Background: Gout is the most prevalent inflammatory arthritis in developed countries. A gout flare is mediated by phagocytosis of monosodium urate crystals by macrophages and neutrophils leading to subsequent activation of neutrophils contributing to synovitis, local joint destruction, and systemic inflammation. We hypothesize that biomarkers from activated neutrophils reflect gout disease activity. The objective of this study therefore was to investigate the clinical utility of neutrophil-derived biomarkers in gout disease activity.
Methods: Plasma samples from 75 gout patients participating in the "Reade gout cohort Amsterdam" were compared with 30 healthy controls (HC). Levels of neutrophil extracellular traps (NETs) and neutrophil activation markers (calprotectin and peroxidase activity) were analyzed by ELISA and fluorimetry, compared to healthy controls, and related to markers of inflammation and disease activity.
Results: Levels of NETs, as well as neutrophil activation markers, were increased in gout patients compared to HC (p < 0.01). No associations were found between markers of cell death (cell-free DNA and NETs) and disease activity. Cell-free levels of genomic DNA were elevated among gout patients compared to HC (p < 0.05) and related to the number of gout attacks in the last year (β = 0.35, p < 0.01). Peroxidase activity correlated with disease activity (RAPID score: β = 0.49, p < 0.01, MHAQ: β = 0.66, p < 0.01) and inflammation markers (CRP: β = 0.25, p = 0.04, and ESR: β = 0.57, p < 0.001). Involvement of ankle or wrist resulted in significant higher peroxidase levels compared to mono-articular disease (β = 0.34, p < 0.01), indicating that peroxidase activity is a marker of poly-articular gout. Calprotectin (S100A8/A9) correlated with the inflammation marker CRP (β = 0.23, p = 0.05) and morning stiffness, especially in patients with chronic poly-articular gout (β = 0.71, p < 0.01).
Conclusions: Neutrophil activation markers are associated with characteristics of active, polyarticular gout. Furthermore, NETs are present in the peripheral blood of gout patients. However, NETs do not associate with markers of disease activity or inflammation. Future research should point out if peroxidase and calprotectin could be used in clinical practice as biomarkers for monitoring gout disease activity.
Keywords: Crystal-induced arthritis; Disease activity; Gout; Innate immunity; Neutrophils.