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Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase
  1. M G H van de Sande1,
  2. M J H de Hair1,
  3. C van der Leij2,
  4. P L Klarenbeek1,
  5. W H Bos3,
  6. M D Smith4,
  7. M Maas2,
  8. N de Vries1,
  9. D van Schaardenburg3,
  10. B A C Dijkmans5,
  11. D M Gerlag1,
  12. P P Tak1
  1. 1Division of Clinical Immunology and Rheumatology, Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Radiology, Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands
  3. 3Jan van Breemen Instituut, Amsterdam, The Netherlands
  4. 4Rheumatology Research Unit, Repatriation General Hospital, Adelaide, Australia
  5. 5Department of Rheumatology, Free University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Professor Dr P P Tak, Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; p.p.tak{at}


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.

Conclusion 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.

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  • Funding This research was funded by the Dutch Arthritis Association (nr 06-1-303) and the European Community's FP6 funding (AutoCure). This publication reflects only the authors' views; the European Community is not liable for any use that may be made of the information herein. The sponsors did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the ethics committee of the Academic Medical Center – University of Amsterdam, Amsterdam, The Netherlands.

  • Provenance and peer review Not commissioned; externally peer reviewed.