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To evaluate the progression rate and identify potential genetic risk factors for poor visual outcome in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy.
Methods
Ocular variables, including best-corrected visual acuity (BCVA), hypoautofluorescent area in fundus autofluorescence (FAF) and others were analyzed in patients with a diagnosis of CQ/HCQ retinopathy based on comprehensive ocular and demographic examinations. Whole exome sequencing (WES) was used to investigate the candidate genes associated with inherited retinal diseases. Multivariate analysis was used to analyze the correlation between pathogenic genetic mutation and visual outcome, with poor vision defined as BCVA < 6/12.
Results
Forty-one patients with an average age of 61.1 ± 13.6 years, daily dose of 8.2 ± 3.6 mg/kg, and treatment period of 12.4 ± 5.6 years were recruited with a mean follow-up of 3.3 ± 2.8 years. Longitudinal observation revealed that eyes continued to have visual acuity decline with a mean progression rate of 0.065 ± 0.164 (ΔLogMAR/year) and structural change with a mean progression rate of 2.16 ± 4.32 (Δhypoautofluorescent area-to-disc-area ratio per year) despite drug cessation. Pathogenic genetic mutations were found in nine of 29 patients (31%) and were associated with poor visual acuity (odds ratio, OR = 17.402, p = 0.024). Elevated HCQ dose and renal disease were related to increased hypoautofluorescent area in FAF (OR = 17.659, p < 0.001, and OR = 7.285, p = 0.007, respectively).
Conclusions
The study highlights the importance of identifying genetic mutations and monitoring hypoautofluorescent areas in FAF for predicting and managing visual outcomes in patients with CQ/HCQ retinopathy.
Prior presentation: e-poster at AAO (American Academy of Ophthalmology) in San Francisco (November 3–November 6, 2023).
Key Summary Points
Why carry out this study?
Chloroquine or hydroxychloroquine (CQ/HCQ) is used to manage several rheumatic diseases. Although effective, CQ/HCQ can cause irreversible retinal toxicity, leading to a significant socioeconomic burden. However, the potential role of genetic susceptibility in HCQ retinopathy remains unclear and represents an unmet need for risk prevention.
We propose that genetic risk factors may exist for HCQ retinopathy susceptibility or even its visual outcome, and this study aimed to evaluate the progression rate of HCQ retinopathy after drug cessation and investigate the genetic susceptibility and its association with poor visual outcome.
What was learned from this study?
In this study, pathogenic genetic mutations, including SEMA4A: c.232G > A, ABCA4: c.1531C > T, ABCA4: c.2123T > A, PDE6B: c.694G > A, RP1: c.377C > T, RP1: c.884C > G, RP1: c.3841C > T, RDH12: c.505C > G, and BEST1: c.1677dup, were found in 9 of 29 patients (31%), and were associated with poor visual acuity (odds ratio, OR = 17.402, p = 0.024). Elevated HCQ dose and renal disease were related to increased hypoautofluorescent area (OR = 17.659, p < 0.001, and OR = 7.285, p = 0.007, respectively).
This study provided quantitative progression rates of visual acuity decline and fundus autofluorescent change in HCQ retinopathy after drug cessation, and uncovered pathogenic mutations in SEMA4A, ABCA4, PDE6B, RP1, RDH12, and BEST1 genes associated with poor visual outcome. These findings could help to identify high-risk individuals and guide personalized monitoring strategies for clinical practice in the future.
Introduction
Chloroquine or hydroxychloroquine (CQ/HCQ) are medications that have been used to treat various rheumatic diseases since the 1950s, due to their low risk of systemic side effects [1]. However, CQ/HCQ retinopathy, first described in 1959 and 1967 [2, 3], has been found to occur in 0.65% of cases within the first 5 years of use and 3.1% within the first 20 years [1, 4]. With the use of advanced imaging techniques such as spectral-domain optical coherence tomography (SD-OCT), automated visual field (VF) perimetry, fundus autofluorescence (FAF), and multifocal electroretinography (mfERG), the overall prevalence of CQ/HCQ retinopathy has been found to be 7.5% after 10 years of use, and it increases to 20% after 20 years of use [5, 6].
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Early CQ/HCQ retinopathy is often asymptomatic, but once symptoms appear, patients may experience reduced visual acuity, glare, flashes of light, and constricted visual field. Fundus examination reveals abnormalities in the retinal pigment epithelium (RPE) in the paramacular area, but the fovea is typically spared. Extended perimacular patterns of RPE abnormalities are more common among Asians [7]. SD-OCT shows the “flying saucer” sign, which is defined as paramacular/perimacular ellipsoid zone (EZ) loss with preservation of EZ in the fovea. Fundus autofluorescence reveals early RPE damage as hyper-autofluorescence, and hypo-autofluorescence in the atrophic RPE area. Automated perimetry may show a cecocentral/paracentral scotoma. Multifocal electroretinography shows depression in the paramacular/perimacular area. In more advanced toxicity, bull’s eye maculopathy with concentric parafoveal RPE loss and even RPE atrophy involving the fovea may develop. Although the ocular toxicities of CQ/HCQ are well established, the associated symptoms can be difficult to detect in the early stages.
