Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

Area of Science:

• Immunology
• Genomics
• Systems Biology

Background:

• Systemic autoimmune diseases exhibit significant clinical heterogeneity, complicating diagnosis and treatment.
• Molecular patterns offer a potential avenue for reclassifying these diseases beyond clinical presentation.

Purpose of the Study:

• To identify molecular clusters for reclassifying systemic autoimmune diseases.
• To validate these clusters using longitudinal data and assess their stability over time.

Main Methods:

• Unsupervised clustering of integrated whole blood transcriptome and methylome data from 955 patients and 267 controls.
• Prospective follow-up of an inception cohort for 6-14 months to validate cluster stability.

Main Results:

• Four distinct molecular clusters were identified and validated: three pathological (inflammatory, lymphoid, interferon) and one healthy/low activity.
• Pathological clusters were stable over time, with patients transitioning to the healthy cluster during remission.
• Each cluster was characterized by specific genetic, clinical, serologic, and cellular features.

Conclusions:

• Systemic autoimmune diseases can be stratified into three stable, molecularly defined pathological clusters.
• These molecular signatures provide insights into distinct disease mechanisms and may inform personalized treatment strategies.
• This molecular classification represents a paradigm shift for clinical trials and understanding treatment nonresponse.