Circulating cytokines (e.g., IL-1, IL-6, IL-12, tumor necrosis factor [TNF], interferon-γ, granulocyte–macrophage colony-stimulating factor), chemokines (e.g., monocyte chemotactic protein-1, macrophage inflammatory protein-1) and common markers of inflammation such as C-reactive protein have all been shown to increase progressively during the preclinical stages of RA, paralleling or even preceding the appearance and maturation of pathogenic autoantibodies (194–196). This evidence concerns the gene CRP and rheumatoid arthritis.