It has been observed that CQ/HCQ retinopathy can continue to progress even after discontinuation of the medication. Michaelides et al. [8] reported progression of the disease was observed in six patients even after stopping the medication, over a 7-year follow-up using mfERG and VF. Mititelu et al. [9] demonstrated expansion of hypoautofluorescent area in FAF examination for 37 months after HCQ cessation. However, it was difficult to predict which patients will experience progression after discontinuing the medication. Using multiple imaging modalities to quantify changes may help to monitor progression, identify risk factors, and understand the underlying mechanisms of the disease progression.
The American Academy of Ophthalmology [10] recommended that the use of CQ/HCQ should be avoided or closely monitored in individuals who have a daily dose of more than 5 mg/kg of real weight, prolonged use for more than 5 years, pre-existing maculopathy, or use of tamoxifen, or concomitant renal disease. However, there have been cases of retinal toxicity in patients with minimal exposure and without the aforementioned risk factors [11]. The genetic or molecular factors that may predispose individuals to CQ/HCQ toxicity are not yet fully understood. The ABCA4 ATP-binding Cassette Transporter Retina-specific (ABCR, ABCA4) gene has been identified as a candidate gene associated with CQ/HCQ retinopathy. In a study [12], two out of eight patients with missense ABCA4 mutations, including c.3385C > T, c.6320G > A, and c.3602T- > G, had CQ/HCQ retinopathy. Additionally, one subject with triple missense mutations developed toxic retinopathy after 1.5 years of exposure to CQ at the recommended daily dose. The Kalev and Columbia University group also reported that eight patients with genetically confirmed Stargardt disease developed the SD-OCT phenotypic features of CQ/HCQ retinopathy without exposure to CQ/HCQ [13]. Our previous study [14], using whole exome sequencing (WES) and genome-wide association study (GWAS) in patients with HCQ retinopathy, demonstrated several candidate susceptibility genes, including RP1L1 (Retinitis Pigmentosa-1-Like-1), RPGR (Retinitis Pigmentosa GTPase Regulator), RPE65 (Retinoid Isomerohydrolase 65) and Coiled-Coil Domain Containing 66 gene (CCDC66). Whether CQ/HCQ exposure can predispose to retinal toxicity in pre-existing genetic susceptibility is not known. In this study, we aim to evaluate the progression rate of HCQ retinopathy after drug cessation, and investigate the genetic susceptibility and its association with poor visual outcome.
Methods
Patient Enrollment
This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board for Human Research of Taipei Veterans General Hospital (approval numbers 2020-08-006B and 2022-12-002AC). Informed consent was obtained from all patients for the genetic testing. We studied patients who had visited the ophthalmology department of Taipei Veterans General Hospital, a tertiary hospital in Taipei, Taiwan, between September 2020 and December 2021. All medical records and images were reviewed up until December 2021 or the patient’s last visit. We included patients who had been treated with chloroquine or hydroxychloroquine (CQ/HCQ) and who had a diagnosis of CQ/HCQ retinopathy based on clinical and imaging evidence, and were between the ages of 20 and 85 years old. Patients with a family history of retinitis pigmentosa (RP), other types of retinopathy (such as RP, cone-rod dystrophy, etc.), or who were younger than 20 or older than 85 years old were excluded from the study.
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Diagnosis of Patients with HCQ Retinopathy
Demographic information, including age, gender, medical comorbidities, daily and accumulated dose of CQ/HCQ, duration of medication before discontinuation of CQ/HCQ, ideal and actual body weight, renal and liver function, were collected for all patients. All patients underwent comprehensive ophthalmic examinations of both eyes, including best-corrected visual acuity (using Snellen charts), slit-lamp examination, optical coherence tomography (SD-OCT, Optovue Inc., Fremont, CA), fundus autofluorescence (FAF, excitation 486 nm; emission > 500 nm; Canon Inc.) and automated visual field testing (24–2 or 30–2, Humphrey Field Analyzer; Carl Zeiss Meditec, Dublin, CA). Clinical diagnosis was based on the patient’s exposure history to CQ/HCQ, pattern of retinal pigment epithelium (RPE) changes on autofluorescence, loss of outer retinal layers in the ellipsoid zone or external limiting membrane on SD-OCT, and visual field abnormalities such as cecocentral or central scotomas or generalized constriction. The pattern of involvement of RPE changes was defined as parafoveal (2–6° from the center of the fovea), perifoveal/pericentral (more than 6° from the center of the fovea), or mixed (parafoveal and perifoveal/pericentral involvement) [7, 15]. The clinical charts and images were carefully reviewed by two ophthalmologists, AG Wang and HI Chiu.
Longitudinal Follow-Up
We evaluated the functional outcomes (best-corrected visual acuity and visual field) and anatomical outcomes (optical coherence tomography, fundus autofluorescence) of the patients at each baseline visit (time of drug cessation) and at subsequent follow-up visits. We analyzed the change over time by calculating the difference in variables between the baseline visit and the most recent visit, divided by the length of the follow-up period in years.
