Predictive modeling of aspirin-triggered resolvin D1 pharmacokinetics for the study of Sjögren's syndrome.

OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS-like features in NOD/ShiLtJ mice can be systemically halted using AT-RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti-inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT-RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration. MATERIALS AND METHODS: Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT-RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK-Sim® and MoBi® Version 7.4 software. RESULTS: The model provides high-value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design. CONCLUSIONS: Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short-term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.

Influence of total glucosides of paeony on PD-1/PD-L1 expression in primary Sjögren's syndrome.

AIM: To study the influence of total glucosides of paeony (TGP) on the expression of peripheral blood programmed cell death protein 1 (PD-1) and its ligand (PD-L1) in patients with primary Sjögren's syndrome (pSS). METHOD: Ten patients with new-onset pSS were selected as the experimental group and were treated with 1.8 g of TGP (the main ingredient is Radix Paeoniae Alba) daily for 3 months; furthermore, 10 physically healthy individuals were selected as the control group. Peripheral blood mononuclear cells were isolated, and flow cytometry was used to detect PD-1 expression on the surface of CD4+ T and CD8+ T lymphocytes and PD-L1 expression on the surface of CD14+ monocytes and CD19+ B cells before and after treatment in the experimental and control groups. Furthermore, plasma levels of soluble PD-1 (sPD-1), interleukin (IL)-10, and IL-17A were also determined using enzyme-linked immunosorbent assay. RESULTS: The PD-1 expression on the surface of CD4+ T and CD8+ T lymphocytes in the peripheral blood of patients with pSS were significantly higher than in the control group (P < 0.001). However, PD-L1 expression on the surface of CD14+ monocytes declined but not significantly (P > 0.05), and PD-L1 expression on the surface of CD19+ B cells increased significantly (P < 0.001). Moreover, sPD-1 and IL-17A levels in the plasma of the experimental group were significantly higher than in the control group (P < 0.001), but the IL-10 level was significantly lower than in the control group (P < 0.001). After TGP treatment, PD-1 expression on the surface of CD4+ T and CD8+ lymphocytes in the peripheral blood of patients with pSS had decreased significantly (P < 0.001); the PD-L1 expression on the surface of CD19+ cells had decreased significantly (P < 0.001); and the PD-L1 expression on the surface of CD14+ monocytes did not differ significantly (P > 0.05). Furthermore, the levels of sPD-1 and IL-17A in plasma had decreased (P < 0.01) and IL-10 levels had increased after TGP treatment (P < 0.01). CONCLUSION: PD-1/PD-L1 molecules expressed on the surface of T cells, B cells, and monokaryon participated in the pathogenesis and development of SS through interactions. Therefore, TGP, which may increase the expression of PD-1 and its relevant ligand PD-L1 in the peripheral blood mononuclear cells, may play a role in the pathogenesis and development of SS through the PD-1/PD-L1 pathway by regulating regulatory T cells/T helper cell 17.

Down-regulation of increased TRAF6 expression in the peripheral mononuclear cells of patients with primary Sjögren's syndrome by an EBV-EBER1-specific synthetic single-stranded complementary DNA molecule.

AIM: We described earlier a simultaneously increased that the increased expression of miRNA-146a/b was accompanied by an increase in the expression of and TRAF6 and a decrease in the expression of IRAK1 genes in the peripheral mononuclear cells (PBMCs) of patients with primary Sjogren's syndrome (pSS) patients. Recently, the expression of EBV encoded. RNA (EBER) was published in the B cells of salivary glands of in pSS. In the present study, we applied an EBV-EBER1 specific synthetic single stranded complementary DNA molecule (EBV-EBER1-cDNA) to test whether any EBER1 related effect exists also in PBMCs of pSS patients. METHODS: In the PBMCs of pSS patients and healthy controls, we investigated in vitro the effects of a synthetic single stranded EBV-EBER1-cDNA molecule, synthetic double-stranded (ds)RNA polyinosinic-polycytidylic acid [poly (I:C)] and polyadenylic acid potassium salt poly-adenylic acid [poly-(A)] on the expression of TRAF6 gene tested by qRTPCR. The release of interferon -α was detected by ELISA. RESULTS: EBV-EBER1-cDNA resulted in a significant reduction in the expression of TRAF6 in the cells of patients, but in the healthy controls not, whereas the treatments with poly (I:C) and poly-(A) could not reduce the TRAF6 over-expression. No release of EBER1 could be observed in the culture supernatants of patients with pSS. Only the treatment with poly (I:C) resulted in a significant increase of interferon -α release, and only in the heathy controls. No release of EBER1 molecules took place during the culturing of cells. EBV-EBER- cDNA acted functionally on the cells of patients only. CONCLUSION: These findings give a further evidence of the linkage between EBV and pSS, furthermore, they show the possible role of EBV-EBER1 in the induction of increased TRAF6 expression in the peripheral B cells of Sjögren's patients.

[Xinfeng Capsule reduces hypercoagulative state in patients with Sjogren's syndrome by inhibiting miR-155/SOCS1/NF-κB signaling pathway].

Objective To explore the relationship between Xinfeng Capsule (XFC) improving the hypercoagulative state in patients with Sjogren's syndrome (SS) and miR-155/suppressor of cytokine signaling 1 (SOCS1)/nuclear factor κB (NF-κB) signaling pathway. Methods Sixty-six SS patients were randomly divided into XFC-treated group and hydroxychloroquine (HCQ)-treated control group (n=33 per group), which were respectively treated with XFC and HCQ. In addition, 20 healthy volunteers were enrolled as a normal control group. The levels of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIG), thrombin time (TT) and D-dimer (D-D) were detected using automatic coagulation analyzer. Interleukin-1ß (IL-1ß), IL-4, IL-10, tumor necrosis factor-α (TNF-α), P50, P65, inhibitor of NF-κB α (IκBα) were tested using ELISA. Meanwhile, the mRNA expressions of p50, p65 and IκBα were determined using quantitative real-time PCR, and the level of microRNA-155 (miR-155) was examined by one-step fluorescence quantitative PCR. The protein levels of P50, P65 and SOCS1 were detected using Western blotting. Erythrocyte sedimentation rate (ESR) was evaluated by Westergren method. Hypersensitive C-reactive protein (hs-CRP) was detected using automatic biochemical analyzer. Results Compared with the normal control group, the levels of D-D and FIB significantly increased in SS group; simultaneously, the serum levels of miR-155, IL-1ß, TNF-α, P50, P65, IκBα, hs-CRP, ESR were significantly elevated in SS patients, while IL-4 and IL-10 were significantly reduced. Spearman correlation analysis showed that the coagulation parameters were remarkably correlated with cytokines, NF-κB and activity indexes. In the two treated groups, coagulation parameters and related indexes were demonstrated having some improvement, especially in the XFC group, which had a much higher efficiency, and better outcomes in reducing the levels of FIB, D-D, miR-155, TNF-α, IL-1ß, P50, P65, ESR and hs-CRP, as well as increasing the expressions of SOCS1, IL-4 and IL-10. Conclusion XFC can significantly alleviate the hypercoagulative state of patients with SS, and the mechanisms may be related to the inhibition of miR-155/SOCS1/NF-κB signaling pathway.

Endogenous event-related potentials in patients with primary Sjögren's syndrome without central nervous system involvement.

OBJECTIVES: Endogenous cognitive event-related potentials (CERPs) reflect higher-level processing of sensory information and can be used to evaluate cognitive functions. The aim of this paper was to determine whether there are any abnormalities in the electrophysiological parameters of CERPs in patients with primary Sjögren's syndrome (pSS) but without symptoms of central nervous system (CNS) involvement or mental disorder. The analysis of CERP parameters was then correlated with the clinical status of the patients and with some of the immunological parameters in the patient group. METHOD: Thirty consecutive patients with pSS (29 females, one male) were included in the study. All the patients underwent CERP examination. RESULTS: There was a significant prolongation of the latency of P300 and N200 potentials in patients with pSS. Abnormalities in electrophysiological parameters of CERPs correlated with the duration of the disease, salivary gland abnormalities, and elevated erythrocyte sedimentation rate (ESR) values. Patients with coexisting chronic fatigue syndrome (CFS) had larger P300 amplitudes. There were no statistically significant changes in the electrophysiological parameters of CERPs in patients with pSS dependent on the presence of peripheral nervous system (PNS) lesions, skin changes, arthritis, abnormalities in white blood cells and the immune system or the levels of blood lipids. CONCLUSIONS: The results of the study suggest the presence of a minor cognitive dysfunction in patients with pSS without symptoms of CNS involvement or mental disorder. Cognitive dysfunction correlated with the disease duration time and the severity of inflammatory changes (salivary gland abnormalities and inflammatory markers in the blood). Further and larger longitudinal studies are necessary for confirmation of this correlation.

