Objective Hydroxychloroquine (HCQ) is a cornerstone therapy in systemic lupus erythematosus (SLE), but the weight‐based dosing does not account for clinical factors that can introduce individual variability in drug metabolism and clearance. We leveraged longitudinal data from a prospective SLE cohort to identify clinical factors that predict significant variations in HCQ blood levels despite weight‐based HCQ dosing, and we examined if maintaining therapeutic HCQ levels (750–1,150 ng/mL) improved SLE outcomes. Methods We analyzed 962 visits from 247 patients in a prospective SLE cohort. Generalized linear mixed models with random intercepts and slopes assessed associations among variables such as chronic kidney disease, HCQ dose, and HCQ blood levels over time. Next, within‐ and between‐subject decomposition models evaluated the impact of intra‐ and inter‐individual changes in HCQ blood levels and therapeutic HCQ blood levels on active SLE and flares over time. Results At baseline visit, the mean patient age was 47 years; 91% were female, 66% were White, 45% had subtherapeutic HCQ levels (<750 ng/mL), and 79% received an HCQ dose of ≤5 mg/kg/day. Despite receiving 5 mg/kg/day, patients with kidney function ≤75 mL/min/1.73m 2 had supratherapeutic levels over time. Next, very low (<200 ng/mL) and subtherapeutic levels (200 to <750 ng/mL) predicted 6.7‐fold and 2.6‐fold higher odds of active SLE vs therapeutic levels over time. At the individual patient level, increases of 100 ng/mL in HCQ levels at each visit predicted 33% and 22% lower odds of active SLE and flares, respectively. Conclusion HCQ blood level monitoring could improve SLE control, particularly in patients with estimated glomerular filtration rate ≤75, and enable optimal HCQ use.

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