Identification of Three Rheumatoid Arthritis Disease Subtypes by Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data

Abstract

Objective In this study, we sought to refine histologic scoring of rheumatoid arthritis (RA) synovial tissue by training with gene expression data and machine learning. Methods Twenty histologic features were assessed in 129 synovial tissue samples (n = 123 RA patients and n = 6 osteoarthritis [OA] patients). Consensus clustering was performed on gene expression data from a subset of 45 synovial samples. Support vector machine learning was used to predict gene expression subtypes, using histologic data as the input. Corresponding clinical data were compared across subtypes. Results Consensus clustering of gene expression data revealed 3 distinct synovial subtypes, including a high inflammatory subtype characterized by extensive infiltration of leukocytes, a low inflammatory subtype characterized by enrichment in pathways including transforming growth factor β, glycoproteins, and neuronal genes, and a mixed subtype. Machine learning applied to histologic features, with gene expression subtypes serving as labels, generated an algorithm for the scoring of histologic features. Patients with the high inflammatory synovial subtype exhibited higher levels of markers of systemic inflammation and autoantibodies. C‐reactive protein (CRP) levels were significantly correlated with the severity of pain in the high inflammatory subgroup but not in the others. Conclusion Gene expression analysis of RA and OA synovial tissue revealed 3 distinct synovial subtypes. These labels were used to generate a histologic scoring algorithm in which the histologic scores were found to be associated with parameters of systemic inflammation, including the erythrocyte sedimentation rate, CRP level, and autoantibody levels. Comparison of gene expression patterns to clinical features revealed a potentially clinically important distinction: mechanisms of pain may differ in patients with different synovial subtypes.

Rheumatoid Arthritis Morning Stiffness Is Associated With Synovial Fibrin and Neutrophils

“…Tissue samples were stained with Harris’ modified hematoxylin solution and eosin Y (both from Sigma‐Aldrich). Ten features (synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells, detritus, neutrophils, and mucin) were scored as previously described (http://www.hss.edu/pathology-synovitis.asp).…”

Histologic and Transcriptional Evidence of Subclinical Synovial Inflammation in Patients With Rheumatoid Arthritis in Clinical Remission

“…To gain insight into the underlying cellular and transcriptional mechanisms of RA, we recently performed histologic and RNA‐Seq analyses on RA synovium . Clustering of synovial gene expression data identified 3 synovial subtypes of RA: “low inflammatory,” “high inflammatory,” and “mixed” .…”

“…To gain insight into the underlying cellular and transcriptional mechanisms of RA, we recently performed histologic and RNA‐Seq analyses on RA synovium . Clustering of synovial gene expression data identified 3 synovial subtypes of RA: “low inflammatory,” “high inflammatory,” and “mixed” . Though these synovial subsets were significantly associated with autoantibodies such as cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) and systemic markers of inflammation such as C‐reactive protein (CRP) level and erythrocyte sedimentation rate (ESR), they were not associated with clinical features (i. e., swollen and tender joint counts or pain scores).…”

HBEGF+macrophages identified in rheumatoid arthritis promote joint tissue invasiveness and are reshaped differentially by medications

“…To examine the impact of therapeutically targeting HBEGF + macrophages in RA joints, we directly assayed synovial tissue from RA patients with definitive RA diagnoses ( 40, 41 ) and extensive joint inflammation confirmed by histologic scoring ( 42, 43 ) (Table S1, n=8). Specifically, in an ex vivo tissue assay, synovium was dissociated into cell suspensions ( 44 ) and cultured with FDA-approved RA medications (Fig.…”