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Ratios of S100A12 to CXCL9 and of S100A12 to CXCL10 were also higher in samples from patients with systemic JIA-MAS and distinguished between these disease entities ( figure 2C). Ratios of IL-18 to CXCL9, and IL-18 to CXCL10-considered to be surrogates of IFNγ signalling-were significantly elevated in samples from patients with systemic JIA-MAS compared to those with primary or secondary HLH and could distinguish between disease entities ( figure 2C).
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A subset of serum proteins was selectively elevated in patients with HLH compared with systemic JIA-MAS (ie, monocyte chemotactic protein -2, macrophage colony stimulating factor, cathepsin B, and soluble FASL figure 2B) others were overexpressed during episodes of systemic JIA-MAS compared with HLH (eg, IL-18 and S100A12 figure 2C). When analysing all markers quantified in discovery cohort samples individually for their ability to discriminate between HLH and systemic JIA-MAS using multiple-comparison statistics, we identified a set of serum proteins that were selectively elevated in secondary HLH, primary HLH, or systemic JIA-MAS ( figure 2A, appendix pp 5-6, 8). Corresponding principal component analyses separated samples from patients with HLH from those with systemic JIA-MAS, despite some overlap with healthy controls ( figure 1B). Cluster 3 comprised markers selectively elevated in systemic JIA-MAS or healthy controls ( figure 1A). Biomarkers with elevated concentrations in both healthy controls and systemic JIA-MAS were assigned to cluster 2 this cluster included several biomarkers that were not differentially expressed between patients with systemic JIA-MAS and those with HLH. Biomarkers selectively increased in serum from patients with secondary HLH and primary HLH constituted cluster 1. The study complied with the Standards for Reporting of Diagnostic Accuracy guidelines ( appendix pp 2-3).Īmong discovery cohort samples, unsupervised hierarchical clustering of biomarker expression profiles identified three distinct clusters ( figure 1A). Following unblinding, the performance of biomarkers in distinguishing systemic JIA-MAS from primary HLH, or secondary HLH, or both, was evaluated by receiver operating characteristic analyses. Validation cohort samples were analysed in a blinded manner using the commercial multiplex assay and S100A12 ELISA, and samples were designated as either HLH or systemic JIA-MAS based on the previously determined cutoff values. Biomarkers with a between-assay Spearman's correlation coefficient of r>0♷ were selected for testing in the validation cohort (along with S100A12), with cutoff values determined according to the Youden index. Details on the number of samples collected in the various patient groups from different centres are detailed in the appendix (p 1).īiomarkers that were able to distinguish between these clinical entities were re-tested using a commercially available multiplex bead array assay (ProcartaPlex multiplex immunoassay platform, Thermo Fisher Scientific, Waltham, MA, USA), and correlation between data generated from the custom multiplex assay and the commercially available multiplex assay was assessed.
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The discovery cohort also included ten healthy controls ( appendix p 7). Samples from patients with primary HLH, secondary HLH, or systemic JIA-MAS were split into a discovery cohort (primary HLH secondary HLH, systemic JIA-MAS ) and a validation cohort (primary HLH secondary HLH systemic JIA-MAS ). Were collected from patients treated at seven different centres in Europe and North America (University Hospital Freiburg, Freiburg, Germany University Medical Center Utrecht, Utrecht, Netherlands Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Rome, Italy Karolinska Institute, Stockholm, Sweden University Children's Hospital Muenster, Muenster, Germany and University Hospital Leuven, Leuven, Belgium). The Lancet Regional Health – Western Pacific.The Lancet Regional Health – Southeast Asia.The Lancet Gastroenterology & Hepatology.