Neutrophil extracellular traps in rheumatoid arthritis: biomarkers, drivers, and emerging therapeutic targets

Neutrophil extracellular traps (NETs) are web-like structures composed of DNA, histones, and granule proteins released by activated neutrophils. While originally characterized as part of the innate immune response, NETs are now recognized as contributors to the pathogenesis of immune-mediated inflammatory diseases, including rheumatoid arthritis (RA). This review summarizes current clinical evidence linking NETs to RA, with a focus on their utility as biomarkers for disease activity and treatment response and their potential mechanistic role in disease progression. Elevated levels of NET components, such as myeloperoxidase-DNA complexes, citrullinated histones, and calprotectin, have been reported in RA and correlate with inflammatory markers and clinical disease activity scores. Treatment with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor alpha and interleukin-6 inhibitors, reduces NET markers, whereas persistent NET formation is associated with poor response. NETs also promote pathogenic processes, including anti-citrullinated protein antibody formation, Th17 activation, and osteoclastogenesis. Although no therapies currently target NET formation directly, preclinical studies using PAD4 inhibitors and antibodies against citrullinated histones show promising effects. Standardizing NET biomarkers and conducting longitudinal studies will be essential for clinical translation. Overall, NETs represent both a biomarker and a mechanistic driver in RA, offering a novel opportunity for therapeutic intervention.