Anti CCP (ACPA) antibodies are directed against citrulline residues on various proteins formed by posttranslational deimination of arginine residues by the enzyme peptidylarginine deiminase (PAD). They are often found in patients with RA with a sensitivity similar to RF (67%), but with increased specificity (95%). Both RF and anti-CCP can occur years before the onset of symptomatic disease. Environmental factors such as smoking may trigger an autoimmune reaction that involve the shared epitope (in HLA-DR4) and citrulline-modified peptide. Local inflammation may induce the PAD enzyme to citrullinate more proteins locally contributing to the perpetuation of the autoimmune response. There is good evidence for an association of anti–CCP with diagnostically separate RA from other disease such as hepatitis C, which can present with polyarthalgias and a positive RF that resembles RA but have negative anti-CCP antibodies.