title: Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis.
abstract: BACKGROUND
  Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment.
  
  
  METHODS
  A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines.
  
  
  RESULTS
  27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra.
  
  
  CONCLUSIONS
  MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.
authors.affiliation: Department of Pediatric Rheumatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. v_boom@hotmail.com.
authors.forename: V
authors.initials: V
authors.lastname: Boom
authors.affiliation: Pediatric Rheumatology Unit, Hospital Sant Joan de Déu. Universitat de Barcelona, Barcelona, Spain. JAnton@hsjdbcn.org.
authors.forename: J
authors.initials: J
authors.lastname: Anton
authors.affiliation: Department of Pediatrics, Children's Hospital, University Hospital Helsinki, Helsinki, Finland. Pekka.Lahdenne@hus.fi.
authors.forename: P
authors.initials: P
authors.lastname: Lahdenne
authors.affiliation: Pediatric Immunology-Hematology and Rheumatology Unit and IMAGINE Institute, Necker-Enfants Malades Hospital, Assistance Publique Hopitaux de Paris and Universite Paris-Descartes, Paris, France. pierre.quartier@nck.aphp.fr.
authors.forename: P
authors.initials: P
authors.lastname: Quartier
authors.affiliation: Department of pediatric rheumatology, Instituto Giannini Gaslini, Genua, Italy. angeloravelli@ospedale-gaslini.ge.it.
authors.forename: A
authors.initials: A
authors.lastname: Ravelli
authors.affiliation: Department of Pediatric Rheumatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. N.Wulffraat@umcutrecht.nl.
authors.forename: N M
authors.initials: NM
authors.lastname: Wulffraat
authors.affiliation: Department of Pediatric Rheumatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. b.vastert@umcutrecht.nl.
authors.forename: S J
authors.initials: SJ
authors.lastname: Vastert
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000150:complications*; D015415:Biomarkers / Q000032:analysis; D016572:Cyclosporine / Q000008:administration & dosage / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D055501:Macrophage Activation Syndrome / Q000175:diagnosis* / Q000188:drug therapy / Q000209:etiology
chemical_list: D000305:Adrenal Cortex Hormones; D015415:Biomarkers; D007166:Immunosuppressive Agents; D016572:Cyclosporine