A groundbreaking study conducted by researchers from the United Kingdom, Sweden, and the Netherlands has shed new light on the early mechanisms of rheumatoid arthritis (RA) development. Published in a leading medical journal, the findings demonstrate that signs of immune aging manifest long before the clinical presentation of the disease. This discovery challenges existing paradigms by suggesting that immune system changes are not merely a consequence of chronic inflammation in RA but may actually precede and potentially contribute to disease development.
Immune Aging
Rheumatoid arthritis is a chronic autoimmune disorder characterized by synovitis and systemic inflammation. While RA typically manifests in middle age, its development is closely linked to processes resembling immune aging. In older individuals, characteristic changes include reduced production of new T-lymphocytes in the thymus (thymic involution), decreased numbers of naive T and B cells, accumulation of senescent immune cells, and the establishment of chronic low-grade inflammation, or inflammaging.
Until now, it remained unclear whether these changes are a cause or consequence of rheumatoid arthritis. To address this question, researchers conducted a prospective study involving 224 participants, including healthy donors and patients at various disease stages – from clinically suspected arthralgia and undifferentiated arthritis to early and established RA. The selection criteria excluded patients receiving anti-rheumatic medications.
Until now, it remained unclear whether these changes are a cause or consequence of rheumatoid arthritis. To address this question, researchers conducted a prospective study involving 224 participants, including healthy donors and patients at various disease stages – from clinically suspected arthralgia and undifferentiated arthritis to early and established RA. The selection criteria excluded patients receiving anti-rheumatic medications.
Methodology:
Scientists performed a comprehensive analysis of the immune profile using peripheral blood samples at baseline and after 18 months of observation. The following methods were employed:
· Flow cytometry to determine lymphocyte subpopulations
· Measurement of inflammatory and regulatory cytokine levels in serum
· Transcriptomic analysis of blood cells
· Calculation of IMM-AGE – a composite immunological age indicator based on the ratio of different immune cell types
This multi-level approach enabled the identification of immune change patterns at the earliest stages of the pathological process.
· Flow cytometry to determine lymphocyte subpopulations
· Measurement of inflammatory and regulatory cytokine levels in serum
· Transcriptomic analysis of blood cells
· Calculation of IMM-AGE – a composite immunological age indicator based on the ratio of different immune cell types
This multi-level approach enabled the identification of immune change patterns at the earliest stages of the pathological process.
Key Findings: Early Manifestation of Immune Aging
The study revealed several important patterns:
1. Early thymic function decline: Patients with arthralgia and undifferentiated arthritis already showed reduced levels of naive CD4⁺ T cells recently migrated from the thymus. This finding indicates early impairment of thymic function, typically associated with age-related immune aging.
2. Progressive inflammatory profile: More pronounced signs of immune aging – increased numbers of regulatory Tregs, pro-inflammatory Th17 cells, and senescent CD28⁻CD57⁺ T cells – appeared as the disease progressed to clinically evident RA.
3. Elevated IMM-AGE: The composite immunological age indicator was higher in patients with undifferentiated arthritis compared to healthy donors, and significantly increased in early and established RA.
4. Systemic inflammation: Levels of IL-6, TNFα, IL-17, and C-reactive protein were elevated even in patients with arthralgia, and increased further as the disease progressed to RA.
5. Genetic markers: Transcriptomic analysis revealed activation of inflammatory pathways (NF-κB, IL-23) and reduced activity of genes responsible for autophagy, potentially contributing to the accumulation of damaged cells and maintenance of chronic inflammation.
Notably, among patients with arthralgia who later progressed to RA, elevated IMM-AGE scores and increased proportions of age-associated B cells – known for their ability to produce autoantibodies – were already present at the initial assessment.
1. Early thymic function decline: Patients with arthralgia and undifferentiated arthritis already showed reduced levels of naive CD4⁺ T cells recently migrated from the thymus. This finding indicates early impairment of thymic function, typically associated with age-related immune aging.
2. Progressive inflammatory profile: More pronounced signs of immune aging – increased numbers of regulatory Tregs, pro-inflammatory Th17 cells, and senescent CD28⁻CD57⁺ T cells – appeared as the disease progressed to clinically evident RA.
3. Elevated IMM-AGE: The composite immunological age indicator was higher in patients with undifferentiated arthritis compared to healthy donors, and significantly increased in early and established RA.
4. Systemic inflammation: Levels of IL-6, TNFα, IL-17, and C-reactive protein were elevated even in patients with arthralgia, and increased further as the disease progressed to RA.
5. Genetic markers: Transcriptomic analysis revealed activation of inflammatory pathways (NF-κB, IL-23) and reduced activity of genes responsible for autophagy, potentially contributing to the accumulation of damaged cells and maintenance of chronic inflammation.
Notably, among patients with arthralgia who later progressed to RA, elevated IMM-AGE scores and increased proportions of age-associated B cells – known for their ability to produce autoantibodies – were already present at the initial assessment.
Theoretical and Clinical Implications
This research is the first to demonstrate that immune aging is not merely a consequence of prolonged inflammation in RA but manifests before the clinical onset of the disease and likely plays a role in its pathogenesis. This perspective opens new horizons in understanding the mechanisms of autoimmune diseases.
New Therapeutic Perspectives
The findings suggest potential benefits of applying geroprotective agents to slow disease progression in at-risk patients. Possible strategies include:
· Using metformin to modulate metabolic pathways
· Applying senolytics to eliminate senescent cells
· Activating autophagy with spermidine or similar compounds
Such approaches could form part of a personalized prevention strategy for RA in patients with early signs of immune aging, potentially preventing the development of full-blown disease.
· Using metformin to modulate metabolic pathways
· Applying senolytics to eliminate senescent cells
· Activating autophagy with spermidine or similar compounds
Such approaches could form part of a personalized prevention strategy for RA in patients with early signs of immune aging, potentially preventing the development of full-blown disease.
Conclusion
This study represents a significant step forward in understanding rheumatoid arthritis pathogenesis, establishing a connection between immune aging processes and autoimmune pathology. Early detection of immune aging signs could become the foundation for new prevention and early intervention strategies, ultimately leading to reduced RA incidence and improved quality of life for patients.
Publication date: 12.09.2025
Source:
Raza K. et al. Specific features of immune ageing are detected in the earliest stages in rheumatoid arthritis development. EBioMedicine. 2025 Sep 1:105900. doi: 10.1016/j.ebiom.2025.105900. Epub ahead of print. PMID: 40908179.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00344-5/fulltext
Source:
Raza K. et al. Specific features of immune ageing are detected in the earliest stages in rheumatoid arthritis development. EBioMedicine. 2025 Sep 1:105900. doi: 10.1016/j.ebiom.2025.105900. Epub ahead of print. PMID: 40908179.
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00344-5/fulltext