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

Objective. Recent clinical trials suggest that etanercept is ineffective in controlling Sjogren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-alpha (IFN alpha) and BAFF, we quantified those mediators in plasma from etanercept- and placebotreated 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. IFNa activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay. Results. Baseline IFNa plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean +/- SD IFN alpha 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 IFN alpha 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 IFNa and the IFN alpha-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF. Conclusion. IFNa activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFNa and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS.