Thrasher Research Fund - Medical research grants to improve the lives of children

Project Details

Early Career

Status: Funded - Open

Optimizing Hydroxychloroquine to Reduce Disease Activity in Pediatric Lupus

Rachel Randell, MD


BACKGROUND: Systemic lupus erythematosus (lupus) is a chronic autoimmune disease that causes inflammation, organ damage, and early death. Up to 20% of cases are diagnosed during childhood, and younger patients suffer more severe disease and worse outcomes. GAP: Hydroxychloroquine (HCQ) decreases inflammation and improves outcomes in adults with lupus. Despite its widespread use in children with lupus, no pediatric- specific dosing guidelines exist, putting children at risk of routine under-dosing, therapeutic failure, uncontrolled inflammation, and poor outcomes. HYPOTHESIS: Optimal HCQ dosing will result in simulated HCQ concentrations ≥500 ng/mL in 90% of children, resulting in suppression of inflammatory biomarkers and clinical disease activity. METHODS: This is an observational, pharmacokinetic/pharmacodynamic study nested within an existing pediatric lupus clinical trial (iPERSONAL NCT04358302). RESULTS: Between October 23, 2020 and June 16, 2021, we enrolled 26 children from across the country, exceeding our original goal of 20 patients. The majority (85%) were female, ages ranged 9 to 17 years, and 35% were White, 12% Black, 12% Asian, and 42% other. Clinical disease activity (Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]) scores at baseline ranged from 0-22, with a median of 3. A total of 88 blood samples underwent analysis for inflammatory biomarkers including cytokines and gene expression, plus HCQ and metabolite levels. We found a strong association between SLEDAI scores and several cytokines, most notably interferon gamma (IFNg). IFNg also showed an exposure-response relationship, with higher HCQ concentrations associated with reductions in IFNg. Initial gene expression findings did not show relationships with SLEDAI scores or HCQ concentrations, but additional analysis is underway. IMPACT: The results of this study will support development of the first pediatric-specific dosing guidelines for HCQ in lupus, which can be immediately applied in clinical practice to optimize treatment, decrease inflammation, and improve outcomes.

Supervising Institution:
Duke University

Stephen Balevic

Project Location:
North Carolina

Award Amount: