Cellular deconstruction of inflamed synovium defines diverse inflammatory phenotypes in rheumatoid arthritis

Rheumatoid arthritis (RA) is a prototypical autoimmune disease that causes destructive tissue inflammation in joints and elsewhere. Clinical challenges in RA include the empirical selection of drugs to treat patients, inadequate responders with incomplete disease remission, and lack of a cure. We profiled the full spectrum of cells in inflamed synovium from patients with RA with the goal of deconstructing the cell states and pathways characterizing pathogenic heterogeneity in RA. Our multicenter consortium effort used multi-modal CITE-seq, RNA-seq, and histology of synovial tissue from 79 donors to build a >314,000 single-cell RA synovial cell atlas with 77 cell states from T, B/plasma, natural killer, myeloid, stromal, and endothelial cells. We stratified tissue samples into six distinct cell type abundance phenotypes (CTAPs) individually enriched for specific cell states. These CTAPs demonstrate the striking diversity of RA synovial inflammation, ranging from marked enrichment of T and B cells (CTAP-TB) to a congregation of specific myeloid, fibroblast, and endothelial cells largely lacking lymphocytes (CTAP-EFM). Disease-relevant cytokines, histology, and serology metrics are associated with certain CTAPs. This comprehensive RA synovial atlas and molecular, tissue-based CTAP stratification reveal new insights into RA pathology and heterogeneity, which could lead to novel targeted-treatment approaches in RA. ### Competing Interest Statement A.H.J. reports research support from Amgen, outside the submitted work. K.W. is a consultant for Mestag Therapeutics and Gilead Sciences and reports grant support from Gilead Sciences. S.M.G. reports research support from Novartis and is a consultant for UCB, outside the submitted work. V.M.H. is a co-founder of Q32 Bio and has previously received sponsored research from Janssen and been a consultant for Celgene and BMS, outside the submitted work. A.F. reports personal fees from Abbvie, Roche, and Janssen and grant support from Roche, UCB, Nascient, Mestag, GlaxoSmithKline, and Janssen, outside the submitted work. D.A.R. reports personal fees from Pfizer, Janssen, Merck, Scipher Medicine, GlaxoSmithKline, and Bristol-Myers Squibb and grant support from Janssen and Bristol-Myers Squibb, outside the submitted work. In addition, D.A.R. is a co-inventor on a patent submitted on T peripheral helper cells. M.B.B. is a founder for Mestag Therapeutics and a consultant for GlaxoSmithKline, 4FO Ventures, and Scailyte AG. S.R. is a founder for Mestag Therapeutics, a scientific advisor for Janssen and Pfizer, and a consultant for Gilead and Rheos Medicines.