Synovial gene expression and histology were used to distinguish between various subtypes of rheumatoid arthritis. Machine-learning techniques were followed to analyze clinical, histologic, and gene-expression data from 123 patients.

Synovial gene expression and histology could be used to divide rheumatoid arthritis (RA) into high, low, and mixed inflammatory subtypes, according to results from the Accelerating Medicine Partnership.

"The actionable implication of these findings was that it might be worth considering synovial biopsies in patients who were not responding to several usual immune-targeting therapies,” Dr. Dana E. Orange from New York Genome Center.

Extensive synovial inflammation in RA could lead to joint destruction, but the classification of RA synovium has not yet included in current RA diagnostic or treatment guidelines.

Dr. Orange and colleagues used machine-learning techniques to analyze clinical, histologic, and gene-expression data from 123 RA patients and six osteoarthritis patients, with the aim of gaining insights into tissue inflammation and subclassification of RA.

The researchers collected 20 histologic features of the synovial samples, finally settling on ten features present in at least 5% of samples with at least good inter-pathologist reliability.

Ribonucleic acid (RNA) sequencing data suggested three distinct subtypes of RA synovium: low inflammatory rheumatoid arthritis, high inflammatory rheumatoid arthritis, and mixed rheumatoid arthritis.

Expression scores corresponding with immunity, immune-cell signaling pathways, cytokines, and chemokines increased with progression from the low to high inflammatory subtypes.

The expression scores corresponding with gene sets encoding glycoproteins, and protocadherins were higher in low-inflammatory and mixed subtypes than in the high-inflammatory subtype.

The high-inflammatory subtype also demonstrated high expression of both myeloid genes and lymphoid genes, whereas the low-inflammatory subtype was enriched in neuronal and transforming growth factor-beta signaling pathway genes.

Histologic findings most strongly represented in the high-inflammatory subtype included three plasma-cell features: binucleate plasma cells, plasma-cell%, and Russell bodies.

Patients with the high-inflammatory synovial subtype had higher levels of markers of systemic inflammation and autoantibodies, and their C-reactive protein (CRP) levels correlated significantly with pain.

In contrast, patients with the low-inflammatory synovial subtype had little tissue inflammation, and their pain levels did not correlate with the C-reactive protein levels.

“We were surprised to find that some patients with rheumatoid arthritis had high tender and swollen joint counts while exhibiting minimal inflammation in their tissue and normal erythrocyte sedimentation rates (ESRs) and CRP,” Dr. Orange said.

One interpretation of the result was that these patients might have developed osteoarthritis in the joint that was evaluated and had active rheumatoid arthritis in their other joints.

However, the discrepancy between high joint counts and normal acute-phase reactants raises the question of whether any of their other joints were highly inflamed.

“We are working now to understand mechanisms of pain in this subgroup better,” she said. “In the future, we also hope to develop blood and imaging biomarkers to identify this subset and thereby guide treatment decisions.”