Evidence Based Recommendations for Genetic Diagnosis of Familial Mediterranean Fever

Gabriella Giancane¹, Nienke ter Haar², Nico Wulffraat³, Bas Vastert⁴, Karyl Barron⁵, Veronique Hentgen⁶, Tilmann Kallinich⁷, Huri Ozdogan⁸, Jordi Anton⁹, Paul Brogan¹⁰, Luca Cantarini¹¹, Joost Frenkel⁴, Caroline Galeotti¹², Marco Gattorno¹³, Gilles Grateau¹⁴, Michael Hofer¹⁵, Isabelle Kone-Paut¹⁶, J B. Kuemmerle-Deschner¹⁷, Helen Lachmann¹⁸, Anna Simon¹⁹, Brian Feldman²⁰, Yosef Uziel²¹ and Seza Ozen²², ¹Pediatric Immunology, UMC, Utrecht, Netherlands, Utrecht, Netherlands, ²Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Pediatric rheumatology, Wilhelmina Children's Hospital/ UMC Utrecht, Utrecht, Netherlands, ⁴University Medical Center Utrecht, Utrecht, Netherlands, ⁵NIH, Bethesda, MD, ⁶Versailles Hospital, Le Chesnay Cedex, France, ⁷Charite, University Medicine Berlin, Berlin, Germany, ⁸Division of Rheumatology, Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey, ⁹Pediatric Rheumatology Unit. Hospital Sant Joan de Déu. Universitat de Barcelona, Barcelona, Spain, ¹⁰Rheumatology Unit, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom, ¹¹University of Siena, Siena, Italy, ¹²Bicêtre Hospital, University of Paris SUD, Paris, France, ¹³Istituto Giannina Gaslini, Genova, Italy, ¹⁴Service De Médecine Interne, Hopital Tenon, Paris, France, ¹⁵Centre Multisite Romand de Rhumatologie Pediatrique, Lausanne, Switzerland, ¹⁶Department of Pediatric Rheumatology, Reference Centre for Autoinflammatory Disorders CEREMAI, Bicêtre Hospital, University of Paris SUD, Paris, France, ¹⁷Division of Pediatric Rheumatology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany, ¹⁸UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom, ¹⁹Radboudumc, Nijmegen, Netherlands, ²⁰Rheumatology, The Hospital for Sick Children, Toronto, ON, Canada, ²¹Tel-Aviv University, Sackler School of Medicine, Tel-Aviv, Israel, ²²Deptartment. of Pediatric Rheumatology, Hacettepe University, Ankara, Turkey

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease, familial Mediterranean fever and genetics

Session Information

Title: Miscellaneous Rheumatic and Inflammatory Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose: Familial Mediterranean Fever (FMF) is a disease that starts in childhood and can lead to significant morbidity. In 2013, an initiative called SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) has been launched for children and young adults with rheumatic diseases. For FMF, attention was focused on genetics. The aim of the SHARE recommendations in FMF is to provide a diagnostic tool for inexperienced pediatric rheumatologists to cope with FMF in their clinical practice. This is possible through a correct interpretation of the diagnostic value of MEFVmutations in predicting FMF phenotype.

Methods: An expert committee was instituted, consisting of pediatric rheumatologists, and search terms for the systematic literature review were defined. Two independent experts scored articles for validity and level of evidence. Recommendations derived from the literature were evaluated by an online survey. Those with less than 80% agreement during the online survey were reformulated. Subsequently, all recommendations were discussed at a consensus meeting using the nominal group technique. Recommendations were accepted if more than 80% agreement was reached.

Results: The literature search yielded 3386 articles, of which 25 considered relevant and therefore scored for validity and level of evidence. 17 articles were scored valid and used in the formulation of the recommendations. 8 recommendations were finally accepted with 100% agreement after the consensus meeting (Table 1). Topics covered for diagnosis were: clinical versus genetic diagnosis of FMF; genotype-phenotype correlation; genotype-age at onset correlation; silent carriers and risk for amyloidosis; role of the specialist in FMF diagnosis.

Conclusion: The SHARE initiative provides recommendations for the diagnosis of FMF and thereby facilitates improvement and uniformity of care.

FMF Recommendations

1.FMF is a clinical diagnosis, which can be supported but not excluded by genetic testing.

2.Consider patients homozygotes for M694V at risk of developing, with very high probability, a severe phenotype.

3.FMF patients carrying two of the common mutated alleles (homozygotes or compound heterozygotes), especially for M694V mutation or mutations in the position 680 to 694 on exon 10, must be considered at risk of having a more severe disease than those carrying only one mutated allele (heterozygotes).

4.The E148Q variant is common, of unknown pathogenic significance and as the only MEFV variant does not support the diagnosis of FMF.

5.Patients homozygous for M694V mutation are at risk for an early onset disease.

6.Individuals, homozygous for M694V, who are not reporting symptoms, should be evaluated and followed closely in order to consider therapy.

7.For individuals with two pathogenic mutations for FMF who don’t report symptoms, if there are risk factors for AA amyloidosis (such as country of origin, family history and persistently elevated inflammatory markers) treatment and close follow-up should be considered.

8.Consultation with an autoinflammatory disease specialist may be helpful, in order to aid in the indication and interpretation of the genetic testing and diagnosis.

Disclosure:

G. Giancane,
None;

N. ter Haar,
None;

N. Wulffraat,
None;

B. Vastert,

Novartis Pharmaceutical Corporation,

K. Barron,
None;

V. Hentgen,

Novartis Pharmaceutical Corporation,

Novartis, Pfizer, Roche,

T. Kallinich,

Novartis, SOBI,

Novartis Pharmaceutical Corporation,

H. Ozdogan,
None;

J. Anton,
None;

P. Brogan,

Novartis, Roche,

Novartis Pharmaceutical Corporation,

L. Cantarini,

Novartis Pharma AG, SOBI,

J. Frenkel,

European Union ERANET,

Novartis Pharmaceutical Corporation,

SOBI,

C. Galeotti,

Novartis Pharmaceutical Corporation,

M. Gattorno,
None;

G. Grateau,
None;

M. Hofer,
None;

I. Kone-Paut,
None;

J. B. Kuemmerle-Deschner,

Novartis Pharmaceutical Corporation,

SOBI,

H. Lachmann,
None;

A. Simon,

Servier,

Novartis, SOBI, Xoma,

B. Feldman,
None;

Y. Uziel,

Novartis Pharmaceutical Corporation,

Abbvie, Neopharm, Novartis, Roche,

S. Ozen,
None.

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