Definition of Severity
We used established criteria [16] as a framework to define the severity of changes on SD-OCT as stages 1–4, ranging from subtle to severe changes. Stage 1 was defined as subtle changes but with no definite disruption of the ellipsoid zone (EZ) or external limiting membrane (ELM) in the parafoveal/perifoveal area. Stage 2 was defined as localized changes of the parafoveal/perifoveal EZ or ELM on one side of the fovea. Stage 3 was defined as extensive parafoveal/perifoveal EZ and ELM disruption but with intact EZ/ELM in the central foveal area. Stage 4 represented EZ and ELM disruption in the central 1500-μm foveal area.
Longitudinal Changes of Functional Outcome
Best-corrected visual acuity (BCVA) was measured using the Snellen chart for both eyes. The progression rate of visual acuity was calculated by taking the difference between the most recent logMAR BCVA and the initial logMAR BCVA, divided by the length of the follow-up period in years. BCVA less than 6/12 (or 20/40) was considered as poor vision based on the American Academy’s Vision Rehabilitation Committee’s guidelines [17]. Results of automated visual field testing (24-2 or 30-2) were also reviewed. Mean deviation (MD), pattern standard deviation (PSD), and visual field index (VFI) were obtained for both eyes. MD represents the average deviation across all locations from the threshold value in persons of the same age and ethnicity. PSD represents the absolute deviation between the threshold value and the average sensitivity at each point. VFI represents a percentage of visual field status adjusted for age. The progression rate of the visual field was calculated by taking the difference between the most recent MD/PSD/VFI values and the initial MD/PSD/VFI values, divided by the length of the follow-up period in years.
Longitudinal Changes of Fundus Autofluorescence (FAF)
FAF was obtained using a 30-degree field of view. The area was measured using ImageJ software version 13.0.6 (https://imagej.nih.gov/ij/download.html) by one reader (HI Chiu) in a masked fashion. Because there was no built-in scale in our fundus camera, the hypoautofluorescent area, which was associated with RPE loss in CQ/HCQ retinopathy, was measured and then divided by the disc area to obtain the FAF hypoautofluoresecent area-to-disc-area ratio (HDR) (Fig. 1A, B). The progression rate in FAF per year was calculated by subtracting the initial HDR from the recent HDR, and dividing by the length of follow-up in years.
Fig. 1
An increase of the areas of the hypoautofluorecence in the fundus autofluorescence between the initial scan (A) and the follow-up scan at 2.5 years after hydroxychloroquine cessation (B). The hypoautofluorescent area, which was associated with RPE loss in hydroxychloroquine retinopathy, was measured and then divided by the disc area to obtain the hypoautofluoresecent area-to-disc-area ratio (HDR). In this case, there was an increase in hypoautofluorescent area, from 0.69 to 2.94 HDR, and the progression rate was + 0.90 HDR/year. Length of the ellipsoid zone (EZ)/ external limiting membrane (ELM) and choroidal thickness (CT) between the initial scan (C) and the follow-up scan at 2.5 years after hydroxychloroquine cessation (D). For cases in which EZ/ELM disruptions were present on both sides of the fovea, the length of the intact central EZ/ELM was measured. Choroidal thickness was measured from the hyperreflective line to the hyporeflective line, corresponding to the retinal pigment epithelium to the scleral–choroidal interface, beneath the foveal pit region. In this case, the mean lengths of EZ/ELM/CT change were from 814.82 to 566.95 μm, 975.24 to 765.40 μm, and 103.74 to 115.40 μm, respectively. The progression rate of EZ/ELM/EZ/choroid thickness of OCT was − 99.15, − 83.94, and + 4.66 μm/year, respectively
SD-OCT images were obtained by capturing horizontal and vertical lines through the fovea. The lengths of the external limiting membrane (ELM), ellipsoid zone (EZ), and choroidal thickness were measured using methods from previous literature [16] and analyzed by one reader (HI Chiu) in a masked fashion. The built-in plotting scale was used to quantify the length of disruption using ImageJ software version 13.0.6 (https://imagej.nih.gov/ij/download.html). The average values of the horizontal and vertical measurements were taken. The SD-OCT findings of EZ, ELM, and choroidal thickness were only measured in stage 3 because ELM/EZ had no clear endpoints in stages 1 and 2 and were extensively disrupted in stage 4. Choroidal thickness was measured from the hyperreflective line to the hyporeflective line, corresponding to the retinal pigment epithelium to the scleral–choroidal interface beneath the foveal pit region. Measurements were presented in Fig. 1C and D. The progression rate of EZ/ELM/choroidal thickness per year was calculated by subtracting the initial measurement from the last measurement and divided by the length of the follow-up in years.
Genotyping and Whole Exome Sequencing (WES)
To identify the causative candidate gene associated with HCQ retinopathy, whole exome sequencing was performed according to the referenced paper as the following [18]. Genomic DNA was extracted from peripheral blood samples from participants. The samples were fragmented and captured using the SureSelect Human All Exon V6 kit and then amplified and sequenced on the Illumina NovaSeq 6000 (Illumina, Inc.). Reads were aligned to the human reference genome (hg38 assembly) and variants were detected using the Genome Analysis Toolkit 4.1 (GATK, www.broadinstitute.org/gatk). Variants were annotated using the Variant Effect Predictor (VEP) (https://www.ensembl.org/info/docs/tools/vep/index.html) and filtered against public databases such as 1000 Genomes (1000 genomes release phase 3, http://www.1000genomes.org/), dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP/snp_summary.cgi), and Genome Aggregation Database (gnomad.broadinstitute.org). A total of 917 comprehensive genes of interest from Online Mendelian Inheritance in Man® (OMIM), associated with achromatopsia, congenital stationary night blindness, Leber congenital amaurosis, retinitis pigmentosa, cone-rod dystrophy, cone dystrophy, and macular dystrophy, were included. The variants that passed the filters were validated by PCR and Sanger sequencing. Allele frequency < 0.05 was considered to be significantly different. Only variants with a CADD score > = 25 or REVEL score > = 0.7 were considered deleterious for missense variants, and they were classified as “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” based on the guidelines for the interpretation of sequence variants of the American College of Medical Genetics and Genomics (ACMG) or the Association for Molecular Pathology (AMP).
