Augmented interferon-alpha pathway activation in patients with Sjögren's syndrome treated with etanercept

Arthritis Rheum. 2007 Dec;56(12):3995-4004. doi: 10.1002/art.23062.


Objective: Recent clinical trials suggest that etanercept is ineffective in controlling Sjögren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-alpha (IFNalpha) and BAFF, we quantified those mediators in plasma from etanercept- and placebo-treated SS patients.

Methods: We studied plasma samples from 20 patients with SS treated with etanercept (25 mg twice weekly) or placebo in a 12-week, randomized, double-blind clinical trial. In addition, we studied plasma samples from 29 healthy controls. IFNalpha activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay.

Results: Baseline IFNalpha plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean +/- SD IFNalpha plasma activity score 4.43 +/- 2.60 versus 2.08 +/- 0.91; P < 0.0001) (mean +/- SD BAFF level 0.83 +/- 0.27 ng/ml versus 0.60 +/- 0.15 ng/ml; P = 0.008). A significant increase in IFNalpha activity was detected after 12 weeks of treatment in the etanercept group, but not in the placebo group (P = 0.04 and P = 0.58, respectively). Furthermore, a statistically significant increase in BAFF levels was noted in patients receiving etanercept, but not in those receiving placebo (P = 0.01 and P = 0.56, respectively). In vitro culture of control peripheral blood mononuclear cells with etanercept resulted in a dose-dependent increase in the expression of IFNalpha and the IFNalpha-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF.

Conclusion: IFNalpha activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFNalpha and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antirheumatic Agents / pharmacology
  • Antirheumatic Agents / therapeutic use*
  • Autoantibodies / blood
  • B-Cell Activating Factor / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Etanercept
  • Humans
  • Immunoglobulin G / metabolism
  • Immunoglobulin G / pharmacology
  • Immunoglobulin G / therapeutic use*
  • Immunoglobulin M / metabolism
  • Interferon-alpha / metabolism*
  • Interferon-alpha / pharmacology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Sjogren's Syndrome / drug therapy*
  • Sjogren's Syndrome / metabolism*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / metabolism


  • Antirheumatic Agents
  • Autoantibodies
  • B-Cell Activating Factor
  • Immunoglobulin G
  • Immunoglobulin M
  • Interferon-alpha
  • Receptors, Tumor Necrosis Factor
  • TNFSF13B protein, human
  • Tumor Necrosis Factor-alpha
  • Etanercept