Scoping Review of Human Longitudinal Studies of Biomarkers Associated with Risk of Developing Systemic Lupus Erythematosus (SLE) to Inform the Development of a Novel SLE Risk Stratification Index

OBJECTIVE: SLE is often preceded by a preclinical phase in which autoantibodies and other biomarkers are detectable, offering an opportunity to identify at-risk individuals for early monitoring and testing interventions to halt progression. To inform an effort to develop SLE risk-stratification criteria, we conducted a scoping review of longitudinal human studies of biomarkers measured before SLE onset. METHODS: Following PRISMA-ScR, we searched three databases and used a Population, Exposure, Comparator, Outcome framework to select longitudinal studies in which biomarkers were measured before an incident diagnosis or classification of SLE. Study characteristics, biomarkers, and outcomes were extracted from included studies. RESULTS: We included 59 original studies and two meta-analyses including heterogeneous at-risk populations, in which the proportion progressing to SLE varied widely. Most evidence concerned conventional serological markers, whereas interferon and cytokine signatures, proteomic panels, and genetic risk scores were examined in fewer, recent cohorts. Few biomarkers were studied across multiple populations or with comparable follow-up, outcome definitions, and analytic methods, and most associations came from single studies without external validation. Longitudinal biomarker trajectories before onset were rarely characterized, and non-European populations were under-represented. CONCLUSION: his review maps the breadth of candidate biomarkers associated with the risk of developing SLE and the heterogeneity of the evidence supporting them. Building a clinically useful SLE risk-stratification index will need a shared definition of the at-risk state, and prospective studies that follow biomarkers over time, in populations from broader geographical regions.