Statistical Analysis
SPSS software (version 26.0.0.0) was used to perform statistical analyses. Right and left eyes were obtained together for ocular variables. To account for the correlation between right and left eye measurements, we conducted a generalized estimating equations (GEE) model. An exchangeable correlation structure was applied to model the within-subject dependence. The progression rate per year, defined as the difference in variables between the baseline visit and the last visit, divided by the length of follow-up in years, was analyzed for functional and anatomic parameters. The progression change comparing baseline and recent follow-up was evaluated using the GEE model across time points. Stage 1 and stage 2 were combined into stage 1/2 for statistical analysis due to the small number of stage 1 cases (n = 2). In the subgroup analysis between the three severity stages, the progression rate of BCVA, visual field, and FAF ratio was evaluated for normality and analyzed using repeated measures analysis of variance (ANOVA) and post hoc analysis with Tukey’s corrections. Pathogenic genetic mutations were based on the interpretation of sequence variants in American College of Medical Genetics (ACMG) criteria. A poor functional outcome was defined as best-corrected visual acuity (BCVA) less than 6/12 in the Snellen chart. A poor anatomical outcome was defined as stage 4 or “foveal involvement” in SD-OCT, which disrupted the ellipsoid zone in the central 1500-μm foveal area. GEE multivariate logistic regression was performed, including both patient-level factors (e.g., age, HCQ dose, treatment duration, accumulated dose, renal disease) and eye-level factors (e.g., lens status), for risk factor analysis in functional outcome. Multivariate logistic regression and generalized linear regression adjusted for age, HCQ dose, treatment duration, accumulated dose, renal disease, lens status, and pathogenic mutation were used for risk factor analysis in structural outcome. We applied complete case analysis to address missing data, given the limited proportion of missing values. We have reported effect sizes alongside p values for all statistical analyses. Statistical significance was set at p value ≤ 0.05.
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Results
Demographic Factors and Medication History
Forty-one patients (40 females and one male) with HCQ retinopathy were reviewed in the present study. The average age was 61.1 ± 13.6 years (range, 30–84 years). The average daily dose of HCQ was 8.2 ± 3.6 (3.0–19.1) mg/kg/day of actual body weight (ABW), with 63% (n = 26) of patients receiving daily doses higher than 5 mg/kg/day of ABW. The mean cumulative dose per person was 1669.0 ± 721.1 (292–3504) g. None of the patients received tamoxifen or had pre-existing maculopathy. Three patients had chronic kidney disease and none had hepatic disease. The mean duration of CQ/HCQ medication before cessation was 12.4 ± 5.6 (3–25) years. The follow-up period after drug cessation was 3.3 ± 2.8 (0.06–10.21) years. Two patients who did not have CQ/HCQ cessation and five patients who had follow-ups less than 6 months were excluded from the ocular parameter analysis of longitudinal changes.
Changes in Ocular Characteristics
Significant changes were observed in BCVA, FAF, ELM length, EZ length, and severity grading compared to baseline with the latest visit. The initial and the final average logMAR BCVA were 0.32 ± 0.34 and 0.56 ± 0.69, respectively (p = 0.004). There was an increase in FAF HDR (from 12.78 ± 16.45 to 20.50 ± 20.58 disc of ratio, p = 0.003) which represented structural progression even after discontinuation of therapy. The mean length of ELM and EZ declined in stage 3 groups (from 891.34 ± 872.82 to 751.46 ± 915.27, p < 0.001, and 728.20 ± 857.30 to 638.48 ± 804.18, p = 0.004, respectively). EZ disruption in the central fovea on SD-OCT was noted in 31.7% of eyes initially and 36.6% of eyes in the latest follow-up. There was no statistical difference for changes in VFI/MD/PSD of visual field and choroidal thickness. The demographic characteristics and ocular characteristics are listed in Table 1 and Table S1.
