Cellular deconstruction of inflamed synovium defines diverse inflammatory phenotypes in rheumatoid arthritis
Authors: Zhang Fan , Jonsson Anna Helena , Nathan Aparna , Wei Kevin , Millard Nghia , Xiao Qian , Gutierrez-Arcelus Maria , Apruzzese William , Watts Gerald F. M. , Weisenfeld Dana , Kang Joyce B. , Rumker Laurie , Mears Joseph , Slowikowski Kamil , Weinand Kathryn , Orange Dana E. , Rangel-Moreno Javier , Geraldino-Pardilla Laura , Deane Kevin D. , Tabechian Darren , Ceponis Arnold , Firestein Gary S. , Maybury Mark , Sahbudin Ilfita , Ben-Artzi Ami , Mandelin Arthur M. , Nerviani Alessandra , Rivellese Felice , Pitzalis Costantino , Hughes Laura B. , Horowitz Diane , DiCarlo Edward , Gravallese Ellen M. , Boyce Brendan F. ,   Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Moreland Larry W. , Goodman Susan M. , Perlman Harris , Holers V. Michael , Liao Katherine P. , Filer Andrew , Bykerk Vivian P. , Rao Deepak A. , Donlin Laura T. , Anolik Jennifer H. , Brenner Michael B. , Raychaudhuri Soumya , Albrecht Jennifer , Barnas Jennifer L. , Bathon Joan M. , Boyle David L. , Bridges S. Louis , Campbell Debbie , Carr Hayley L. , Chicoine Adam , Cordle Andrew , Curtis Michelle , Dunn Patrick , Forbess Lindsy , Gregersen Peter K. , Guthridge Joel M. , Ivashkiv Lionel B. , Ishigaki Kazuyoshi , James Judith A. , Keras Gregory , Korsunsky Ilya , Lakhanpal Amit , Lederer James A. , Li Zhihan J. , Li Yuhong , McDavid Andrew , Meednu Nida , Mantel Ian , McGeachy Mandy J. , Raza Karim , Reshef Yakir , Ritchlin Christopher , Robinson William H. , Sakaue Saori , Seifert Jennifer A. , Smith Melanie H. , Scheel-Toellner Dagmar , Utz Paul J. , Weisman Michael H. , Zhu Zhu 
Published: March 2022

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.