Lack of efficacy of etanercept in Sjögren syndrome correlates with failed suppression of tumour necrosis factor alpha and systemic immune activation.
OBJECTIVE
To provide insight into the clinical failure of the tumour necrosis factor alpha (TNFalpha) 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 TNFalpha were significantly increased after treatment.


CONCLUSIONS
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.
Moutsopoulos
N M
NM
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Katsifis
G E
GE
Angelov
N
N
Leakan
R A
RA
Sankar
V
V
Pillemer
S
S
Wahl
S M
SM
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D016207:Cytokines / Q000097:blood; D004311:Double-Blind Method; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D010865:Pilot Projects; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000276:immunology; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept