Abstract
Objective: Recent studies have uncovered diverse cell types and states in the rheumatoid arthritis (RA) synovium; however, limited data exist correlating these findings with patient-level clinical information. Using the largest cohort to date with clinical and multicell data, we determined associations between RA clinical factors with cell types and states in the RA synovium. Methods: The Accelerated Medicines Partnership Rheumatoid Arthritis study recruited patients with active RA who were not receiving disease-modifying antirheumatic drugs (DMARDs) or who had an inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors. RA clinical factors were systematically collected. Biopsies were performed on an inflamed joint, and tissue were disaggregated and processed with a cellular indexing of transcriptomes and epitopes sequencing pipeline from which the following cell type percentages and cell type abundance phenotypes (CTAPs) were derived: endothelial, fibroblast, and myeloid (EFM); fibroblasts; myeloid; T and B cells; T cells and fibroblasts (TF); and T and myeloid cells. Correlations were measured between RA clinical factors, cell type percentage, and CTAPs. Results: We studied 72 patients (mean age 57 years, 75% women, 83% seropositive, mean RA duration 6.6 years, mean Disease Activity Score-28 C-reactive Protein 3 [DAS28-CRP3] score 4.8). Higher DAS28-CRP3 correlated with a higher T cell percentage (P < 0.01). Those receiving MTX and not a biologic DMARD (bDMARD) had a higher percentage of B cells versus those receiving no DMARDs (P < 0.01). Most of those receiving bDMARDs were categorized as EFM (57%), whereas none were TF. No significant difference was observed across CTAPs for age, sex, RA disease duration, or DAS28-CRP3. Conclusion: In this comprehensive screen of clinical factors, we observed differential associations between DMARDs and cell phenotypes, suggesting that RA therapies, more than other clinical factors, may impact cell type/state in the synovium and ultimately influence response to subsequent therapies.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 356-362 |
| Number of pages | 7 |
| Journal | Arthritis and Rheumatology |
| Volume | 76 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2024 |
Funding
Members of the Accelerating Medicines Partnership Program: RA and Systemic Lupus Erythematosus Network are as follows: Joan M. Bathon, Laura Geraldino-Pardilla (Columbia University College of Physicians and Surgeons, New York, New York); Ami Ben-Artzi, Lindsy Forbess (Cedars-Sinai Medical Center, Los Angeles, California); Jennifer Albrecht, Jennifer L. Barnas, Christopher Ritchlin, Darren Tabechian, Nida Meednu, Javier Rangel-Moreno, Brendan F. Boyce (University of Rochester Medical Center, Rochester, New York); David L. Boyle, Arnold Ceponis, Gary S. Firestein (University of California at San Diego, La Jolla); S. Louis Bridges Jr., Lionel B. Ivashkiv, Amit Lakhanpal, Ian Mantel, Anvita Singaraju (Weill Cornell Medicine, and Hospital for Special Surgery, New York, New York); Hayley L. Carr, Mark Maybury, Saba Nayar, Karim Raza, Dagmar Scheel-Toellner (NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK); Andrew Cordle, Aaron Wyse (University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania); Michelle Curtis, Siddarth Gurajala, Joyce B. Kang, Ilya Korsunsky, Joseph Mears, Nghia Millard, Aparna Nathan, Yakir Reshef, Laurie Rumker, Saori Sakaue, Kathryn Weinand, Qian Xiao (Brigham and Women's Hospital and Harvard Medical School, Boston, and Broad Institute of MIT and Harvard, Cambridge, Massachusetts); Kevin D. Deane, Jennifer A. Seifert (University of Colorado School of Medicine, Aurora); Edward DiCarlo, Melanie H. Smith (Hospital for Special Surgery, New York, New York); Patrick Dunn (National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, and Northrop Grumman Health Solutions, Rockville, Maryland); Peter