A recent study published in Clinical and Experimental Rheumatology found that anti-neutrophil extracellular trap (anti-NET) antibodies were present in approximately 40% of patients with autoimmune rheumatic diseases and were associated with distinct clinical features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc). In SLE, anti-NET positivity was associated with antiphospholipid syndrome (APS) and arterial thrombosis, suggesting potential value as a biomarker of thrombotic complications.
Neutrophil extracellular traps (NETs) are web-like structures released by neutrophils to capture pathogens. Although NET formation is an important component of innate immunity, excessive or impaired clearance of NETs can expose self-antigens and promote inflammation and autoimmunity. Dysregulated NET formation has been implicated in several rheumatic diseases, including SLE, RA, small-vessel vasculitis, SSc, and gout. NETs may also contribute to vascular injury and thrombosis through interactions with platelets, coagulation pathways, and endothelial cells.
The case-control study evaluated anti-NET antibodies in patients with SLE, RA, and SSc. Serum samples were tested for anti-NET IgG using a laboratory-developed enzyme-linked immunosorbent assay (ELISA) coated with phorbol myristate acetate-induced NETs. Positivity was defined using the 99th percentile of antibody levels in healthy donors.
The study included 349 patients, comprising 136 with SLE, 131 with RA, and 82 with SSc. Approximately 40% were positive for anti-NET antibodies. Among patients with SLE, 50 of 136 (36.8%) were anti-NET positive. Positivity was significantly associated with APS (odds ratio [OR] 3.37, 95% confidence interval [CI] 1.22–9.36; p=0.02) and arterial thrombosis, irrespective of coexisting APS (OR 5.52, 95% CI 1.07–28.52; p=0.032).
The association with arterial thrombosis is clinically relevant because thrombotic events are an important complication of SLE. NETs have been proposed to promote thrombosis by providing a scaffold for platelet activation and coagulation and by interacting with vascular and inflammatory pathways. The study findings therefore support a potential link between NET-related autoimmunity and thrombotic complications in SLE.
Anti-NET antibodies were also detected in RA and SSc. Among 131 patients with RA, 52 (39.7%) were positive, with anti-NET positivity significantly associated with anti-citrullinated protein antibodies (ACPA) (p=0.049). This finding is consistent with the proposed role of NET formation in exposing or generating citrullinated antigens involved in RA-associated autoimmunity.
Among 82 patients with SSc, 33 (40%) were anti-NET positive. Anti-NET levels showed a significant direct correlation with CCL-18 (r=0.289, 95% CI 0.04–0.50; p=0.02), a biomarker associated with fibrotic activity and adverse outcomes, particularly in SSc-associated interstitial lung disease.
The findings suggest that NET-related immune responses may represent a common biological pathway across autoimmune rheumatic diseases, while also being associated with disease-specific manifestations. However, the study establishes associations rather than demonstrating that anti-NET antibodies independently predict future thrombosis. The laboratory-developed assay also requires further standardisation before anti-NET testing can be considered for routine clinical use.
Prospective studies will be needed to determine whether anti-NET antibodies provide additional information beyond established thrombotic risk factors, particularly antiphospholipid antibodies in SLE, and whether antibody levels can predict thrombotic events before they occur. The findings highlight the potential of anti-NET antibodies as a biomarker of thrombotic risk in SLE and support further investigation of NET-related mechanisms in autoimmune rheumatic diseases.
References
- Mancuso S, Rapino L, Riccieri V, Alessandri C, Spinelli FR, Ceccarelli F, Truglia S, Mohammed Reza Beigi D, Garufi C, Pecani A, Conti F. Anti-neutrophil extracellular trap antibodies in autoimmune rheumatic diseases: a suitable biomarker of thrombosis in systemic lupus erythematosus. Clin Exp Rheumatol. 2026 Sep;44(9):1736-1741.
- Apel F, Zychlinsky A, Kenny EF. The role of neutrophil extracellular traps in rheumatic diseases. Nat Rev Rheumatol. 2018 Aug;14(8):467-475.