title: Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis.
abstract: OBJECTIVE
  Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS).
  
  
  METHODS
  FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-α (sIL-2Rα). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC).
  
  
  RESULTS
  Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Rα, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS.
  
  
  CONCLUSIONS
  Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA.
authors.affiliation: Division of Rheumatology, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center (UPMC), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA. mgoreli6@jhmi.edu
authors.forename: Mark
authors.initials: M
authors.lastname: Gorelik
authors.forename: Ndate
authors.initials: N
authors.lastname: Fall
authors.forename: Mekibib
authors.initials: M
authors.lastname: Altaye
authors.forename: Michael G
authors.initials: MG
authors.lastname: Barnes
authors.forename: Susan D
authors.initials: SD
authors.lastname: Thompson
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.forename: Raphael
authors.initials: R
authors.lastname: Hirsch
mesh_terms: D001171:Arthritis, Juvenile / Q000097:blood* / Q000150:complications / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001799:Blood Sedimentation; D002648:Child; D002675:Child, Preschool; D005260:Female; D005293:Ferritins / Q000097:blood*; D038702:Follistatin-Related Proteins / Q000097:blood*; D015870:Gene Expression; D006801:Humans; D055501:Macrophage Activation Syndrome / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D008297:Male
chemical_list: D015415:Biomarkers; D038702:Follistatin-Related Proteins; D005293:Ferritins
keywords: BIOMARKERS; FOLLISTATIN-LIKE PROTEIN 1; MACROPHAGE ACTIVATION SYNDROME; SENSITIVITY; SPECIFICITY; SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS