Research Signal – Source date 2025-09-03
Joint pain can arise for many reasons, and some people with early symptoms will later develop rheumatoid arthritis (RA). A study published on September 3, 2025, found that certain features associated with immune ageing were already present in people with joint symptoms who had not yet been diagnosed with RA. Other changes appeared mainly after diagnosis.
The findings raise a careful question: could patterns in immune cells help identify who is more likely to progress? The study offers an early clue, but its small number of participants who developed RA means the result is not ready to guide an individual’s risk assessment.
The study compared distinct stages of joint symptoms
Researchers assessed 224 people in five groups: healthy controls; people with clinically suspected arthralgia, meaning joint pain without established arthritis; people with undifferentiated arthritis, whose symptoms included joint swelling or stiffness but did not yet meet the study’s definition of RA; and people with newly diagnosed or more established RA. The RA groups had not started disease-modifying antirheumatic drugs when they entered the study.
The team measured immune-cell populations in blood using flow cytometry and examined gene activity for signs linked to immune ageing. Comparing different groups can show which patterns are associated with each stage. It cannot, by itself, show how an individual’s immune system changed as that person moved from symptoms to diagnosis.
Some signs appeared before diagnosis, others later
People with arthralgia and undifferentiated arthritis had lower proportions of naïve CD4 T cells than healthy controls. These are T cells that have not yet been trained to respond to a particular target. The researchers also found fewer recent thymic emigrants, newly formed T cells that have recently left the thymus, across the symptom groups and both RA groups.
Together, these measurements point to a changed supply of fresh immune cells in the blood. They do not reveal why the pattern arose or establish that it drove the development of RA. The average group differences in recent thymic emigrants were modest, which also limits their use as a marker on their own.
Other T-cell changes were more concentrated in diagnosed disease. Th17 cells, a type associated with inflammatory activity, and senescent-like T cells were more frequent in the early and established RA groups, but not in the arthralgia or undifferentiated-arthritis groups. Regulatory T cells, which can help restrain immune responses, were more frequent in the established RA group, whose participants had symptoms for more than three months. Their increased frequency does not tell us whether those cells were functioning effectively; the study could not test immune-cell function.
The B-cell pattern began earlier. Age-associated B cells, a measured cell population identified by particular surface markers, were expanded in people with arthralgia and undifferentiated arthritis, with further increases in the diagnosed RA groups. Several inflammatory measures, including IL-1 beta, IL-6, TNF-alpha and C-reactive protein, were also higher in the arthralgia group than among healthy controls, and were further elevated with established disease. These are accompanying observations; the study does not show that one change caused another.
A combined score offered a small prediction clue
The researchers used eight immune-cell frequencies to calculate an IMM-AGE score, an estimate of the overall degree of immune ageing. The score was higher in both RA groups than in healthy controls; the difference in undifferentiated arthritis was less clear (reported p = 0.052). It was not higher in the arthralgia group overall.
A separate analysis asked whether the score distinguished participants who later developed RA. During 24 months of follow-up, nine people in the arthralgia group developed RA. At the start, the score was higher among the small subgroup who were positive for anti-citrullinated protein antibodies (ACPA) and later developed RA. In the undifferentiated-arthritis group, four participants developed RA; their scores were also higher than those of participants who did not progress.
These subgroup findings are exploratory. They involve few people, and the score was not shown to accurately predict an individual’s diagnosis. The authors also observed an expansion of age-associated B cells among arthralgia participants who later developed RA, including people with and without ACPA. A combination of immune measurements and existing clinical markers may be more useful to investigate than any single measure, but it would need validation before clinical use.
What the comparisons can and cannot tell us
Most of the study compared different people at different stages rather than following the same people through the full path from health to RA. Such comparisons can identify patterns associated with groups, but cannot establish that immune ageing caused RA or trace an individual’s changing immune system over time.
The progression analyses were especially small: nine people with arthralgia and four with undifferentiated arthritis developed RA. The researchers could not test immune-cell function because the available blood volume was limited. The participants also came from a specific clinical cohort, so larger and more diverse studies would be needed to check whether the patterns hold more broadly.
The researchers discussed approaches that target ageing-related processes, including drugs that affect inflammation, autophagy or senescent cells. Those possibilities were not tested as treatments in this study, which provides no evidence that they prevent RA.
What an earlier immune warning could change
If future studies confirm that a combination of immune and clinical markers can identify people most likely to progress, clinicians and researchers could focus preventive trials on those at higher risk. That could make it easier to test whether an intervention helps before RA is established and to direct it more precisely. Larger, diverse studies that follow participants over time—and evidence that an intervention improves outcomes—are needed before this possibility can benefit people with concerning joint symptoms.
Key Sources
- Primary source: Specific features of immune ageing are detected in the earliest stages in rheumatoid arthritis development.
DOI or Journal Page · Peer-Reviewed Paper · 2025-09-03
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