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Clinical efficacy of leflunomide in primary Sjögren's syndrome is associated with regulation of T-cell activity and upregulation of IL-7 receptor α expression
  1. Angela Bikker1,
  2. Jan-Maarten van Woerkom1,
  3. Aike A Kruize1,
  4. Kim M G van der Wurff-Jacobs1,
  5. Johannes W J Bijlsma1,
  6. Floris P J G Lafeber1,
  7. Joel A G van Roon1
  1. 1Department of Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr J A G van Roon, Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Heidelberlaan 100, F02.127, Utrecht 3584 CX, The Netherlands; J.vanRoon{at}umcutrecht.nl

Abstract

Objectives To investigate whether the immunomodulatory capacities of leflunomide are associated with clinical efficacy in the treatment of primary Sjögren's syndrome (SS) in a phase II pilot study.

Methods Peripheral blood mononuclear cells from 13 primary SS patients were obtained at baseline and after 24 weeks of leflunomide treatment. Ex-vivo production of interleukin (IL) 1β and tumour necrosis factor α (TNFα) and of interferon (IFN), IL-4, as well as TNFα ELISA measured production on T-cell and monocyte stimulation. In addition, the authors investigated the ability of leflunomide to influence systemic levels of inflammatory cytokines, as well as T-cell activation markers and the expression of IL-7 receptor α by flow cytometry. Correlations between changes in cytokine levels and changes in clinical response parameters were studied.

Results Ex-vivo production of IL-1β and TNFα was decreased at 24 weeks in the whole patient group, whereas IFN and IL-4 production were not significantly changed. However, a significant decrease in T-cell-stimulated IFN and TNFα production was observed in clinical responders, but not in non-responders. Moreover, significant correlations were found between increased sialometry values and decreased IFN and TNFα production. In addition, leflunomide reduced levels of inflammatory serum cytokines and CD40L expression, whereas it upregulated IL-7Rα expression on CD4 T cells with persistent serum IL-7 concentrations.

Conclusions Leflunomide treatment suppressed cytokine release from circulating immune cells. Inhibition of T-helper 1 cell cytokine production was related to clinical efficacy. This suggests that selective T-cell targeting might be a relevant therapeutic strategy in primary SS, possibly enhancing clinical efficacy and safety.

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Footnotes

  • Funding This study was financially supported by the Dutch Arthritis Association (het Nationaal Reumafonds).

  • Competing interests None.

  • Ethics approval The study was performed according to the medical ethical regulations of the University Medical Centre Utrecht.

  • Patient consent Obtained.

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

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