Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients

Highlights

• Clinical and transcriptional profiling of 158 lupus patients up to a period of 4 years

• Neutrophil-related signatures associate with progression to active nephritis

• Molecular correlates of disease activity stratify patients into seven major groups

• Molecular stratification may improve the outcome of clinical trials in SLE

Summary

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.

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