Scientists who say dramatic immune changes occur years before rheumatoid arthritis (RA) symptoms appear have now mapped the hidden immune battle that unfolds way beforehand.
By studying people with RA-linked antibodies over seven years, they discovered sweeping inflammation, malfunctioning immune cells, and even epigenetic reprogramming in cells that had never encountered a threat.
These changes show that the body is preparing for autoimmune attack long before joints become damaged, they said, or before the first aches or stiffness appear.
Instead of starting when joint pain becomes noticeable, the chronic autoimmune disease quietly builds over many years.
The researchers – from the Allen Institute, CU Anschutz, University of CaliforniaSan Diego, and the Benaroya Research Institute – worked together to uncover these early immune changes.
Their findings, published in Science Translational Medicine, offer the most detailed view yet of how RA takes shape. By charting immune activity in individuals at risk, the team showed that the disease process is already under way long before joint problems are noticeable.
These insights may help guide earlier intervention and possibly prevent disease onset.
“Overall, we hope this study raises awareness that rheumatoid arthritis begins much earlier than previously thought and that it enables researchers to make data-driven decisions on strategies to disrupt disease development,” said Mark Gillespie, PhD, assistant investigator at the Allen Institute and co-senior author with Kevin Deane (CU Anschutz), MD/PhD; Adam Savage (Allen Institute), PhD; Troy Torgerson (Allen Institute), MD/PhD; and Gary Firestein (UC San Diego), MD.
The research followed people with ACPA antibodies over seven years.
These antibodies are well-established biomarkers for those at risk for RA, and during the study, the team uncovered previously unrecognised contributors to disease progression, including widespread inflammation, immune system malfunction, and shifts in how certain immune cells function.
“We expect that … the findings will support additional studies to identify ways to better predict who will get RA, identify potential biologic targets for preventing RA as well as identify ways to improve treatments for those with existing RA,” said Deane.
Key findings
Widespread inflammation:
The researchers observed that people at risk for RA already showed signs of systemic inflammation throughout the body, which was not limited to the joints. Instead, it resembled the body-wide inflammatory pattern commonly seen in individuals with active RA.
Immune cell dysfunction:
Multiple immune cell types showed unusual behaviour. B cells, which normally create protective antibodies, were found in a heightened pro-inflammatory state.
T helper cells, especially those similar to Tfh17 cells, had expanded far beyond typical levels. These cells help co-ordinate immune responses, including the creation of autoantibodies (antibodies that attack the body’s own tissues). Their expansion helps explain why the immune system begins targeting healthy tissue.
Cellular reprogramming:
One of the most striking discoveries was that even “naïve” T cells, which have not yet encountered pathogens, showed epigenetic changes. Although their DNA sequence remained intact, the regulation of their genes had shifted.
This altered gene activity suggests these cells were being reprogrammed before encountering any threats.
Joint-like inflammation detected in blood:
The team also found that monocytes (a type of white blood cell) circulating in the bloodstream were producing high amounts of inflammatory molecules. Remarkably, these closely resembled the macrophages typically found in the inflamed joints of RA patients, indicating that the immune system was already setting the stage for joint inflammation
Toward early detection
The findings highlight new early-warning indicators (biomarkers and immune signatures) that could help doctors determine which at-risk individuals are most likely to develop RA.
Identifying the disease during this hidden phase may make it possible to monitor patients more closely and begin treatment earlier, they said. If this process is caught in time, RA may be prevented before joint damage begins – potentially sparing patients years of pain and disability.
The research supports a shift from reacting to joint damage after it appears to preventing RA at its earliest stages.
Study details
Progression to rheumatoid arthritis in at-risk individuals is defined by systemic inflammation and by T and B cell dysregulation
Ziyuan He, Marla Glassm, Pravina Venkatesan, Marie Feser et al.
Published in Science Translational Medicine on 24 September 2025
Abstract
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). Pre-emptive 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, pro-inflammatory 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 titres. Epigenetic changes in naïve CD4 T cells suggested a predisposition to differentiate into effector cells capable of B cell help. These findings characterise pathogenesis of the ACPA+ 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.
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