Multi-lineage transcriptional and cell communication signatures define evolving personalized mechanisms that initiate and perpetuate rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease arising from loss of tolerance and autoantibody development in at-risk individuals. Targeted therapies yield variable responses and current preventive strategies delay but do not stop disease onset. We propose that a set of transcription factors (TFs) and their downstream pathways regulate inflammatory cell communication networks in at-risk populations and RA. These networks enable multiple pathogenic cell types and mediators and could account for variable responses to targeted agents. To test this hypothesis, we identified anti-citrullinated protein antibody (ACPA)-positive at-risk individuals, patients with early and established RA and healthy controls. Single cell chromatin accessibility and transcriptomic profiles from blood mononuclear r cells were integrated and identified share pathogenic mechanisms, especially SUMOylation, RUNX2, YAP1, NOTCH3, and {beta}-Catenin Pathways. Surprisingly, this signature was found in multiple cell types. Individualized gene expression patterns were then confirmed in RA synovium. Cell communication analysis revealed that multiple lineages can deliver a core set of pro-inflammatory mediators to receiver cells. Longitudinal analysis showed that the signature cell types evolve in individual at-risk participants. Cell-type-specific signature pathways could contribute to the differing clinical responses to targeted therapies. This study describes how a common clinical phenotype could arise from multiple pathogenic mechanisms.