) and connective tissue disease (CTD) (p value <.05). Furthermore, we demonstrated a significant enlargement of FAZ area at MCP level in the high-risk group patients with SS and CTD (p value <.05). We demonstrated an increase of VD in patients who underwent HCQ treatment, so we suggest that HCQ retinal toxicity is not vascular mediated.

A novel 5-ring multifocal electroretinography stimulus for detecting hydroxychloroquine retinal toxicity

PurposeMultifocal electroretinogram (mfERG) shows great utility as a screening tool to detect early hydroxychloroquine (HCQ) retinopathy, but its widespread use is limited by the lack of accessibility and long test duration. In this study, we evaluated a novel concentric 5-ring mfERG stimulus to provide a simplified and rapid protocol for screening HCQ toxicity.MethodsPatients referred for HCQ retinopathy screening were consented to this observational cross-sectional study. Patients with amblyopia, high refractive error (more than 8 diopters), other retinal diseases precluding appropriate evaluation or history of retinal surgery were excluded. The data were collected from patients undergoing HCQ screening at a single center from July 2019 to March 2020. Patients were tested with the new concentric 5-ring mfERG stimulus, standard 61-hexagon mfERG stimulus, spectral domain optical coherence tomography and automated 10-2 visual fields. For the main outcome, the 5-ring mfERG was compared to 61-hexagon stimulus to determine the time-to-test completion and assess the association between ring (R1–R5) amplitude and ring ratio compared against cumulative dose, dose by real body weight and duration of therapy using Pearson correlation.ResultsIn total, 52 patients (104 eyes; 5 males and 47 females) were recruited with a mean age of 59 years (range 23–85 years). The 5-ring protocol was markedly quicker to perform (1.3 ± 0.2 min; mean (SD)) compared to the 61-hexagon protocol (5.2 ± 0.6 min), p < 0.0001; n = 10 patients. The new R2/R5 ring ratio showed a moderate correlation with daily dose (r = − 0.640), cumulative dose (r = − 0.581) and duration of therapy (r = − 0.417). Similar correlations were observed with the new R2/R4 ring ratio which were not significantly different from the new R2/R5 correlation coefficients. The new R2/R5 ring ratio demonstrated a stronger correlation with daily (p = 0.002) and cumulative dose (p = 0.0001) compared to the 61-hexagon stimulus.ConclusionsIn this exploratory study, our novel 5-ring mfERG protocol significantly shortened data acquisition time while providing comparable results to the standard 61-hexagon stimulus for detecting HCQ-induced electrophysiological changes that are correlated with HCQ dosages and treatment duration. Our protocol has the potential to be more clinically practical by simplifying routine screening.

Deep Learning-Based Automatic Detection of Ellipsoid Zone Loss in Spectral-Domain OCT for Hydroxychloroquine Retinal Toxicity Screening.

PurposeRetinal toxicity resulting from hydroxychloroquine use manifests photoreceptor loss and disruption of the ellipsoid zone (EZ) reflectivity band detectable on spectral-domain (SD) OCT imaging. This study investigated whether an automatic deep learning-based algorithm can detect and quantitate EZ loss on SD OCT images with an accuracy comparable with that of human annotations.DesignRetrospective analysis of data acquired in a prospective, single-center, case-control study.ParticipantsEighty-five patients (168 eyes) who were long-term hydroxychloroquine users (average exposure time, 14 ± 7.2 years).MethodsA mask region-based convolutional neural network (M-RCNN) was implemented and trained on individual OCT B-scans. Scan-by-scan detections were aggregated to produce an en face map of EZ loss per 3-dimensional SD OCT volume image. To improve the accuracy and robustness of the EZ loss map, a dual network architecture was proposed that learns to detect EZ loss in parallel using horizontal (horizontal mask region-based convolutional neural network [M-RCNNH]) and vertical (vertical mask region-based convolutional neural network [M-RCNNV]) B-scans independently. To quantify accuracy, 10-fold cross-validation was performed.Main Outcome MeasuresPrecision, recall, intersection over union (IOU), F1-score metrics, and measured total EZ loss area were compared against human grader annotations and with the determination of toxicity based on the recommended screening guidelines.ResultsThe combined projection network demonstrated the best overall performance: precision, 0.90 ± 0.09; recall, 0.88 ± 0.08; and F1 score, 0.89 ± 0.07. The combined model performed superiorly to the M-RCNNH only model (precision, 0.79 ± 0.17; recall, 0.96 ± 0.04; IOU, 0.78 ± 0.15; and F1 score, 0.86 ± 0.12) and M-RCNNV only model (precision, 0.71 ± 0.21; recall, 0.94 ± 0.06; IOU, 0.69 ± 0.21; and F1 score, 0.79 ± 0.16). The accuracy was comparable with the variability of human experts: precision, 0.85 ± 0.09; recall, 0.98 ± 0.01; IOU, 0.82 ± 0.12; and F1 score, 0.91 ± 0.06. Automatically generated en face EZ loss maps provide quantitative SD OCT metrics for accurate toxicity determination combined with other functional testing.ConclusionsThe algorithm can provide a fast, objective, automatic method for measuring areas with EZ loss and can serve as a quantitative assistance tool to screen patients for the presence and extent of toxicity.

