Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes
Authors: Zhang Fan , Jonsson Anna Helena , Nathan Aparna , Millard Nghia , Curtis Michelle , Xiao Qian , Gutierrez-Arcelus Maria , Apruzzese William , Watts Gerald F. M. , Weisenfeld Dana , Nayar Saba , Rangel-Moreno Javier , Meednu Nida , Marks Kathryne E. , Mantel Ian , Kang Joyce B. , Rumker Laurie , Mears Joseph , Slowikowski Kamil , Weinand Kathryn , Orange Dana E. , Geraldino-Pardilla Laura , Deane Kevin D. , Tabechian Darren , Ceponis Arnoldas , Firestein Gary S. , Maybury Mark , Sahbudin Ilfita , Ben-Artzi Ami , Mandelin Arthur M. , Nerviani Alessandra , Lewis Myles J. , Rivellese Felice , Pitzalis Costantino , Hughes Laura B. , Horowitz Diane , DiCarlo Edward , Gravallese Ellen M. , Boyce Brendan F. ,   Accelerating Medicines Partnership: RA/SLE Network, Albrecht Jennifer , Barnas Jennifer L. , Bathon Joan M. , Boyle David L. , Bridges S. Louis , Campbell Debbie , Carr Hayley L. , Chicoine Adam , Cordle Andrew , 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 , McGeachy Mandy J. , Raza Karim , Reshef Yakir , Ritchlin Christopher , Robinson William H. , Sakaue Saori , Seifert Jennifer A. , Singaraju Anvita , Smith Melanie H. , Scheel-Toellner Dagmar , Utz Paul J. , Weisman Michael H. , Wyse Aaron , Zhu Zhu , Moreland Larry W. , Goodman Susan M. , Perlman Harris , Holers V. Michael , Liao Katherine P. , Filer Andrew , Bykerk Vivian P. , Wei Kevin , Rao Deepak A. , Donlin Laura T. , Anolik Jennifer H. , Brenner Michael B. , Raychaudhuri Soumya 
Published: November 2023

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.