Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels

Area of Science:

• Immunology
• Genomics
• Rheumatology

Background:

• Chronic primary vasculitis involves complex blood vessel inflammation.
• Current classification relies on vessel size and clinical presentation.
• Improved classification, based on underlying biology, is needed for small-to-medium sized vessel vasculitis to guide treatment.

Purpose of the Study:

• To define disease subtypes of small-to-medium sized vessel vasculitis based on underlying biology.
• To explore gene expression patterns in pediatric and adult patients.
• To identify novel classification criteria for vasculitis subtypes.

Main Methods:

• RNA sequencing (RNA-Seq) was performed on blood samples from pediatric (n=41) and adult (n=11) patients.
• Unsupervised hierarchical clustering of gene expression data was combined with clinical metadata.
• Disease subtypes (endotypes) were identified using differential gene expression analysis.

Main Results:

• Two primary endotypes were identified in both children and adults, differing in thousands of gene expressions at diagnosis.
• These endotypes were also observed during disease flares and could be distinguished by as few as 20 genes.
• Endotypes were associated with distinct immune processes: neutrophil degranulation and T cell receptor signaling.

Conclusions:

• Small-to-medium sized vessel vasculitis subtypes may be driven by different innate versus adaptive immune mechanisms.
• Gene expression analysis reveals distinct biological endotypes within phenotypically similar vasculitis.
• This mechanistic classification offers an alternative to current subtyping methods for vasculitis.