Article Text

Download PDFPDF
Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS)
  1. Jasmin B Kuemmerle-Deschner1,
  2. Seza Ozen2,
  3. Pascal N Tyrrell3,
  4. Isabelle Kone-Paut4,
  5. Raphaela Goldbach-Mansky5,
  6. Helen Lachmann6,
  7. Norbert Blank7,
  8. Hal M Hoffman8,
  9. Elisabeth Weissbarth-Riedel9,
  10. Boris Hugle10,
  11. Tilmann Kallinich11,
  12. Marco Gattorno12,
  13. Ahmet Gul13,
  14. Nienke Ter Haar14,
  15. Marlen Oswald1,
  16. Fatma Dedeoglu15,16,
  17. Luca Cantarini17,
  18. Susanne M Benseler18
  1. 1Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
  2. 2Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey
  3. 3Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada
  4. 4Department of Pediatric Rheumatology, Reference Centre for Autoinflammatory Disorders CEREMAI, Bicêtre Hospital, University of Paris SUD, Paris, France
  5. 5Translational Autoinflammatory Disease Section, NIAMS/NIH, Bethesda, Maryland, USA
  6. 6National Amyloidosis Centre, University College London Medical School, London, UK
  7. 7Haematologie, Onkologie und Rheumatologie, Universitaetsklinikum Heidelberg, Heidelberg, Germany
  8. 8University of California at San Diego, San Diego, California, USA
  9. 9Kinderrheumatologische Ambulanz, Universitaetsklinikum Eppendorf, Hamburg, Germany
  10. 10German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen, Germany
  11. 11Department of Rheumatology, Charité, University Medicine Berlin, Berlin, Germany
  12. 12UO Pediatria 2, G. Gaslini Institute, Genoa, Italy
  13. 13Istanbul University, Istanbul, Turkey
  14. 14Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  15. 15Department of Rheumatology, Boston Children's Hospital, Boston, Massachusetts, USA
  16. 16Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
  17. 17Rheumatology Unit, Policlinico Le Scotte, University of Sienna, Italy
  18. 18Rheumatology, Department of Paediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
  1. Correspondence to Dr Jasmin B Kuemmerle-Deschner, Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Hoppe-Seyler-Strasse 1, Tuebingen 72076, Germany; kuemmerle.deschner{at}


Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene 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 of NLRP3 mutation. 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.

  • Fever Syndromes
  • Epidemiology
  • Health services research
  • Multidisciplinary team-care

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Handling editor Tore K Kvien

  • Contributors JBK-D, SO and SMB conceived of the study, organised the project, wrote and revised the manuscript; PNT conducted the statistical analyses; IK-P, RG-M, HL, NB, HMH, EW-R, BH, TK, MG, AG, FD and LC participated in the expert surveys and consensus conferences; NTH and MO conducted the standardised literature search and evaluated the papers for scientific content applying to this study.

  • Competing interests JBK-D performed clinical studies with Novartis and received speaking honoraria from Novartis and SOBI.

  • Provenance and peer review Not commissioned; externally peer reviewed.