title: Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.
abstract: OBJECTIVE
  For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis.
  
  
  METHODS
  Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor.
  
  
  RESULTS
  A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis
  
  
  CONCLUSIONS
  Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: L
authors: L
authors: Yeo
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: N
authors: N
authors: Adlard
authors: Johann Bernoulli Institute for Mathematics and Computer Science, University of Groningen, University of Groningen, Groningen, The Netherlands.
authors: M
authors: http://orcid.org/0000-0001-5148-4568
authors: M
authors: Biehl
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: M
authors: M
authors: Juarez
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: T
authors: T
authors: Smallie
authors: Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, UK.
authors: M
authors: M
authors: Snow
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: C D
authors: CD
authors: Buckley
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
authors: K
authors: K
authors: Raza
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
authors: A
authors: A
authors: Filer
authors: Rheumatology Research Group, Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: D
authors: D
authors: Scheel-Toellner
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D000069550:Machine Learning; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010978:Platelet Factor 4 / Q000235:genetics* / Q000378:metabolism; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D001620:beta-Thromboglobulin / Q000235:genetics* / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D010978:Platelet Factor 4; D040201:Platelet Membrane Glycoprotein IIb; D012333:RNA, Messenger; D001620:beta-Thromboglobulin; D014841:von Willebrand Factor; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C061615:PPBP protein, human
keywords: Cytokines; Early Rheumatoid Arthritis; Inflammation; Rheumatoid Arthritis; Synovitis