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Classification criteria for autoinflammatory recurrent fevers
  1. Marco Gattorno1,
  2. Michael Hofer2,3,
  3. Silvia Federici4,
  4. Federica Vanoni5,
  5. Francesca Bovis6,
  6. Ivona Aksentijevich7,
  7. Jordi Anton8,
  8. Juan Ignacio Arostegui9,
  9. Karyl Barron10,
  10. Eldad Ben-Cherit11,
  11. Paul A Brogan12,
  12. Luca Cantarini13,
  13. Isabella Ceccherini14,
  14. Fabrizio De Benedetti15,
  15. Fatma Dedeoglu16,
  16. Erkan Demirkaya17,
  17. Joost Frenkel18,
  18. Raphaela Goldbach-Mansky19,
  19. Ahmet Gul20,
  20. Veronique Hentgen21,
  21. Hal Hoffman22,
  22. Tilmann Kallinich23,
  23. Isabelle Kone-Paut24,
  24. Jasmin Kuemmerle-Deschner25,
  25. Helen J Lachmann26,
  26. Ronald M Laxer27,
  27. Avi Livneh28,
  28. Laura Obici29,
  29. Seza Ozen30,
  30. Dorota Rowczenio26,
  31. Ricardo Russo31,
  32. Yael Shinar32,
  33. Anna Simon33,
  34. Nataša Toplak34,
  35. Isabelle Touitou35,
  36. Yosef Uziel36,37,
  37. Marielle van Gijn38,
  38. Dirk Foell39,
  39. Claudia Garassino40,
  40. Dan Kastner10,
  41. Alberto Martini40,
  42. Maria Pia Sormani6,41,
  43. Nicolino Ruperto42
  1. 1UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  2. 2Department of Paediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
  3. 3University Hospital of Geneva, Geneva, Switzerland
  4. 4Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy
  5. 5Department of Pediatrics, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland
  6. 6Department of Health Sciences (DISSAL), University of Genova, Genova, Italy
  7. 7Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  8. 8Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Catalunya, Spain
  9. 9Immunology Department, CDB, Hospital Clínic/IDIBAPS, Barcelona, Spain
  10. 10Division of Intramural Research, NIH-NIAID, Bethesda, Maryland, USA
  11. 11Rheumatology Unit, Hadassah-Hebrew University Hospital, Ein Kerem, Jerusalem, Israel
  12. 12Institute of Child Health, University College London, London, UK
  13. 13Department of Medical Sciences, University of Siena, Siena, Italy
  14. 14Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  15. 15Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  16. 16Pediatric Rheumatology, Harvard University Children's Hospital, Boston, Massachusetts, USA
  17. 17Unit of Pediatric Rheumatology, Western University Children’s Hospital, London, Ontario, Canada
  18. 18Department of Pediatrics, Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands
  19. 19Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  20. 20Division of Rheumatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
  21. 21National Referral Centre of Auto-Inflammatory Diseases and Inflammatory Amyloidosis, CEREMAIA, Versailles Hospital, Le Chesnay (Paris), France
  22. 22Department of Pediatrics, University of California at San Diego, San Diego, California, USA
  23. 23Pediatric Pneumology and Immunology, Charite University Medicine Berlin, Berlin, Germany
  24. 24Department of Paediatric Rheumatology and CEREMAI, Hôpital de Bicêtre, National Reference Centre for Auto-Inflammatory Diseases, Le Kremlin-Bicêtre, Paris, France
  25. 25Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
  26. 26Division of Medicine, UCL Medical School, Royal Free Campus, National Amyloidosis Centre, London, UK
  27. 27Unit of Pediatric Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada
  28. 28Sheba Medical Center, Heller Institute, Ramat Gan, Israel
  29. 29Fondazione IRCCS Policlinico San Matteo, Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Pavia, Italy
  30. 30Department of Pediatrics, Hacettepe University, Ankara, Turkey
  31. 31Servicio de Inmunología/Reumatología, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina
  32. 32Heller Institute of Medical Research, Sheba Medical Center, Ramat Gan, Israel
  33. 33Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  34. 34Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, Ljubljana, Slovenia
  35. 35National Referral Centre of Auto-Inflammatory Diseases and Inflammatory Amyloidosis, CEREMAIA, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, France
  36. 36Department of Pediatrics, Meir Medical Centre, Kfar Saba, Israel
  37. 37Tel Aviv University, Tel Aviv, Israel
  38. 38Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  39. 39Department of Pediatrics, Universitätsklinikum Münster, Münster, Germany
  40. 40IRCCS Istituto Giannina Gaslini, Genoa, Italy
  41. 41Ospedale Policlinico San Martino IRCCS, Genoa, Italy
  42. 42Clinica Pediatrica e Reumatologia, PRINTO, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  1. Correspondence to Dr Marco Gattorno, UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa 16147, Italy; marcogattorno{at}


Background Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)—and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.

Methods Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients’ diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.

Results The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94–1 and specificity of 0.95–1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).

Conclusion Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.

  • classification criteria
  • inherited periodic fevers
  • mevalonate kinase deficiency
  • CAPS
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  • MG and MH contributed equally.

  • Handling editor Josef S Smolen

  • Contributors MG, MH and NR coordinated the study, analysed the data and drafted the manuscript. SF, FV and CG analysed the data. FB and MPS performed statistical analysis. IA, JA, JIA, KB, EB-C, PAB, LC, IC, FDB, FD, ED, JF, RG-M, AG, VH, HH, TK, IK-P, JK-D, HJL, RML, AL, LO, DR, RR, YS, AS, NT, IT, YU, MvG, DK, DF and AM participated in the Delphi, patient evaluation and Consensus Conference. All authors evaluated and approved the manuscript.

  • Funding The project has been funded by E-Rare-3 project (INSAID, grant 003037603). Eurofever was supported by the Executive Agency For Health and Consumers (EAHC, Project No 2007332) and by Istituto G Gaslini. Novartis and SOBI provided unrestricted grants for the Consensus Conference.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Independent ethical committee approval for enrolling patients into the registry was obtained from the participating centres in accordance with the local requirements. The study was performed according to the principles of the Declaration of Helsinki.

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

  • Data availability statement Data are available in a public, open access repository. There are no data in this work. Data are available upon reasonable request. Data may be obtained from a third party and are not publicly available. No data are available. All data relevant to the study are included in the article or uploaded as supplementary information.

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