In conclusion, we demonstrate that progression from preclinical autoimmunity to clinical RA is associated with (i) progressive epitope spreading of the ACPA response, as evidenced by the targeting of additional citrullinated epitopes (both intramolecular and intermolecular spreading), (ii) inflammation, as evidenced by increases in blood cytokine levels, and (iii) that citrullinated protein epitopes derived from fibrinogen, histones and vimentin are targeted at the earliest observable break in tolerance to citrullinated antigens in at least a subset of individuals with preclinical RA. This evidence concerns the gene PRTN3 and Autoimmunity.