Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever: Annals of the Rheumatic Diseases

H. Van Gorp, L. Huang, P. Saavedra, M. Vuylsteke, T. Asaoka, G. Prencipe, A. Insalaco, B. Ogunjimi, J. Jeyaratnam, I. Cataldo, P. Jacques, K. Vermaelen, M. Dullaers, R. Joos, V. Sabato, A. Stella, J. Frenkel, F. De Benedetti, J. Dehoorne, F. HaerynckG. Calamita, P. Portincasa, M. Lamkanfi

Research output: Contribution to journalArticlepeer-review


Background and objective Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay. Results The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance. Conclusion The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation. © 2020 Royal Society of Chemistry. All rights reserved.
Original languageEnglish
Pages (from-to)960-968
Number of pages9
JournalAnn. Rheum. Dis.
Issue number7
Publication statusPublished - 2020


  • familial mediterranean fever
  • fever syndromes
  • inflammation
  • interleukin 18
  • interleukin 1beta
  • pyrin
  • colchicine
  • MEFV protein, human
  • adolescent
  • adult
  • aged
  • Article
  • assay
  • asymptomatic disease
  • autoinflammatory disease
  • blood examination
  • child
  • clinical article
  • cohort analysis
  • colchicine assay
  • controlled study
  • ex vivo study
  • familial Mediterranean fever
  • female
  • gene mutation
  • genetic variability
  • human
  • human cell
  • Luminex assay
  • male
  • MEFV gene
  • pathogenicity
  • peripheral blood mononuclear cell
  • priority journal
  • blood
  • case control study
  • genetic association study
  • genetics
  • immunophenotyping
  • middle aged
  • mononuclear cell
  • mutation
  • phenotype
  • preschool child
  • procedures
  • very elderly
  • young adult
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Colchicine
  • Familial Mediterranean Fever
  • Female
  • Genetic Association Studies
  • Humans
  • Immunophenotyping
  • Leukocytes, Mononuclear
  • Male
  • Middle Aged
  • Mutation
  • Phenotype
  • Pyrin
  • Young Adult


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