Multiple Serum Cytokine Profiling to Identify Combinational Diagnostic Biomarkers in Attacks of Familial Mediterranean Fever

Abstract

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.

Longitudinal analysis of serum interleukin-18 in patients with familial Mediterranean fever carrying MEFV mutations in exon 10

“…However, systemic circulating levels of IL-1β are undetectable in most patients with FMF, even during attacks [5][6][7]. No or little elevation of serum IL-1β has also been found in most patients with cryopyrin-associated periodic syndromes, which are also IL-1β activation disorders and are caused by gain-of-function mutations in NLRP3 [12,14].…”

“…It is characterized by recurrent episodes of fever with serositis, synovitis, or skin rash, and is caused by autosomal recessive mutations in the MEFV gene, which has 10 exons encoding a 781-amino acid protein called pyrin [1]. and IL-18, during attacks, and shown the utility of a combination of these cytokines as a diagnostic biomarker [3][4][5][6][7]. IL-18 was identified as an interferon-gamma-inducing factor that promotes a variety of innate immune processes associated with infection, inflammation, and autoimmunity [8].…”

An adult case of atypical familial Mediterranean fever (pyrin‐associated autoinflammatory disease) similar to adult‐onset Still’s disease

“…IL‐18 is a pro‐inflammatory cytokine of the IL‐1 family that is thought to play a key role in the pathogenesis of AOSD . Higher IL‐18 levels are also reported in attack‐phase FMF patients than in healthy subjects, and in patients with an exon 10 MEFV mutation relative to those without …”

“…ALT, alanine aminotransferase (IU/L); AST, aspartate aminotransferase (IU/L); CRP, C-reactive protein (mg/dL); CTRX, intravenous ceftriaxone; FDP, fibrin degradation products (µg/mL); Hb, hemoglobin; LDH, lactate dehydrogenase (IU/L); MEPM, intravenous meropenem; PLT, platelet count (×10 4 /mm 3 ); WBC, white blood cell count (/mm 3 ) patients than in healthy subjects, and in patients with an exon 10 MEFV mutation relative to those without. 6 Several studies have investigated the association between-MEFV gene mutations and AOSD or systemic-onset juvenile idiopathic arthritis. [7][8][9] MEFV gene mutations were observed more frequently in 20 Turkish AOSD patients (15%) than in healthy controls, but the difference was not significant.…”

Microarray analysis of circulating microRNAs in familial Mediterranean fever

“…Circulating miRNAs examined in this study were prepared from serum or plasma between FMF attacks, at a time when all patients were afebrile and felt completely well. White blood cell counts, acute phase reactants, and serum cytokines usually normalize during this clinically stable, afebrile phase in patients with FMF, regardless of genotypic and phenotypic variations [29]. The characteristic expression patterns of circulating miRNAs in FMF patients between attacks may suggest the presence of persistent subclinical inflammation, which could lead to the next FMF attack.…”