Rheumatoid Synovium Characterized by Six Cell Type Phenotypes Save

Research work from the Accelerating Medicines Partnership (AMP: RA/SLE) Network, was published in Nature and more specifically characterizes RA synovium into several cell-type abundance phenotypes (CTAPs). Could CTAPs known disease features or more effective future therapies? 

The AMP:RA/SLE Network collected inflamed synovial tissue from 70 rheumatoid arthritis (RA) patients with RA from multiple centers in the US and UK and usied multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue to build single-cell atlas of RA synovial tissue that includes more than 314,000 cells.  They classified CTAPs on the basis of relatively enriched cell types:

1. Endothelial, fibroblast and myeloid cells (EFM);
2. Fibroblasts (F);
3. T cells and fibroblasts (TF);
4. T and B cells (TB);
5. T and myeloid cells (TM); and
6. Myeloid cells (M)

They identified six CTAP groups each characterized by selectively enriched cell states, that may be correlated with cytokines, risk genes, histology and serology. The authors suggest that CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes.

CTAPs were independent of smoking history and sex, and did not correlate with disease activity measures (DAS28-CRP), HLA-DRB1 alleles or serologies. But they did find that CCP titers differed across CTAPs (P = 0.023, 18% variance), with CTAP-M having the lowest CCP titres, even after restricting the analysis to seropositive patients (P = 0.0047) CTAPs.

By not finding correlations between CTAP and clinical measures the authors believe that "CTAPs reflect distinct inflammatory phenotypes driving arthritis rather than differences in clinical disease activity".

Analysis of samples from the R4RA trial (Pitzalis et al), they showed that CTAPs are dynamic and that two-thirds of patients changed to a different CTAP, regardless of treatment (rituximab or tocilizumab), with most (53%) changing to the CTAP-F (fibroblast) state.  Similarly, they found that responses to biologic therapy varied significantly by CTAP (P = 0.0105), with CTAP-F having the poorest response to treatments.

This comprehensive atlas and molecular, tissue-based stratification of RA synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.  This CTAP paradigm provides a potentially new classification system for RA that may explain disease heterogeneity, but allow for better targeted treatment approaches.