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Autoinflammatory disorders
Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor
  1. Flora Magnotti1,
  2. Tiphaine Malsot1,
  3. Sophie Georgin-lavialle2,3,
  4. Fatima Abbas4,
  5. Amandine Martin1,
  6. Alexandre Belot1,3,5,
  7. Maxime Fauter6,7,
  8. Muriel Rabilloud4,
  9. Mathieu Gerfaud-Valentin6,
  10. Pascal Sève6,
  11. Agnes Duquesne5,
  12. Arnaud Hot8,
  13. Stephane Durupt9,
  14. Léa Savey2,
  15. Irina Giurgea10,
  16. Gilles Grateau2,3,
  17. Thomas Henry1,
  18. Yvan Jamilloux1,6
  1. 1 Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard-Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon, France
  2. 2 Internal Medicine, Tenon Hospital, AP-HP, Paris, France
  3. 3 CEREMAIA (Centre de Référence des Maladies Autoinflammatoires et des Amyloses), Paris, France
  4. 4 Biostatistics, Pôle de Santé Publique,CNRS UMR5308, Hospices Civils de Lyon, Lyon, France
  5. 5 Department of Paediatric Nephrology, Rheumatology, Dermatology, Hôpital Femme-Mère Enfant, Université Claude Bernard-Lyon 1, Hospices Civils de Lyon, Bron, France
  6. 6 Internal Medicine, University Hospital Croix-Rousse, Hospices Civils de Lyon, Lyon, France
  7. 7 Internal Medicine, Hospices Civils de Lyon, Lyon, France
  8. 8 Internal Medicine, University Hospital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
  9. 9 Internal Medicine, University Hospital Lyon Sud, Hospices Civils de Lyon, Lyon, France
  10. 10 Genetics, Armand-Trousseau Hospital, APHP, Sorbonne University, Paris, Île-de-France, France
  1. Correspondence to Yvan Jamilloux, Internal Medicine, Hospices Civils de Lyon, Lyon 69002, France; yvan.jamilloux{at}chu-lyon.fr

Abstract

Background and objective Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease. Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic MEFV variants. MEFV encodes pyrin, an inflammasome sensor. Using a kinase inhibitor, UCN-01, we recently identified that dephosphorylation of FMF-associated pyrin mutants leads to inflammasome activation. The aim of this study was to assess whether quantifying UCN-01-mediated inflammasome activation could discriminate FMF patients from healthy donors (HD) and from patients with other inflammatory disorders (OID).

Methods Real-time pyroptosis and IL-1β secretion were monitored in response to UCN-01 in monocytes from FMF patients (n=67), HD (n=71) and OID patients (n=40). Sensitivity and specificity of the resulting diagnostic tests were determined by receiver operating characteristic curve analyses.

Results Inflammasome monitoring in response to UCN-01 discriminates FMF patients from other individuals. Pyroptosis assessment leads to a fast FMF diagnosis while combining pyroptosis and IL-1β dosage renders UCN-01-based assays highly sensitive and specific. UCN-01-triggered monocytes responses were influenced by MEFV gene dosage and MEFV mutations in a similar way as clinical phenotypes are.

Conclusions UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity.

  • familial mediterranean fever
  • cytokines
  • inflammation

http://dx.doi.org/10.1136/annrheumdis-2020-218366

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    Footnotes

    • TH and YJ are joint senior authors.

    • Handling editor Josef S Smolen

    • Twitter @SophieGeorgin

    • Contributors TH and YJ designed the study; FM, TM, AM, MF, TH performed experiments; FM, FA, MR, TH and YJ analysed the data. FM, TH and YJ wrote the manuscript with input from all authors; SG-L, AB, MG-V, PS, AD, AH, SD, GG and YJ included patients, provided clinical information and samples; TH and YJ oversaw the project.

    • Funding The study (Depist-FMF, registered at clinicaltrials.gov under the unique identifier NCT03747315) was founded by a grant from the Hospices Civils de Lyon (Jeune Chercheur HCL) and a grant from the Agence Nationale de la Recherche/Direction Générale de l’Offre de Soin (FMFgeneToDiag #ANR-17-CE17-0021) and funding from the European Union's Horizon 2020 research and innovation programme under grant agreement #779295 (ImmunAID).

    • Competing interests YJ, FM, AB, AM and TH are coinventors and owners of a patent 'Methods and kits for diagnosis of familial Mediterranean fever' (WO/2019/048569).

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by the French Comité de Protection des Personnes (CPP,#L16‐189) and by the French Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (CCTIRS, #16.864). The experiments conformed to the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services’Belmont Report. The Etablissement Français du Sang provided HD blood in the framework of the convention #14-1820. Informed consent was received from each participant prior to inclusion in the study.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Additional data are available upon reasonable request.