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  • Oral presentation
  • Open Access

PReS-FINAL-2194: Evidence-based clinical classification criteria for periodic fevers

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Pediatric Rheumatology201311 (Suppl 2) :O29

  • Published:


  • Clinical Criterion
  • Classification Criterion
  • Standard Patient
  • Classification Score
  • Autosomal Recessive Disease


No evidence-based classification criteria are so far available for the majority of autoinflammatory diseases


To elaborate and validate a set of clinical criteria able to correctly classify patients affected with the most common periodic fevers


All FMF, TRAPS, MKD and CAPS patients enrolled in the Eurofever registry until March 2013 were evaluated. For each disease gold standards were considered according to the following criteria: i) clinical validation by centers and disease-principal investigator, ii) confirmative molecular analysis (2 mutations for MEFV with at least one mutation in exon 10, 2 mutations of MVK gene, 1 mutation of TNFRFS1A with exclusion of low-penetrance variants, 1 mutation of NLRP3 with exclusion of low-penetrance variants), iii) PFAPA patients validated by disease-principal investigator and confirmed by the centers on the basis of the follow-up. Clinical criteria were formulated on the basis of a univariate and multivariate analysis in a first group of patients (training set) and then validated in an independent set of patients (validation set).


A total of 1204 consecutive patients with periodic fevers were enrolled in the registry. Among them 743 consecutive gold standard patients (288 FMF, 73 MKD, 96 TRAPS, 87 CAPS, 199 PFAPA) were evaluated (440 in the training set and 303 in the validation set). The multivariate analysis identified the clinical variables (either as presence or absence) independently correlated to for each disease with their specific weight. The cut off value of the classification score was chosen on the ROC curve in order to guarantee the highest sensitivity and specificity.

The classification score was than tested in an independent set of patients (validation set) revealing a sensitivity of 93% and specificity of 89% for FMF; a sensitivity of 100% and specificity of 74% for TRAPS; a sensitivity of 80% and specificity of 90% for MKD and sensitivity of 97% and specificity of 92% for CAPS; sensitivity of 99% and specificity of 96% for PFAPA. The performance in non-gold standard patients (i.e. heterozygous patients in autosomal recessive diseases or patients with low-penetrance mutations) revealed a variable percentage of patients (70% FMF, 75% TRAPS, 41% MKD and 94% CAPS) positive for the respective criteria.


Evidence-based clinical criteria for the classification of patients with inherited periodic fevers have been elaborated. These clinical criteria could be used in association with molecular analysis and other variables (i.e. metabolic examinations, response to specific treatments) for patients classification.

Disclosure of interest

None declared.

Authors’ Affiliations

2nd Division of Pediatric, Gaslini Institute, Genoa, Italy
Department of Pediatric Nephrology&Rheumatology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
Division of Pediatric Rheumatology, Bicêtre Hospital, Paris, France
University College Medical School, London, UK
UCL, London, UK
Rheumatology Unit, University of Siena, Siena, Italy
Republican Children's FMF Center, Yerevan State Medical University, Yerevan, Armenia
Department of rheumatology, Ospedale Bambin Gesù, Rome, Italy
Division of Pediatric Rheumatology, University Hospital Tübingen, Tuebingen, Germany
Hôpital Necker-Enfants Malades, Paris, France
Gaslini Institute, Genoa, Italy
Department of Paediatrics, Meir Medical Center, Kfar Saba, Israel
Department of Pediatric Sciences, Università Cattolica del Sacro Cuore, Roma, Italy
Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
Clinica Pediatrica, University of Torino, Torino, Italy
Department of General Internal Medicine, Radboud University of Nijmegen Medical Center, Nijmegen, The Netherlands
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, USA
Department of Internal Medicine, Istanbul University, Istanbul, Turkey
University Medical Center Utrecht, Utrecht, The Netherlands
Centre Multisite Romand de Rhumatologie Pediatrique, CHUV, Lausanne, Switzerland


© Federici et al.; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.