title: Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis.
abstract: OBJECTIVE
  To compare the pro-inflammatory cytokine profiles and the cytokine kinetics in patients with secondary macrophage activation syndrome (MAS) due to systemic-onset juvenile idiopathic arthritis (s-JIA) and in both active and inactive disease states of s-JIA (but no MAS), with those demonstrated in EBV-induced haemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD), and to investigate the significance of IL-18 in the pathogenesis of s-JIA.
  
  
  METHODS
  Five patients with MAS complicating s-JIA (MAS/s-JIA), 10 with HLH due to EBV infection (EBV-HLH), 22 with KD and 28 healthy controls were analysed. Cytokine concentrations (IL-18, IL-6, neopterin and TNF-alpha receptor Types I and II) were quantified in serum by ELISA. Results were compared with clinical features of MAS/s-JIA, including ferritin concentrations.
  
  
  RESULTS
  Serum IL-18 concentrations in MAS/s-JIA patients were significantly higher than those in EBV-HLH or KD patients (P < 0.05). Serum IL-6 concentrations in KD patients were significantly higher than those in EBV-HLH or MAS/s-JIA patients. Serum neopterin concentrations in EBV-HLH patients were significantly higher than those in MAS/s-JIA or KD patients. Serum IL-18 correlated positively with the following measurements of disease activity: CRP, ferritin, lactate dehydrogenase and other cytokines (P < 0.05). Serum concentrations of IL-18 in s-JIA patients remained elevated in the inactive phase of disease, whereas clinical parameters and other cytokines normalized.
  
  
  CONCLUSIONS
  IL-18 may be an important mediator in s-JIA. Although serum Il-18 concentrations correlated with markers of the disease activity, IL-18 concentrations remained elevated even when other markers of disease activity normalized. Serum IL-18 concentration may be a promising indicator of the disease activity. The cytokine release pattern in MAS/HLH is different among patients with different aetiologies. Monitoring the cytokine profile, including IL-18, may be useful for differentiation of MAS/HLH and evaluation of disease activity in s-JIA.
authors.affiliation: Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8641, Japan. mshimizu@ped.m.kanazawa-u.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimizu
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kaneda
authors.forename: Hideo
authors.initials: H
authors.lastname: Wada
authors.forename: Taizo
authors.initials: T
authors.lastname: Wada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toma
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Ohta
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kasahara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D015415:Biomarkers; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D020382:Interleukin-18 / Q000276:immunology*; D055501:Macrophage Activation Syndrome / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D013223:Statistics as Topic; D013997:Time Factors
chemical_list: D015415:Biomarkers; D020382:Interleukin-18