Abstract:
OBJECTIVES:Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterised by flares of sterile arthritis with neutrophil infiltrate and the overproduction of interleukin (IL)-1β. The purpose of this study was to elucidate the potential role of neutrophil subsets and neutrophil extracellular traps (NET) in the pathogenesis of PAPA. METHODS:Neutrophils and low-density granulocytes (LDG) were quantified by flow cytometry. Circulating NETs were measured by ELISA and PAPA serum was tested for the ability to degrade NETs. The capacity of NETs from PAPA neutrophils to activate macrophages was assessed. Skin biopsies were analysed for NETs and neutrophil gene signatures. RESULTS:Circulating LDGs are elevated in PAPA subjects. PAPA neutrophils and LDGs display enhanced NET formation compared with control neutrophils. PAPA sera exhibit impaired NET degradation and this is corrected with exogenous DNase1. Recombinant human IL-1β induces NET formation in PAPA neutrophils but not healthy control neutrophils. NET formation in healthy control neutrophils is induced by PAPA serum and this effect is inhibited by the IL-1 receptor antagonist, anakinra. NETs from PAPA neutrophils and LDGs stimulate IL-6 release in healthy control macrophages. NETs are detected in skin biopsies of patients with PAPA syndrome in association with increased tissue IL-1β, IL-8 and IL-17. Furthermore, LDG gene signatures are detected in PAPA skin. CONCLUSIONS:PAPA syndrome is characterised by an imbalance of NET formation and degradation that may enhance the half-life of these structures in vivo, promoting inflammation. Anakinra ameliorates NET formation in PAPA and this finding supports a role for IL-1 signalling in exacerbated neutrophil responses in this disease. The study also highlights other inflammatory pathways potentially pathogenic in PAPA, including IL-17 and IL-6, and these results may help guide new therapeutic approaches in this severe and often treatment-refractory condition.
journal_name
Ann Rheum Disjournal_title
Annals of the rheumatic diseasesauthors
Mistry P,Carmona-Rivera C,Ombrello AK,Hoffmann P,Seto NL,Jones A,Stone DL,Naz F,Carlucci P,Dell'Orso S,Gutierrez-Cruz G,Sun HW,Kastner DL,Aksentijevich I,Kaplan MJdoi
10.1136/annrheumdis-2018-213746subject
Has Abstractpub_date
2018-12-01 00:00:00pages
1825-1833issue
12eissn
0003-4967issn
1468-2060pii
annrheumdis-2018-213746journal_volume
77pub_type
杂志文章abstract::In the use of anti-inflammatory compounds, sustained serum levels are thought to be related to drug efficacy. This study shows that frequent clinical administration of indomethacin can result in sustained serum levels of the drug and that food and antacid may have important modifying effects on serum indomethacin conc...
journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.35.4.333
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abstract::The adherent cells remaining after short-term culture of synovial fluid and synovial membrane cells from rheumatoid and non-rheumatoid patients were examined for the presence of a productive virus infection and for various viral antigens. Labelling was carried out with 3H-thymidine and 3H-uridine followed by sucrose d...
journal_title:Annals of the rheumatic diseases
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,评审
doi:10.1136/ard.2004.027367
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更新日期:2001-04-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,多中心研究
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journal_title:Annals of the rheumatic diseases
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journal_title:Annals of the rheumatic diseases
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pub_type: 杂志文章,多中心研究
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journal_title:Annals of the rheumatic diseases
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doi:10.1136/ard.2002.005546
更新日期:2004-01-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.52.11.790
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.58.2.72
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journal_title:Annals of the rheumatic diseases
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1136/ard.2004.023572
更新日期:2005-03-01 00:00:00
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pub_type: 杂志文章,meta分析,评审
doi:10.1136/ard.2007.071415
更新日期:2008-02-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.2009.127175
更新日期:2010-12-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.2008.092288
更新日期:2009-06-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/annrheumdis-2015-207483
更新日期:2016-08-01 00:00:00
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pub_type: 杂志文章
doi:10.1136/ard.2008.099713
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pub_type: 共识发展会议,杂志文章,评审
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doi:10.1136/ard.61.1.55
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pub_type: 杂志文章
doi:10.1136/annrheumdis-2012-202328
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.2006.057406
更新日期:2007-02-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章,随机对照试验
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更新日期:2020-10-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/annrheumdis-2020-217840
更新日期:2021-02-01 00:00:00
abstract::The phenomenon of increased spontaneous incorporation of 3H-thymidine (3H-TdR) into peripheral blood mononuclear cells in rheumatoid arthritis (RA) has been investigated. The activity was found to be short lived and affected less than 1% of cells. Using a Percoll density gradient we identified two populations of activ...
journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.43.5.703
更新日期:1984-10-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.61.1.10
更新日期:2002-01-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
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更新日期:2020-02-01 00:00:00
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journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.2011.151712
更新日期:2012-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1136/ard.2006.052571
更新日期:2006-09-01 00:00:00
abstract::In this retrospective study of 57 patients with primary hyperparathyroidism who underwent parathyroidectomy, the overall incidence of chondrocalcinosis was 40%. Neither joint symptoms nor chondrocalcinosis regressed after the operation. In several patients the condition appeared to deteriorate both clinically and radi...
journal_title:Annals of the rheumatic diseases
pub_type: 杂志文章
doi:10.1136/ard.35.6.521
更新日期:1976-12-01 00:00:00