Alteration of peripheral blood dendritic cells in patients with primary Sjögren's syndrome

OBJECTIVE: We recently identified 3 fractions of human peripheral blood (PB) dendritic cells (DC), including the monocyte-associated fractions 1 and 2 (CD1a+,CD11c+ and CD1a-,CD11c+, respectively) and the lymphoid-associated fraction 3 (CD1a-,CD11c-). We attempted to determine whether these fractions were altered in Sj?gren's syndrome (SS). METHODS: We examined 23 patients with primary SS and 22 normal control subjects. DC were purified from PB and analyzed by flow cytometry. Immunohistochemical staining of labial salivary glands of SS patients was performed with monoclonal antibodies against fascin, which is known to be specific for DC. RESULTS: The total numbers of PB DC and fraction 1 DC were decreased in SS. Immunohistochemical staining demonstrated that fascin+,CD11c+,HLA-DR+ mononuclear cells were present and scattered among numerous fascin-hyperfiltrating cells in SS patients. Interferon-gamma (IFNgamma)-producing Th1 cells were shown to be increased in both PB and salivary glands of patients, indicating the presence of general IFNgamma-producing Th1 polarization in SS. Furthermore, numbers of Thl cells were increased when naive T cells were cocultured with fraction 1 DC in vitro. CONCLUSION: These findings suggest selective trafficking of fraction 1 DC into focal sites of inflammation and subsequent promotion of Th1 balance, suggesting a novel pathogenesis of SS.     

Gluten sensitivity in patients with primary Sjögren's syndrome

Objective. To evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren's syndrome (pSS). Material and methods. Rectal challenges with wheat gluten were performed in 20 patients with pSS and 18 healthy control subjects. Fifteen hours after challenge the mucosal production of nitric oxide (NO) was measured. Results. Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren's syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms. Conclusions. Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.     

Gluten sensitivity in patients with primary Sjögren's syndrome

OBJECTIVE: To evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sj?gren's syndrome (pSS). MATERIAL AND METHODS: Rectal challenges with wheat gluten were performed in 20 patients with pSS and 18 healthy control subjects. Fifteen hours after challenge the mucosal production of nitric oxide (NO) was measured. RESULTS: Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sj?gren's syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms. CONCLUSIONS: Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease.     

Psychological well-being in patients with primary Sjögren's syndrome

OBJECTIVES: To evaluate quality of life and psychological symptoms in patients with primary Sj?gren's syndrome and to compare this with patients with rheumatoid arthritis. METHODS: A standardised questionnaire, the Psychological General Well-Being Index (PGWB), was used to examine the quality of life and psychological symptoms in patients with primary Sj?gren's syndrome (pSS; n = 34). Patients with rheumatoid arthritis (RA; n = 32) were used as patient controls. RESULTS: The total mean score +/- SD for PGWB was 84.9 +/- 16.2 in pSS patients and significantly lower (p = 0.001) than in RA patients (97.7 +/- 17.5). Patients with pSS had an increased propensity for depressed mood (p = 0.0009), and suffered from reduced well-being (p = 0.002) and impaired vitality (p = 0.003). CONCLUSION: The results suggest that patients with pSS have a reduced quality of life, a higher degree of distress and a lower sense of well-being than patients with RA.     

Sympathetic dysfunction in patients with primary Sjögren's syndrome

OBJECTIVE: To investigate autonomic nervous system function in patients with primary Sj?gren's syndrome (SS) and relate the findings to clinical variables. METHODS: Autonomic nervous system function was determined in 30 patients with primary SS using the finger skin blood flow test [vasoconstrictory (VAC) index], deep-breathing test [expiration/inspiration (E/I) ratio], and the tilt table (orthostatic) test [acceleration index (AI), brake index (BI), and orthostatic blood pressure]. The results were compared with age matched control materials (finger skin blood flow test, n = 80, and deep-breathing and tilt table tests, n = 56). RESULTS: The VAC index was found to be significantly increased and the E/I ratio significantly decreased in patients compared to controls, indicating both a sympathetic and a parasympathetic dysfunction. Further, the patients, especially the anti-SSA and anti-SSB antibody seropositives, were found to have an abnormal blood pressure reaction to tilt compared to controls. No correlations were found between autonomic nerve function variables measured and the clinical ophthalmologic or the oral tests, performed at the time of diagnosis. CONCLUSION: Patients with primary SS show signs of both sympathetic and parasympathetic dysfunction. Further, immunological mechanisms seem to influence blood pressure in patients with primary SS.     

