Signs of immune system aging appear years before rheumatoid arthritis takes hold, offering new hope for early diagnosis and treatments that could slow or stop the disease before it starts, according to new research.
Rheumatoid arthritis (RA) results when the immune system mistakenly starts attacking healthy joint tissues, leading to inflammation of the tissue lining the joints, and chronic, painful swelling.
A new study led by the University of Birmingham in the UK has discovered that the immune system in people at risk of developing RA shows signs of premature aging, known as immune aging, even before the disease has fully developed.
“We’ve discovered that immune aging isn’t just a consequence of rheumatoid arthritis – it may be a driver of the disease itself,” said the study’s corresponding author, Assistant Professor Niharika Duggal, PhD, from the University’s Department of Inflammation and Aging. “We found that people in the early stages of rheumatoid arthritis, i.e., before a clinical diagnosis, show signs of faster immune system aging.”
The researchers studied 69 healthy controls, 32 people with joint pain (arthralgia) but no RA diagnosis, 44 with undifferentiated arthritis (symptoms but not yet RA), 23 with very early RA (symptoms for less than three months), and 56 with established RA (more than three months of symptoms). After collecting blood samples and looking at different immune cell populations, they combined eight immune cell measures into a single “immune age” (IMM-AGE) score. They measured the activity of hundreds of immune-related genes and measured levels of inflammatory proteins (cytokines) like IL-6, TNF⍺, IL-17, and CRP. Some study participants were tracked for up to 24 months to see who developed RA.
Signs of immune aging appeared before RA developed. People with arthralgia or undifferentiated arthritis already had fewer naïve T cells and reduced thymic output. The thymus produces new, naïve T cells; a reduced output, often due to age, means there are fewer “new” immune cells being produced. Once RA was established, stronger immune aging features were observed. A higher IMM-AGE score and certain immune features predicted which patients with arthralgia or undifferentiated arthritis were more likely to develop RA.
Patients with early or established RA showed a higher number of Th17 cells (a subset of T cells that produce inflammatory IL-17), more aged or “worn out” (senescent) T cells, and more regulatory T cells (Tregs). The higher number of Tregs, which are crucial for balancing immune activation, may have been to counterbalance the self-attacking response of the immune system. People with arthralgia already had elevated inflammatory molecules (IL-6, TNFα, CRP), but these levels increased further once RA was established.
B cells, white blood cells that produce antibodies to fight infections and foreign substances, also showed signs of aging. There were reduced numbers of naïve B cells across patient groups, and an expansion of “age-associated B cells” that have been linked with autoantibody production, even in arthralgia patients with no definitive RA diagnosis. These changes were linked with anti-CCP antibodies, a type of protein that mistakenly attacks the body’s healthy tissues and serves as a key marker for RA diagnosis.
“These findings suggest we might be able to intercept the disease development in at-risk individuals and prevent it from developing by using treatments that slow aging, such as boosting the body’s natural process for clearing out damaged cells (autophagy),” Duggal said.
The study had some limitations. Its cross-sectional design provided mostly snapshots of different groups, not long-term tracking of the same people. Small sample sizes were used, especially in the subgroups that later developed RA. Also, the researchers weren’t able to test how well the immune cells functioned, only their numbers and types. More research is needed in larger and more varied populations to confirm the findings.
The study suggests a method of early diagnosis of RA and risk prediction, using IMM-AGE score and immune aging features to identify people who are at high risk of RA before symptoms fully develop. It also hints at new treatment strategies that target aging-related processes to slow or prevent RA. Crucially, intervening at the “arthralgia” stage may prevent RA altogether.
The study was published in the journal eBioMedicine.
Source: University of Birmingham via EurekAlert!
