Validation of a High-Throughput Target Trial Emulation Platform for Drug Repurposing in Systemic Lupus

High-throughput target trial emulation (HT-TTE) using real-world data has been proposed as a scalable approach for drug repurposing, yet its operating characteristics remain insufficiently evaluated. Using systemic lupus erythematosus (SLE) as an application, this study assesses the sensitivity and specificity of an HT-TTE platform to identify repurposing candidates using the French nationwide healthcare database. The platform simultaneously evaluated hydroxychloroquine, the standard-of-care therapy for SLE, alongside 52 eligible topical or locally applied drugs (negative control drugs). Among more than 44,000 patients with mild-to-moderate SLE, HT-TTE blindly identified hydroxychloroquine as being associated with a reduced risk of lupus exacerbations with organ involvement, without prior specification of its expected effect. False-positive rates were quantified using negative control drugs, yielding high to very high specificity (88-98%), depending on comparator strategy. These findings provide empirical evidence that HT-TTE can support scalable screening for drug repurposing in large healthcare databases and underscore the importance of comparator choice.