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Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study

Wilco de Jager¹, Esther P A H Hoppenreijs², Nico M Wulffraat¹, Lucy R Wedderburn³, Wietse Kuis¹, Berent J Prakken¹

¹ Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands; IACOPO Institute for Translational Medicine, Utrecht, The Netherlands; San Diego, California, USA
² Department of Pediatrics, University Medical Center Nijmegen, Nijmegen, The Netherlands
³ Rheumatology Unit, Institute of Child Health, University College, London, UK

Correspondence to:
Professor B J Prakken
Department of Pediatric Immunology (KC010690), University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands; bprakken{at}umcutrecht.nl

Background: Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators.

Objective: To identify a panel of cytokines specifically related to the inflammatory process in JIA.

Methods: Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease.

Results: Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor , macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested.

Conclusion: It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

Abbreviations: CRP, C reactive protein; ESR, erythrocyte sedimentation rate; IFN, interferon; IL, interleukin; JIA, juvenile idiopathic arthritis; MIA, multiplex immunoassay; MIF, macrophage inhibitory factor; NK, natural killer; OSM, oncostatin M; RANKL, receptor activator of nuclear factor B ligand; Th, T helper (cell); TNF, tumour necrosis factor

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