Defining Optimally Safe and Effective Blood Levels of Hydroxychloroquine in Lupus: An Important Step toward Precision Drug Monitoring

Background Using hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. Methods This observational study included patients (n=2010) across the Systemic Lupus International Collaborating Clinics (SLICC), Wisconsin, International, and French studies, who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross‐sectional data, we first identified a HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for SLE Disease Activity Index 2000 (SLEDAI‐2K ≥6). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. Results Among 1842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ related toxicity. Odds of toxicity were 2.1‐fold higher with blood levels ≥1150 ng/mL, and 1.7‐fold higher with cumulative HCQ dose per 1000g increase. Blood levels ≥1150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3‐fold higher odds of having supratherapeutic levels (≥1150 ng/mL). Conclusion The therapeutic reference range for HCQ blood level monitoring is 750‐<1150 ng/ml. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing. image