Table 1
Clinical and ocular characteristics of patients with hydroxychloroquine retinopathy
All (n = 41, 82 eyes)
Baseline visit
Last visit
p value (odds ratio)
Age (years, mean ± SD)
61.1 ± 13.6 (30–84)
Female/male (%)
F (97.5%)
Daily HCQ dose (mg/kg of ABW)
8.2 ± 3.6 (3.0–19.1)
Drug duration (years)
12.4 ± 5.6 (3.0–25.0)
Lens status
Phakic 56
Pseudophakic 26
Phakic 54
Pseudophakic 28
0.311 (0.894)
BCVA (logMAR, mean ± SD)
0.32 ± 0.34
0.56 ± 0.69
0.002 (1.273)
Visual field
MD (dB)
− 19.54 ± 10.06
− 19.91 ± 10.42
0.502 (0.637)
VFI (%)
44 ± 31
32 ± 32
0.901 (1.022)
PSD (dB)
6.38 ± 4.60
7.06 ± 4.18
0.340 (1.731)
FAF (HDR)
12.78 ± 16.45
20.50 ± 20.58
0.004 (2593.7)
ELM length (µm)
891.34 ± 872.82
751.46 ± 915.27
< 0.001 (4.859 × 1068)
EZ length (µm)
728.20 ± 857.30
638.48 ± 804.18
0.017 (3.624 × 1032)
Choroidal thickness (µm)
192.26 ± 55.78
184.58 ± 55.59
0.877 (0.255)
Severity grade, based on SD-OCTa
Stage 1: 2
Stage 2: 16
Stage 3: 38
Stage 4: 26
Stage 1: 2
Stage 2: 15
Stage 3: 35
Stage 4: 30
0.017 (1.063)
HCQ hydroxychloroquine, ABW actual body weight, BCVA best-corrected visual acuity, SD standard deviation, MD mean deviation, VFI visual field index, PSD pattern standard deviation, FAF fundus autofluorescence, HDR hypoautofluorescent area-to-disc-area ratio, ELM external limiting membrane, EZ ellipsoid zone, SD-OCT spectral-domain optical coherence tomography
aSeverity grade: stage 1 to stage 4, from subtle to severe changes of EZ/ELM
Progression Rate
Mean progression rate for visual acuity was 0.065 ± 0.164 logMAR/year in a total of 82 eyes with an average follow-up period of 3.3 ± 2.8 years. Mean progression rate for MD/VFI/PSD of VF was − 0.27 ± 4.32 dB/year, − 1.31 ± 19.01 Δ%/year, and 1.02 ± 2.69 dB/year, respectively. Mean progression rate for hypoautofluorescent area in FAF was 2.16 ± 4.32 HDR/year. The mean progression rate of ELM/EZ/choroid thickness of OCT was − 78.32 ± 156.94 μm/year, − 19.57 ± 69.25 μm/year, and − 5.07 ± 26.78 μm/year, respectively (Table 2).
Table 2
Functional and structural progression rate by severity grade
Progression rate
All (n = 82)
Stage 1/2 (n = 17)
Stage 3 (n = 38)
Stage 4 (n = 26)
BCVA (ΔLogMAR/year)
0.065 ± 0.164
0.013 ± 0.11
0.026 ± 0.079
0.14 ± 0.23
Visual field
MD (ΔdB/year)
− 0.27 ± 4.32
− 0.61 ± 0.95
0.06 ± 4.55
− 0.27 ± 0.92
VFI (Δ%/year)
− 1.31 ± 19.01
− 6.65 ± 50.88
− 2.05 ± 14.06
− 1.47 ± 28.81
PSD (ΔdB/year)
1.02 ± 2.69
1.80 ± 1.59
− 0.57 ± 3.45
− 0.33 ± 1.27
FAF (ΔHDR/year)
2.16 ± 4.32
0.03 ± 1.23
4.08 ± 5.04
1.30 ± 3.93
ELM length (Δμm/year)
–
–
− 78.32 ± 156.94
–
EZ length (Δμm/year)
–
–
− 19.57 ± 69.25
–
choroidal thickness (Δμm/year)
–
–
− 5.07 ± 26.78
–
BCVA best-corrected visual acuity, MD mean deviation, VFI visual field index, PSD pattern standard deviation, Stage 1/2 stage 1 and stage 2, FAF fundus autofluorescence, HDR hypoautofluorescent area-to-disc-area ratio, ELM external limiting membrane, EZ ellipsoid zone
Group comparisons using ANOVA revealed no statistically significant differences; therefore, only descriptive statistics are presented
Whole Exome Sequencing (WES)
Twelve patients refused blood collection (P8, P10, P11, P13, P15, P16, P20, P21, P23, P30, P33, P40). Twenty-nine cases (28 female and one male patient) were analyzed for genetic study. There were no significant differences of age, daily dose, cumulative dose, HCQ duration, initial BCVA, and final BCVA between cases with (n = 29) and without gene analysis (n = 12) (Table S1). The 29 cases were genotyped using 1000 ng of genomic DNA. Nine patients (31%) were found to have pathogenic genetic mutations after filtering variants with a CADD (combined annotation-dependent depletion) score > = 25 or REVEL (rare exome variant ensemble learner) > = 0.7 for missense variants and fulfilling the criteria of ACMG/AMP for the interpretation of pathogenic sequence variants, which included SEMA4A: c.232G > A, ABCA4: c.1531C > T, ABCA4: c.2123T > A, PDE6B: c.694G > A, RP1: c.377C > T, RP1: c.884C > G, RP1: c.3841C > T, RDH12: c.505C > G, and BEST1: c.1677dup. Genetic characteristics of patients with HCQ retinopathy are listed in Table 3 and Table S3.
Table 3
Genetic characteristics of patients with hydroxychloroquine retinopathy with pathogenic or likely pathogenic mutation
Subject no.
