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

TL;DR

Neutrophil extracellular traps (NETs) are linked to rheumatoid arthritis (RA), acting as both a biomarker for disease activity and a potential target for new treatments.

Contribution

This paper reviews the role of NETs in RA, highlighting their dual function as biomarkers and drivers of disease progression.

Findings

Elevated NET components correlate with RA disease activity and treatment response.

Biological therapies reduce NET markers, while persistent NETs are linked to poor outcomes.

NETs contribute to autoantibody formation, Th17 activation, and bone destruction in RA.

Abstract

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.

Neutrophil extracellular traps (NETs) play an important role in the development of rheumatoid arthritis (RA). Clinical evidence shows that components of NETs are linked to disease activity in RA, treatment response, and important disease processes such as autoantibody formation and bone destruction. Altogether, NETs have the potential to serve as both a useful biomarker and a therapeutic target for RA.

Graphical AbstractNETosis can be triggered by various environmental factors in genetically or immunologically susceptible individuals. These initial triggers lead to the activation of PAD enzymes, mucosal cells, and neutrophils, ultimately resulting in the formation of neutrophil extracellular traps (NETs). As a rich source of autoantigens, NETs stimulate local B cells to produce anti-citrullinated protein antibodies (ACPAs). The ACPA pool then expands and enters systemic circulation, forming immune complexes. Immune complexes along with proinflammatory mediators released during NET formation activate various circulating immune cells, thereby further amplifying the NETosis response. In target tissues, NETs and their components activate a range of cell types, including fibroblast-like synoviocytes (FLSs), monocytes, macrophages, dendritic cells (DCs), T cells, and B cells. This cascade of interactions creates a highly inflammatory milieu that contributes to cartilage degradation and bone erosion [Created in BioRender. Kumari, S. (2026) https://BioRender.com/sx5nxrq].For image description, please refer to the figure legend and surrounding text.

NETosis can be triggered by various environmental factors in genetically or immunologically susceptible individuals. These initial triggers lead to the activation of PAD enzymes, mucosal cells, and neutrophils, ultimately resulting in the formation of neutrophil extracellular traps (NETs). As a rich source of autoantigens, NETs stimulate local B cells to produce anti-citrullinated protein antibodies (ACPAs). The ACPA pool then expands and enters systemic circulation, forming immune complexes. Immune complexes along with proinflammatory mediators released during NET formation activate various circulating immune cells, thereby further amplifying the NETosis response. In target tissues, NETs and their components activate a range of cell types, including fibroblast-like synoviocytes (FLSs), monocytes, macrophages, dendritic cells (DCs), T cells, and B cells. This cascade of interactions creates a highly inflammatory milieu that contributes to cartilage degradation and bone erosion [Created in BioRender. Kumari, S. (2026) https://BioRender.com/sx5nxrq].

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