title: 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: OBJECTIVE
  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.affiliation: Department of Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Bikker
authors.forename: Jan-Maarten
authors.initials: JM
authors.lastname: van Woerkom
authors.forename: Aike A
authors.initials: AA
authors.lastname: Kruize
authors.forename: Kim M G
authors.initials: KM
authors.lastname: van der Wurff-Jacobs
authors.forename: Johannes W J
authors.initials: JW
authors.lastname: Bijlsma
authors.forename: Floris P J G
authors.initials: FP
authors.lastname: Lafeber
authors.forename: Joel A G
authors.initials: JA
authors.lastname: van Roon
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000276:immunology; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D000077339:Leflunomide; D008875:Middle Aged; D010865:Pilot Projects; D020395:Receptors, Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; D007555:Isoxazoles; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D023201:CD40 Ligand; D000077339:Leflunomide