Gene
Chromosome position
Exon
Transcript DNA change
Amino acid change
Zygosity
Variant type
Hereditary pattern
CADD/REVEL
Max pop Freq
Max pop
Taiwan biobank Freq
ClinVar
ACMG/AMP
dbSNP
P5
RP1
chr8:54649081
4/30
NM_001375654.1:c.884C > G
NP_001362583.1:p.Ser295Ter
het
Stop_gained
AD, AR
36/NA
0.02899
exac_nontcgaeas_af
0.007
NA
Likely pathogenic
rs192986134
P6
SEMA4A
Chr1:156156506
3/15
NM_022367.4:c.232G > A
NP_071762.2:p.Val78Met
het
Missense variant
AD, AR
27/0.808
0.0002543
exac_nontcgaeas_af
NA
NA
Uncertain significance
rs763670204
P7
RP1
Chr8:54865844
29/30
NM_001375654.1:c.3980G > A
NP_001362583.1:p.Trp1327Ter
het
Stop_gained
AD, AR
40/NA
0.0195
tw_af
0.0195
NA
Benign
rs141992026
P7
ABCA4
Chr1:94,077,713
11/50
NM_000350.3:c.1531C > T
NP_000341.2:p.Arg511Cys
het
Missense variant
AD, AR
22.6/0.699
0.002289
exac_nontcga eas_af
0.0015
Pathogenic/Likely pathogenic
Likely pathogenic
rs752786160
P18
ABCA4
Chr1:94060574
14/50
NM_000350.3:c.2123 T > A
NP_000341.2:p.Met708Lys
het
Missense variant
AD, AR
26.2/0.947
0.0001271
exac_nontcgaeas_af
NA
NA
Likely pathogenic
rs754874649
P24
PDE6B
Chr4:635952
3/22
NM_000283.3:c.694G > A
NP_000274.2:p.Glu232Lys
het
Missense variant
AD, AR
29.4/0.69
0.002
KG_eas_af
0.0005
Uncertain significance
Uncertain significance
rs201593198
P26
RP1
chr8:54621343
2/4
NM_006269.2:c.377C > T
NP_006260.1:p.Pro126Leu
het
Missense variant
AD, AR
25.2/0.503
0.0001291
exac_nontcga
eas_af
NA
NA
Uncertain significance
rs759385909
P35
RP1
Chr8:54852678
27/30
NM_001375654.1:c.3841C > T
NP_001362583.1:p.Arg1281Ter
het
Stop_gained
AD, AR
35/NA
NA
NA
NA
NA
Likely pathogenic
rs945145260
P39
RDH12
Chr14:67727037
7/9
NM_152443.3:c.505C > G
NP_689656.2:p.Arg169Gly
het
Missense variant
AD, AR
28.8/0.922
0.0002543
exac_nontcga eas_af
NA
NA
Likely pathogenic
rs761167763
P41
BEST1
Chr11:61962830
10/11
NM_004183.4:c.1677dup
NP_004174.1:p.Pro560ThrfsTer23
het
Frameshift_variant
AD, AR
NA/NA
NA
NA
NA
NA
Likely pathogenic
NA
CADD combined annotation-dependent depletion, RAVEL rare variant enrichment learning, Pop population, Freq frequency, ClinVar clinical variants database, ACMG/AMP American College of Medical Genetics and Genomics/Association for Molecular Pathology, dbSNP Single-Nucleotide Polymorphism Database, chr chromosome, NM NCBI RefSeq mRNA accession number, NP NCBI RefSeq protein accession number, Het heterozygous, AD autosomal dominant, AR autosomal recessive, exac_nontcga_eas_af Exome Aggregation Consortium, non-TCGA East Asian Allele Frequency, tw_af Taiwan Allele Frequency, KG_eas_af 1000 Genomes East Asian Allele Frequency, NA not applied, RP1 Retinitis Pigmentosa 1, SEMA4A semaphorin 4A, ABCA4 ATP-Binding Cassette Sub-Family A Member 4, PDE6B phosphodiesterase 6B, RDH12 retinol dehydrogenase 12, BEST1 bestrophin 1
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Genetic Mutation and Clinical Correlation
These 29 patients with hydroxychloroquine (HCQ) were further divided into two groups: those with genetic mutations (n = 9 patients with 18 eyes) and those without (n = 20 patients with 40 eyes). There was no significant difference in age, HCQ dose, or duration between the two groups (table S2). Multivariate analysis was used to examine the relationship between genetic mutations and poor visual and structural outcomes. Results showed that patients with genetic mutations had a higher risk of poor visual acuity (OR = 17.402, p = 0.024) after adjusting for age, HCQ dose, treatment duration, renal disease and lens status (Table 4). However, there were no risk factors significantly associated with higher progression rate in BCVA (Table 4). In addition, multivariate generalized linear regression analysis found that patients with increased daily dose of HCQ (OR = 17.659, p < 0.001) and renal disease (OR = 7.285, p = 0.007) had a higher risk of rapid progression in fundus autofluorescence (Table 5). There were no risk factors significantly associated with poor structural outcome, i.e., disruption, of the ellipsoid zone in the central 1500-μm foveal area (Table 5). No significant risk factors were found for higher progression rate in visual field, ELM length, EZ length, and choroidal thickness (data was not shown).
