Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation
Rheumatoid arthritis (RA) is preceded by an at-risk stage of disease that can be marked by the presence of anticitrullinated protein antibodies (ACPAs) but the absence of clinically apparent synovitis (clinical RA). Preemptive intervention in at-risk individuals could prevent or delay future tissue damage; however, the immunobiology of this stage is unclear. Using integrative multiomics, we longitudinally profiled at-risk individuals, where one-third of participants developed clinical RA on study. We found evidence of systemic inflammation and signatures of activation in naïve T and B cells of at-risk individuals. During progression to clinical RA, proinflammatory skewing of atypical B cells and expansion of memory CD4 T cells with signatures of activation and B cell help were present without elevations in circulating ACPA titers. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterize pathogenesis of the ACPA<sup>+</sup> at-risk stage and support the concept that the disease begins much earlier than clinical RA. Additionally, an extensive immune resource of the at-risk stage and progression to clinical RA with interactive tools was developed to enable further investigation.
Authors
- Laura Moss (ORCID: https://orcid.org/0000-0002-6138-3573)
- Tylor Thai
- Amy Westermann (ORCID: https://orcid.org/0000-0003-1209-4043)
- Vaishnavi Parthasarathy
- Kevin D. Deane (ORCID: https://orcid.org/0000-0003-2211-4861)
- Veronica Hernandez (ORCID: https://orcid.org/0000-0003-2568-2565)
- Thomas F. Bumol
- David L. Boyle (ORCID: https://orcid.org/0000-0002-1454-2834)
- Jane H. Buckner (ORCID: https://orcid.org/0000-0002-9005-1885)
- Vlad Tsaltskan (ORCID: https://orcid.org/0000-0002-1359-0674)
- Gary S. Firestein (ORCID: https://orcid.org/0000-0003-3495-960X)
- Cara Lord (ORCID: https://orcid.org/0000-0002-7827-2159)
- Qiuyu Gong (ORCID: https://orcid.org/0009-0006-3885-0862)
- Chelsie Fleischer (ORCID: https://orcid.org/0000-0001-5706-7618)
- Claire E. Gustafson (ORCID: https://orcid.org/0000-0002-1437-6709)
- Padmapriyadarshini Ravisankar (ORCID: https://orcid.org/0000-0002-7061-9875)
- Lauren Okada (ORCID: https://orcid.org/0000-0002-5691-3373)
- V. Michael Holers (ORCID: https://orcid.org/0000-0002-5634-7746)
- Christopher E. Collora (ORCID: https://orcid.org/0009-0000-0183-3475)
- Palak C. Genge (ORCID: https://orcid.org/0000-0002-0851-6445)
- Nhung T. T. Tran (ORCID: https://orcid.org/0000-0002-9660-8904)
- Leander Lazaro
- Adam K. Savage (ORCID: https://orcid.org/0000-0003-1913-5485)
- Mark-Phillip Pebworth (ORCID: https://orcid.org/0000-0001-8224-9480)
- CE Bennett
- M. Kristen Demoruelle (ORCID: https://orcid.org/0000-0002-2563-5155)
- Marla C. Glass (ORCID: https://orcid.org/0000-0003-3763-0842)
- Pravina Venkatesan
- Ziyuan He (ORCID: https://orcid.org/0000-0003-3556-8248)
- Katherine Nguyen (ORCID: https://orcid.org/0000-0002-8620-8616)
- Christopher C. Striebich (ORCID: https://orcid.org/0000-0003-2582-7752)
- Emma L. Kuan (ORCID: https://orcid.org/0000-0002-5824-2016)
- Charles R. Roll (ORCID: https://orcid.org/0000-0002-0726-2076)
- Elliott Swanson (ORCID: https://orcid.org/0000-0002-0351-6446)
- Ananda W. Goldrath (ORCID: https://orcid.org/0000-0002-5900-508X)
- Lynne A. Becker (ORCID: https://orcid.org/0000-0003-1541-4655)
- Alexander T. Heubeck (ORCID: https://orcid.org/0000-0002-9312-4090)
- Kristine A. Kuhn (ORCID: https://orcid.org/0000-0002-6900-4195)
- Morgan Weiss (ORCID: https://orcid.org/0000-0002-4189-1992)
- Ruoxin Li (ORCID: https://orcid.org/0000-0001-7493-7443)
- Fan Zhang (ORCID: https://orcid.org/0000-0002-6102-2970)
- Upaasana Krishnan (ORCID: https://orcid.org/0000-0001-8589-7061)
- Saman Barzideh
- Troy R. Torgerson (ORCID: https://orcid.org/0000-0003-3489-5036)
- Elizabeth A. Bemis (ORCID: https://orcid.org/0000-0002-3556-3175)
- Peter J. Skene (ORCID: https://orcid.org/0000-0001-8965-5326)
- Julian Reading (ORCID: https://orcid.org/0000-0002-8533-3992)
- Lucas T. Graybuck (ORCID: https://orcid.org/0000-0002-8814-6818)
- Zachary Thomson (ORCID: https://orcid.org/0000-0002-3861-9998)
- Samir Rachid Zaim (ORCID: https://orcid.org/0009-0007-9256-2324)
- Mark A. Gillespie (ORCID: https://orcid.org/0000-0001-7820-8598)
- Elisabeth M. Dornisch (ORCID: https://orcid.org/0009-0009-6969-8690)
- Chong Pedrick
- Cate Speake (ORCID: https://orcid.org/0000-0003-1480-4272)
- Cole Phalen (ORCID: https://orcid.org/0000-0002-0196-2805)
- Marie L. Feser (ORCID: https://orcid.org/0009-0003-0598-853X)
- Jessica Garber (ORCID: https://orcid.org/0009-0007-8773-9754)
- Hideto Takada (ORCID: https://orcid.org/0009-0005-4541-2636)
- Nguyen Trieu
- Jennifer Seifert (ORCID: https://orcid.org/0000-0001-5851-7246)
- Tyanna Stuckey (ORCID: https://orcid.org/0009-0003-3262-8441)
- Brian C. Hattel
- Xiaojun Li (ORCID: https://orcid.org/0000-0003-0832-9479)
- Wei Wang (ORCID: https://orcid.org/0000-0003-4377-5060)
- Yudong D. He (ORCID: https://orcid.org/0000-0003-0818-605X)
- Tao Peng (ORCID: https://orcid.org/0000-0003-0550-9183)
- Andrea Ochoa (ORCID: https://orcid.org/0000-0001-9873-6144)
- Christian M. LaFrance
- Erin K. Kawelo (ORCID: https://orcid.org/0009-0004-0329-9914)
- Kevin J. Lee
- A. Ferrannini
- Blessing Musgrove
- R Mettey
- Najeeb A. Arishi
- Ashley G. Asamoah
- Megan A. L. Criley
- Marguerite D. Siedschlag
Institutions
- University of California San Diego (US)
- Society of Interventional Radiology (US)
- Allen Institute for Immunology (US)
- University of Colorado Anschutz Medical Campus (US)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-09-24
- DOI
- https://doi.org/10.1126/scitranslmed.adt7214
- Citations
- 8
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 6.38