title: Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS).
abstract: Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated withNLRP3gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless ofNLRP3mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.
authors.affiliation: Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Jasmin B
authors.initials: JB
authors.lastname: Kuemmerle-Deschner
authors.affiliation: Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Seza
authors.initials: S
authors.lastname: Ozen
authors.affiliation: Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Pascal N
authors.initials: PN
authors.lastname: Tyrrell
authors.affiliation: Department of Pediatric Rheumatology, Reference Centre for Autoinflammatory Disorders CEREMAI, Bicêtre Hospital, University of Paris SUD, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Kone-Paut
authors.affiliation: Translational Autoinflammatory Disease Section, NIAMS/NIH, Bethesda, Maryland, USA.
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.affiliation: National Amyloidosis Centre, University College London Medical School, London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Lachmann
authors.affiliation: Haematologie, Onkologie und Rheumatologie, Universitaetsklinikum Heidelberg, Heidelberg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Blank
authors.affiliation: University of California at San Diego, San Diego, California, USA.
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: Kinderrheumatologische Ambulanz, Universitaetsklinikum Eppendorf, Hamburg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Weissbarth-Riedel
authors.affiliation: German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hugle
authors.affiliation: Department of Rheumatology, Charité, University Medicine Berlin, Berlin, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Kallinich
authors.affiliation: UO Pediatria 2, G. Gaslini Institute, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.affiliation: Istanbul University, Istanbul, Turkey.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Gul
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Nienke
authors.initials: N
authors.lastname: Ter Haar
authors.affiliation: Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Oswald
authors.affiliation: Department of Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Fatma
authors.initials: F
authors.lastname: Dedeoglu
authors.affiliation: Rheumatology Unit, Policlinico Le Scotte, University of Sienna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cantarini
authors.affiliation: Rheumatology, Department of Paediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Benseler
mesh_terms: D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000002:abnormalities; D002097:C-Reactive Protein / Q000378:metabolism; D002908:Chronic Disease; D056587:Cryopyrin-Associated Periodic Syndromes / Q000097:blood / Q000150:complications / Q000175:diagnosis* / Q000209:etiology; D006319:Hearing Loss, Sensorineural / Q000209:etiology; D006801:Humans; D008582:Meningitis, Aseptic / Q000209:etiology; D009140:Musculoskeletal Diseases / Q000209:etiology; D000685:Serum Amyloid A Protein / Q000378:metabolism; D014581:Urticaria / Q000209:etiology
chemical_list: D015415:Biomarkers; D000685:Serum Amyloid A Protein; D002097:C-Reactive Protein
keywords: Epidemiology; Fever Syndromes; Health services research; Multidisciplinary team-care