Hydroxychloroquine retinal toxicity- Can we do better with SD-OCT?

Hydroxychloroquine used in the management of connective tissue diseases also used to treat a wide spectrum of diseases. This disease-modifying anti-rheumatic drug can cause irreversible retinal damage and there are preferred practice guidelines for early screening to aid ophthalmologists and all those involved in the management of these patients. Spectral-Domain Optical Coherence Tomography (SD-OCT) currently an important tool in early detection of possible toxicity. Even with the current guideline-recommended 5mg/kg/day dosage, a baseline SD-OCT of the macula should be taken and repeated at 5 years. Many cross-sectional studies using SD-OCT have shown earlier retina damages, but none had monitored continuously from the beginning of Hydroxychloroquine usage. To evaluate sequential changes of the retina thickness in patients newly treated with hydroxychloroquine. We compared the mean central macular and Retinal Nerve Fiber Layer (RNFL) thickness pre, 3 months and 6 months post hydroxychloroquine using SD-OCT in order to find an association between them over the three time-points.33 previously healthy patients who were newly confirmed clinically and serologically with connective tissue disease planned for hydroxychloroquine who fulfilled the inclusion and exclusion criteria were recruited over 2 years. In consideration of selection criteria and drop-out rate, finally, 26 patients were included in the study.26 eyes of 26 patients (20 females and 6 males) were included in the study. The mean age was 33.92. The macula was significantly thinner (P&amp;#60;0.05) at superior (P&amp;#60;0.032), temporal (P&amp;#60;0.025), and inferior (P&amp;#60;0.016) parafoveal areas. RNFL showed significantly thinning at the temporal quadrant (P&amp;#60;0.041). Further analysis showed significant occurrences of parafoveal inferior thinning at 3 (P&amp;#60;0.035) and 6 (P&amp;#60;0.032) months. Correlation analysis between parafoveal thinning and the mean optic disc RNFL showed a significant result (p =0.004, r=0.55). The mean optic disc RNFL thickness significantly affected lesser (p =0.004, r =0.302) than the perifoveal area (p =0.001, r =0.784) when compared to the typical parafoveal pattern of thinning in this toxicity.There is a need for an earlier repetition of SD-OCT imaging before 5 years to detect potential toxicity. Involvement of RNFL requires further investigation and monitoring.

Visual Impact of Early Hydroxychloroquine-Related Retinal Structural Changes in Patients with Systemic Lupus Erythematosus

Purpose: The aim of the study was to assess the early retinal structural changes due to hydroxychloroquine (HCQ) use and its impact on visual acuity (VA) of patients with systemic lupus erythematosus (SLE). Patients and Methods: The study was conducted as a case-control study that included 60 eyes of 30 SLE patients treated with HCQ compared with 50 eyes of 25 healthy individuals. Patients were kept on 200 or 400 mg as daily maintenance dose. SLE patients were subgrouped into patients with normal VA and patients with decreased VA. All participants were assessed by the optical coherence tomography (OCT), and early structural abnormalities were recorded. The main outcomes and measures were best-corrected VA, drug exposure time, central macular thickness (CMT), inner segment-outer segment (IS-OS) junction disruption, ganglion cell complex † (GCC†, ganglion cell layer + inner plexiform layer), ganglion cell complex †† (GCC††, nerve fiber layer + GCC†), and peripapillary retinal nerve fiber layer. The characteristics of HCQ retinal toxicity were correlated to VA. Results: All OCT parameters were found to be significantly lower (p < 0.001) in HCQ patients with decreased VA than in controls. Patients receiving a daily dose of 400 mg had lower (p < 0.05) parameters than those receiving 200 mg. Patients with IS-OS disruption had lower CMT, GCC †, and GCC †† than those without (p < 0.05). VA was significantly correlated (p < 0.05) with CMT and drug exposure time. Conclusions: The HCQ use caused OCT changes that precede clinically visible retinopathy and might be associated with slight VA reduction. Screening with OCT of patients receiving HCQ is essential to detect early vision loss.

POS1393 QUANTITATIVE AUTOFLUORESCENCE FINDINGS IN PATIENTS UNDERGOING HYDROXYCHLOROQUINE TREATMENT

Background:Hydroxychloroquine (HCQ) is a relatively safe and effective drug widely used as primary or adjunctive treatment for several rheumatological and dermatological disorders1. HCQ modulates immune response through several mechanisms and has a tropism for pigmented ocular tissues, particularly retinal pigment epithelium (RPE)2. Its accumulation within RPE cells can lead to sight threatening retinal toxicity, with bull’s eye maculopathy (BEM) representing its advanced phenotype. 3 Quantitative Auto-Fluorescence (qAF) is an imaging modality that allows the measurement of retinal auto-fluorescence following short-wavelength light (488nm) excitation of retinal fluorophores (lipofuscin). 4 Two recent studies have focused on qAF values in patients treated with HCQ 5,6. In both cases qAF was increased in eyes with BEM. Furthermore, Reichel et al.6 were able to detect increased values of qAF in patients without BEM as early as 6 months after the start of HCQ treatment using an experimental imaging analysis procedure.Objectives:To measure quantitative autofluorescence (qAF) in patients under treatment with hydroxychloroquine (HCQ) with no apparent signs of retinal toxicity and to compare it with that of untreated subjects.Methods:Consecutive patients at risk for the development of HCQ retinal toxicity (duration of treatment &gt;5 years or daily HCQ dose &gt;5 mg/kg of actual body weight (ABW) and/or renal insufficiency)7 but no alterations on Spectral Domain - Optical Coherence Tomography, Short-Wavelength Autofluorescence and 10-2 Visual Field examination were recruited. Healthy subject matched by age and sex were also enrolled in the study. All subjects underwent qAF measurements in one eye. Images were analyzed using the conventional qAF grid by Delori calculating the qAF of 8 sectors of the intermediate ring and the mean of those values (qAF8).Results:Thirty-nine patients treated with HCQ (38 females, mean age 52,1 ± 8,6 years) and 39 untreated subjects (38 females, mean age 51,2 ± 8,6 years). In both HCQ patients and untreated subjects, qAF8 was positively correlated with age (p=0.004) (Figure 1). Although HCQ patients showed a higher mean qAF8 compared to untreated subjects (294,7 ±65,3 vs 268,9 ± 57,5), the difference was not significant (p=0.068). HCQ patients showed significantly higher mean qAF values in the inferior-temporal, inferior and inferior-nasal sectors of the intermediate ring of qAF grid compared to untreated subjects (all p&lt;0.05).Figure 1.Visual representation of a model predicting the standardized qAF values as influenced by age and HCQ daily dose/ABW, calculated for a treatment duration of 15 years.Conclusion:These results suggest a possible preclinical increase of qAF values in inferior parafoveal sectors probably induced by HCQ exposure. Further studies are required to improve our understanding of preclinical stages of HCQ retinopathy and the possible role of qAF in the HCQ toxicity screening.

Hydroxychloroquine and SARS-CoV-2 (COVID-19): An Old Problem and New Considerations in Ophthalmology

The antimalarial hydroxychloroquine (HCQ) has been suggested as a potential drug for treatment and prevention against severe acute respiratory syndrome–coronavirus 2 (SARS–CoV-2). Currently, there is insufficient scientific evidence available on HCQ retinal toxicity associated with the current treatment regimen and dosing for COVID-19 patients. In the sight of the current public health crisis, our recommendations aim to reduce the probability of unfavorable HCQ treatment outcomes and emphasize the importance of monitoring and early detection for HCQ retinopathy by simple means and the need for correlating clinical observations with multimodal imaging. We, therefore, recommend the use of Threshold Amsler grid (TAG) as a screening tool for high risk COVID-19 patients as well as treated patients with visual symptoms. Clinical decisions should be made on an individual basis, taking into consideration any pre-existing liver and kidney disease as well as macular pathology.

Longitudinal Retinal Changes Induced by Hydroxychloroquine in Eyes without Retinal Toxicity

Introduction: This study aimed to evaluate the longitudinal changes in retinal layer thickness in patients treated with hydroxychloroquine without retinal toxicity. Methods: This is a longitudinal retrospective study of patients taking hydroxychloroquine followed in a hydroxychloroquine retinal toxicity screening program of a tertiary hospital between January 2010 and April 2019. Patients who performed 2 optical coherence tomography (OCT) scans at least 1 year apart were included. All subjects with hydroxychloroquine suspected or confirmed retinal toxicity, glaucoma, retinal pathology, or poor segmented images were excluded. Spectral-domain optical coherence tomography (Spectralis HRA-OCT, Heidelberg) was used to evaluate the macular area. Automatically segmented ETDRS retinal thickness maps were compared between the first and the last OCT evaluation available. Full retina (FR), inner retina (IRL), ganglion cells (GCL), inner nuclear (INL), and outer retina (ORL) layer thicknesses were measured in the foveolar, paracentral, and peripheral area. Results: The population included 144 eyes of 144 patients. The mean interval between OCT scans was 38.1 ± 18.4 months, and the mean cumulative dose was 406.9 ± 223.9 g. Foveolar (p = 0.040, p = 0.006, and p = 0.001, respectively) and paracentral (p = 0.006, p = 0.001, and p = 0.005, respectively) FR, IRL, and GCL decreased overtime. No differences were found in INL or ORL. A very weak correlation was found between age and foveal IRL change overtime (p = 0.037; R = 0.175), as well as between the hydroxychloroquine time of use and foveal GCL variation (p = 0.032; R = 0.179). Conclusion: Hydroxychloroquine was found to cause progressive thinning of the inner retinal layers, specifically in the GCL of the foveolar and paracentral areas, but no changes were observed in the outer retina.

