To systematically evaluate the association between hydroxychloroquine (HCQ) dosage and disease activity, flare risk, and safety outcomes in patients with systemic lupus erythematosus (SLE), and to explore optimal dosing strategies balancing efficacy and retinal toxicity.

A comprehensive literature search was conducted in PubMed, Embase, CENTRAL, CNKI, VIP, WanFang, and CBM databases from inception to December 2024, following PRISMA 2020 guidelines (PROSPERO CRD42024624158). Studies comparing high-dose HCQ (>5 mg/kg/day or >400 mg/day) with low-dose HCQ (≤5 mg/kg/day or ≤400 mg/day) were included. Outcomes included SLE flares, disease activity scores, and adverse events (AEs). Data were pooled using random- or fixed-effects models, and study quality was appraised using the National Heart, Lung, and Blood Institute (NHLBI) tools.

 Eleven studies involving 2,459 SLE patients were included, comprising three randomized controlled trials, five cohort studies, two case-crossover studies, and one pre–post study. Pooled analysis showed that higher HCQ doses (>5 mg/kg/day) were associated with a significantly lower risk of SLE flares (OR = 0.40; 95% CI 0.25–0.67; P = 0.0004; I² = 0%), without significant increases in overall or organ-specific adverse events. No significant difference was observed in flare risk when stratified at 400 mg/day (OR = 0.61; 95% CI 0.16–2.27; P = 0.46). Disease activity scores improved more in higher-dose groups, particularly in studies using SLEDAI-2K. Most included studies were of fair methodological quality, with limitations including incomplete blinding and unadjusted confounders.

This systematic review and meta-analysis demonstrated that HCQ doses above 5 mg/kg/day were associated with a lower risk of SLE flares and greater improvement in disease activity without a corresponding increase in adverse events. These findings suggest that the conventional 6.5 mg/kg/day or 400 mg/day regimen remains clinically reasonable for most patients, provided regular ophthalmologic surveillance is maintained. Future high-quality prospective studies are needed to establish validated therapeutic concentration ranges and confirm whether TDM-guided dosing can improve long-term outcomes.