Vitamin D in "early" primary Sjögren's syndrome: does it play a role in influencing disease phenotypes?

Beyond its well-established role in the maintenance of mineral homeostasis, 25-OH-vitamin D deficiency seems to be involved in the development and severity of several autoimmune diseases. To date, contrasting data have been reported regarding the presence of hypovitaminosis D in primary Sjögren's syndrome (pSS). To assess the prevalence of hypovitaminosis D in pSS at an early stage of the disease and to evaluate its impact on pSS clinical manifestations and disease activity, unselected consecutive subjects with recent onset dry mouth and/or dry eyes who underwent a comprehensive diagnostic algorithm for pSS (AECG criteria) were prospectively included in the study. The levels of 25[OH]-D3 were measured by monoclonal antibody immunoradiometric assay. Conditions of 25[OH]-D3 severe deficiency, deficiency, and insufficiency were defined as levels <10, <20, and 20-30 ng/ml, respectively, and their frequencies were investigated in pSS patients and controls. The levels of 25[OH]-D3 were also correlated with patients' demographic, clinical, and serologic features. Seventy-six consecutive females were included: 30/76 patients fulfilled the AECG criteria for pSS. The remaining 46/76 patients represented the control group. No statistical differences were found in the serum levels of 25[OH]-D3 between pSS patients [median levels = 20 ng/ml (IQR 9.3-26)] and controls [median levels = 22.5 ng/ml (IQR 15.6-33)]. In particular, the frequency of 25[OH]-D3 severe deficiency was not significantly different in patients with pSS when compared to controls (23 vs. 17.4 %, p value = 0.24). We found a significant correlation between serum 25[OH]-D3 levels and white blood cells count (r = 0.29, p = 0.01). More specifically, leukocytopenia was significantly associated with 25[OH]-D3 severe deficiency, being documented in 40 % of the subjects with a 25[OH]-D3 severe deficiency and in 11 % of the subjects without a severe vitamin D deficiency (p = 0.02). We did not observe any further association or correlation between hypovitaminosis D and pSS glandular and extra-glandular features. Although the role of hypovitaminosis D in pSS pathogenesis remains controversial, the results of this study encourage the assessment of vitamin D in specific pSS subsets that could mostly benefit from a supplementation.

Effect of Chinese herbal medicine for nourishing yin, supplementing qi, and activating blood on the Th1/Th2 immune balance in peripheral blood in patients with primary Sjogren's syndrome.

OBJECTIVE: To observe the effect of Chinese herbal medicine for nourishing yin, supplementing qi, and activating blood on the expression of interferon-γ (IFN-γ)/interleukin-4 (IL-4) in peripheral blood and disease activity in primary Sjogren's syndrome (pSS) patients, and to study the relationship between the immune balance of Th1/Th2 and the disease activity. METHODS: A total of 66 pSS patients were randomized with tossing coins method into two groups: the integrative therapy group (34 cases) and the control group (32 cases); and 28 healthy subjects were taken as the normal group. The integrative therapy group was treated by Chinese herbal medicines for nourishing yin, supplementing qi, and activating blood combined with hydroxychloroquine sulfate tablets and the control group was treated with hydroxychloroquine sulfate tablets. The treatment course was 3 months for both groups. The levels of serum immunoglobulin G (IgG), erythrocyte sedimentation rate (ESR), IFN-γ and IL-4 in peripheral blood were measured before and after treatment. RESULTS: Compared with the normal group, the levels of IgG, ESR, IFN-γ and IL-4 were significantly increased in pSS patients (P<0.05). Remarkably, after 3 months of treatment, these levels were dramatically decreased in both the integrative therapy group and the control group, although still higher than the normal group. The levels of IgG, ESR, IFN-γ and IL-4 in the integrative therapy group were lower than the control group and the same group before treatment (P<0.05). The ratio of IFN-γ/IL-4 also significantly decreased after treatment. Moreover, the level of IFN-γ and the ratio of IFN-γ/IL-4 in the integrative therapy group were significantly lower than the control group (P<0.05). For all patients the ratio of IFN-γ/IL-4 before and after treatment was positive correlated with the levels of IgG and ESR. CONCLUSION: Chinese herbal medicine for nourishing yin, supplementing qi, and activating blood can alleviate the disease activity of pSS by regulating the immune balance of Th1/Th2.

[Effect of prescriptions replenishing vital essence, tonifying Qi and activating blood on TNF-alpha, IL-1beta expressions in serum and submaxillary gland of NOD mice with Sjogren's syndrome].

OBJECTIVE: To observe effect of prescriptions replenishing vital essence, tonifying Qi and activating blood on expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-IP (IL-1beta) in serum and submaxillary gland of non-obese diabetic (NOD) mice with Sjogren's syndrome. METHOD: Thirty-two NOD mice were divided into four groups at random: the model group, the traditional Chinese medicine (TCM) group, the hydroxychloroquine group, the TCM and western medicine (WM) group, with 8 mice in each group. Eight Balb/C mice were taken as the normal normal control group. The TCM group was orally administered with 0.4 mL decoction replenishing vital essence, tonifying Qi and activating blood (100 g x kg(-1)) everyday; the hydroxychloroquine group were given 0.4 mL hydroxychloroquine (60 mg x kg(-1)) everyday; the TCM WM group were given 0.4 mL decoction, replenishing vital essence tonifying Qi and activating blood (50 g x kg(-1)) and hydroxychloroquine (60 mg x kg(-1)) everyday. Mice were sacrificed after eight weeks, and their arterial blood and tissues of submaxillary gland were collected. The levels of TNF-alpha, IL-1beta in serum were detected by ELISA. Expressions of TNF-alpha, IL-1beta protein in submaxillary gland were detected by immunohisto-chemistry. RESULT: Compared with other groups, TNF-alpha, IL-1beta in serum and submaxillary gland in the model group were higher (P < 0.05). The normal group showed lower serum TNF-alpha level than other groups (P < 0.05), but without statistical significance compared with the TCM group. IL-1beta in serum in the TCM group and the TCM WM group were lower than that of the hydroxychloroquine group (P < 0.05), but without statistical significance compared with the normal group. TNF-alpha protein expression in the TCM group and the TCM WM group showed no significant difference compared with the normal group, whereas the TCM WM group were notably lower than that of the hydroxychloroquine group (P < 0.05). IL-1beta expression in the TCM WM group showed no significant difference compared with the normal group. CONCLUSION: The decoction replenishing vital essence, tonifying Qi and activating blood can decrease the levels of TNF-alpha, IL-1beta in serum and submaxillary gland of NOD mice with Sjogren's syndrome. It may improve pathological damage of submaxillary gland by regulating Th1/Th2 cell factors, in order to achieve the therapeutic effect on SS.

[Effect of nourishing Yin, strengthening Qi and activating blood decoction on Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression].

OBJECTIVE: To observe the effect of nourishing Yin, strengthening Qi and activating blood decoction on Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression. METHOD: Thirty-two NOD mice were randomly divided into the model group, the traditional Chinese medicine group (TCM group, orally given 0.4 mL nourishing Yin, strengthening Qi and activating blood decoction as per 100 g x kg(-1) everyday), the hydroxychloroquine group (given 0.4 mL hydroxychloroquine as per 60 mg x kg(-1) everyday), the traditional Chinese medicine and western medicine group (TCM WM group, given nourishing Yin, Strengthening Qi and activating blood decoction 50 g x kg(-1) and hydroxychloroquine 60 mg x kg(-1), 0.4 mL everyday), with eight mice in each group. Eight Balb/C mice were selected as the normal control group (normal group). All of mice were killed after eight weeks, and their submaxillary glands were dissected. The expression levels of Fas/FasL were examined by immunohistochemical method, and the FasL mRNA was detected by RT-PCR. RESULT: The expression levels of Fas/FasL in salivary glands of the model group were higher than that of other groups (P < 0.05). The expression level of FasL of the normal group was much lower than that in the hydroxychloroquine group (P < 0.05). The relative expression level of Fas mRNA in salivary glands of the model group was higher than that in other groups, but the control group was notably lower than other groups (P < 0.05). The expression level of FasL mRNA in salivary glands of the model group was higher than that in TCM and TCM WM groups (P < 0.05). But the expression level in TCM WM group was notably lower than the hydroxychloroquine group (P < 0.05). CONCLUSION: The nourishing Yin, strengthening Qi and activating blood decoction could down-regulate the expression level of Fas/FasL in salivary glands of NOD mice with Sjogren's syndrome and their mRNA expression, and had a better efficacy after being combined with hydroxychloroquine. The nourishing Yin, strengthening Qi and activating blood decoction might treat the Sjogren's Syndrome by reducing apoptosis which is regulated by Fas/FasL

[Effect of yangyin yiqi huoxue recipe on immune balance of Th1/Th2 in serum and submaxillary glands of NOD mice with Sjogren's syndrome].

OBJECTIVE: To observe the effect of Yangyin Yiqi Huoxue Recipe (YYHR) on expression of interferon-gamma (IFN-gamma), IL-2, IL-4, IL-10, and immune balance of Th1/Th2 in serum and submaxillary glands of non-obese diabetic (NOD) mice with Sjogren's syndrome (SS), and to explore its mechanisms. METHODS: Totally 32 NOD mice were randomly into 4 groups, i.e., the model group, the Chinese medicine group [CM, administered with YYHR at the dose of 0.4 mL by gavage (100 g/kg)], the Western medicine group [WM group, administered with hydroxychloroquine 0.4 mL by gavage (60 mg/kg)], and the combined group [administered with YYHR (50 g/kg) and hydroxychloroquine (60 mg/kg) 0.4 mL by gavage], 8 mice in each group. Eight Balb/C mice were recruited as the normal control group. Mice were sacrificed to withdraw blood after 8 weeks. The submaxillary gland was excised. Serum levels of IFN-gamma, IL-2, IL-4, and IL-10 were detected by ELISA. Protein expression of IFN-gamma, IL-2, IL-4, and IL-10 in submaxillary glands was detected by SP method. RESULTS: Compared with the normal group, levels of IFN-gamma, IL-2, IL-4, and IL-10 in serum and submaxillary glands all increased in the model group (P < 0.05). Levels of IFN-gamma and IL-10 in serum in the CM group and the combined group were lower than those of the WM group (P < 0.05). Serum levels of IFN-gamma and IL-2 in submaxillary glands in combined group were lower than those of the WM group (P < 0.05). The ratio of IFN-gamma/IL-4 in serum and submaxillary glands in the model group were higher than that of the rest groups (P < 0.05). Besides, it was the nearest to that of the normal group. CONCLUSIONS: YYHR could decrease the levels of Th1 and Th2 related cytokines and the ratio of IFN-gamma/IL-4 in serum and submaxillary glands of NOD mice with SS. It could achieve therapeutic effects through adjusting immune balance of Th1/Th2 in SS mice.

Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjögren's syndrome.

BACKGROUND/PURPOSE: Primary Sjögren's syndrome (SS) is a chronic autoimmune disease primarily involving the exocrine glands. The clinical picture of SS ranges from exocrinopathy to systemic disease affecting the lung, kidney, liver, skin, musculockeletal and nervous systems. The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. Environmental and hormonal factors, such as vitamin-D may play a role in the pathogenic process and disease expression. Thus, we aimed to evaluate levels of vitamin-D and their association with manifestations of SS. METHODS: Vitamin-D levels were determined in 176 primary SS patients and 163 matched healthy volunteers utilizing the LIAISON chemiluminescent immunoassays (DiaSorin-Italy). A correlation between vitamin-D levels and clinical and serological manifestations of SS was performed. RESULTS: Mean vitamin-D levels were comparable between SS patients and control 21.2 ± 9.4 ng/ml and 22.4 ± 10 ng/ml, respectively. Peripheral neuropathy was diagnosed in 23% of SS patients and associated with lower vitamin-D levels (18.6 ± 5.5 ng/ml vs. 22.6±8 ng/ml (p = 0.04)). Lymphoma was diagnosed in 4.3% of SS patients, who had lower levels of vitamin-D (13.2 ± 6.25 ng/ml), compared to SS patients without lymphoma (22 ± 8 ng/ml), (p = 0.03). Other clinical and serological manifestations did not correlate with vitamin-D status. CONCLUSIONS: In this study, low levels of vitamin-D correlated with the presence of peripheral neuropathy and lymphoma among SS patients. The link between vitamin-D and neuropathy or lymphoma was reported in other conditions, and may support a role for vitamin-D in the pathogenesis of these processes. Plausible beneficial effect for vitamin-D supplementation may thus be suggested.

Therapeutic effect of Chinese herbal medicine for strengthening qi, nourishing yin, and removing stasis on serum osteopontin and quality of life of patients with primary Sjogren's syndrome.

