Signs of early immune aging appear in those at risk of rheumatoid arthritis (RA) before the disease fully develops, suggesting that these changes caught sooner could contribute to the start of the condition, according to a new study published in The Lancet’s eBioMedicine.
Rheumatoid arthritis is a chronic autoimmune disease that becomes more common with age, but researchers are still attempting to understand how aging processes influence its development. Typically, the immune system remodels gradually over time, leaving folks more vulnerable to infections and less responsive to vaccines.
However, this remodeling seems to occur much earlier.
Patients often show signs such as thymic shrinkage, shortened telomeres in immune cells and imbalances between regulatory and inflammatory T cells well before their healthy peers. These shifts can ignite the chronic inflammation and autoimmunity that fuel RA.
According to the American Academy of Orthopaedic Surgeons, about 1.5 million adults in the U.S. are living with RA, and roughly 71 out of every 100,000 people are diagnosed with the condition each year.
Early immune aging signals emerge in individuals at risk for rheumatoid arthritis, highlighting potential pathways for early intervention and disease prevention.
In this study, researchers found a buildup of “senescent-like” T cells—which are aged, non-dividing immune cells that release inflammatory signals. This process is known as inflammaging. Researchers also found similar age-related changes in B cells, including the loss of protective types and the expansion of disease-linked subgroups.
For researchers, a constant question has been whether these immune aging patterns are a cause of RA or a consequence of the disease. By examining patients at multiple stages—before and after diagnosis—the research gives an idea into when immune aging begins and how it could influence disease progression.
The study included participants with early arthritis from hospitals in Birmingham, U.K., as part of the BEACON cohort. At enrollment, all patients who weren’t yet treated with medication showed clear signs of joint inflammation or were considered at risk for developing RA based on symptoms or antibody markers.
Patients were followed for 18 months and categorized as having persistent RA, persistent non-RA arthritis or resolving arthritis. Healthy volunteers from the community served as controls.
In addition, blood samples were collected to examine immune cell populations, including T and B cell subsets, using flow cytometry. Researchers also measured cytokine levels, examined gene expression and calculated an “immune age” score to assess premature immune aging.
Overall, 224 participants were included, broken out of 59 healthy controls, 47 with arthralgia, 46 with undifferentiated arthritis, 35 with early RA and 37 with established RA. Immune changes were evident well before the disease began.
Compared with healthy controls, patients with arthralgia and undifferentiated arthritis showed a 30% to 40% reduction in naïve T cells and recent thymic emigrants, both signs of early immune aging. These reductions were strongly linked to higher levels of the inflammatory marker IL-6.
In patients with early and established RA, these immune changes were more dramatic. Central and effector memory T cells were two to three times higher, and there were more activated and senescent-like T cells that release inflammatory molecules, which may speed up chronic inflammation. Levels of pro-inflammatory Th17 cells and follicular helper T cells were also higher, while regulatory T cells increased only in established RA, further upsetting the immune balance.
B cell changes followed a similar pattern. Newer B cells were reduced by nearly half, while age-associated B cells and plasmablasts expanded—both linked to RA progression.
Based on the overall findings, a strength of the study is its focus on drug-naïve patients at different stages of RA, which allowed researchers to detect immune aging changes that occur before diagnosis.
The team also combined cellular, inflammatory, and gene expression data to build a detailed picture of disease development.
However, the study does include limitations.
For example, its cross-sectional design and small sample sizes limited the ability to track changes over time or capture the full diversity of patients. Only a handful of patients with arthralgia went on to develop RA, restricting the ability to test immune aging as a predictive biomarker.
The authors suggested that larger and longer-period studies are needed, along with trials of anti-aging therapies—such as metformin, spermidine or senolytics—as potential strategies to slow or even prevent the progression of RA.