Objective:

To identify robust molecular subtypes in systemic lupus erythematosus (SLE) and assess their reproducibility across different cohorts and platforms.

Approach:

• Cohort Utilization: Leveraged three large SLE cohorts: ILLUMINATE, LOTUS, and Genuity Science to define and validate molecular subtypes.
• Data Analysis: Used whole-blood transcriptomic module scores and serum proteomics to characterize each subtype and evaluate clinical features.
• Clustering Methodology: Employed consensus clustering on transcriptomic cellular module scores to identify patient clusters.

Key Findings:

• Identified six distinct molecular subtypes in SLE that correlate with specific disease activity measures and serological profiles.
• Subtypes demonstrated reproducibility across the ILLUMINATE, LOTUS, and Genuity Science cohorts.
• Evaluated longitudinal stability and domain-specific clinical improvement in the LOTUS cohort.

Interpretation:

The study links specific immune programs to clinical manifestations and disease activity in SLE.

Limitations:

• Cohort sizes may limit the generalizability of findings across diverse populations.
• The heterogeneous manifestations of SLE complicate the definitions and identification of molecular subtypes.

Conclusion:

The identification of consistent molecular subtypes in SLE enhances understanding of disease mechanisms.