Lack of efficacy of etanercept in Sjogren syndrome correlates with failed suppression of tumour necrosis factor   and systemic immune activation

Abstract

Etanercept is an ineffective therapeutic agent in pSS consistent with the absence of suppression of TNFalpha and other indicators of immune activation in this patient population. These data suggest that TNFalpha may not be a pivotal cytokine in the pathogenesis of pSS, impelling continued molecular characterisation of disease parameters to define appropriate intervention targets.

Systemic and Local Interleukin-17 and Linked Cytokines Associated with Sjögren’s Syndrome Immunopathogenesis

“…As detailed in prior studies, 5,6,17 a pilot study of etanercept (25 mg twice weekly) (n ϭ 14; 12 female and 2 male; median age 55.5 years ͓range, 46 to 59 years͔ and median biopsy focus score ͓FS͔ ϭ 11 ͓range, 5 to 12͔; anti-Ro ͓SSA͔ antibodies 86%; anti-La ͓SSB͔ antibodies 50%) compared with placebo (n ϭ 14; 14 female and 0 male; age 54.5 years ͓range, 46 to 66 years͔ and FS ϭ 7 ͓range 4 to 12͔; anti-Ro ͓SSA͔ antibodies 86%; anti-La ͓SSB͔ antibodies 50%) was performed with SS patients for 12 weeks (approved by the National Institute of Dental and Craniofacial Research institutional review board).…”

“…The data were examined using the 2 Ϫ⌬⌬Ct method, and results are expressed as fold increase. 6 Each sample was tested in triplicate, and tests were repeated twice.…”

“…6 Samples and standards were analyzed in duplicate; analyses were repeated twice, and only variation coefficients Ͻ15% were accepted. IL-23 was determined by an enzyme-linked immunosorbent assay (Biosource International).…”

“…In our recent studies, we determined that etanercept not only did not diminish the signs and symptoms of SS but also was associated with an unexpected increase in circulating TNF␣ levels. 6 Systemically, increased levels of additional cytokines were detected in the plasma of patients with SS compared with plasma of healthy control subjects, including IL-17, a product of a newly recognized population of CD4 ϩ Th17 cells with pro-inflammatory pathogenic potential.…”

“…In this regard, based on prior evidence that Th1 cells dominated in the immunopathogenesis of exocrine gland lesions, therapeutic interventions have been targeted for this population and/or their products. However, antagonists of tumor necrosis factor-␣ (TNF␣), successful in other autoimmune diseases, have been tested in SS without efficacy, [5][6][7][8] further suggesting that alternative pathways must underlie the evolution of exocrinopathies associated with SS. In our recent studies, we determined that etanercept not only did not diminish the signs and symptoms of SS but also was associated with an unexpected increase in circulating TNF␣ levels.…”