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Draft criteria for autoinflammatory recurrent fevers comprise clinical, genetic variables
A European panel has developed a set of classification criteria for various hereditary recurrent fevers, as well as non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis, that combine clinical manifestations with genotype.
The panel, which published its work in the Annals of the Rheumatic Diseases, drafted the criteria in part using statistical evaluations of 360 real patients in the Eurofever Registry.
“In the last 20 years, the discovery of the inflammasome and the related genes of the now called systemic autoinflammatory diseases (SAIDs) has led to a completely new line of research,” Marco Gattorno, MD, of the UOSD Center for Autoinflammatory Diseases and Immunodeficiencies at the IRCCS Istituto Giannina Gaslini in Genoa, Italy, and colleagues wrote.
“So far, several clinical diagnostic and classification criteria have been proposed for [hereditary recurrent fevers (HRF)] and [periodic fever, aphthosis, pharyngitis and adenitis (PFAPA)],” they added. “Overall, these criteria lack accuracy and do not consider the results of genetic analyses, now an essential tool for the accurate diagnosis and classification of HRF.”
The process of developing and validating new evidence-based classification criteria for HRF and PFAPA began when 162 international adult and pediatric clinicians completed Delphi questionnaires to propose, select and rank variables. Investigators randomly selected from the Eurofever Registry 360 patients with classic variations of HRF — familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS) — as well as PFAPA and undefined recurrent fevers.
A panel of 25 experienced clinicians and researchers, along with eight geneticists, participated in a multi-round, online process to classify each of the 360 patients into one of six exclusive diagnoses. Clinicians and geneticists initially worked separately, then collaborated to reach a consensus. The panelists then used statistical and consensus techniques to select the best candidate classification criteria, and the final set of criteria were solidified at the NGT Consensus Conference on March 18-21, 2017, in Genoa, Italy. Researchers tested the criteria using the original treating physician patients’ diagnosis as a reference standard in a separate group of 1,018 patients randomly selected from the Eurofever Registry.
The panelists ultimately developed and reach a consensus on two sets of criteria for each of the four HRFs — one including genetic and clinical variables and another with clinical variables only. Additionally, the criteria using only clinical variables included new criteria for PFAPA. According to the panelists, the new classification criteria for PFAPA included patients with at least seven of these eight variables: Pharyngotonsillitis, episode durations of 3-6 days, cervical lymphadenitis, periodicity, the absence of diarrhea, the absence of chest pain, no skin rash and no arthritis.
The PFAPA criteria demonstrated a sensitivity of 0.97 and a specificity of 0.93. The four HRF criteria demonstrated sensitivities of 0.94–1 and specificities of 0.95–1. Further, in validation tests with the 10,018 independently selected patients, the criteria demonstrated high accuracy, from 0.81 to 0.98.
“Although these criteria may at times be helpful in clinical practice, they are explicitly not meant to be employed as diagnostic criteria,” Gattorno and colleagues wrote. “The use of these classification criteria is highly recommended for inclusion of patients in translational and clinical studies, including clinical trials, and should not be misused as diagnostic criteria. The possible identification of new genetic entities in the heterogeneous group of undefined periodic fevers could require an update of the criteria in the future.” – by Jason Laday
Disclosures: The researchers report no relevant financial disclosures.