# Multi-lineage transcriptional and cell communication signatures define pathways in individuals at-risk for developing rheumatoid arthritis that initiate and perpetuate disease

## TL;DR

This study identifies shared pathways in blood cells of people at risk for rheumatoid arthritis, revealing how different cell types contribute to the disease and suggesting new ways to prevent or treat it.

## Contribution

The study reveals a unifying transcription factor signature across multiple cell types in at-risk individuals and early RA patients, offering new insights into personalized disease mechanisms.

## Key findings

- A distinctive transcription factor signature involving SUMOylation, RUNX2, YAP1, NOTCH3, and β-Catenin pathways was found in T cells, B cells, and monocytes.
- Cell communication analysis showed that diverse cell lineages can deliver pro-inflammatory signals in rheumatoid arthritis.
- The findings suggest that personalized gene expression patterns in blood cells are relevant to synovial disease in RA.

## Abstract

Elevated anti-citrullinated protein antibodies (ACPA) levels in the peripheral blood are associated with an increased risk for developing rheumatoid arthritis (RA). Currently, no treatments are available that prevent progression to RA in these at-risk individuals. In addition, diverse pathogenic mechanisms underlying a common clinical phenotype in RA complicate therapy as no single agent is universally effective. We propose that a unifying set of transcription factor and their downstream pathways regulate a pro-inflammatory cell communication network, and that this network allows multiple cell types to serve as pathogenic drivers in at-risk individuals and in early RA. To test this hypothesis, we identified ACPA-positive at-risk individuals, patients with early ACPA-positive RA and matched controls. We measured single cell chromatin accessibility and transcriptomic profiles from their peripheral blood mononuclear cells. The datasets were then integrated to define key TF, as well as TF-regulated targets and pathways. A distinctive TF signature was enriched in early RA and at-risk individuals that involved key pathogenic mechanisms in RA, including SUMOylation, RUNX2, YAP1, NOTCH3, and β-Catenin Pathways. Interestingly, this signature was identified in multiple cell types, including T cells, B cells, and monocytes, and the pattern of cell type involvement varied among the at-risk and early RA participants, supporting our hypothesis. Similar patterns of individualized gene expression patterns and cell types were confirmed in single cell studies of RA synovium. Cell communication analysis provided biological validation that diverse lineages can deliver the same core set of pro-inflammatory mediators to receiver cells
in vivo
that subsequently orchestrate rheumatoid inflammation. These cell-type-specific signature pathways could explain the personalized pathogenesis of RA and contribute to the diversity of clinical responses to targeted therapies. Furthermore, these data could provide opportunities for stratifying individuals at-risk for RA, and selecting therapies tailored for prevention or treatment of RA. Overall, this study supports a new paradigm to understand how a common clinical phenotype could arise from diverse pathogenic mechanisms and demonstrates the relevance of peripheral blood cells to synovial disease.