Quadrant-Specific Retinal Nerve Fiber Layer Thinning in Hydroxychloroquine Retinal Toxicity: A Controlled OCT-Based Structural and Exposure Analysis in Systemic Lupus Erythematosus

Background: Hydroxychloroquine (HCQ) is widely used in systemic lupus erythematosus (SLE), yet cumulative exposure may result in progressive retinal toxicity. Structural biomarkers capable of identifying subclinical damage remain incompletely defined. Methods: In this cross-sectional controlled study, 60 female SLE patients receiving HCQ for ≥5 years (22 with clinically detectable maculopathy and 38 without) and 30 healthy controls underwent a comprehensive ophthalmologic assessment including spectral-domain optical coherence tomography (SD-OCT). Peripapillary retinal nerve fiber layer (RNFL) and macular thickness parameters were analyzed. Logistic regression and ROC analysis evaluated exposure-related risk. Results: Patients with clinically detectable maculopathy demonstrated significant superior and temporal RNFL thinning compared with patients with clinically undetectable maculopathy and controls (p ≤ 0.021). Inferior quadrant thinning was detectable in patients without ophthalmoscopic changes, suggesting subclinical neuroaxonal involvement. Parafoveal macular thinning was observed exclusively in the clinically detectable maculopathy group (p = 0.041). Cumulative dose >1000 g independently predicted toxicity (OR 3.84; 95% CI 1.72–8.56). The combined structural–exposure model demonstrated strong discrimination (AUC 0.89). Conclusions: HCQ-related retinal structural changes may be detectable on OCT in the absence of clinically apparent retinal findings. Our results support the concept of a dose-associated structural continuum in HCQ-related retinal injury, involving both inner retinal neuroaxonal parameters and parafoveal macular alterations. However, the cross-sectional design does not allow determination of the temporal sequence of inner versus outer retinal changes. Further longitudinal studies with combined inner and outer retinal layer-specific analysis are required before these findings can inform modifications to current screening strategies.