LC-MS based metabolomics reveals metabolic pathway disturbance in retinal pigment epithelial cells exposed to hydroxychloroquine

Hydroxychloroquine (HCQ) is frequently used medications for many auto-immunity diseases. However, HCQ induced retinal toxicity, which might result in irreversible retinopathy, is one of the most important complications of HCQ. However, the molecular mechanism underlying the HCQ retinal toxicity is still not well known. Retinal pigment epithelium, in which HCQ is highly enriched due to the tissue-specific affinity of HCQ, is considered to play important role in HCQ retinopathy. Herein, we used a metabolomics approach based on liquid chromatography-mass spectrometry to investigate the metabolic changes in retinal pigment epithelial cells (ARPE-19) with HCQ exposure at 6 h and 24 h. ARPE-19 cells were treated with HCQ at sub-lethal concentration 20 (IC 20), which was determined with MTT assay. Untargeted metabolic profiling revealed 9 and 15 metabolites that were significantly different between control group and HCQ exposure group at 6 h and 24 h, respectively. Enrichment and pathway analysis highlighted ascorbate and aldarate metabolism, d-Glutamine and d-glutamate metabolism and C5-Branched dibasic acid metabolism were disturbed after HCQ exposure. These findings increased our knowledge about the metabolic perturbation induced by HCQ exposure and indicated that metabolic profiling in the ARPE-19 cells might be helpful in understanding the mechanism of HCQ retinal toxicity and exploring potential biomarker.

Screening for Hydroxychloroquine Retinal Toxicity in Indian Patients.

Several studies have reported hydroxychloroquine (HCQ) retinal toxicity in East Asian patients. However, at present, there are limited data from Indian patients. The aim of this study was to investigate the prevalence and pattern of HCQ retinal toxicity in Indian population and to see if screening protocol for retinal toxicity in Indian patients should be any different to others. This was a cross-sectional study involving adult patients with autoimmune rheumatic diseases who had received HCQ for at least 5 years or a cumulative dose of at least 500 g. Retinal toxicity was evaluated using fundus examination, visual fields 10-2 and 30-2 protocol, and spectral domain optical coherence tomography. Of 110 patients screened, retinal toxicity was found in 7 patients (6.36%). A parafoveal pattern was found in 4 patients, whereas a mixed parafoveal and perifoveal pattern was found in 3 patients. None of the patients had isolated perifoveal pattern. Except for the one patient, all the patients with retinal toxicity had more than 10 years (mean, 13 ± 4.89 years; range, 5-20 years) of HCQ usage with a mean cumulative dose of 1573.7 ± 771.5 g. The mean daily dose was 5 ± 1.6 mg/kg per day. Hydroxychloroquine retinal toxicity is more common than previously recognized in patients who have used the drug for more than 5 years. The toxicity manifests as a parafoveal or a mixed parafoveal and perifoveal pattern in Indian patients.

Outer Nuclear Layer Damage for Detection of Early Retinal Toxicity of Hydroxychloroquine.

In hydroxychloroquine (HCQ) retinopathy, early detection of asymptomatic retinal changes and the interruption of the drug are essential to prevent permanent vision loss. Our purpose was to investigate the roles of ganglion cell layer (GCL) and outer nuclear layer (ONL) thicknesses measured by optical coherence tomography (OCT) in the early diagnosis of retinopathy. One hundred and fourteen eyes of 76 individuals with HCQ treatment were enrolled in the study (42 eyes with impaired visual field (VF) and 72 eyes with nondamaged VF). We found that ONL was significantly decreased in the HCQ retinopathy group compared with the control group in the nasal macula (p = 0.032) as well as in four sectors (p < 0.044), whereas no significant differences were found comparing GCL in both groups. If VF were altered superiorly or temporarily, ONL was significantly thinned inferiorly (p = 0.029) and nasally (p = 0.008), respectively. Duration of HCQ treatment was significantly related with ONL in seven sectors of ONL (p < 0.047). We suggest that ONL measured with OCT might be used to assess early HCQ retinal toxicity.