title: Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase.
abstract: BACKGROUND
  The aetiology of rheumatoid arthritis (RA), a prototype immune-mediated inflammatory disorder, is poorly understood. It is currently unknown whether the disease process starts in the synovium, the primary target of RA, or at other sites in the body.
  
  
  OBJECTIVE
  To examine, in a prospective study, the presence of synovitis in people with an increased risk of developing RA.
  
  
  METHODS
  Thirteen people without evidence of arthritis, who were positive for IgM rheumatoid factor and/or anticitrullinated protein antibodies, were included in the study. To evaluate synovial inflammatory changes, all participants underwent dynamic contrast-enhanced MRI and arthroscopic synovial biopsy sampling of a knee joint at inclusion. Results were compared with knee MRI data and synovial biopsy data of 6 and 10 healthy controls, respectively.
  
  
  RESULTS
  MRI findings evaluated by measurement of maximal enhancement, rate of enhancement, synovial volume and enhancement shape curve distribution were similar between the autoantibody-positive subjects and the healthy controls. Consistent with these findings, all but one autoantibody-positive subject showed very low scores for phenotypic markers, adhesion molecules and vascularity, all in the same range as those in normal controls. The one person with higher scores had patellofemoral joint space narrowing.
  
  
  CONCLUSIONS
  Subclinical inflammation of the synovium does not coincide with the appearance of serum autoantibodies during the pre-RA stage. Thus, systemic autoimmunity precedes the development of synovitis, suggesting that a 'second hit' is involved. This study supports the rationale for exploring preventive strategies aimed at interfering with the humoral immune response before synovial inflammation develops.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M G H
authors.initials: MG
authors.lastname: van de Sande
authors.forename: M J H
authors.initials: MJ
authors.lastname: de Hair
authors.forename: C
authors.initials: C
authors.lastname: van der Leij
authors.forename: P L
authors.initials: PL
authors.lastname: Klarenbeek
authors.forename: W H
authors.initials: WH
authors.lastname: Bos
authors.forename: M D
authors.initials: MD
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Maas
authors.forename: N
authors.initials: N
authors.lastname: de Vries
authors.forename: D
authors.initials: D
authors.lastname: van Schaardenburg
authors.forename: B A C
authors.initials: BA
authors.lastname: Dijkmans
authors.forename: D M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000276:immunology / Q000473:pathology; D001182:Arthroscopy; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007719:Knee Joint / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood; D013583:Synovial Membrane / Q000473:pathology; D013585:Synovitis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor