Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever.
The precise cytokine networks in the serum of individuals with familial Mediterranean fever (FMF) that are associated with its pathogenesis have been unknown. Here, we attempted to identify specific biomarkers to diagnose or assess disease activity in FMF patients. We measured serum levels of 45 cytokines in 75 FMF patients and 40 age-matched controls by multisuspension cytokine array. FMF in "attack" or "remission" was classified by Japan College of Rheumatology-certified rheumatologists according to the Tel Hashomer criteria. Cytokines were ranked by their importance by a multivariate classification algorithm. We performed a logistic regression analysis to determine specific biomarkers for discriminating FMF patients in attack. To identify specific molecular networks, we performed a cluster analysis of each cytokine. Twenty-nine of the 45 cytokines were available for further analyses. Eight cytokines' serum levels were significantly elevated in the FMF attack versus healthy control group. Nine cytokines were increased in FMF attack compared to FMF remission. Multivariate classification algorithms followed by a logistic regression analysis revealed that the combined measurement of IL-6, IL-18, and IL-17 distinguished FMF patients in attack from the controls with the highest accuracy (sensitivity 89.2%, specificity 100%, and accuracy 95.5%). Among the FMF patients, the combined measurement of IL-6, G-CSF, IL-10, and IL-12p40 discriminated febrile attack periods from remission periods with the highest accuracy (sensitivity 75.0%, specificity 87.9%, and accuracy 84.0%). Our data identified combinational diagnostic biomarkers in FMF patients based on the measurement of multiple cytokines. These findings help to improve the diagnostic performance of FMF in daily practice and extend our understanding of the activation of the inflammasome leading to enhanced cytokine networks.
From the Unit of Translational Medicine, Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences (TK, MU, FN, S-YK, NI, KI, MT, HN, TO, AK), Nagasaki; Department of Rheumatology and Clinical Research Center (KM), Nagasaki Medical Center, Omura; Nagasaki University Hospital (SS), Clinical Research Center, Nagasaki; Department of Internal Medicine (FN), Sasebo City General Hospital; Center for Rheumatic Disease (YU, KE), Sasebo Chuo Hospital, Sasebo; Department of Pathology (JM), Ehime University Graduate School of Medicine and Proteo-Science Center, Toon, Ehime; Department of Infectious Immunology (KA), Shinshu University, Graduate School of Medicine, Matsumoto; Department of Pediatrics (AY), School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa; and Department of Human Genetics (K-IY), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Tomohiro
T
Koga
Kiyoshi
K
Migita
Shuntaro
S
Sato
Masataka
M
Umeda
Fumiaki
F
Nonaka
Shin-Ya
SY
Kawashiri
Naoki
N
Iwamoto
Kunihiro
K
Ichinose
Mami
M
Tamai
Hideki
H
Nakamura
Tomoki
T
Origuchi
Yukitaka
Y
Ueki
Junya
J
Masumoto
Kazunaga
K
Agematsu
Akihiro
A
Yachie
Koh-Ichiro
KI
Yoshiura
Katsumi
K
Eguchi
Atsushi
A
Kawakami
D000328:Adult; D017668:Age of Onset; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood*; D010505:Familial Mediterranean Fever / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015203:Reproducibility of Results
D015415:Biomarkers; D016207:Cytokines