RESEARCH - Lack of efficacy of Enbrel in Sjögren's syndrome correlates with failed suppression of TNF and systemic immune activation

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Ann Rheum Dis. Published Online First: 15 January 2008.

doi:10.1136/ard.2007.077891

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Extended Report

Lack of efficacy of etanercept in Sjögren’s syndrome correlates with failed

suppression of TNF and systemic immune activation

Niki M Moutsopoulos 1, Gikas E. Katsifis 1, Nikola Angelov 2, Rose A. Leakan

3, Vidya Sankar 3, Stanley Pillemer 3 and Sharon M. Wahl 4*

1 Oral Infection and Immunity Branch, NIDCR, NIH, United States

2 Loma University, United States

3 Gene Therapy and Therapeutics Branch, NIDCR, United States

4 Oral Infection and Immunity Branch, NIDCR, United States

Abstract

Objective: To provide insight into the clinical failure of the TNF

inhibitor, etanercept, in primary Sjögren’s syndrome (pSS), we perform an

extensive analysis of the systemic immune profile of pSS patients and

monitor the effect of etanercept treatment on these immune parameters.

Methods: Peripheral blood mononuclear cells (PBMC) of primary SS patients

and healthy controls were compared by flow cytometry for differences in

distribution of specific cell populations (T cells, B cells, monocytes), as

well as for their expression of activation markers (CD25, HLADR), TNF

receptors and chemokine receptors (CXCR1, 2) before and after treatment.

Systemic cytokine levels were measured by multiplex ELISA assay in plasma

and in LPS stimulated whole blood from healthy controls and from pSS

patients before and after etanercept. Baseline cytokine levels were

correlated with clinical markers of disease.

Results: Prior to treatment, salivary gland inflammatory focus scores did

not correlate with circulating TNF levels. Further consistent with 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 TNF were significantly increased after treatment.

Conclusion: Etanercept is an ineffective therapeutic agent in pSS consistent

with the absence of suppression of TNF and other indicators of immune

activation in this patient population. These data suggest that TNF may not

be a pivotal cytokine in the pathogenesis of pSS, impelling continued

molecular characterization of disease parameters to define appropriate

intervention targets.

http://ard.bmj.com/cgi/content/abstract/ard.2007.077891v1?papetoc

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