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When and how chronicity develops in rheumatoid arthritis: towards a temporal and tissue-integrated perspective
Alper Cevirgel1, Annette H M van der Helm-van Mil1
1Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.
The Lancet. Rheumatology
|July 14, 2026
Summary
Rheumatoid arthritis develops over years before joint inflammation appears. Understanding these preclinical phases, including autoimmunity and immune shifts, is key to identifying modifiable checkpoints for preventing chronic disease.
Area of Science:
- Rheumatology
- Immunology
- Disease Pathogenesis
Background:
- Rheumatoid arthritis (RA) diagnosis typically occurs after clinical joint inflammation is evident.
- The biological onset of RA precedes clinical symptoms, involving years of preclinical disease development.
- Understanding the RA disease trajectory is crucial for early intervention and prevention strategies.
Purpose of the Study:
- To review the chronicity development in rheumatoid arthritis from a temporal and tissue perspective.
- To explore the preclinical phases of RA, including autoimmunity and systemic inflammation.
- To identify potential modifiable checkpoints in RA progression.
Main Methods:
- Narrative review integrating temporal and tissue perspectives.
- Discussion of early disease phases: autoimmunity, systemic inflammation, and joint inflammation.
- Analysis of anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA trajectories.
Main Results:
- RA progresses through preclinical phases characterized by autoimmunity and systemic inflammation before joint involvement.
- Immune perturbations can either resolve or progress to self-sustaining disease, with varying reversibility.
- Evolving hypotheses, omics studies, and prevention trials offer insights into modifiable disease checkpoints.
Conclusions:
- The development of chronic rheumatoid arthritis is a multi-year process with distinct preclinical stages.
- Identifying and targeting early immune dysregulation may offer opportunities to prevent RA progression.
- Further research into RA pathogenesis and prevention is essential for improving patient outcomes.
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