Neutrophil activation identifies patients with active polyarticular gout
Tóm tắt
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. 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. 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). 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.
Tài liệu tham khảo
So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol. 2017;13(11):639–47.
Schauer C, Janko C, Munoz LE, Zhao Y, Kienhofer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med. 2014;20(5):511–7.
Hahn J, Knopf J, Maueroder C, Kienhofer D, Leppkes M, Herrmann M. Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation. Clin Exp Rheumatol. 2016;34(4 Suppl 98):6–8.
Lee KH, Kronbichler A, Park DD, Park Y, Moon H, Kim H, et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun Rev. 2017;16(11):1160–73.
Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5(178):178ra40.
Moore S, Juo HH, Nielsen CT, Tyden H, Bengtsson AA, Lood C. Neutrophil extracellular traps identify patients at risk of increased disease activity and cardiovascular comorbidity in systemic lupus erythematosus. J Rheumatol. 2019;jrheum.190875.
Schett G, Schauer C, Hoffmann M, Herrmann M. Why does the gout attack stop? A roadmap for the immune pathogenesis of gout. RMD Open. 2015;1(Suppl 1):e000046.
Pieterse E, Jeremic I, Czegley C, Weidner D, Biermann MH, Veissi S, et al. Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals. Sci Rep. 2016;6:38229.
Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74(10):1789–98.
Maska L, Anderson J, Michaud K. Measures of functional status and quality of life in rheumatoid arthritis: Health Assessment Questionnaire Disability Index (HAQ), Modified Health Assessment Questionnaire (MHAQ), Multidimensional Health Assessment Questionnaire (MDHAQ), Health Assessment Questionnaire II (HAQ-II), Improved Health Assessment Questionnaire (Improved HAQ), and Rheumatoid Arthritis Quality of Life (RAQoL). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S4–13.
Pincus T, Yazici Y, Bergman MJ. RAPID3, an index to assess and monitor patients with rheumatoid arthritis, without formal joint counts: similar results to DAS28 and CDAI in clinical trials and clinical care. Rheum Dis Clin N Am. 2009;35(4):773–8 viii.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med. 2016;22(2):146–53.
Duvvuri B, Lood C. Cell-free DNA as a biomarker in autoimmune rheumatic diseases. Front Immunol. 2019;10:502.
Bach M, Moon J, Moore R, Pan T, Nelson JL, Lood C. A neutrophil activation biomarker panel in prognosis and monitoring of patients with rheumatoid arthritis. Arthritis Rheumatol. 2020;72(1):47–56.
Lood C, Hughes GC. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford). 2017;56(4):638–43.
Perez-Ruiz F, Martinez-Indart L, Carmona L, Herrero-Beites AM, Pijoan JI, Krishnan E. Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis. 2014;73(1):177–82.
Stamp LK, Khanna PP, Dalbeth N, Boers M, Maksymowych WP, Schumacher HR Jr, et al. Serum urate in chronic gout--will it be the first validated soluble biomarker in rheumatology? J Rheumatol. 2011;38(7):1462–6.