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.

The IL-1 family comprises key pro-inflammatory cytokines that are central to host defence against noxious stimuli, as evidenced by their prominent expression at barrier tissues and their shared myeloid differentiation primary response 88 (MyD88)-dependent signalling pathways with Toll-like receptors. The generation of biologically active IL-1 agonists is tightly controlled by proteolytic processing (including inflammasome-dependent and independent mechanisms), which converts inactive precursors into mature cytokines or substantially amplifies the activity of selected family members. IL-1 signalling is further regulated at multiple levels by endogenous inhibitors, decoy receptors and receptor antagonists, ensuring a finely tuned balance between pro-inflammatory and anti-inflammatory responses; this balance is essential for effective antimicrobial immunity while limiting immunopathology. Converging evidence from human studies and experimental disease models demonstrates that disruption of this regulatory balance underlies a broad spectrum of inflammatory diseases. Numerous therapies that target IL-1 cytokines have been approved for the treatment of inflammatory diseases or are in development, and the clinical efficacy of these therapies provides compelling validation of their pathogenic role in numerous disease contexts.