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


CONCLUSIONS
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.
Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021, USA.
Clio P
CP
Mavragani
Timothy B
TB
Niewold
Niki M
NM
Moutsopoulos
Stanley R
SR
Pillemer
Sharon M
SM
Wahl
Mary K
MK
Crow
D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001323:Autoantibodies / Q000097:blood; D053264:B-Cell Activating Factor / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007075:Immunoglobulin M / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D018501:Antirheumatic Agents; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016898:Interferon-alpha; D018124:Receptors, Tumor Necrosis Factor; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept