Childhood-Onset Systemic Lupus Erythematosus: Genetic Mechanisms and Therapeutic Strategies

Objective Childhood-onset systemic lupus erythematosus (cSLE) is more aggressive than adult SLE, with higher rates of lupus nephritis, organ damage, and early mortality. This review synthesizes recent advances in cSLE genetics and targeted therapies.Methods We conducted a comprehensive literature search in PubMed and Web of Science using keywords including “childhood-onset SLE,” “monogenic lupus,” “type I interferon,” “targeted therapy,” “JAK inhibitors,” and “CAR-NK.” We prioritized high-quality original research, systematic reviews, randomized controlled trials, and landmark case reports.Results High-throughput sequencing has identified monogenic variants in 3.5–15% of cSLE patients, predominantly in complement, type I interferon, and immune tolerance genes. Single-cell and spatial transcriptomics have established type I interferon overactivation as a central driver, revealed age-specific B-cell defects, and uncovered early molecular alterations in the kidney microenvironment. Therapeutically, belimumab, telitacicept, anifrolumab, JAK inhibitors, rituximab and emerging CAR-NK therapy are shifting treatment toward precision targeting, with genotype-guided therapy showing notable success in monogenic lupus.Conclusion Major challenges persist, including scarce pediatric-specific trials, delayed translation of genetic findings, heterogeneous treatment responses, and unknown long-term safety. Addressing these gaps through multicenter cohorts, pediatric-specific randomized controlled trials, and biomarker-driven algorithms will transform cSLE management from adult-data extrapolation to molecular subtyping and tailored therapy.