Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the 
presence of rheumatoid factor (RF) and anti-citrullinated protein/peptide 
autoantibodies (ACPAs). Citrulline derives from arginine by peptidyl arginine 
deiminases, and ACPAs are directed against different citrullinated antigens, 
including fibrinogen, fibronectin, α-enolase, collagen type II, histones. ACPAs 
are present in two thirds of RA patients have higher specificity than RF for RA, 
and are associated with joint radiographic damage and extra-articular 
manifestations and they are detected years before the onset clinical arthritis. 
Recent studies suggest that citrullinated antigens are most likely arthritogenic 
autoantigens in RA. ACPA production is associated with the HLA-DRB1 shared 
epitope (HLA-DRB1 SE) and accounts for the well-known RA-HLA-DRB1 SE 
association, as T cells recognize citrullinated peptides. Smoking and 
periodontitis, known environmental risk factors for RA promote protein 
citrullination and ACPA production. Cirullinated proteins are capable of 
inducing arthritis in transgenic mice carrying HLA-DRB1 SE genes, and ACPAs 
induce macrophage TNF-α production, osteoclastogenesis and complement 
activation. They also induce the formation of neutrophil extracellular traps 
(NETs). NETs, increased in RA, are a source of citrullinated autoantigens in RA 
and induce fibroblast interleukin-8 production. This knowledge is likely to have 
therapeutic implications, as there is a need of matching therapy with patient 
profile. Abatacept, a T cell activation modulator, is the best therapy for 
ACPA(+) RA patients, although clinical data are sparse at present. Rituximab, a 
monoclonal antibody that depletes B cells, is also the best therapy for ACPA(+) 
RA patients, and clinical data support this view.