Abstract
BackgroundGout 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.MethodsPlasma 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.ResultsLevels 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).ConclusionsNeutrophil 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.
Highlights
IntroductionA 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
Gout is the most prevalent inflammatory arthritis in developed countries
The median duration of a gout flare was 5 days (IQR 3– 7) while the last experienced attack was of significantly longer duration
Summary
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. A gout flare is an inflammatory response to deposited monosodium urate (MSU) crystals, mediated by activation of the innate immune system with attraction and activation of macrophages and neutrophils. During phagocytosis of the crystals, macrophages activate the inflammasome with subsequent release of interleukin (IL-) 1B and other pro-inflammatory cytokines [1] These cytokines increase the attraction and activation of neutrophils, which in turn participate in host defense through several mechanisms, including phagocytosis of the MSU crystals and release of various proteolytic enzymes, as well as formation of neutrophil extracellular traps (NETs) [2]. Even though local NET formation is suggested to play a crucial role in the gout pathogenesis, as demonstrated in in vitro and in vivo in animal models [8], the role of neutrophil activation and circulating NETs in systemic inflammation in gout patients has not been carefully investigated
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