New study shows rheumatoid arthritis begins long before symptoms

According to new research, people who are at higher risk for RA undergo major changes in their immune system well before symptoms surface. Their bodies are already engaged in an unseen autoimmune struggle during this early, silent period.

A Multi-Institution Study Maps RA's Hidden Early Phase

Researchers from the Allen Institute, CU Anschutz, University of California San 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 to date of how RA takes shape. By charting immune activity in individuals at risk, the team showed that the disease process is already underway 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, Ph.D., assistant investigator at the Allen Institute and co-senior author with Kevin Deane (CU Anschutz), M.D./Ph.D.; Adam Savage (Allen Institute), Ph.D.; Troy Torgerson (Allen Institute), M.D./Ph.D.; and Gary S. Firestein (UC San Diego), M.D. The research followed individuals with ACPA antibodies over seven years. These antibodies are well-established biomarkers for those at risk for RA. During the study, the team uncovered previously unrecognized contributors to disease progression, including widespread inflammation, immune system malfunction, and shifts in how certain immune cells function.

"We expect that going forward the findings from this study 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 Kevin Deane, M.D./Ph.D.

Key Findings

• Widespread inflammation: The researchers observed that people at risk for RA already showed signs of systemic inflammation throughout the body. This inflammation 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 behavior.
• 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 coordinate 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 "naive" 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 cells 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 and Preventive Treatment

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. 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.