Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers

Ann Rheum Dis. 2015 May;74(5):799-805. doi: 10.1136/annrheumdis-2014-206580. Epub 2015 Jan 30.


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.

Keywords: Familial Mediterranean Fever; Fever Syndromes; Inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cryopyrin-Associated Periodic Syndromes / classification
  • Cryopyrin-Associated Periodic Syndromes / diagnosis
  • Evidence-Based Medicine
  • Familial Mediterranean Fever / classification
  • Familial Mediterranean Fever / diagnosis
  • Female
  • Fever
  • Hereditary Autoinflammatory Diseases / classification
  • Hereditary Autoinflammatory Diseases / diagnosis*
  • Humans
  • Infant
  • Male
  • Mevalonate Kinase Deficiency / classification
  • Mevalonate Kinase Deficiency / diagnosis
  • Middle Aged
  • ROC Curve
  • Registries*
  • Sensitivity and Specificity
  • Young Adult

Supplementary concepts

  • Periodic fever, familial, autosomal dominant