Background/Purpose: Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (NETs). Excessive neutrophil activation has been linked to inflammation and autoimmunity, including gout. In gout models, uric acid crystals induce NETosis. NETs are known to induce inflammation and partake in induction of tissue damage. The role of NETs, however, in human gout has not been extensively investigated.

Our objective is to investigate the clinical utility of neutrophil-derived biomarkers in gout. We hypothesize that uric acid crystals activate neutrophils to form NETs contributing to immune cell activation, with subsequent arthritis and joint damage.

Methods: Plasma samples from 75 gout patients participating in the ‘Reade gout cohort Amsterdam’ were compared with 30 healthy controls (HC). Levels of NETs, and NET-derived markers (cell-free DNA and peroxidase activity) were analyzed using a MPO-DNA ELISA, as well as fluorimetry. Levels of calprotectin were analyzed by ELISA. Mitochondrial as well as genomic DNA levels were analyzed by qPCR. All markers were compared with HC and related to markers of inflammation and disease activity.

Results: Levels of NETs, as well as other neutrophil biomarkers, were increased in gout patients as compared to HC (p< 0.01, Figures 1A-B). No associations were found between markers of cell death (cfDNA and NETs) and disease activity. Genomic DNA, but not mitochondrial DNA, was elevated among gout patients (p< 0.05), and related to number of gout attacks (r=0.44, p=0.002). Peroxidase activity correlated with disease activity (RAPID score: r=0.43, p=0.01, RAPID function: r=0.54, p=0.001) and inflammation markers (CRP: r=0.40, p< 0.001, and ESR: r=0.43, p< 0.001). Involvement of ankle and wrist resulted in significant higher peroxidase levels compared to mono-articular disease (p=0.01, and p=0.03, respectively), indicating peroxidase activity being a marker of polyarticular gout (Figure 1C). Calprotectin (S100A8/A9) correlated with the inflammation markers CRP and ESR (r=0.30, p=0.01, and r=0.30, p=0.001, respectively) and morning stiffness, especially in patients with chronic polyarticular gout (r=0.61, p=0.001).

Conclusion: To our knowledge, this is the first report demonstrating presence of NETs in the peripheral blood of gout patients. Although markedly elevated, levels of NETs did not associate with markers of disease activity or inflammation, possibly due to the lack of inflammatory mitochondrial DNA within the NETs. Even so, our data demonstrate an important role of neutrophils in gout pathogenesis, with neutrophil activation markers associating with characteristics of active, and more pronounced polyarticular disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutrophil-activation-identifies-patients-with-active-polyarticular-gout-a-role-for-neutrophil-biomarkers-in-monitoring-gout-disease-activity-and-severity/