Project Details

Optimizing Hydroxychloroquine to Reduce Disease Activity in Pediatric Lupus

Rachel Randell, MD

Summary

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 widespread use in children with lupus, optimal dosing and target concentrations for HCQ in children with lupus remain unknown. HYPOTHESIS: An inflammatory biomarker (interferon gene expression) will relate to disease activity and response to treatment with HCQ in children with lupus, and simulations will identify optimal HCQ dosing to reduce interferon gene expression and disease activity in children with lupus. METHODS: This observational, pharmacokinetic/pharmacodynamic (PK/PD) study was nested within a pediatric lupus clinical trial (iPERSONAL NCT04358302). Lupus disease activity was measured using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Systemic Lupus Activity Questionnaire (SLAQ). Inflammatory biomarkers included traditional lupus biomarkers (DNA antibody, C3, C4), serum inflammatory cytokines, and interferon gene expression (two methods including quantitative real-time polymerase chain reaction of 10 interferon-inducible genes downstream of HCQ’s target, and a commercial interferon test for lupus). Descriptive and inferential statistics, graphical analysis, and PK/PD modeling methods were used to relate HCQ concentrations, inflammatory biomarkers, and clinical disease activity measures. RESULTS: Between October 23, 2020 and June 16, 2021, the iPERSONAL trial enrolled 26 children from across the country, completed 97 in-home visits, and collected a total of 88 blood samples over six months. SLEDAI scores at baseline ranged from 0-22, with a median of 3. Linear regression showed relationships between SLEDAI scores and traditional lupus biomarkers (DNA antibody 0.497, p<0.01; C3 0.293, p=0.01; C4 0.248, p=0.02) and cytokines (interferon alpha [IFNa] 0.763, p<0.01; interferon gamma [IFNg] 0.433, p<0.01; tumor necrosis factor alpha [TNFa] 0.770, p<0.01) but not interferon gene expression using either method. SLAQ scores did not relate to any biomarker. Among all biomarkers, only IFNg and to a lesser extent IFNa appeared to relate to HCQ concentrations. However, the magnitude of these relationships was small and appeared to be influenced by a few data points, which were insufficient to complete PK/PD modeling using either simultaneous or sequential modeling approaches. Negative findings are likely explained by small sample size, generally low and stable levels of disease activity among trial participants, and narrow range of HCQ concentrations, as all participants were taking HCQ at time of enrollment and continued therapy with generally high adherence throughout the duration of the trial. IMPACT: Serum cytokines (especially IFNg) emerged as potential biomarkers of treatment-response in pediatric lupus. Future studies should evaluate cytokines among other inflammatory biomarkers of disease activity and treatment response, enroll participants with a wider range of disease activity and severity, and obtain pretreatment samples before starting HCQ. Interferon gene expression did not relate to disease activity in this study, and requires additional, pediatric-specific investigation prior to widespread use in clinical care for children with lupus.