Clinical efficacy of leflunomide in primary Sjogren's syndrome is associated with regulation of T-cell activity and upregulation of IL-7 receptor α expression.

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.

• Authors: Angela Bikker, Jan-Maarten van Woerkom, Aike A Kruize, Kim M G van der Wurff-Jacobs, Johannes W J Bijlsma, Floris P J G Lafeber, Joel A G van Roon
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 71 Issue 12 Pg. 1934-41 (Dec 2012) ISSN: 1468-2060 [Electronic] England
• PMID: 22563027 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Cytokines
• Isoxazoles
• Receptors, Interleukin-7
• interleukin-7 receptor, alpha chain
• CD40 Ligand
• Leflunomide

Topics

• Adult
• Antirheumatic Agents (administration & dosage)
• CD4-Positive T-Lymphocytes (cytology, drug effects, immunology)
• CD40 Ligand (immunology, metabolism)
• Cells, Cultured
• Cytokines (blood, immunology)
• Female
• Humans
• Isoxazoles (administration & dosage)
• Leflunomide
• Middle Aged
• Pilot Projects
• Receptors, Interleukin-7 (immunology, metabolism)
• Sjogren's Syndrome (drug therapy, immunology)
• Up-Regulation (drug effects, immunology)
• Young Adult