Anxiety and depression in patients with primary Sjögren's syndrome

OBJECTIVE: To examine the degree of anxiety and depression and to assess well being and general symptoms in patients with primary Sj?gren's syndrome (SS). METHODS: A standardized questionnaire, the Hospital Anxiety and Depression Scale, was used to examine the degree of anxiety and depression in patients with primary SS (n = 62) and in age matched healthy female controls. The Gothenburg quality of life instrument (GQOL) was used to assess well being and general symptoms. Patients with rheumatoid arthritis (RA; n = 38) were used as patient controls. RESULTS: The patients with primary SS had significantly higher scoring rate for "possible" clinical anxiety (48%) and for "possible" clinical depression (32%) compared with reference groups (p<0.05). The physical and mental well being of the patients with primary SS were significantly reduced compared with controls. Furthermore, patients with primary SS complained more commonly of low mood, irritability, headache, gastrointestinal symptoms, and impaired concentration and memory than the patients with RA. CONCLUSION: The results indicate that patients with primary SS often have psychiatric symptoms and worse well being, which may affect their quality of life.     

Precocious intima-media thickening in patients with primary Sjögren's syndrome

OBJECTIVE: Systemic lupus erythematosus and rheumatoid arthritis represent independent risk factors for atherosclerosis (ATS), although this may be confounded by continuous pharmacologic treatment. Primary Sj?gren's syndrome (SS) shares several features of these diseases and may therefore represent an interesting model for verifying the presence of accelerated ATS in the absence of pharmacologic interference. The present study therefore used this model to describe the presence of accelerated ATS in a group of young women. METHODS: Thirty-seven untreated white women with primary SS were evaluated clinically and serologically. Carotid and femoral artery intima-media thickness (IMT) was evaluated in the patients and in 35 age-matched healthy women who served as controls. RESULTS: The patients had a higher IMT than did the controls at both the carotid (mean +/- SD 0.82 +/- 0.24 mm versus 0.63 +/- 0.20 mm; P < or = 0.001) and the femoral (0.81 +/- 0.26 mm versus 0.67 +/- 0.23 mm; P < or = 0.019) levels, and had a higher prevalence of carotid intima-media thickening (49% versus 11% of controls; P < or = 0.001). The patient subset with high carotid IMT showed an increased prevalence of leukopenia and circulating anti-SSA antibodies; interestingly, the number of leukocytes was inversely correlated with the level of arterial IMT in patients with SS. Multivariate analysis demonstrated that anti-SSA antibodies were independent predictors of carotid artery thickening, while leukopenia was a predictor of both carotid and femoral artery thickening. CONCLUSION: Subclinical ATS was evident in about one-half of the patients with SS. Its association with some features typical of connective tissue diseases, such as the presence of anti-SSA and leukopenia, suggests that the immune dysregulation characterizing this autoimmune disorder may play a key role in inducing early ATS.     

Prevalence of antiphospholipid antibodies in patients with primary Sjögren's syndrome

The aim of this study was to determine prevalence of antiphospholipid antibodies (aPL) including anticardiolipin antibodies (aCL), and anti-beta2GP1 in a cohort of 32 patients with primary Sjogren's syndrome (pSS) diagnosed according to revised European criteria. aPL were found in 9/32 (28%) patients (IgG in 8 and IgM in one case). Anti-beta2GPI antibodies were detected only in two patients. Titres were usually low.     

Incidence of thromboembolic events in patients with primary Sjögren's syndrome

Primary Sj?gren's syndrome (pSS) is a connective tissue disease with symptoms and serological findings often overlapping with systemic lupus erythematosus (SLE) (1). Thromboembolic events are common in SLE but not in pSS (2)(3). However, case reports have described pSS patients who developed fulminant multiorgan disease due to thrombotic diathesis 4, and we have presented a case with acute catastrophic anti-phospholipid syndrome (APS) in a pSS patient (5). In this study we wanted to examine the incidence of thromboembolic episodes and relate these to the presence of autoantibodies and coagulation abnormalities in 90 pSS patients during a 4.6-year follow-up.     

Antibodies to CD4 in primary Sjögren's syndrome

OBJECTIVE: The purpose of this study was to examine whether antibodies against CD4 are present in patients with primary Sj?gren's syndrome, and to explore the possible correlation between these antibodies and the CD4+ T lymphocyte depletion that is seen in some Sj?gren patients. METHODS: Sera from 214 patients with primary Sj?gren's syndrome, 154 healthy blood donors, 38 age- and sex-matched controls without autoimmune disease, and 77 HIV-1-seropositive individuals were analysed by an enzyme-linked immunosorbent assay (ELISA) using recombinant soluble CD4 as the antigen. RESULTS: Anti-CD4 antibodies were observed more frequently in patients with Sj?gren's syndrome (12.6%) as compared with the control groups (0.6%) (P < 0.001), and at a level similar to that seen among the HIV-1 patients (13.0%). However, no correlation was found between the presence of anti-CD4 antibodies and CD4+ T lymphocytopenia in the Sj?gren patients. CONCLUSION: This is the first study that shows anti-CD4 antibodies in patients with primary Sj?gren's syndrome. The significance of these antibodies in the immunopathogenesis of Sj?gren's syndrome remains to be determined.     

Augmented interferon-alpha pathway activation in patients with Sjögren's syndrome treated with etanercept

OBJECTIVE: Recent clinical trials suggest that etanercept is ineffective in controlling Sj?gren's syndrome (SS). To address the hypothesis that tumor necrosis factor blockade can result in increased levels of interferon-alpha (IFNalpha) and BAFF, we quantified those mediators in plasma from etanercept- and placebo-treated SS patients. METHODS: We studied plasma samples from 20 patients with SS treated with etanercept (25 mg twice weekly) or placebo in a 12-week, randomized, double-blind clinical trial. In addition, we studied plasma samples from 29 healthy controls. IFNalpha activity was determined by reporter cell assay, and BAFF levels were determined by enzyme-linked immunosorbent assay. RESULTS: Baseline IFNalpha plasma activity and BAFF levels were increased in SS patients compared with healthy controls (mean +/- SD IFNalpha plasma activity score 4.43 +/- 2.60 versus 2.08 +/- 0.91; P < 0.0001) (mean +/- SD BAFF level 0.83 +/- 0.27 ng/ml versus 0.60 +/- 0.15 ng/ml; P = 0.008). A significant increase in IFNalpha activity was detected after 12 weeks of treatment in the etanercept group, but not in the placebo group (P = 0.04 and P = 0.58, respectively). Furthermore, a statistically significant increase in BAFF levels was noted in patients receiving etanercept, but not in those receiving placebo (P = 0.01 and P = 0.56, respectively). In vitro culture of control peripheral blood mononuclear cells with etanercept resulted in a dose-dependent increase in the expression of IFNalpha and the IFNalpha-inducible genes IFN-induced protein with tetratricopeptide repeats 1 and BAFF. CONCLUSION: IFNalpha activity and BAFF levels are elevated in the plasma of patients with SS compared with healthy controls. Etanercept treatment exacerbates IFNalpha and BAFF overexpression, providing a possible explanation for the lack of efficacy of this agent in SS.     

Hematologic parameters and disease activity in patients with primary Sjögren's syndrome

