title: Association of circulating miR-223 and miR-16 with disease activity in patients with early rheumatoid arthritis.
abstract: BACKGROUND
  Identification of parameters for early diagnosis and treatment response would be beneficial for patients with early rheumatoid arthritis (ERA) to prevent ongoing joint damage. miRNAs have features of potential biomarkers, and an altered expression of miRNAs was shown in established rheumatoid arthritis (RA).
  
  
  OBJECTIVE
  To analyse RA associated miRNAs in the sera of patients with ERA to find markers of early disease, clinical activity or predictors of disease outcome.
  
  
  METHODS
  Total RNA was isolated from whole sera in ERA patients (prior to and after 3 and 12 months of therapy with disease modifying antirheumatic drugs), in patients with established RA and in healthy controls (HC) using phenol-chloroform extraction. Expression of miR-146a, miR-155, miR-223, miR-16, miR-203, miR-132 and miR-124a was analysed by TaqMan Real Time PCR.
  
  
  RESULTS
  From all analysed miRNAs, levels of miR-146a, miR-155 and miR-16 were decreased in the sera of ERA patients in comparison with established RA. A change in circulating miR-16 in the first 3 months of therapy was associated with a decrease in DAS28 in long term follow-up in ERA (p=0.002). Levels of circulating miR-223 in treatment naïve ERA correlated with C reactive protein (p=0.008), DAS28 (p=0.031) and change in DAS28 after 3 months (p=0.003) and 12 months (p=0.011) of follow-up. However, neither miR-16 nor miR-223 could distinguish ERA from HC.
  
  
  CONCLUSIONS
  Differential expression of circulating miR-146a, miR-155 and miR-16 in the sera of ERA patients may characterise an early stage of the disease. We suggest miR-223 as a marker of disease activity and miR-16 and miR-223 as possible predictors for disease outcome in ERA.
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Mária
authors.initials: M
authors.lastname: Filková
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Borbala
authors.initials: B
authors.lastname: Aradi
authors.affiliation: Department of Clinical and Experimental Rheumatology of the 1st Faculty of Medicine, Institute of Rheumatology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Senolt
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Ospelt
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Serena
authors.initials: S
authors.lastname: Vettori
authors.affiliation: Department of Clinical and Experimental Rheumatology of the 1st Faculty of Medicine, Institute of Rheumatology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Heřman
authors.initials: H
authors.lastname: Mann
authors.affiliation: University of Birmingham, Birmingham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filer
authors.affiliation: University of Birmingham, Birmingham, UK.
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.affiliation: University of Birmingham, Birmingham, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: Royal Orthopaedic Hospital Birmingham NHS Foundation Trust, Birmingham, UK.
authors.forename: Martyn
authors.initials: M
authors.lastname: Snow
authors.affiliation: Department of Clinical and Experimental Rheumatology of the 1st Faculty of Medicine, Institute of Rheumatology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Vencovský
authors.affiliation: Department of Clinical and Experimental Rheumatology of the 1st Faculty of Medicine, Institute of Rheumatology, Charles University in Prague, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Pavelka
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D042241:Early Diagnosis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D008875:Middle Aged; D011379:Prognosis; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D035683:MicroRNAs; C505362:MIRN16 microRNA, human; C525067:MIR223, human
keywords: DAS28; Early Rheumatoid Arthritis; Rheumatoid Arthritis
references.citation: Arthritis Res Ther. 2010;12(3):R76
references.pmid: 20444271
references.citation: Clin Immunol. 2010 Jul;136(1):1-15
references.pmid: 20223711
references.citation: Arthritis Res Ther. 2005;7(4):R784-95
references.pmid: 15987480
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5003-8
references.pmid: 21383194
references.citation: Arthritis Rheum. 2010 Dec;62(12):3537-46
references.pmid: 20722031
references.citation: Arthritis Rheum. 2008 May;58(5):1284-92
references.pmid: 18438844
references.citation: Arthritis Res Ther. 2008;10(4):R101
references.pmid: 18759964
references.citation: Arthritis Rheum. 1988 Mar;31(3):315-24
references.pmid: 3358796
references.citation: Rheumatology (Oxford). 2004 Jul;43(7):906-14
references.pmid: 15113999
references.citation: BMC Musculoskelet Disord. 2010 Sep 15;11:209
references.pmid: 20840794
references.citation: Arthritis Rheum. 2008 Apr;58(4):1001-9
references.pmid: 18383392
references.citation: Ann Rheum Dis. 2011 Mar;70 Suppl 1:i88-91
references.pmid: 21339227
references.citation: Clin Chem. 2010 Nov;56(11):1733-41
references.pmid: 20847327
references.citation: J Rheumatol. 2012 Jul;39(7):1326-33
references.pmid: 22589265
references.citation: PLoS One. 2008 Sep 05;3(9):e3148
references.pmid: 18773077
references.citation: Arthritis Res Ther. 2010;12(3):R81
references.pmid: 20459811
references.citation: Ann Rheum Dis. 2012 Jun;71(6):989-92
references.pmid: 22402142
references.citation: Nat Rev Immunol. 2007 Jun;7(6):429-42
references.pmid: 17525752
references.citation: BioDrugs. 2012 Jun 1;26(3):131-41
references.pmid: 22494429
references.citation: Arthritis Rheum. 2011 Feb;63(2):373-81
references.pmid: 21279994
references.citation: Commun Integr Biol. 2010 Sep;3(5):478-81
references.pmid: 21057646
references.citation: Nat Cell Biol. 2011 Apr;13(4):423-33
references.pmid: 21423178
references.citation: Arthritis Rheum. 2002 Apr;46(4):894-8
references.pmid: 11953964
references.citation: Arthritis Rheum. 2011 Jun;63(6):1582-90
references.pmid: 21425254
references.citation: Curr Opin Rheumatol. 2011 May;23(3):241-4
references.pmid: 21346574
references.citation: Biochem Biophys Res Commun. 2010 Mar 26;394(1):184-8
references.pmid: 20188071
references.citation: Ann Rheum Dis. 2012 Dec;71(12):1921-3
references.pmid: 22941769
references.citation: Arthritis Rheum. 2009 May;60(5):1294-304
references.pmid: 19404929
references.citation: Arthritis Rheum. 2012 Oct;64(10):3240-5
references.pmid: 22674011
references.citation: J Rheumatol. 2013 May;40(5):572-8
references.pmid: 23588939
references.citation: Arthritis Rheum. 2003 Jan;48(1):46-53
references.pmid: 12528102
references.citation: Cell. 2007 Jun 29;129(7):1401-14
references.pmid: 17604727
references.citation: Arthritis Rheum. 2011 May;63(5):1281-8
references.pmid: 21321928
references.citation: Nat Rev Genet. 2008 Feb;9(2):102-14
references.pmid: 18197166
references.citation: Best Pract Res Clin Rheumatol. 2008 Apr;22(2):239-52
references.pmid: 18455682
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11193-8
references.pmid: 21690378
references.citation: Arthritis Rheum. 2001 Jun;44(6):1248-53
references.pmid: 11407682
references.citation: Cell Res. 2008 Oct;18(10):997-1006
references.pmid: 18766170
references.citation: Clin Exp Rheumatol. 2011 Nov-Dec;29(6):1058-9
references.pmid: 22032299
references.citation: Hum Immunol. 2010 Feb;71(2):206-11
references.pmid: 19931339
references.citation: PLoS One. 2010 Oct 20;5(10):e13515
references.pmid: 20976003
references.citation: Arthritis Res Ther. 2010;12(3):R86
references.pmid: 20470394
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8
references.pmid: 18663219
references.citation: Arthritis Rheum. 2010 Sep;62(9):2569-81
references.pmid: 20872595