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

Erin E Gill,Jinko Graham,Kelly L Brown,David A Cabral,Robert E W Hancock,Kimberly A Morishita,Dirk Foell,Amy H Y Lee,Kristen M Gibson,Raashid A Luqmani,Reza Falsafi,Colin J Ross,Susanne M Benseler,Maren L Smith

doi:10.3389/fimmu.2021.638571

Abstract

Objectives: Chronic primary vasculitis describes a group of complex and rare diseases that are characterized by blood vessel inflammation. Classification of vasculitis subtypes is based predominantly on the size of the involved vessels and clinical phenotype. There is a recognized need to improve classification, especially for small-to-medium sized vessel vasculitides, that, ideally, is based on the underlying biology with a view to informing treatment.Methods: We performed RNA-Seq on blood samples from children (n = 41) and from adults (n = 11) with small-to-medium sized vessel vasculitis, and used unsupervised hierarchical clustering of gene expression patterns in combination with clinical metadata to define disease subtypes.Results: Differential gene expression at the time of diagnosis separated patients into two primary endotypes that differed in the expression of ~3,800 genes in children, and ~1,600 genes in adults. These endotypes were also present during disease flares, and both adult and pediatric endotypes could be discriminated based on the expression of just 20 differentially expressed genes. Endotypes were associated with distinct biological processes, namely neutrophil degranulation and T cell receptor signaling.Conclusions: Phenotypically similar subsets of small-to-medium sized vessel vasculitis may have different mechanistic drivers involving innate vs. adaptive immune processes. Discovery of these differentiating immune features provides a mechanistic-based alternative for subclassification of vasculitis.

Highlights

Vasculitis [1] is a group of complex rare diseases that are characterized by inflammation in the blood vessel walls
It is noteworthy that granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) have overlapping clinical features with polyarteritis nodosa (PAN), and other small-to-medium sized vessel vasculitides that remain “unclassifiable” according to existing classification criteria
Despite the disease being especially rare in children compared to adults, we focused on a cohort of children and adolescents with smallto-medium sized vessel vasculitis for mechanistic discovery

Summary

Introduction

Vasculitis [1] is a group of complex rare diseases that are characterized by inflammation in the blood vessel walls. The primary framework for classifying vasculitis syndromes is according to the predominant size of the involved vessels (small, medium, large), the clinical phenotype (pattern of organs affected), and histopathology of involved vessels [2,3,4,5]. Distinctive etiological/pathological processes have been incorporated in the classification framework; for example, an association with antineutrophil cytoplasmic antibodies (ANCA) against intracellular granule proteins proteinase-3 (PR3) and myeloperoxidase (MPO) enables classification of small-to-medium sized, ANCAassociated vasculitis (AAV) [3, 4, 6, 7]. PR3-ANCA, despite being predominantly associated with GPA, is present in one-quarter of patients with MPA. It is noteworthy that GPA and MPA have overlapping clinical features with polyarteritis nodosa (PAN) (a medium-sized vessel vasculitis), and other small-to-medium sized vessel vasculitides that remain “unclassifiable” according to existing classification criteria

Objectives

Methods

Results

Conclusion