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

AbstractThe 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.

[1]  K. Migita,et al.  Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis , 2017, International journal of rheumatic diseases.

[2]  K. Ohashi,et al.  Successful treatment with humanized anti–interleukin-6 receptor antibody (tocilizumab) in a case of AA amyloidosis complicated by familial Mediterranean fever , 2016, Modern rheumatology.

[3]  K. Migita,et al.  IL-18 serum concentration is markedly elevated in typical familial Mediterranean fever with M694I mutation and can distinguish it from atypical type , 2016, Modern rheumatology.

[4]  V. Kraus,et al.  Colchicine--Update on mechanisms of action and therapeutic uses. , 2015, Seminars in arthritis and rheumatism.

[5]  D. Kastner,et al.  Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β , 2015, Journal of Experimental Medicine.

[6]  H. Erdem,et al.  Tocilizumab in the treatment of patients with AA amyloidosis secondary to familial Mediterranean fever. , 2015, Rheumatology.

[7]  M. Sormani,et al.  Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers , 2015, Annals of the rheumatic diseases.

[8]  N. Wulffraat,et al.  Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever , 2015, Annals of the rheumatic diseases.

[9]  H. Yamanaka,et al.  IL-6, IL-8, and IL-10 Are Associated with Hyperferritinemia in Rapidly Progressive Interstitial Lung Disease with Polymyositis/Dermatomyositis , 2014, BioMed research international.

[10]  Y. Berkun,et al.  Diagnostic criteria of familial Mediterranean fever. , 2014, Autoimmunity reviews.

[11]  G. Kilic,et al.  Efficacy and Safety of Biologic Treatments in Familial Mediterranean Fever , 2013, The American journal of the medical sciences.

[12]  D. Teachey,et al.  Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017-4023. , 2016, Blood.

[13]  K. Migita,et al.  Interleukin-6 targeting therapy in familial Mediterranean fever. , 2013, Clinical and experimental rheumatology.

[14]  M. McDermott,et al.  Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases , 2012, Current opinion in rheumatology.

[15]  K. Migita,et al.  Expression of CD64 on polymorphonuclear neutrophils in patients with familial Mediterranean fever , 2011, Clinical and experimental immunology.

[16]  S. Yamasaki,et al.  A Japanese case of familial Mediterranean fever presenting diffuse bone marrow uptake of FDG-PET and high levels of neutrophil membrane CD64 expression. , 2011, Rheumatology.

[17]  D. Kastner,et al.  Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. , 2011, Immunity.

[18]  D. Kastner,et al.  Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade , 2011, Proceedings of the National Academy of Sciences.

[19]  I. Ben-Zvi,et al.  Chronic inflammation in FMF: markers, risk factors, outcomes and therapy , 2011, Nature Reviews Rheumatology.

[20]  J. Rocklöv,et al.  Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. , 2010, Arthritis and rheumatism.

[21]  H. Hoffman.  Therapy of autoinflammatory syndromes. , 2009, The Journal of allergy and clinical immunology.

[22]  R. Nurieva,et al.  Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. , 2009, Immunity.

[23]  R. Aminov,et al.  Cytokine profile of Armenian patients with Familial Mediterranean fever. , 2008, Clinical biochemistry.

[24]  S. Way,et al.  Deviation from a Strong Th1-Dominated to a Modest Th17-Dominated CD4 T Cell Response in the Absence of IL-12p40 and Type I IFNs Sustains Protective CD8 T Cells1 , 2008, The Journal of Immunology.

[25]  Kathleen M. Smith,et al.  Development, cytokine profile and function of human interleukin 17–producing helper T cells , 2007, Nature Immunology.

[26]  C. Dinarello,et al.  IL-18 in autoimmunity: review. , 2006, European cytokine network.

[27]  E. Erken,et al.  Plasma interleukin-10 and interleukin-12 levels in patients with familial Mediterranean fever , 2006, Rheumatology International.

[28]  M. Rotondi,et al.  CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production. , 2005, The Journal of allergy and clinical immunology.

[29]  B. Sancak,et al.  Serum interleukin 17 and interleukin 18 levels in familial Mediterranean fever. , 2005, Clinical and experimental rheumatology.

[30]  S. Akira,et al.  IL-12p40 and IL-18 in crescentic glomerulonephritis: IL-12p40 is the key Th1-defining cytokine chain, whereas IL-18 promotes local inflammation and leukocyte recruitment. , 2005, Journal of the American Society of Nephrology : JASN.

[31]  T. Hsieh,et al.  Association of intercellular adhesion molecule-1 with clinical manifestations and interleukin-18 in patients with active, untreated adult-onset Still's disease. , 2005, Arthritis and rheumatism.

[32]  S. Akar,et al.  Levels of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) in familial Mediterranean fever (FMF) patients and their first degree relatives. , 2004, Clinical and experimental rheumatology.

[33]  S. Bağcı,et al.  Continuity of cytokine activation in patients with familial Mediterranean fever , 2004, Clinical Rheumatology.

[34]  G. Trinchieri,et al.  The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. , 2003, Immunity.

[35]  D. V. van Thiel,et al.  The importance of serial measurements of cytokine levels for the evaluation of their role in pathogenesis in familial Mediterraean fever. , 2003, European journal of medical research.

[36]  T. Yoshino,et al.  Essential role of ICAM-1/LFA-1 interaction in synergistic effect of IL-18 and IL-12 on IFN-γ production in human PBMC , 2002, Naunyn-Schmiedeberg's Archives of Pharmacology.

[37]  A. Hamzaoui,et al.  Cytokine profile in Behçet's disease patients , 2002, Scandinavian journal of rheumatology.

[38]  M. Sano,et al.  Role of ICAM-1 in the aggregation and adhesion of human alveolar macrophages in response to TNF-alpha and INF-gamma. , 2001, Mediators of inflammation.

[39]  Leo Breiman,et al.  Random Forests , 2001, Machine Learning.

[40]  H. Rabb,et al.  IL‐1 and TNF independent pathways mediate ICAM‐1/VCAM‐1 up‐regulation in ischemia reperfusion injury , 2001, Journal of leukocyte biology.

[41]  H. Moriwaki,et al.  High levels of serum interleukin-10 and tumor necrosis factor-alpha are associated with fatality in fulminant hepatitis. , 2000, The Journal of infectious diseases.

[42]  H. Yazıcı,et al.  Serum soluble intercellular adhesion molecule 1 and interleukin 8 levels in familial Mediterranean fever. , 1999, The Journal of rheumatology.

[43]  D. Zemer,et al.  Activation of the cytokine network in familial Mediterranean fever. , 1999, The Journal of rheumatology.

[44]  D. Zemer,et al.  Criteria for the diagnosis of familial Mediterranean fever. , 1997, Arthritis and rheumatism.

[45]  E. Sohar,et al.  Familial Mediterranean fever. , 1955, Klinische Padiatrie.

[46]  J. Tschopp,et al.  The Inflammasomes , 2010, Cell.

[47]  John Calvin Reed,et al.  The PYRIN Connection: Novel Players in Innate Immunity and Inflammation , 2004 .

[48]  C. Dinarello.  IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. , 1999, The Journal of allergy and clinical immunology.