title: Selective involvement of ERK and JNK mitogen-activated protein kinases in early rheumatoid arthritis (1987 ACR criteria compared to 2010 ACR/EULAR criteria): a prospective study aimed at identification of diagnostic and prognostic biomarkers as well as therapeutic targets.
abstract: OBJECTIVE
  To investigate the expression and activation of mitogen-activated protein kinases in patients with early arthritis who are disease-modifying antirheumatic drug (DMARD) naïve.
  
  
  METHODS
  A total of 50 patients with early arthritis who were DMARD naïve (disease duration <1 year) were prospectively followed and diagnosed at baseline and after 2 years for undifferentiated arthritis (UA), rheumatoid arthritis (RA) (1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) criteria), or spondyloarthritis (SpA). Synovial biopsies obtained at baseline were examined for expression and phosphorylation of p38, extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by immunohistochemistry and digital analysis. Synovial tissue mRNA expression was measured by quantitative PCR (qPCR).
  
  
  RESULTS
  ERK and JNK activation was enhanced at inclusion in patients meeting RA criteria compared to other diagnoses. JNK activation was enhanced in patients diagnosed as having UA at baseline who eventually fulfilled 1987 ACR RA criteria compared to those who remained UA, and in patients with RA fulfilling 2010 ACR/EULAR criteria at baseline. ERK and JNK activation was enhanced in patients with RA developing progressive joint destruction. JNK activation in UA predicted 1987 ACR RA classification criteria fulfilment (R(2)=0.59, p=0.02) after follow-up, and disease progression in early arthritis (R(2)=0.16, p<0.05). Enhanced JNK activation in patients with persistent disease was associated with altered synovial expression of extracellular matrix components and CD44.
  
  
  CONCLUSIONS
  JNK activation is elevated in RA before 1987 ACR RA classification criteria are met and predicts development of erosive disease in early arthritis, suggesting JNK may represent an attractive target in treating RA early in the disease process.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: de Launay
authors.forename: Marleen G H
authors.initials: MG
authors.lastname: van de Sande
authors.forename: Maria J H
authors.initials: MJ
authors.lastname: de Hair
authors.forename: Aleksander M
authors.initials: AM
authors.lastname: Grabiec
authors.forename: Gijs P M
authors.initials: GP
authors.lastname: van de Sande
authors.forename: K Aad
authors.initials: KA
authors.lastname: Lehmann
authors.forename: Carla A
authors.initials: CA
authors.lastname: Wijbrandts
authors.forename: Lisa G M
authors.initials: LG
authors.lastname: van Baarsen
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
authors.forename: Kris A
authors.initials: KA
authors.lastname: Reedquist
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D042241:Early Diagnosis; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D010766:Phosphorylation; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D013583:Synovial Membrane / Q000201:enzymology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases