Seven-year study reveals early warning signs that could help doctors catch rheumatoid arthritis before symptoms begin potentially saving patients years of pain and disability
A groundbreaking study led in part by researchers at University of Colorado Anschutz reveals that rheumatoid arthritis (RA) doesn't begin when symptoms appear. Instead, it starts silently, years earlier.
Published today in Science Translational Medicine, the seven-year study was a collaboration between CU Anschutz, the Allen Institute, UC San Diego and Benaroya Research Institute. It offers the most detailed view yet of how RA develops, mapping immune changes in people at risk long before joint pain begins.
"This study builds on years of work identifying and tracking people at risk for RA," said Kevin Deane, MD, professor of rheumatology at CU Anschutz School of Medicine, Director of the newly established Autoimmune Disease Prevention Center at CU Anschutz, and one of the study's senior authors. "By applying cutting-edge technologies, we were able to uncover how the immune system shifts long before the first swollen joints that define the presence of full-blown RA appear."
Like a volcano building pressure beneath the surface
RA is a chronic autoimmune disease that causes painful joint inflammation and long-term damage. This research shows the body begins fighting an invisible internal battle well before the tell-tale joint swelling from inflammation appears. Think of it like a volcano building pressure beneath the surface, quietly reshaping the landscape until one day it erupts.
Researchers followed individuals with anti-CCP antibodies, a known biomarker for RA risk, and uncovered previously unknown biological changes that occur before the first swollen joints. CU Anschutz played a central role in recruiting anti-CCP positive individuals who are at-risk for RA, collecting samples and tracking immune changes over time.
Key Findings
- Systemic Inflammation: Even before symptoms and joint swelling, at-risk individuals showed body-wide inflammation, similar to what's seen in active RA but without joint inflammation.
- Immune Cell Shifts:
- B cells, which normally protect the body, were promoting inflammation.
- T helper cells, especially a type linked to harmful antibodies, were overactive and attacking healthy tissue.
- Cellular Reprogramming: Even "naive" T cells, those that hadn't yet encountered threats, showed changes in gene activity that primed them for autoimmune behavior.
- Joint-Targeting Signals in Blood: Monocytes in the bloodstream produced inflammatory molecules and resembled the cells found in RA-affected joints suggesting the immune system was already preparing to target joint tissue.
These findings offer new early-warning signs, biomarkers and immune signatures, that could help healthcare providers identify which at-risk individuals are most likely to develop RA. With earlier detection, interventions could begin before joint damage occurs, shifting care from reactive treatment to proactive prevention.
"This gives us multiple biological targets to explore for prevention," said Deane. "It also helps us better predict who will actually develop RA, because not everyone with risk markers like anti-CCP will get the disease. This new data will help accelerate research into how RA starts and how we can stop it."
A Second Study: Ruling Out Hydroxychloroquine
In a separate study published last month in The Arthritis and Rheumatology Journal, CU Anschutz researchers found that hydroxychloroquine (HCQ), a drug commonly used to treat RA, did not prevent the disease in people at high risk.
The trial called 'StopRA' followed 144 participants with elevated anti-CCP antibodies over three years. Participants in the HCQ or placebo developed RA in similar numbers, and both groups reported comparable symptoms and side effects.
"This helps us rule out a treatment many healthcare providers and researchers hoped might delay RA, and may have been using already," said Deane, who also helped lead this research. "Furthermore, the findings from StopRA trial, as well as forthcoming mechanistic studies which were done as part of the trial, will help us identify more effective prevention strategies."
Studies give hope for future of autoimmune treatment and prevention
Together, these studies add to a growing body of work from CU Anschutz researchers aimed at understanding and ultimately stopping RA before it starts.
"We're continuing to build a network of at-risk individuals through studies like StopRA and the Allen project. Combining these efforts will help validate findings and move the field closer to the point where we implement prevention of RA, and ultimately other autoimmune diseases, in routine health care," said Deane.
CU Anschutz investigators who participated in the Allen project also include Michael Holers, MD, Kristi Kuhn, MD, PhD, Kristen Demoruelle, MD, PhD, and Fan Zhang, PhD.
