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 Linda University, United States
³ Gene Therapy and Therapeutics Branch, NIDCR, United States
⁴ Oral Infection and Immunity Branch, NIDCR, United States

^* To whom correspondence should be addressed. E-mail: smwahl{at}dir.nidcr.nih.gov.

Accepted 20 December 2007

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.

Keywords: Sj�gren�s syndrome, TNF&[alpha], etanercept

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