Association between hydroxychloroquine intake and damage to the outer nuclear layer in eyes without manifest retinal toxicity

Abstract

Background: Hydroxychloroquine (HCQ) is widely used to treat various autoimmune diseases but carries a risk of retinal toxicity, particularly with prolonged use. Despite advancements, uncertainty persists regarding optimal screening methods. Recent advances in OCT have enabled early detection of retinal damage, with studies suggesting that thinning of specific retinal layers may be an early indicator of toxicity. However, there is a gap in research on outer nuclear layer (ONL) thinning in HCQ users without apparent retinal toxicity. This information is crucial for improving screening and identifying the ONL as a reliable biomarker for screening. Therefore, this study aimed to investigate the association between HCQ intake and ONL damage in eyes without manifest retinal toxicity.

Methods: A case‒control study was conducted at the ophthalmology department of Eye and Ear Hospital International from July 2022 to June 2023. The study included 20 individuals on HCQ and 20 age-matched controls. The data were obtained through chart reviews, and participants underwent comprehensive ophthalmic assessments.

Results: A total of 80 eyes were analyzed. Patients on HCQ exhibited significantly thinner perifoveal, parafoveal, and overall ONL compared to controls (P < .001, P < .012, and P < .004, respectively). Similarly, this association was found in the nasal, inferior, and temporal quadrants of both the inner (region 3: P < .01, region 4: P < .001, and region 5: P < .03) and outer zones (region 7: P < .04, region 8: P < .001, region 9: P < .02), most pronounced in the inferior regions. The cumulative dose was weakly associated with decreased ONL thickness only in the nasal quadrant of the inner zone (region 3: P < .047). Correlation analysis of the initial and most recent OCT scans in the same individuals revealed a weak association with ONL thinning in the central zone (region 1: P < .0048).

Conclusion: The thickness of the ONL can significantly decrease in patients taking HCQ, even in the absence of of manifest retinal toxicity. This study is the first to evaluate this association in eyes with negative screening and diagnostic tests for HCQ retinopathy. The findings suggest that ONL thickness could serve as an early diagnostic indicator for HCQ retinal toxicity.

Keywords: Autoimmune diseases; Early detection of retinopathy; Hydroxychloroquine; Outer nuclear layer thinning.

Fig. 1

Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay. The ETDRS grid includes concentric circles of 1, 3, and 6 mm around the fovea, illustrating the nine subfields within each of the nine ETDRS regions. This grid is used to assess and quantify retinal thickness. (a) Right eye and (b) left eye

Fig. 2

Distribution of autoimmune diseases among patients taking hydroxychloroquine. The pie chart shows that 35% of the patients were treated for systemic lupus erythematosus (SLE), 30% for Sjogren syndrome, 25% for rheumatoid arthritis (RA), and 10% for scleroderma

Fig. 3

Analysis of outer nuclear layer (ONL) thickness in patients on hydroxychloroquine (HCQ) therapy compared to healthy controls. These are ETDRS grids of the right eye: (a) illustrates a significantly thinner overall ONL region in HCQ-treated patients compared to controls (P < .004). (b) highlights the differences in ONL thickness within the perifoveal and parafoveal regions, showing marked thinning in HCQ patients (P < .001 and P < .012, respectively), with the most pronounced thinning occurring in the perifoveal region. (c) shows the regional variations within the ETDRS grid, with significant thinning observed in the nasal, inferior, and temporal quadrants of both the inner (region 3: P < .01, region 4: P < .001, and region 5: P < .03) and outer zones (region 7: P < .04, region 8: P < .001, region 9: P < .02) most pronounced in the inferior regions

Fig. 4

Correlation between HCQ intake and the thickness of the ONL in different retinal regions. This is an ETDRS grid of the right eye. The cumulative dose of HCQ shows a significant decrease in ONL thickness in the nasal quadrant of the inner zone (region 3: P < .047)

Fig. 5

Correlation between initial and most recent OCT findings among individuals who were prescribed HCQ. This is an ETDRS grid of the right eye. A significant association with ONL thinning in the foveal zone was observed (region 1: P < .048)