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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
  44. for the Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO)
  1. 1 UOSD Centro Malattie Autoinfiammatorie e Immunodeficienze, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  2. 2 Department of Paediatrics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
  3. 3 University Hospital of Geneva, Geneva, Switzerland
  4. 4 Clinica Pediatrica e Reumatologia, IRCCS Istituto Giannina Gaslini, Genova, Italy
  5. 5 Department of Pediatrics, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland
  6. 6 Department of Health Sciences (DISSAL), University of Genova, Genova, Italy
  7. 7 Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, Maryland, USA
  8. 8 Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Catalunya, Spain
  9. 9 Immunology Department, CDB, Hospital Clínic/IDIBAPS, Barcelona, Spain
  10. 10 Division of Intramural Research, NIH-NIAID, Bethesda, Maryland, USA
  11. 11 Rheumatology Unit, Hadassah-Hebrew University Hospital, Ein Kerem, Jerusalem, Israel
  12. 12 Institute of Child Health, University College London, London, UK
  13. 13 Department of Medical Sciences, University of Siena, Siena, Italy
  14. 14 Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  15. 15 Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
  16. 16 Pediatric Rheumatology, Harvard University Children's Hospital, Boston, Massachusetts, USA
  17. 17 Unit of Pediatric Rheumatology, Western University Children’s Hospital, London, Ontario, Canada
  18. 18 Department of Pediatrics, Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands
  19. 19 Translational Autoinflammatory Disease Studies Unit, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  20. 20 Division of Rheumatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
  21. 21 National Referral Centre of Auto-Inflammatory Diseases and Inflammatory Amyloidosis, CEREMAIA, Versailles Hospital, Le Chesnay (Paris), France
  22. 22 Department of Pediatrics, University of California at San Diego, San Diego, California, USA
  23. 23 Pediatric Pneumology and Immunology, Charite University Medicine Berlin, Berlin, Germany
  24. 24 Department of Paediatric Rheumatology and CEREMAI, Hôpital de Bicêtre, National Reference Centre for Auto-Inflammatory Diseases, Le Kremlin-Bicêtre, Paris, France
  25. 25 Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
  26. 26 Division of Medicine, UCL Medical School, Royal Free Campus, National Amyloidosis Centre, London, UK
  27. 27 Unit of Pediatric Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada
  28. 28 Sheba Medical Center, Heller Institute, Ramat Gan, Israel
  29. 29 Fondazione IRCCS Policlinico San Matteo, Centro per lo Studio e la Cura delle Amiloidosi Sistemiche, Pavia, Italy
  30. 30 Department of Pediatrics, Hacettepe University, Ankara, Turkey
  31. 31 Servicio de Inmunología/Reumatología, Hospital de Pediatria Juan P Garrahan, Buenos Aires, Argentina
  32. 32 Heller Institute of Medical Research, Sheba Medical Center, Ramat Gan, Israel
  33. 33 Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  34. 34 Department of Allergology, Rheumatology and Clinical Immunology, University Children's Hospital, Ljubljana, Slovenia
  35. 35 National Referral Centre of Auto-Inflammatory Diseases and Inflammatory Amyloidosis, CEREMAIA, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, France
  36. 36 Department of Pediatrics, Meir Medical Centre, Kfar Saba, Israel
  37. 37 Tel Aviv University, Tel Aviv, Israel
  38. 38 Department of Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  39. 39 Department of Pediatrics, Universitätsklinikum Münster, Münster, Germany
  40. 40 IRCCS Istituto Giannina Gaslini, Genoa, Italy
  41. 41 Ospedale Policlinico San Martino IRCCS, Genoa, Italy
  42. 42 Clinica 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

  • Correction notice This article has been corrected since it published Online First. Table 4 has been amended.

  • 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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