Retinopathy affecting the macula in both eyes due to long-term administration of chloroquine (CQ) was first reported in 1959. In Japan, case reports appeared in 1962, and by 1975 many cases had become a social issue, leading to restrictions on CQ use as one of the three major drug-induced disasters.
Hydroxychloroquine (HCQ, brand name Plaquenil®) is a relatively safer alternative introduced based on those lessons. Its toxicity is considered about half that of CQ 4), and it is widely used for autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome. In Japan, after domestic clinical trials led by the rheumatology and dermatology societies, it received regulatory approval for SLE and cutaneous LE in September 2015, and the number of patients requiring this drug has been steadily increasing.
Like CQ, HCQ carries a risk of retinal toxicity with long-term use. Its mechanism of action involves accumulation in lysosomes, raising pH, and inhibiting Toll-like receptor (TLR) activation, thereby exerting immunomodulatory effects 8). It also has anti-inflammatory, immunomodulatory, and anticoagulant properties 4, 8).
With long-term use over 5 years, the incidence reaches about 0.5%. Reports indicate it rises to about 2% at 10 years and about 20% at 20 years or more 8, 12). Retinal toxicity is usually irreversible, making early detection and drug discontinuation the best management strategy.
In the early stages, it is often asymptomatic, but examination reveals decreased central visual field sensitivity. By the time symptoms appear, considerable retinal damage has often already progressed.
The main subjective symptoms are as follows:
Since early stages are often asymptomatic, it cannot be judged by subjective symptoms alone. If you notice changes in color vision (especially red), difficulty seeing in the center, trouble reading, glare, or distortion, it is important to see an ophthalmologist promptly. Regular screening tests (see Diagnosis and Examination Methods) are essential for early detection of toxicity.
Characteristic findings appear depending on the disease stage.
Early findings: Loss of foveal reflex, fine granular appearance of the macula, depigmented spots. There are almost no subjective symptoms.
Progressive findings: Bull’s eye maculopathy (annular atrophy) is a characteristic finding. It is a ring-shaped RPE atrophy centered on the fovea, named for its resemblance to a bull’s eye. With further progression, arteriolar narrowing and optic atrophy may occur.
SD-OCT findings: Thinning starting from the outer layer (ellipsoid zone) of the parafovea is detected as an early change.
Racial differences in distribution patterns: There are typical parafoveal type (common in Caucasians) and pericentral foveal type (common in Asians and Blacks). In Asians, 55%; in Blacks, 21%; and in Hispanics, 5% present with the pericentral foveal type, which is significantly different from 1.8% in Caucasians10).
Macular edema (CME) complication: Although rare, cystoid macular edema may complicate HCQ toxicity3, 10).
Skin pigmentation: In addition to ocular findings, some patients also show blue/gray skin pigmentation4).
Peng et al. (2024) reported a 65-year-old RA patient who developed bull’s eye maculopathy and skin pigmentation after long-term HCQ administration (400 mg/day for 3 years)4). Skin and eye lesions may progress in parallel.
Alex et al. (2025) reported a case series of a 68-year-old SLE patient in whom ellipsoid zone (EZ) disruption was overlooked after 7 years of HCQ administration (200 mg twice daily)6). Despite regular screening, subtle changes were missed, and careful interpretation of tests is necessary.
Multiple risk factors are involved in the development of CQ/HCQ retinal toxicity.
The following table shows the duration of administration and approximate risk8, 12).
| Duration of administration | Toxicity risk |
|---|---|
| Within 5 years | Less than 1% |
| 10 years | Approximately 2% |
| 20 years or more | Approximately 20% |
Dosage
HCQ threshold: Daily dose >5 mg/kg/day (ideal body weight) increases risk11). Previously, >6.5 mg/kg/day was considered the danger zone, but AAO 2016 tightened it to HCQ >5 mg/kg/day (ideal body weight).
CQ threshold: >3.0 mg/kg/day increases risk.
Cumulative dose: HCQ >1,000 g, CQ >460 g are indicators of high risk.
Duration of Use
Within 5 years: Risk is low, less than 1%.
20 years or more: Risk increases to approximately 20%8, 12). Long-term use over 5 years reaches about 0.5%.
Renal Impairment
eGFR<60: Reduced renal excretion increases HCQ blood concentration, raising toxicity risk8).
Patients with kidney disease require particularly careful monitoring.
Other Risk Factors
Obesity: Dosing based on ideal body weight rather than actual body weight is recommended8).
Concomitant tamoxifen use: Additive retinal toxicity risk.
Advanced age and liver dysfunction: Affect metabolism and excretion, leading to increased blood concentration.
Pre-existing retinal disease or maculopathy: Makes toxicity assessment difficult.
The risk is low (<1%) within 5 years of treatment, but increases to about 2% at 10 years and up to about 20% after 20 years8, 12). Keeping the dose at 5 mg/kg/day or less (based on ideal body weight)11), regular monitoring of kidney function, and avoiding overlap with tamoxifen are also important risk management measures.
Screening using multiple modalities is recommended for the diagnosis of CQ/HCQ retinal toxicity.
Baseline examination: Performed before starting HCQ or within one year after initiation. Establishing a baseline before treatment is essential for later evaluation.
Timing of regular screening: Annually starting 5 years after initiation. For patients with risk factors (kidney dysfunction, high dose, tamoxifen use, etc.), screening should begin earlier. If no risk factors, annual screening is sufficient; if risk factors are present, shorter intervals are desirable. Enhanced collaboration between the prescribing physician (rheumatologist, dermatologist) and ophthalmologist is important11).
SD-OCT
Ellipsoid zone (EZ) disruption: The earliest abnormal finding. Characterized by thinning starting from the outer parafoveal layer.
Flying saucer sign: A characteristic finding visible on OCT 6, 7). Confirm the entire macular cube with vertical and radial scans 10).
10-2 Visual Field
Central visual field test (Humphrey 10-2): The most important screening. Detects paracentral scotomas (2–6 degrees) 6, 10).
Caution for Asian populations: For Asians and Black individuals, who often have perifoveal type, 24-2/30-2 visual field tests are also necessary 6, 10).
FAF (Fundus Autofluorescence)
Early stage: Appears as a hyperautofluorescent area.
Progression: As RPE metabolic dysfunction progresses, it changes to hypoautofluorescence. Combined with OCT to improve diagnostic accuracy.
mfERG / FA
Multifocal electroretinogram (mfERG): Captures functional changes electrophysiologically as reduced parafoveal amplitude.
Full-field ERG: Evaluates overall rod and cone function. Expected to be combined with AI analysis 6).
Fluorescein angiography (FA): Recognized as useful in advanced cases.
Sensitivity and specificity of 10-2 visual field by target color are as follows 2).
| Parameter | Red target | White target |
|---|---|---|
| Sensitivity | 91% | 78% |
| Specificity | 57% | 84% |
Centner et al. (2024) reported cases where HCQ toxicity was detected only by visual field changes, even without obvious abnormalities on OCT or visual field testing 2). Standard white-target perimetry alone may miss findings, and combining red-target perimetry is meaningful.
Differential diagnoses are listed below. Regular ophthalmologic observation before drug administration is extremely important for differentiating from diseases that cause bilateral circular macular atrophy, and collaboration between the prescribing physician and ophthalmologist is recommended.
| Differential diagnosis | Key differentiating points |
|---|---|
| Cone dystrophy | Hereditary, slowly progressive |
| Stargardt disease (macular dystrophy) | Young onset, silent choroid |
| Atrophic age-related macular degeneration | Drusen, aging |
| Autoimmune retinopathy | Rapid progression, anti-retinal antibodies |
| Central serous chorioretinopathy | Unilateral, history of SRF |
| Crystalline retinopathy (CYP4V2 gene mutation) | Corneal limbal crystal deposits, genetic testing |
| Tamoxifen retinopathy | Tamoxifen use history, macular crystal deposits |
Ahn et al. (2025) reported a case where a history of central serous chorioretinopathy (CSCR) presented findings similar to HCQ toxicity 7). In SLE patients receiving HCQ, a history of CSCR complicates the differential diagnosis.
Pandit et al. (2022) reported a delayed detection case of predominantly pericentral HCQ toxicity in a Dominican patient 10). Standard 10-2 visual field and parafoveal OCT alone may miss pericentral toxicity, and they concluded that full vertical scans and wider field testing are necessary.
Baseline examination should be performed before starting HCQ or within one year after initiation. Thereafter, annual screening should continue from the fifth year onward 11). For patients with risk factors such as renal dysfunction, tamoxifen use, or high dose, screening should start earlier. A combination of SD-OCT and 10-2 visual field (consider 24-2/30-2 for Asian patients) is recommended.