Aim of the workTo evaluate hematologic parameters in patients with primary Sjögren's syndrome (PSS) and their association with disease activity.Patients and methodsSixty-five PSS patients and 65 age and sex matched control were studied. Neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV), red blood cells distribution width (RDW), platelet to lymphocyte ratio (PLR) and platelet count were evaluated. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured. The European league against rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) was assessed.ResultsThe mean age of patients was 47.8 ± 12.1 years and disease duration 5.71 ± 1.2 years and they were 63 females and 2 males. The mean ESSDAI was 6.4 ± 7.9 (3–25). 11 had neurological involvement. 92.3% of patients received low-dose prednisolone (<10 mg/day) and hydroxychloroquine (HCQ). The mean NLR (1.83 ± 0.8), PLR (131.9 ± 32.5) and MPV (8.82 ± 1.4) in patients was significantly higher than in control (NLR 1.57 ± 0.56, PLR 109.9 ± 24.7 and MPV 7.71 ± 1.3; p = 0.036, p < 0.001 and p < 0.001 respectively). The RDW tended to be higher in patients (13 ± 1.56) compared to control (12.83 ± 1.13) (p = 0.46). There was a significant correlation between ESSDAI with NLR (r = 0.29, p = 0.02), RDW (r = 0.37, p = 0.002), ESR (r = 0.32, p = 0.01) and CRP (r = 0.33, p = 0.007) and between MPV with CRP (r = 0.27, p = 0.03) and between RDW and ESR (r = 0.36, p = 0.003).On regression analysis, NLR and RDW were significant predictors of disease activity (p = 0.01 and p = 0.02 respectively).ConclusionThe MPV, PLR and NLR, were significantly increased in PSS. NLR and RDW can be used as indicators of disease activity.     

Increased salivary interleukin-6 levels in patients with primary Sjögren's syndrome

This study's purpose was to evaluate salivary interleukin-6 (IL-6) levels in patients with primary Sjögren's syndrome (SS). Salivary and serum IL-6 concentrations were evaluated by ELISA in 36 patients with SS and compared with 19 patients complaining of dry mouth and with normal controls. Salivary IL-6 levels were significantly elevated (P<0.01) in the 36 patients with SS as compared to the 19 patients with dry mouth (200.5±43.6 and 12.6±6.8 pg/ml, respectively). No significant differences were noted in the serum IL-6 levels between these two groups (105.8±17.1 and 84.8±17.1 pg/ml, respectively). Both salivary and serum IL-6 levels in the normal controls were below the level of detection of the assay. Positive correlation (r = 0.8613, P<0.0001) was found between salivary IL-6 levels and the focus score of labial biopsies in SS patients. Elevated salivary IL-6 levels appear to be a consequence of local production and may reflect the component of salivary gland inflammation in SS.     

Infliximab in patients with primary Sjögren's syndrome: a pilot study

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of Sj?gren's syndrome (SS), and blockade of TNFalpha may reduce the activity of the disease. The purpose of this study was to evaluate the safety and potential efficacy of infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody, in patients with active primary SS. METHODS: This was a single-center, open-label pilot study. Sixteen patients with active primary SS received 3 infusions of infliximab (3 mg/kg) at 0, 2, and 6 weeks. Standard clinical assessment, complete ophthalmologic testing, and functional evaluation of salivary flow were performed at baseline and at weeks 2, 6, 10, and 14. RESULTS: All patients completed the study. There was statistically significant improvement in all clinical and functional parameters, including global assessments (patient's global assessment, patient's assessment of pain and fatigue, physician's global assessment), erythrocyte sedimentation rate, salivary flow rate, the Schirmer I test, tender joint count, fatigue score, and dry eyes and dry mouth. This clinical benefit was observed at week 2 and was maintained throughout the study and the 2-month followup period. The treatment was well tolerated in all patients, and no significant adverse events were seen. No lupus-like syndrome was observed, and no anti-double-stranded DNA antibodies were observed that were attributable to infliximab therapy. CONCLUSION: In patients with active primary SS, a loading-dose regimen of 3 infusions of infliximab provided a fast and significant clinical benefit without major adverse reactions. It was possible to maintain statistically significant improvement for up to 8 weeks after the third infusion.     

Monozygotic twins with primary Sjögren's syndrome

Sj?gren's syndrome (SS) is a chronic autoimmune disease mainly characterized by dry mouth and dry eyes due to an inflammatory process in the exocrine glands. We describe a pair of Caucasian monozygotic twin sisters and their mother, all having primary SS. The twins had very similar clinical presentation and almost identical serological data, and histological examination of lower labial salivary glands gave a focus score of 3 in both twins. We also present their family medical history, which shows aggregation of immunological disorders among family members, although the twins and their mother were the only individuals with primary SS.