TOPLINE:

Features of immune aging, characterized by reduced naive T cells and recent thymic emigrants, were noted in patients with arthralgia and undifferentiated arthritis before the diagnosis of rheumatoid arthritis (RA). The Immunological Aging (IMM-AGE) score was higher in patients in early disease stages, while certain features such as increased Th17 cells emerged only in those with early and established RA.

METHODOLOGY:

• Researchers assessed immune phenotypes in patients across different stages of RA to understand disease pathogenesis and identify early intervention opportunities in a study conducted at the University Hospital Birmingham and City and Sandwell Hospitals Birmingham, both in Birmingham, England.
• They recruited 224 age- and sex-matched participants (all naive to disease-modifying antirheumatic drugs), including 32 patients with arthralgia (mean age, 46.50 years; 34.3% men), 44 with undifferentiated arthritis (mean age, 51.96 years; 47.8% men), 23 with early RA with ≤ 3 months symptom duration (mean age, 56.52 years; 30.4% men), and 56 with established RA with > 3 months symptom duration (mean age, 56.41 years; 41.1% men), and 69 healthy control individuals, comprising staff and students from the university and older adults from the community (mean age, 57.12 years; 40.6% men).
• Blood samples were collected, and participants were assessed for immune aging features using flow cytometry and transcriptomic analysis, focusing on naive T cells, thymic output, and inflammatory markers.
• Participants were followed up for 18 months to assess the progression of RA and were categorized as those with persistent RA, persistent non-RA arthritis, or resolving arthritis according to outcomes on the basis of established criteria.
• An IMM-AGE score was generated using a subset of eight immune cell types to assess the degree of immune aging based on a modified algorithm, and cytokine levels in the serum were assessed across groups.

TAKEAWAY:

• Naive T cells were significantly reduced in patients with arthralgia (P = .031) and those with undifferentiated arthritis (P = .0023) and were maintained in those with both early and established RA (P < .0001 for both) compared with healthy control individuals. Reduced frequencies of recent thymic emigrants were observed in patients with arthralgia, undifferentiated arthritis, early RA, and established RA (P < .05 for all).
• In patients with early and established RA vs healthy individuals, the frequency of proinflammatory Th17 cells and senescent-like T cells was higher (P < .0001 and P < .001, respectively) but not in those with arthralgia or undifferentiated arthritis.
• Expansion of autoantibody-secreting age-associated B cells — an early feature of the disease — was observed in patients with arthralgia (P = .0036) and undifferentiated arthritis (P = .02), and further expansion was noted in those with early RA (P = .0031) and established RA (P < .0001).
• The IMM-AGE score was higher in patients with undifferentiated arthritis than healthy individuals (P =.052) and further increased in those with early and established RA (P < .001 for both). A similar increase was noted in systemic inflammation marker levels, including interleukin (IL)-1 beta, IL-6, TNF alpha, and C-reactive protein, which were significantly elevated in those with arthralgia and increased further in those with established RA.

IN PRACTICE:

“We found that people in the early stages of rheumatoid arthritis, ie, before a clinical diagnosis show signs of faster immune system aging,” Niharika Duggal, PhD, senior author of the study and assistant professor in Immunity and Ageing at the University of Birmingham said in a press release. “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).”

SOURCE:

This study was led by Karim Raza, BM BCh, PhD, University of Birmingham in Birmingham, England. It was published online on September 3, 2025, in eBioMedicine.

LIMITATIONS:

Only nine patients with arthralgia progressed to RA, limiting the assessment of the IMM-AGE score as a prognostic biomarker. Limited blood volume collection restricted the assessment of immune cell function. Variations in sex distribution among patient groups may have influenced the data.

DISCLOSURES:

This study was funded by grants from FOREUM and the European Alliance of Associations for Rheumatology. One author reported receiving an in-kind payment from GSK as part of a funding award from the Experimental Medicine Initiative to Explore New Therapies program.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.