Specific features of immune ageing are detected in the earliest stages in rheumatoid arthritis development.

Background: Rheumatoid arthritis is an age-related disease displaying features of an aged immune system. This study aims to determine premature presence of immune ageing in the early stages of RA development, including in patients with clinically suspected arthralgia and undifferentiated arthritis.

Methods: We recruited 224 participants: 69 healthy controls (mean age 57.12 years, 28% male); 32 with clinically suspected arthralgia (mean age 46.50 years, 11% male); 44 with undifferentiated arthritis (mean age 51.96 years, 21% male); 23 with newly presenting DMARD naive RA and 3 months or less symptom duration (mean age 56.5 years, 30% male) and 56 with DMARD naive RA and greater than 3 months symptom duration (mean age 56.41 years, 41% male). Features of immune ageing were assessed via flow cytometry and a subset of 8 immune cell type frequencies were used to generate an integrated score of immune ageing IMM-AGE and transcriptomic analysis for hallmarks of immune ageing was performed.

Findings: Reduced frequencies of naive CD4 T cells and recent thymic emigrants were seen in patients with arthralgia or undifferentiated arthritis. Other features of immune ageing, such as raised frequency of Th17, Tregs and senescent-like T cells, were only seen once RA was established. Overall, the IMM-AGE score and other hallmarks of ageing (inflammation, autophagic defects) were raised in patients during early stages of the disease. Lastly, we have provided evidence of immune ageing features as a predictor of RA development in arthralgia patients.

Interpretation: We have shown that some features of immune ageing are present in the very early stages of RA and may therefore contribute to disease development. Future research should determine whether geroprotective drugs such as spermidine (autophagy booster), senolytics (clearance of senescent cells) and metformin (attenuates inflammation and boosts autophagy) reduce progression of the disease in patients at risk of RA.

Funding: This study was funded by a grant from FOREUM and the European League Against Rheumatism (EULAR).