OBJECTIVE: To observe the therapeutic effect of Chinese herbal medicine for strengthening qi, nourishing yin, and removing stasis on serum osteopontin (OPN) and quality of life (QOL) in patients with primary Sjogren's syndrome (pSS) and to study the correlation between OPN level and the disease. METHODS: Sixty-eight pSS patients were randomly assigned to two groups: the treatment group (35 cases) treated by Chinese herbal medicine for strengthening qi, nourishing yin, and removing stasis combined with hydroxychloroquine sulfate tablet (HCQ) and the control group (33 cases) treated by HCQ only. Both were treated for 3 months. Before and after treatment, immunoglobulin G (IgG) level, erythrocyte sedimentation rate (ESR), and OPN level were measured. The QOL in patients was evaluated using the Short Form-36 Health Survey (SF-36) before and after treatment. Thirty healthy females were taken as the normal control. RESULTS: Before treatment, levels of IgG, ESR, and OPN in patients were higher than those in the normal control. After 3 months of treatment, those in both treatment groups decreased but were lower in the treatment group than those in the control group (P<0.05). The scores of 8 dimensions of SF-36 were lower in the pSS patients than those in the normal control (P<0.05) and higher in the treatment group than in the control group after treatment (P<0.05). Furthermore, there was a positive correlation between the levels of OPN and the levels of IgG and ESR, and a negative correlation between OPN levels and the overall score of SF-36 (P<0.05). CONCLUSIONS: Chinese herbal medicine for strengthening qi, nourishing yin, and removing stasis could alleviate pSS disease and improve the QOL. In addition, the OPN level might be used as an evaluating index for pSS disease.

A prospective analysis of anti-desmoglein antibody profiles in patients with rheumatoid arthritis treated with thiol compounds.

BACKGROUND: Drug-induced pemphigus is mainly caused by drugs containing sulfhydryl (thiol) groups in their molecules. OBJECTIVES: To understand the serial alteration of anti-desmoglein (Dsg) antibody profile in patients with rheumatoid arthritis (RA) receiving thiol compounds. METHODS: Anti-Dsg1 or -Dsg3 antibodies were analysed twice in a 1.6-year interval, in the same series of RA patients. RESULTS: Eleven of 204 serum samples (5.4%) and 6 of 139 samples (4.3%) from the same RA group showed a positive reaction against Dsg1 or Dsg3 in the first and second screening tests, respectively. The positive rates were higher than those in patients with collagen diseases including systemic lupus erythematosus, Sjögren syndrome, mixed connective tissue disease, and systemic sclerosis. In comparison with the results in the first and second screening tests, one RA patient newly gained anti-Dsg3 antibody, and at least 4 patients lost the antibodies in 1.6 years. Three patients produced antibodies to Dsg1 and/or Dsg3 in a similar fashion as did in the first screening tests. Only one RA serum sample exhibited an intercellular reactivity to human skin or monkey esophagus by immunofluorescence, and another sample bound to a 130 kDa protein suggestive of Dsg3 by immunoblotting. Most anti-Dsg antibodies in RA patients recognized EDTA-resistant epitopes of Dsg different from EDTA-sensitive epitopes recognized by pemphigus sera. CONCLUSION: RA patients receiving any of the thiol compounds may gain autoantibodies to non-conformational epitopes of either Dsg1 or Dsg3, and that such autoantibodies alone are not capable of inducing acantholysis.

Effects of Ganoderma lucidum spores on sialoadenitis of nonobese diabetic mice.

BACKGROUND: Sjögren syndrome (SS) is a systematic autoimmune disease, on which traditional therapeutic agents show limited effect. More effective agents with longer-lasting and fewer side effects are needed in the clinic. The aim of this study was to investigate the effects of Ganoderma lucindum spores (GLS) on sialoadenitis of nonobese diabetic (NOD) mice. METHODS: Thirty-two female NOD mice were assigned randomly into 4 groups: low-dose GLS-treated (L-GLS) group and high-dose GLS-treated (H-GLS) group, a dexamethasone group, and a normal saline (NS) control group. Stimulated total saliva flow rate (STFR), area of lymphocytic infiltration in submandibular glands and ratios of CD4(+) and CD8(+) T lymphocytes and B lymphocytes in peripheral blood as well as apoptosis of these subsets and serum IgG level were tested after 10 weeks of treatments. Differences among the groups were analyzed by one-way analysis of variance (ANOVA), Student-Newman-Keuls Test (SNK) was used between each two groups and a P < 0.05 was considered statistically significant. RESULTS: STFR of the high-dose GLS group increased significantly after a 10-week treatment compared with those of the NS control group (P < 0.05). The incidence of sialoadenitis in GLS-treated NOD mice groups showed no significant difference compared with the control group (P > 0.05), but the area of lymphocytic foci in both the H-GLS and L-GLS groups decreased significantly to 50% of the NS control group (P < 0.05); the ratio of CD4(+)/CD8(+) T lymphocytes and apoptosis of B lymphocytes of NOD mice with sialoadenitis were less and apoptosis of CD4(+) and CD8(+) T lymphocytes were significantly increased compared with the control group (P < 0.05). After pretreatment with H-GLS before sialoadenitis onset, the ratio of CD4(+)/CD8(+) T lymphocyte and the serum IgG levels of NOD mice decreased significantly (P < 0.05). CONCLUSIONS: Pretreatment with H-GLS can relieve symptoms of sialoadenitis in NOD mice. GLS has some protective effects on sialoadenitis in NOD mice through increasing STFR and decreasing the area of lymphocytic foci by regulating the ratio of CD4(+)/CD8(+) T and apoptosis of B lymphocytes.

Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren's syndrome; supplementation with dehydroepiandrosterone restores the concentrations.

CONTEXT: Serum levels of the sex steroid prohormones dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) decline upon aging and are reduced in primary Sjogren's syndrome. OBJECTIVE: Our aim was to investigate: 1) effects of 50 mg oral DHEA/day on changes in serum levels of DHEA and 12 of its metabolites; 2) relationships between steroid levels and disease characteristics; and 3) whether these parameters were influenced by DHEA. DESIGN: Twenty-three postmenopausal women with primary Sjogren's syndrome and subnormal levels of DHEA-S were included in a randomized, 9-month, controlled, double blind crossover study. Liquid chromatography/mass spectrometry (MS)/MS and gas chromatography/MS were used to measure the sex steroids. Anti-SS-A/Ro and/or anti-SS-B/La, salivary gland focus score, salivary flow rates, dry mouth and eye symptoms, and routine laboratory tests were assessed. RESULTS: Baseline erythrocyte sedimentation rate was inversely correlated with testosterone (Testo), dihydrotestosterone, and DHEA-S (rs = -0.42, -0.45, and -0.58, respectively). Dry mouth symptoms correlated with low Testo and androstenedione, whereas dry eyes correlated with low estrogens, most strongly estrone (rs = -0.63). Presence of anti-SS-A and/or anti-SS-B was independently associated with low estradiol (area under the receiver operating characteristic curve, 0.82). All metabolites increased during DHEA but not during placebo. The relative increases were less for estrogens and Testo compared to dihydrotestosterone and glucuronidated androgen metabolites. Dry mouth symptoms decreased during DHEA therapy. CONCLUSIONS: Disease manifestations in primary Sjogren's syndrome were associated with low sex hormone levels, dry mouth symptoms with low androgens, and dry eyes with low estrogens. Exogenous DHEA was preferentially transformed into androgens rather than into estrogens.

[Effect of electroacununcture on sex hormone levels in patients with Sjögren's syndrome].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on serum testosterone (T), estradiol (F2), luteotropic hormone (LH), follicle-stimulating hormone (FSH), progesterone (P), and prolactin (PRL) in patients with Sjögren's Syndrome (SS) in order to analyze the correlation between the adjustment effect of EA and changes of hormone levels. METHODS: Fifty-seven middle-aged and old women with SS were divided into medication group (n=27) and acupuncture group (n=30). Patients in acupuncture group were treated with EA (80 Hz, 2.5 mA) of Shenshu (BL 23), Taixi (KI 3), Hegu (LI 4), etc. for 30 min, once every other day, and those of medication group were treated with oral administration of hydroxyl-chloroquine (6 mg/kg per day), oral transfer agent liquid, Vit B1, Vit B2, Vit C, fish-liver oil, one tablet/time, t.i.d., and pilocarpine (20 mg/d), continuously for 2 months. Venous blood samples were collected before and after the treatment to examine contents of the abovementioned sex hormones by using electro-chemiluminescent immunoassay (CLIA). RESULTS: (1) Before the treatment, no significant differences were found between two groups in the levels of serum T, E2, LH, FSH, P and PRL (P > 0.05). After the treatment, self-comparison of each group showed that serum EF and T contents in acupuncture group increased significantly (P < 0.01) and serum LH content decreased significantly (P < 0.01); while in medication group, only serum LH decreased markedly (P < 0.05) in comparison with its basic value of pretreatment. No significant changes were found in serum P, FSH and PRL levels in both groups after the treatment (P > 0.05). The results suggested that the therapeutic effect of acupuncture group was better than that of medication group in regulating multiple sex hormones. CONCLUSION: EA can effectively adjust E2, T and LH levels in Sjögren's Syndrome patients and improve most patients' clinical symptoms, and the therapeutic effect of EA is better than that of medication.

