When and how chronicity develops in rheumatoid arthritis: towards a temporal and tissue-integrated perspective.

Although the diagnosis of rheumatoid arthritis can usually be made once clinical arthritis appears, this moment does not represent the biological onset of disease. Rheumatoid arthritis develops over a period of years in preclinical phases that precede the emergence of persistent joint inflammation. In this narrative Review, we examine how chronicity develops along this trajectory by integrating temporal and tissue perspectives. We discuss early disease phases characterised by the emergence and maturation of autoimmunity and systemic inflammatory shifts, followed by stages marked by subclinical and subsequently clinical joint inflammation, in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative rheumatoid arthritis. We consider how some immune perturbations could resolve in some individuals, while others progress to self-sustaining disease, highlighting that reversibility might differ across disease trajectories. Lastly, we examine how evolving multi-hit hypotheses, recent omics studies, and results from prevention trials inform the identification of checkpoints at which progression to chronic disease might still be modifiable.