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

Authors

  • Clio P. Mavragani,

    1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, and Weill Medical College of Cornell University, New York, New York
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  • Timothy B. Niewold,

    1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, and Weill Medical College of Cornell University, New York, New York
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  • Niki M. Moutsopoulos,

    1. National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland
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  • Stanley R. Pillemer,

    1. National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland
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  • Sharon M. Wahl,

    1. National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland
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  • Mary K. Crow

    Corresponding author
    1. Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, and Weill Medical College of Cornell University, New York, New York
    • Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021
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    • Dr. Crow owns stock in Johnson & Johnson and has applied for a patent for an interferon assay.


Abstract

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-α (IFNα) 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. IFNα activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay.

Results

Baseline IFNα plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean ± SD IFNα 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 IFNα 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 IFNα and the IFNα-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF.

Conclusion

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

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