Sahlström P, Hansson M, Steen J, et al. - This research was sought to apply patient‐derived monoclonal anti-citrullinated protein antibodies (ACPAs), rather than serum autoantibody analysis, to characterize the multireactivity to different protein modifications and to reveal autoantibody subsets in patients with rheumatoid arthritis (RA). Researchers generated twelve human monoclonal ACPAs (positive by the second‐generation cyclic citrullinated peptide test) from 6 RA patients and conducted a head‐to‐head comparison of their reactivities. A complementary DNA–based protein array (Engine GmbH) and 3 peptide‐screening platforms with RA autoantigens (Thermo Fisher Scientific), citrullinated and carbamylated peptides (NimbleGen/Roche), or histone‐derived peptides with different posttranslational modifications (JPT Histone Code), covering > 207,000 peptides (> 7,800 gene products) were applied. The outcomes of this research demonstrate that ACPAs and anti–modified protein autoantibodies represent overlapping facets of RA autoimmunity and bind to a wide variety of modified proteins, extending well beyond the historically recognized set of RA autoantigens. So far, in RA, acetylated lysine (KAc) reactivity has been detected only in the context of anti–carbamylated and anti-citrullinated peptide autoantibody responses, postulating the existence of hierarchies of autoreactivity. Further evaluations of ACPA fine specificities and functionality should take into consideration the presence of consensus Cit/Carb/KAc motifs and the multireactivity of these autoantibodies in individuals with RA.