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
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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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