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. CONCLUSION: 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.

Immunological consequences of thalidomide treatment in Sjögren's syndrome.

OBJECTIVE: To study the immunological consequences of systemic thalidomide treatment in patients with Sjögren's syndrome. METHODS: Cytokine (tumour necrosis factor alpha (TNFalpha), interleukin (IL) 6) and soluble receptor (sIL2R) levels were measured in patient and control plasma (n = 7), before and after thalidomide treatment. Peripheral blood mononuclear cells were examined by FACS analysis for potential changes in specific cell populations (T cells, B cells, monocytes), and for the expression of activation markers (CD25, HLA-DR), costimulatory molecules (CD40, CD40L), TNF receptors, chemokine receptors, and adhesion molecules (L-selectin (L-sel)). RESULTS: Owing to adverse effects of thalidomide, the treatment interval was limited. None the less, statistically significant changes in markers of cell activation were recorded in the four treated patients. Before treatment, HLA-DR, TNFRI, CXCRI, and CXCRII were raised in the patients compared with healthy controls (p<0.05) and their expression was down regulated after treatment. B cell numbers and expression of the adhesion molecule L-sel also declined with thalidomide. CONCLUSION: Significant changes in measures of cell activation were detected during thalidomide treatment within this limited study, which upon further investigation may offer insight into the underlying immunoregulatory pathways of thalidomide.

Serum lipid levels in Sjögren's syndrome.

OBJECTIVES: Altered lipid levels may occur in autoimmune diseases, for example low cholesterol levels have been described in rheumatoid arthritis (RA). Serum lipid profiles in patients with Sjögren's syndrome (SS) have not been investigated. We hypothesized decreased lipid levels in SS patients and an inverse relationship with disease activity. METHODS: Serum lipid levels [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides] and additional data regarding disease measures (clinical immunology parameters, focus score from labial salivary gland biopsy, salivary flow and ophthalmological measures) were available for 46 primary SS patients and 12 xerostomic controls. RESULTS: Significant differences between SS patients and controls means (s.d.) were seen for HDL (P = 0.04) and total cholesterol (P = 0.02). LDL (P = 0.12) and triglyceride (P = 0.08) levels were not different. In SS patients, but not in controls, total cholesterol (P = 0.003) and HDL cholesterol (P = 0.003) predicted immunoglobulin G levels. Anti-SSA antibodies were related to a lower total cholesterol (P = 0.02) and anti-SSB antibodies to a lower HDL cholesterol level (P = 0.0497). CONCLUSIONS: Significant differences were seen in serum lipid levels of primary SS patients and these were associated with serological measures of inflammation. Our results are comparable to earlier findings in RA patients and raise questions related to adverse cardiovascular consequences in SS.

Adult heart block is associated with disease activity in primary Sjögren's syndrome.

OBJECTIVES: Congenital heart block occurring in the foetus and neonate may be associated with maternal anti-SS-A/anti-SS-B autoantibodies (anti-SSA/anti-SSB). The adult atrioventricular node is generally thought to be resistant to the damaging effects of anti-SSA/anti-SSB. However, case reports suggest that heart block developing in adult Sjögren's syndrome (SS) patients may be associated with these autoantibodies. Therefore, we investigated the relationship between serum antibodies and heart block in adult SS patients. METHODS: We abstracted data from clinic patient records. Diagnosis of primary SS was based on American-European classification criteria. Electrocardiograms (EKGs), laboratory immunology parameters, lipid profiles, and focus scores from labial salivary gland biopsies were available for 51 SS patients. Fifteen patients had follow-up EKGs. PR interval200 ms was considered to be first-degree heart block. RESULTS: Five patients showed prolonged PR intervals; the presence of heart block was not related to the presence of anti-SSA antibodies. However, significant differences between patients with prolonged and normal PR intervals were seen for mean focus scores (p<0.0001), anti-cardiolipin immunoglobulin IgG (p = 0.0009), age (p = 0.01), IgG (p = 0.02), anti-SSB antibodies (p = 0.02), and high density lipoprotein (HDL) cholesterol levels (p = 0.03). These parameters correlated with prolonged PR intervals. CONCLUSIONS: These results suggest an association between disease activity, the presence of anti-SSB antibodies, and the occurrence of first-degree heart block in adults with primary SS.