An essential step in the formation of ACPA autoantibodies is the citrullination of self-protein by peptidyl arginine deiminase (PAD), a family of enzymes that modify proteins by converting arginine to citrulline and conferring antigenic potential.^1-3

• In susceptible individuals, tolerance to citrullinated self-proteins breaks down and these PAD-modified self-proteins become self-antigens, driving T-cell activation, differentiation and consequent inflammation.^1,4
• T-cells in turn promote B-cell maturation and activation of B cells, with ultimate production of autoantibodies to citrullinated self-proteins, which may appear many years prior to onset of disease symptoms.^1,4,5
• Circulating ACPA autoantibodies that enter the joint as well as those generated within the joint induce local inflammation through the formation of immune complexes with PAD-citrullinated proteins.^4,6
• PAD-induced anti-citrullinated protein autoantibodies (ACPAs) have been associated with more aggressive autoimmune disease with a poorer prognosis.^3,5