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Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers
  1. Silvia Federici1,
  2. Maria Pia Sormani2,
  3. Seza Ozen3,
  4. Helen J Lachmann4,
  5. Gayane Amaryan5,
  6. Patricia Woo6,
  7. Isabelle Koné-Paut7,
  8. Natacha Dewarrat8,
  9. Luca Cantarini9,
  10. Antonella Insalaco10,
  11. Yosef Uziel11,
  12. Donato Rigante12,
  13. Pierre Quartier13,
  14. Erkan Demirkaya14,
  15. Troels Herlin15,
  16. Antonella Meini16,
  17. Giovanna Fabio17,
  18. Tilmann Kallinich18,
  19. Silvana Martino19,
  20. Aviel Yonatan Butbul20,
  21. Alma Olivieri21,
  22. Jasmin Kuemmerle-Deschner22,
  23. Benedicte Neven13,
  24. Anna Simon23,
  25. Huri Ozdogan24,
  26. Isabelle Touitou25,
  27. Joost Frenkel26,
  28. Michael Hofer8,
  29. Alberto Martini27,
  30. Nicolino Ruperto1,
  31. Marco Gattorno1,
  32. for the Paediatric Rheumatology International Trials Organisation (PRINTO) and Eurofever Project
  1. 1UO Pediatria II–Reumatologia, Istituto Giannina Gaslini, Genova, Italy
  2. 2Unità di Biostatistica, DISSAL, University of Genoa, Genova, Italy
  3. 3Department of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey
  4. 4National Amyloidosis Centre, University College London, London, UK
  5. 5National Pediatric Familial Mediterranean Fever Centre, Institute of Child and Adolescent Health, Yerevan, Armenia
  6. 6Center of Paediatric and Adolescent Rheumatology, UCL, London, UK
  7. 7Centre de référence national des maladies auto-inflammatoires, CEREMAI, rhumatologie pédiatrique, CHU Le Kremlin Bicêtre (APHP, University of Paris SUD), Paris, France
  8. 8Pediatric Rheumatology Unit of Western Switzerland, CHUV, University of Lausanne, Lausanne, and HUG, Geneva, Switzerland
  9. 9Rheumatology Unit, Policlinico le Scotte, University of Siena, Siena, Italy
  10. 10Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  11. 11Department of Pediatrics, Meir Medical Centre, Kfar Saba, Israel
  12. 12Department of Pediatrics, Università Cattolica Sacro Cuore, Roma, Italy
  13. 13Université Paris-Descartes, Hôpital Necker-Enfants Malades, Centre de référence national pour les Arthrites Juveniles, Unité d'Immunologie, Hématologie et Rhumatologie Pédiatrique, Université Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France
  14. 14Gulhane Military Medical Faculty, FMF Arthritis Vasculitis and Orphan Disease Research Center (FAVOR), Ankara, Turkey
  15. 15Department of Pediatrics, Aarhus University Hospital, Pediatric Rheumatology Clinic, Aarhus, Denmark
  16. 16Dipartimento di Pediatria, Unità di Immunologia e Reumatologia Pediatrica, Clinica Pediatrica dell'Università di Brescia, Brescia, Italy
  17. 17Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Clinica Pediatrica II De Marchi, Milano, Italia
  18. 18Kinderklinik, Rheumatologie, Charite University Hospital Berlin, Berlin, Germany
  19. 19Dipartimento di Scienze Pediatriche e dell'Adolescenza, Clinica Pediatrica Universita’ di Torino, Torino, Italy
  20. 20Department of Pediatrics, Rambam Medical Center, Haifa, Israel
  21. 21Dipartimento di Pediatria F Fede, Seconda Universita’ degli Studi di Napoli, Napoli, Italia
  22. 22Universitatsklinik fur Kinderheilkunde und Jugendmedizin, Tübingen, Germany
  23. 23Department of General Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
  24. 24Ic Hastaliklari ABD, Romatoloji BD, Cerrahpasa Tip Fakultesi, Istanbul, Turkey
  25. 25Unit of autoinflammatory diseases, Montpellier, UM1, INSERM U844, Montpellier, France
  26. 26Department of Paediatrics, University Medical Center Utrecht, Utrecht, The Netherlands
  27. 27Istituto Giannina Gaslini, Pediatria II and Università degli Studi di Genova, Genova, Italy
  1. Correspondence to Dr Marco Gattorno, UO Pediatria 2, Istituto G Gaslini, Largo G Gaslini 5, Genova 16147, Italy; marcogattorno{at}


The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be ‘gold standard’ on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

  • Familial Mediterranean Fever
  • Fever Syndromes
  • Inflammation

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