TY - JOUR
T1 - Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor α and systemic immune activation
AU - Moutsopoulos, N. M.
AU - Katsifis, G. E.
AU - Angelov, N.
AU - Leakan, R. A.
AU - Sankar, V.
AU - Pillemer, S.
AU - Wahl, S. M.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2008/10
Y1 - 2008/10
N2 - Objective: To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. Methods: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. Results: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFα were significantly increased after treatment. Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFα and other indicators of immune activation in this patient population. These data suggest that TNFα may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.
AB - Objective: To provide insight into the clinical failure of the tumour necrosis factor α (TNFα) inhibitor, etanercept, in primary Sjögren syndrome (pSS), an extensive analysis of the systemic immune profile of patients with pSS was carried out and the effect of etanercept treatment on these immune parameters monitored. Methods: Peripheral blood mononuclear cells of patients with pSS and healthy controls were compared by flow cytometry to determine differences in distribution of specific cell populations (T cells, B cells, monocytes), and to determine their expression of activation markers (CD25, HLA-DR), TNF receptors and chemokine receptors (CXCR1, 2) before and after treatment. Systemic cytokine levels were measured by multiplex ELISA assay in plasma and in lipopolysaccharide-stimulated whole blood from healthy controls and from patients with pSS before and after etanercept treatment. Baseline cytokine levels were correlated with clinical markers of disease. Results: Before treatment, salivary gland inflammatory focus scores did not correlate with circulating TNF levels. Furthermore, consistent with the lack of evidence of significant clinical benefit, enhanced markers of immune activation, frequency of cell subpopulations and aberrant cytokine profiles were not restored to normal levels by etanercept treatment. Remarkably, the levels of circulating TNFα were significantly increased after treatment. Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFα and other indicators of immune activation in this patient population. These data suggest that TNFα may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.
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U2 - 10.1136/ard.2007.077891
DO - 10.1136/ard.2007.077891
M3 - Article
C2 - 18198195
AN - SCOPUS:53149096567
VL - 67
SP - 1437
EP - 1443
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
SN - 0003-4967
IS - 10
ER -