title: Familial Mediterranean fever is no longer a rare disease in Japan.
abstract: The aim of this study was to evaluate the clinical manifestations and prevalence of familial Mediterranean fever (FMF) in Japanese patients with unexplained fever and rheumatic manifestations.
  
  
  
  We enrolled 601 patients with unexplained fever or suspected FMF throughout Japan between 2009 and 2015. Patients were divided into three groups according to Tel Hashomer criteria: sure FMF, probable FMF, and non-FMF patients, including definitive rheumatic diseases. Mutation detection in exons 1, 2, 3, and 10 of the FMF gene MEFV was performed by direct sequencing.
  
  
  
  A total of 192 patients (31.9 %) were diagnosed with FMF according to FMF diagnostic criteria. These could be divided into sure FMF (56.3 %, n = 108) and probable FMF (43.7 %, n = 84) patients. Fever, abdominal symptoms, and thoracic symptoms were significantly more common in FMF than non-FMF patients. Among FMF patients, 26 (13.5 %) had concomitant rheumatic diseases. Most FMF patients (94.3 %, 181/192) carried at least one MEFV mutation. Allele frequencies of M694I (13.5 % vs 0 %) and E148Q (39.1 % vs 24.8 %) mutations were significantly higher in FMF compared with healthy subjects. Allele frequencies of common MEFV mutations in FMF patients were M694I (13.5 %), P369S (8.6 %), R408Q (8.1 %), G304R (2.9 %), R202Q (4.4 %), E148Q (39.1 %), L110P (11.7 %), and E84K (3.1 %). Patients with a sure FMF phenotype had a higher frequency of MEFV exon 10 mutation (M694I) and a lower frequency of MEFV exon 3 mutations (P369S, R408Q) compared with those with a probable FMF phenotype.
  
  
  
  The high prevalence of FMF in Japanese patients with unexplained fever was confirmed in the present study. FMF should be suspected in cases of unexplained fever or non-specific rheumatic manifestations, and mutational analysis of MEFV could be useful to predict the clinical phenotypes of FMF in Japan.
authors.affiliation: Department of Rheumatology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, Fukushima, 960-1295, Japan. migitakiyoshi@gmail.com.|Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan. migitakiyoshi@gmail.com.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Migita
authors.affiliation: Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Izumi
authors.affiliation: Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Jiuchi
authors.affiliation: Clinical Research Center, NHO Nagasaki Medical Center, Kubara 2-1001-1, Omura, Nagasaki, 856-8562, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Iwanaga
authors.affiliation: Department of Rheumatology, Fukushima Medical University School of Medicine, Hikarigaoka 1, Fukushima, Fukushima, 960-1295, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Kawahara
authors.affiliation: Department of Infectious Immunology, Shinshu University Graduate School of Medicine, Asahi 3-1-1, Matsumoto, Nagano, 390-8621, Japan.
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.affiliation: Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takara13-1, Kanazawa, 920-8640, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.affiliation: Department of Pathology, Ehime University Proteo-Science Center and Graduate School of Medicine, Shitsukawa 454, Toon, Ehime, 791-0295, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Masumoto
authors.affiliation: Department of Rheumatology, Japan Community Health care Organization, Isahaya General Hospital, Eishohigashi-machi 24-1, Isahaya, 854-8501, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Fujikawa
authors.affiliation: Department of Rheumatology, Hiroshima University Hospital, Kasumi 1-2-3, Minami-ku, Hiroshima, 734-8551, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Department of Rheumatology, Kumamoto Shinto General Hospital, Shinyashiki 1-17-27, Kumamoto, 862-8655, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Rheumatology, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo, 105-8470, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ubara
authors.affiliation: Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.affiliation: Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakashima
authors.affiliation: Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Umeda
authors.affiliation: Departments of Rheumatology, Sasebo City General Hospital, Hirase 9-3, Sasebo, 857-8511, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Nonaka
authors.affiliation: Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Yasunami
authors.affiliation: Sasebo Chuo Hospital, Yamato 15, Sasebo, 857-1195, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
authors.affiliation: Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Sakamoto 1-12-4, Nagasaki, 852-8523, Japan.
authors.forename: Koh-Ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.affiliation: Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Sakamoto1-7-1, Nagasaki, 852-8501, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kawakami
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D010505:Familial Mediterranean Fever / Q000453:epidemiology* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D015995:Prevalence; D035583:Rare Diseases / Q000453:epidemiology*; D055815:Young Adult
keywords: Familial Mediterranean fever; MEFV gene; Rheumatic manifestations