Table 4
Multivariate analysis of risk factors and visual outcome
Poor vision outcomea (odds ratio)
p value
BCVA progression rate (odds ratio)
p value
Age
1.021
0.723
0.997
0.044
Daily dose on ABW
1.085
0.661
1.000
0.948
Drug duration
0.961
0.684
1.002
0.682
Renal disease
–
–
0.932
0.280
Lens status
3.665
0.233
1.081
0.287
Genetic mutation
17.402
0.024
1.052
0.140
BCVA best-corrected visual acuity, ABW actual body weight
aPoor vision outcome: the cutoff value was set at BCVA less than 6/12 in Snellen chart
– Insignificance due to missing data of renal disease
All values of p < 0.05 were deemed significant
Table 5
Multivariate analysis of risk factors and structural outcome
Foveal involvementa (odds ratio)
p value
FAF progression rate (odds ratio)
p value
Age
0.978
0.431
3.318
0.069
Daily dose on ABW
1.024
0.777
17.569
< 0.001
Drug duration
0.936
0.297
1.176
0.278
Renal disease
0.640
0.709
7.285
0.007
Genetic mutation
0.781
0.736
0.755
0.385
BCVA best-corrected visual acuity, ABW actual body weight, FAF fundus autofluorescence
aFoveal involvement was defined as disruption of ellipsoid zone in the central 1500-µm foveal area
All values of p < 0.05 were deemed significant
Discussion
The exact mechanism behind CQ/HCQ-induced toxic retinopathy is not fully understood, but it is believed that CQ/HCQ affects the RPE cells and hinders the uptake of all-trans-retinol in the visual cycle [19, 20]. This disturbance in RPE metabolism leads to dysfunction in the phagocytosis of outer segments of the photoreceptors, causing degradation of the RPE and photoreceptors. The accumulation of HCQ in RPE cells can lead to progression even after discontinuation of the medication [21‐23].
However, the progression rate is still not known, and it was difficult to predict who will suffer severe progression after drug cessation. In this study, we evaluated the progression of HCQ retinopathy by using functional and structural variables. The average progression rate of visual acuity was found to be 0.065 logMAR per year, with the most severe deterioration observed in the eyes in stage 4 (0.14 ± 0.23 logMAR/year). Although we found eyes in stage 4 had a higher progression rate for vision decline, there was no significant difference of visual field progression between different severity stages (data was not shown). One plausible reason is that the field change has been subtle and may not be well represented in cases already with extensive field loss.
Our study also investigated the progression of anatomical changes, including ELM, EZ, and FAF. In SD-OCT, we found these cases had continued ELM and EZ loss after a long period of HCQ cessation, associating with pigment clumping and migration, and subsequent RPE atrophy, which is considered a poor prognostic factor in literature [8, 9]. Fundus autofluorescence (FAF) is a sensitive modality for detecting RPE changes and has been hypothesized to correspond to lipofuscin deposition, which may be a clue indicating RPE anomalous metabolism [9]. We found there was continued increase of hypoautofluorescent area in these cases despite long-term cessation of HCQ use, with an average progression rate of 2.16 HDR per year. A higher progression rate was found to be associated with presence of renal disease.
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To identify predisposing factors before exposure, our previous study demonstrated several candidate susceptibility genes, including RP1L1, RPGR, RPE65, CCDC66, were identified to be related to HCQ retinopathy [14]. In this study, pathogenic variants were identified in nine patients (31%), including six missense mutations (SEMA4A: c.232G > A, ABCA4: c.1531C > T and c.2123T > A, PDE6B: c.694G > A, RP1: c.377C > T, RDH12: c.505C > G), two stop gained mutations in RP1 (c.884C > G, c.3841C > T), and one frameshift in BEST1 (c.1677dup). Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease, revealed pathogenic mutations were significantly correlated with worse visual acuity (BCVA < 6/12 in the Snellen charts, OR = 17.402, p = 0.024). PDE6B (Phosphodiesterase 6B) is a subunit of activated cGMP phosphodiesterase, which is related to hyperpolarization of rod photoreceptors. PDE6B dysfunction may impair cGMP hydrolysis and lead to photoreceptor stress. PDE6B: c.694G > A (p.Glu232Lys), found in subject 24, has been reported in a late-onset RP case [24], but its functional impact has not been confirmed. We also identified several novel variants which have not been reported, including RP1 c.884C > G, SEMA4A c.232G > A, ABCA4 c.2123 T > A, RP1 c.377C > T, RP1 c.3841C > T, RDH12 c.505C > G and BEST1 c.1677dup. RP1 (Retinitis Pigmentosa 1) encoded proteins which bind microtubules and regulate microtubule polymerization. RP1 dysfunction may impair photoreceptor cell structure and stability. Its mutations are associated with retinitis pigmentosa 1 [25, 26]. SEMA4A (semaphorin 4A) encodes protein of soluble and transmembrane proteins. It is associated with axonal migration and SEMA4A dysfunction may lead to lipofuscin accumulation and photoreceptor damage. The mutations are related with retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10) [27]. RDH12 (Retinol Dehydrogenase 12) encodes an NADPH-dependent retinal reductase which displays high activity toward 9-cis and all-trans-retinol. RDH dysfunction may reduce the detoxification of reactive aldehydes, heightening oxidative stress induced by HCQ. Mutations in this gene lead to Leber congenital amaurosis type 13 and Retinitis Pigmentosa 53 [28, 29]. Best 1 (bestrophin 1) encodes transmembrane proteins that localized at the basolateral plasma membrane of RPE cells and regulates chloride ion transport in RPE cells. Best 1 dysfunction makes the ion imbalance and worsens intracellular waste accumulation. Mutations are responsible for bestrophinopathy, vitelliform macular dystrophy, vitreoretinochoroidopathy, as well as retinitis pigmentosa 50 [30‐32]. ABCA4 encodes proteins in the recycling of visual pigments. ABCA4 dysfunction would accumulate lipofuscin-like deposits and worsen photoreceptor stress. Mutations in SEMA4A, ABCA4, PDE6B, RP1, RDH12 and BEST1 would impair photoreceptor structure and reduce lipofuscin-like deposits clearance, which increase the retinal stress and HCQ toxicity.
