PRTN3 and rheumatoid arthritis: Subsequently, an association between smoking and ACPA positivity was demonstrated,118, 119 and this association could be mostly observed in individuals positive for HLA‐SE.120, 121, 122 This interaction between the environmental risk factor smoking and the genetic risk factor HLA‐SE has given rise to a prominent hypothesis about RA pathogenesis123, 124: Smoking leads to inflammatory changes in lungs subsequently causing activation of PADs and generation of citrullinated residues in the lung tissue.