K. Gregersen, V. Diane Horowitz (Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York); Joel M. Guthridge, Judith A. James (Oklahoma Medical Research Foundation, Oklahoma City); Maria Gutierrez-Arcelus (Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts); Laura B. Hughes (University of Alabama at Birmingham, Birmingham); Kazuyoshi Ishigaki (Brigham and Women's Hospital and Harvard Medical School, Boston, and Broad Institute of MIT and Harvard, Cambridge, Massachusetts, and RIKEN Center for Integrative Medical Sciences, Yokohama, Japan); Adam Chicoine, Gerald F. M. Watts, Zhu Zhu, Kathryne Marks, Gregory Keras, Yuhong Li, Zhihan J. Li, James A. Lederer (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts); Myles Lewis, Alessandra Nerviani, Costantino Pitzalis, Felice Rivellese (Queen Mary University of London, London, UK); Arthur M. Mandelin II, Harris Perlman (Northwestern University Feinberg School of Medicine, Chicago, Illinois); Andrew McDavid (University of Rochester School of Medicine and Dentistry, Rochester, New York); Mandy J. McGeachy (University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania); Dana E. Orange (Hospital for Special Surgery, and The Rockefeller University, New York, New York); William H. Robinson (Stanford University School of Medicine, Stanford, California); Ilfita Sahbudin (NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, and MRC Versus Arthritis Centre for Musculoskeletal Ageing Research and the Research into Inflammatory Arthritis Centre Versus Arthritis, University of Birmingham, Birmingham, UK); Kamil Slowikowski (Broad Institute of MIT and Harvard, Cambridge, Harvard Medical School, Massachusetts General Hospital, and Massachusetts General Hospital Cancer Center, Boston); Paul J. Utz (Stanford University School of Medicine, Stanford, California); Michael H. Weisman (Cedars-Sinai Medical Center, and University of California Los Angeles, Los Angeles, California). Supported by the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Program (see Appendix A). AMP is a public\u2010private partnership (AbbVie Inc., Arthritis Foundation, Bristol\u2010Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc., NIH/National Institute of Allergy and Infectious Diseases, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, and Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biologic targets for diagnostics and drug development. Supported by NIH (grants UH2\u2010AR\u2010067676, UH2\u2010AR\u2010067677, UH2\u2010AR\u2010067679, UH2\u2010AR\u2010067681, UH2\u2010AR\u2010067685, UH2\u2010AR\u2010067688, UH2\u2010AR\u2010067689, UH2\u2010 AR\u2010067690, UH2\u2010AR\u2010067691, UH2\u2010AR\u2010067694, and UM2\u2010AR\u2010067678). Accelerating Medicines Partnership and AMP are registered service marks of the US Department of Health and Human Services. Supported by NIH P30\u2010AR\u2010072577 (to Ms. Weisenfeld and Dr. Liao); PhRMA (to Dr. Zhang); NIH NIAID R01\u2010AI\u2010148435 (to Dr. Donlin); Rheumatology Research Foundation Investigator Award and Arthritis National Research Foundation award (Dr. Jonsson); NIH NIAMS K08\u2010AR\u2010072791 and Burroughs Wellcome Fund Career Award in Medical Sciences (to Ms. Rao); NIH NIAMS K08\u2010AR\u2010077037, Rheumatology Research Foundation Innovative Research Award, and Burroughs Wellcome Fund Career Award in Medical Sciences (to Dr. Wei); NIH NIAMS R01\u2010AR\u2010073833 and R01\u2010AR\u2010073290 (to Dr. Brenner); NIH NHGRI U01\u2010HG\u2010009379 and NIAMS R01\u2010AR\u2010063759 (to Dr. Raychaudhuri); Research into Inflammatory Arthritis Centre Versus Arthritis (22072), IMI\u2010RTCure (777357), and the NIHR Birmingham Biomedical Research Centre (BRC\u20101215\u201020009) (to Dr. Filer); and NIH NIAMS R21\u2010AR\u2010071670 and P30\u2010AR\u2010069655 (to Dr. Anolik).
ASJC Scopus subject areas
- Immunology and Allergy
- Rheumatology
- Immunology