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The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium
  1. C A Wijbrandts1,
  2. M G W Dijkgraaf2,
  3. M C Kraan1,
  4. M Vinkenoog1,
  5. T J Smeets1,
  6. H Dinant1,3,
  7. K Vos1,3,
  8. W F Lems4,5,
  9. G J Wolbink1,5,
  10. D Sijpkens1,
  11. B A C Dijkmans3,4,5,
  12. P P Tak1
  1. 1
    Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  2. 2
    Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
  3. 3
    Jan van Breemen Institute, Amsterdam, The Netherlands
  4. 4
    Department of Rheumatology, Slotervaart Hospital, Amsterdam, The Netherlands
  5. 5
    VU Medical Center, Amsterdam, The Netherlands
  1. Professor P P Tak, Division of Clinical Immunology and Rheumatology, F4-218, Academic Medical Center/University of Amsterdam, Meibergdreef 9 1105 AZ Amsterdam, The Netherlands; P.P.Tak{at}amc.uva.nl

Abstract

Objective: To determine whether the heterogeneous clinical response to tumour necrosis factor (TNF)α blocking therapy in rheumatoid arthritis (RA) can be predicted by TNFα expression in the synovium before initiation of treatment.

Methods: Prior to initiation of infliximab treatment, arthroscopic synovial tissue biopsies were obtained from 143 patients with active RA. At week 16, clinical response was evaluated using the 28-joint Disease Activity Score (DAS28). Immunohistochemistry was used to analyse the cell infiltrate as well as the expression of various cytokines, adhesion molecules and growth factors. Stained sections were evaluated by digital image analysis. Student t tests were used to compare responders (decrease in DAS28 ⩾1.2) with non-responders (decrease in DAS28 <1.2) and multivariable regression was used to identify the independent predictors of clinical response.

Results: Synovial tissue analysis confirmed our hypothesis that the baseline level of TNFα expression is a significant predictor of response to TNFα blocking therapy. TNFα expression in the intimal lining layer and synovial sublining were significantly higher in responders than in non-responders (p = 0.047 and p = 0.008, respectively). The numbers of macrophages, macrophage subsets and T cells (all able to produce TNFα) were also significantly higher in responders than in non-responders. The expression of interleukin (IL)1β, IL6, IL18, IL10, E-selectin, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was not associated with response to anti-TNFα treatment.

Conclusion: The effects of TNFα blockade are in part dependent on synovial TNFα expression and infiltration by TNFα producing inflammatory cells. Clinical response cannot be predicted completely, indicating involvement of other as yet unknown mechanisms.

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Footnotes

  • Funding: This study was funded by a Health Care Efficiency Research Programme grant from The Netherlands Organization for Health Research and Development (ZonMw) in assignment of The Netherlands Organization for Scientific Research (NWO) (grant number 945-02-029), the Dutch Arthritis Association and the European Community’s FP6 funding (Autocure).

  • Competing interests: PPT has served as a consultant for Abbott, Amgen, Centocor and Wyeth.

  • Ethics approval: The Medical Ethics Committee of the Academic Medical Center, University of Amsterdam approved the protocol. All patients gave written informed consent.

  • This publication reflects only the authors’ views. The European Community is not liable for any use that may be made of the information herein.

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