Hydroxychloroquine (HCQ) is extensively prescribed for autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus[1,13]. Although safer than chloroquine, HCQ retinopathy remains a signi cant cause of preventable vision loss[1,3]. The prevalence of toxicity has been reported to increase with cumulative exposure, reaching nearly 20% after 20 years of therapy[2].

HCQ accumulates in melanin-rich retinal pigment epithelium, leading to lysosomal dysfunction, impaired autophagy, and progressive photoreceptor degeneration[4,15]. Early structural damage occurs in the parafoveal region, preceding functional visual eld defects[9]. The 2016 AAO recommendations shifted emphasis toward weight-based dosing (≤5 mg/kg real body weight) and objective multimodal screening including SD-OCT[1].

Spectral-domain OCT allows precise visualization of outer retinal layers, particularly the outer nuclear layer and ellipsoid zone[7,10]. The classical ying saucer sign re ects parafoveal photoreceptor collapse with relative central foveal sparing[7]. This study analyzes structural biomarkers and dosage correlations in patients with subclinical HCQ toxicity.

This retrospective case series included four consecutive patients on long-term HCQ therapy referred for screening. Inclusion criteria included con rmed rheumatoid arthritis and minimum therapy duration of ve years. Exclusion criteria included macular disease, high myopia (> -6D), or prior retinal surgery, retinal dystrophies, an outer retinal layer damage attributable to causes other than HCQ toxicity. Patients underwent comprehensive eye exams, including visual acuity, slit-lamp biomicroscopy, and IOP measurement, to assess eye health thoroughly. A dilated fundus examination was performed using indirect ophthalmoscopy and +90D lens, focusing on the foveal re ex and parafoveal region. The core of the methodology relied on Spectral Domain Optical Coherence Tomography (SD-OCT)[7,10]. Scanning parameters included 5-line horizontal raster scan, fundus photography, and red- free imaging. SD-OCT biomarkers assessed included outer nuclear layer thinning, ellipsoid zone attenuation, and interdigitation zone loss. Severity grading was performed qualitatively based on structural disruption. Descriptive statistics including mean, standard deviation, and range were calculated for age, duration of therapy, and dosage. Daily dose per kilogram was derived using documented body weight according to AAO guidelines[1]. For further management, HCQ was discontinued and alternative DMARD recommended. Patients were instructed to undergo 10-2 perimetry regularly[12]. Three-month follow-ups were advised to monitor for "wash-out" progression[5].

The study revealed a 100% prevalence of hydroxychloroquine (HCQ) toxicity among the four patients with rheumatoid arthritis (RA), despite normal fundus ndings.

Mean patient age was 61.0 ± 4.7 years (range: 56–67 years). Mean duration of HCQ therapy was 11.5 ± 2.6 years. All patients maintained BCVA between 6/6 and 6/9.

Parafoveal outer nuclear layer thinning was observed in all cases (100%). Ellipsoid zone disruption was present in three patients (75%). The classical ying saucer sign was documented in three cases[7]. The patients had been receiving HCQ at varying doses, with a mean daily dose of 450 mg (SD ± 100) and a mean cumulative dose of approximately 1863 g (range: 1314-2628 g). Speci cally, one patient received 200 mg BD, two patients received 400 mg OD, and one patient received 600 mg OD. No patient exhibited bull's-eye maculopathy on fundus examination, underscoring the subclinical nature of early toxicity.

Table 1: Clinical characteristics and OCT ndings of four patients with HCQ toxicity

Imaging Findings

Five-line horizontal raster scan showed ellipsoid zone disruption in both eyes with preservation of central foveal region while showing thinning of the outer retinal layer in the parafoveal area, creating an ovoid appearance – the "UFO sign"[7].

Although we only included four patients in this analysis, our ndings are concerning, with 100% of patients exhibiting signs of toxicity on OCT, despite normal fundus ndings. This is particularly noteworthy given that these patients were part of a larger cohort attending our OPD, where HCQ is commonly prescribed for RA management.

Our ndings support accumulating evidence that SD-OCT detects structural toxicity prior to visible fundoscopic or functional changes[7,9,10]. The prevalence of ellipsoid zone disruption in 75% of cases despite preserved acuity highlights the importance of imaging- based screening[1,11].

Excess daily dosing remains a major modi able risk factor[1,2]. In this series, the only patient exceeding 5 mg/kg/day demonstrated the most advanced OCT changes. This aligns with prior epidemiological data demonstrating dose-dependent risk escalation[2,6].

Limitations include small sample size and absence of quantitative segmentation analysis. However, consistent structural biomarkers across cases reinforce the indispensability of SD-OCT in routine screening protocols[1,10,11].

Previous research has suggested that the risk of retinal toxicity increases with an increase in the daily and cumulative HCQ doses and the duration of treatment[2,8,16], but other research has indicated con icting results regarding the association between daily HCQ dose and retinal toxicity[13,14,16]. Our study indicated that there was association with daily HCQ dose, though this may be due to the small sample size used.

The pericentral pattern observed in some of our cases is consistent with ndings in Asian populations[14]. The characteristic ying saucer sign observed represents early structural damage to photoreceptors and has been well-documented in the literature as a key OCT biomarker[7,10].

Hydroxychloroquine retinopathy is an insidious yet preventable cause of vision loss[3,4]. This study highlights the critical role of optical coherence tomography (OCT) in the early detection of hydroxychloroquine (HCQ) toxicity, even in patients with normal fundus ndings[7,9,10]. Descriptive statistical correlation in this series demonstrates association between dosage excess and structural severity[2,6]. Routine SD-OCT screening, adherence to AAO dosing recommendations, and interdisciplinary coordination are essential to prevent irreversible vision loss[1,11,12].

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