Risk of Retinopathy Associated with Long-Term Use of Hydroxychloroquine in Patients with Rheumatic Diseases: A Systematic Review and Meta-Analysis

Objectives To determine risk (prevalence and cumulative incidence) and risk factors of Hydroxychloroquine-related Retinopathy (HCQ-R) among long-term HCQ users with rheumatic diseases screened using Spectral-Domain Optical Coherence Tomography (SD-OCT) through a systematic review and meta-analysis of observational studies. Methods A systematic search of PubMed, Scopus, Ovid, Embase, and WHO databases (inception-December 31, 2024) identified observational studies meeting: (1) adults with rheumatic diseases on HCQ ≥1 year; (2) SD-OCT for HCQ-R screening; (3) reported or data to calculate HCQ-R prevalence or cumulative incidence; (4) risk factors reported as hazard ratios (HRs) or odds ratios (ORs) with 95% CIs or calculable data; and (5) English full-text. Study quality was assessed using Newcastle-Ottawa Scale. Random-effects meta-analysis estimated pooled prevalence, cumulative incidence, and risk-factor associations. We assessed heterogeneity with the Q-test and I 2 , then explored sources of variability via subgroup analyses across cohort type, study quality, publication year, and follow-up length. To address confounding effects, we fit multivariate meta-regression on logit-transformed prevalence/cumulative-incidence to quantify each factor’s independent contribution to between-study heterogeneity. Publication bias was assessed with funnel plots and Egger’s test. Results We screened 775 records; 19 met inclusion criteria (18 cohort, 1 case-control). Pooled HCQ-R prevalence (2008-2023) was 5.1% (95% CI: 3.9-6.5) (Figure 1). Pooled HCQ-R cumulative incidence was 0.1% (0.0-0.5) at 5 years, 2.6% (1.6-4.1) at 10 years, and 5.6% (3.2-9.6) at 15 years. Risk factors (HR, 95% CI) were daily dose >5 mg/kg of actual body weight (4.32, 2.80-6.65); chronic kidney disease (CKD) (1.94,1.27-2.96); female sex (3.78, 1.90-7.48) and Asian vs White ethnicity (1.67, 1.07-2.62). There was substantial heterogeneity between studies that reported period prevalence (Q=197.44, p<0.0001; I 2 =94.4%). Subgroup analysis revealed cohort type (retrospective vs prospective) as the only variable which explained part of heterogeneity (p<0.001) (Figure 1). In multivariable meta-regression, retrospective cohorts still showed higher prevalence after adjustment for follow-up length (β=1.72, 95% CI 1.04-2.40; p<0.001) or publication year (β=1.69, 95% CI 0.52-2.85; p<0.01). Heterogeneity among cumulative incidence studies was non-significant (≤5 years (Q=6.47), 5-10 years (Q=6.85), and 10-15 years (Q=3.94); p>0.05). Prevalence studies showed mild small-study funnel asymmetry, but Egger’s test was non-significant (p>0.05). Cumulative-incidence studies showed a symmetric funnel with non-significant Egger’s test. Conclusion Pooled prevalence of 5.1% reflects the overall burden of HCQ-R from 2008 to 2023. HCQ-R risk increases with duration of HCQ use and is dose-dependent, reaching 5.5% by 15 years. Findings support dose optimization with intensified screening for higher-risk patients including CKD, female and Asian patients.