Okamoto Y, Devoe S, Seto N, et al. - In patients At-Risk for rheumatoid arthritis (RA), evidence supports a potential mechanism for mucosal anti-citrullinated protein antibody (ACPA) generation whereby inflammation leads to elevated citrullinated-protein expressing neutrophil extracellular traps (NETs) that promote local ACPA generation.

• Researchers obtained induced sputum in 49 individuals At-Risk for RA, 12 with RA, and 18 with controls.

• They found higher spontaneous citrullinated-histone H3 (cit-H3) expressing NET formation in sputum neutrophils from At-Risk and RA in comparison with controls (median 12% vs. 22% vs. 0%, respectively, p<0.01).

• It was shown that sputum ACPA-IgA was associated with the percentage of neutrophils that had undergone cit-H3+ NET formation (r=0.49, p=0.002) and levels of cit-H3+ NET remnants (r=0.70, p<0.001) in At-Risk patients.

• They observed reduced endocytic capacity of sputum macrophages in At-Risk and RA patients in comparison with controls.

• Sputum inflammatory proteins were associated with sputum ACPA-IgA through a pathway mediated by cit-H3+ NET remnants using a mediation model.

• In At-Risk subjects, sputum-induced cit-H3+ NET formation is also associated with sputum IL-1β, IL-6, and TNF-α levels, implying a causal association.