CQ/HCQ should be discontinued as soon as the first signs of toxicity are confirmed. However, because the drugs are highly lipophilic and accumulate in tissues, elimination from the body is slow. Toxicity may progress even after discontinuation. Early detection and early discontinuation are key to preserving vision.
Hipolito-Fernandes et al. (2021) reported a 43-year-old patient with SLE who received HCQ 400 mg/day for 20 years 9). Toxicity progressed even after discontinuation, and non-central serous chorioretinopathy developed. In long-term users, careful follow-up after discontinuation is necessary.
For prevention of toxicity, planned management before starting treatment is important.
For cystoid macular edema associated with HCQ toxicity, topical steroids, NSAIDs, and carbonic anhydrase inhibitors (CAIs) have been tried. However, some cases did not respond.
Mathai et al. (2024) used dexamethasone intravitreal implant (Ozurdex®) in three cases of cystoid macular edema due to HCQ toxicity and confirmed efficacy in all cases 3). It was effective even in cases where triamcinolone or bevacizumab had failed, and it is noted as a new option.
In SLE patients receiving HCQ, AIR may develop or coexist. If AIR is suspected, sub-Tenon triamcinolone (30–40 mg) is an option 1).
Ma et al. (2023) reported that in SLE patients, HCQ causes cell death in RPE cells, leading to production of anti-retinal autoantibodies and possible addition of AIR 1). Attention is needed for the complex pathology where AIR and HCQ toxicity coexist.
Corneal deposits (vortex keratopathy) due to HCQ are completely reversible and resolve upon discontinuation.
In general, CQ/HCQ retinal toxicity is irreversible. Even after stopping the drug, damaged photoreceptors and RPE do not recover. Moreover, because elimination from the body is slow after discontinuation, toxicity may continue to progress for some time 9). Early detection and early discontinuation are the best strategies to preserve vision. Corneal deposits (vortex keratopathy) are completely reversible and resolve after discontinuation.
The detailed mechanisms of pathogenesis remain unclear, but the following pathways are hypothesized. The drug binds to melanin and is taken up by melanin-containing cells (melanocytes) in the RPE (retinal pigment epithelium) and choroid, leading to lysosomal disruption and impairment of enzymatic and metabolic functions. This results in secondary damage to photoreceptors (mainly cone cells).
The process of accumulation and toxicity is as follows:
Pharmacokinetics8):
The above pharmacokinetics explain why toxicity can progress even after discontinuation (slow release from tissues).
Mechanism of cardiotoxicity: Alkalinization of lysosomes in cardiomyocytes causes lysosomal dysfunction, which can lead to structural heart disease (cardiomyopathy, conduction disorders)8). HCQ is structurally similar to class Ia antiarrhythmic drugs and also carries a risk of QT prolongation.
Measurement of HCQ blood concentration has been shown to be useful for individual dose optimization and toxicity prevention. The therapeutic range is considered to be 750–1,200 ng/mL, and levels above 1,200 ng/mL are considered supratherapeutic, increasing the risk of toxicity 8). In patients with reduced renal function, blood concentrations tend to be higher even with the same oral dose, and the introduction of blood concentration monitoring may lead to future standardization.
Alex et al. (2025) reported that advanced modalities such as OCTA (optical coherence tomography angiography), adaptive optics (AO), and hyperspectral imaging may be useful for detecting early changes that are difficult to detect with conventional OCT and visual field testing 6). mfERG waveform analysis combined with AI (artificial intelligence) is also expected to improve the accuracy of early detection.
It has been suggested that genetic factors may be involved in susceptibility to HCQ toxicity. Genetic polymorphisms in RP1L1, RPGR, RPE65, CCDC66, and other genes may influence susceptibility 6). In the future, personalized medicine based on genetic profiles may become a reality.
Meredith et al. (2024) reported that a systematic HCQ retinopathy monitoring program detected 16 confirmed toxicities over two years (prevalence 1.06%), and that the cost of implementing the program was outweighed by the cost savings from early detection 5). Systematic monitoring is beneficial both for improving patient outcomes and for healthcare economics.
Establishing a screening system for cardiotoxicity (cardiomyopathy, conduction disorders) in patients on long-term CQ/HCQ therapy is a challenge 8). Developing a system for cardiac evaluation in parallel with ophthalmologic monitoring is a future task.
A system in which the prescribing physician (rheumatologist, dermatologist, internist, etc.) and ophthalmologist share examination findings and jointly decide on dose adjustment or discontinuation is important for improving prognosis. In high-risk patients, comprehensive management including renal function and concomitant medications is necessary8, 11).