Serum interleukin-6 level is a useful marker in evaluating therapeutic effects of levamisole and Chinese medicinal herbs on patients with oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T cell-mediated inflammatory disease. Interleukin-6 (IL-6) is a pro-inflammatory cytokine that has effects on cellular and humoral immunities. Previous studies have shown that keratinocytes and tissue-infiltrating mononuclear cells from OLP lesions can secrete IL-6. In some OLP patients, the high serum IL-6 levels are reduced after treatment, suggesting that IL-6 may be a useful marker in evaluating therapeutic effects and in monitoring the disease status of OLP. METHODS: In this study, we used a solid phase, two-site sequential chemiluminescent immunometric assay to determine the baseline serum levels of IL-6 in a group of 180 patients with erosive OLP (EOLP), nonerosive OLP (NEOLP), erythema multiforme (EM), traumatic ulcers (TU), oral submucous fibrosis (OSF), pemphigus vulgaris (PV), or Sjögren's syndrome (SS), and in 77 normal control subjects. Some OLP patients were treated with levamisole plus Chinese medicinal herbs or levamisole only for 0.5-5.5 months and their serum IL-6 levels were measured after treatment. RESULTS: We found that approximately 99% of the normal control subjects and the patients with EM, TU, or OSF had a normal serum IL-6 level less than 5.0 pg/ml. However, 15% (22/149) OLP patients, 15% (20/136) EOLP patients, 20% (5/25) major type EOLP patients, 14% (15/111) minor type EOLP patients, 15% (2/13) NEOLP patients, 14% (1/7) EM patients, 43% (3/7) PV patients, and 100% (6/6) SS patients had a serum IL-6 level greater than 5.0 pg/ml. The mean serum IL-6 level in patients with OLP (3.4 +/- 3.1 pg/ml, P < 0.001), EOLP (3.4 +/- 3.2 pg/ml, P < 0.001), major type EOLP (4.9 +/- 3.5 pg/ml, P < 0.001), minor type EOLP (3.0 +/- 3.0 pg/ml, P < 0.01), or NEOLP (4.2 +/- 1.5 pg/ml, P < 0.001) was significantly higher than that in normal control subjects (2.0 +/- 1.5 pg/ml). A significant difference in the mean serum IL-6 level was also found between major type and minor type EOLP patients (P < 0.01). The mean reduction of serum IL-6 level in OLP patients treated with levamisole plus Chinese medicinal herbs was significantly higher (7.4 +/- 4.7 pg/ml) than that in OLP patients treated with levamisole only (3.8 +/- 2.3 pg/ml, P < 0.05), suggesting that the combination therapy was superior to levamisole only. CONCLUSION: We conclude that levamisole and levamisole plus Chinese medicinal herbs can modulate the serum IL-6 level in OLP patients. IL-6 may be a useful marker in evaluating therapeutic effects and in monitoring the disease status of OLP.

BG-104 enhances the decreased plasma superoxide scavenging activity in patients with Behçet's disease, Sjögren's syndrome or hematological malignancy.

BG-104, a compound of Chinese herbs, has been reported to exert superoxide scavenging activity (SSA) in cell free systems. This report addresses in vivo effects of BG-104 in various disorders. The plasma SSA and laboratory parameters were determined in patients Behçet's disease (BD), Sjögren's syndrome (SjS) or hematological malignancy (M), and the effects of BG-104 treatment on these parameters were studied and compared with those of another antioxidant, vitamin E (alpha-tocopherol). The plasma SSA was significantly lower both in patients with BD and M, and in patients with SjS without antioxidant treatment as compared to that in healthy controls, and it showed an inverse correlation with disease activities. The treatment with BG-104 and/or vitamin E significantly enhanced the plasma SSA in all disorders studied. Both the erythrocyte sedimentation rates, the absolute number of neutrophils, as well as C-reactive protein levels were significantly lower in patients treated with BG-104 and/or vitamin E than those without these drugs. These results indicate that the BG-104 has an anti-inflammatory effect through enhancing plasma SSA in patients with BD, SjS or M.