ABCA4 c.1531 C > T (p. Arg511Cys), in subject 7, has been published as pathogenic variants. It has been classified as likely pathogenic for autosomal recessive ABCA4-related disease, as well as cone-rod dystrophy 3, fundus flavimaculatus, early-onset severe retinal dystrophy and retinitis pigmentosa 19 [33, 34]. Biophysical analysis confirmed that this variant disrupts ABCA4 protein function [35, 36]. Previous research using direct sequencing of the ABCA4 gene found that two out of eight patients with HCQ retinopathy had missense mutations, including c.3385C > T, c.6320G > A, and c.3602T > G [12]. One case with triple ABCA4 missense mutations developed CQ/HCQ retinopathy after 1.5 years of exposure to the drug within recommended daily doses. These findings led to the conclusion that patients with ABCA4 mutations may be at increased risk for retinal toxicity when taking CQ/HCQ. However, other studies have reported inconsistent results, with only one variant SNP related to ABCA4 being identified [37]. In addition, a limited gene panel of 40 candidate genes related to macular dystrophy, complement, and drug metabolism were surveyed in Mack HG’s study. With the advanced technology of WES and GWAS in our previous study [14], more candidate susceptibility genes were identified in patients with HCQ retinopathy, which may have been missed in previous studies with a limited gene panel.
Our study had several limitations. First, the sample size was small, but it is the largest study to date that evaluated candidate predisposing genes using whole exome sequencing. Second, this study only included inherited retinal disease-related genes for WES study and may have missed genes that contribute to HCQ metabolism, such as cytochrome P450 and Toll-like receptors [37]. Further investigation is warranted to assess potential candidate susceptibility genes related to drug metabolism. Third, functional validation experiments were not performed in this study. However, we utilized multiple in silico prediction tools (e.g., CADD and REVEL) to assess the potential impact of variants and functional studies will be pursued in future research. Fourthly, our study is limited to patients with CQ/HCQ retinopathy, and we do not have data from non-CQ/HCQ users to directly assess whether these mutations affect visual outcomes independently. Future studies involving broader cohorts should be needed to address this issue. Additionally, the gender imbalance in our study (40 females, one male) reflects the higher prevalence of autoimmune diseases, which are the primary indication for CQ/HCQ use and are more commonly diagnosed in women. This imbalance is consistent with previous studies [38, 39]. Factors including sex chromosome and hormone differences warrant further exploration. Lastly, the study has limitations inherent to a retrospective longitudinal follow-up. The utilization of varying modes (H24-2 or H30-2) in the automated perimetry might affect the precision and consistency of the results. Despite these limitations, this study quantified the progression rate and was the first study to focus on the genetic susceptibility of HCQ retinopathy via whole exome sequencing analysis.
Conclusions
Eyes with CQ/HCQ retinopathy continue to progress after drug cessation. Increased HCQ daily dose and renal disease are associated with larger area of structural damage. Patients with pathogenic genetic mutations are more vulnerable to poor visual outcomes in HCQ retinopathy.
Acknowledgements
We thank the participants of the study.
Medical Writing, Editorial and Other Assistance
We thank Dr. Shao-Min Wu (Compass bioinfo Inc.) for the assistance and consultation of the whole exome sequencing data analysis. This analysis support was provided as a paid professional service and was funded by the research grant VGH112C-185.
Declarations
Conflict of Interest
Hsun-I Chiu, An-Guor Wang, Hui-Chen Cheng Chih-Chiau Wu, Shih-Jen Chen, De-Kuang Hwang, Yi-Ming Huang, Yu-Bai Chou, Po-Kang Lin, Tai-Chi Lin, Ko-Hua Chen, Pei-Yu Lin and Yu-Fan Chang have nothing to disclose.
Ethical Approval
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Taipei Veterans General Hospital (IRB-TPEVGH No. 2020–08-006B and 2022–12-002AC) for studies involving humans. Informed consent was obtained from all subjects involved in the study for genetic testing.
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Wenn ein Speiserest die Atemwege blockiert, zählt jede Minute. Um gravierende neurologische Schäden zu vermeiden, sollten vor allem ältere Menschen in die Notaufnahme gebracht werden – selbst wenn der Übeltäter bereits entfernt wurde. Das verdeutlicht eine Studie aus Japan.
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