Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis.

BACKGROUND: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. METHODS: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. RESULTS: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = - 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. CONCLUSION: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. TRIAL REGISTRATION: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426 .

Administration of zoledronic acid alleviates osteoporosis in HIV patients by suppressing osteoclastogenesis via regulating RANKL expression.

BACKGROUND: Osteoporosis is a common phenomenon in HIV patients on tenofovir treatment, but its underlying mechanisms remain to be explored. METHODS: Quantitative real-time PCR was performed to analyze the expression of miR-302, miR-101, miR-145 and osteoclast-specific genes in the serum of HIV patients treated with tenofovir and ZOL. ELISA was used to evaluate the expression of RANKL, SMAD3 and PRKACB in the serum of these patients. Luciferase assay was carried out to explore the inhibitory effects of miR-302, miR-101 and miR-145 on the expression of PRKACB, RANKL and SMAD3, respectively. Western blot was used to examine the expression of genes involved in NF­κB and JNK signaling pathways. RESULTS: ZOL treatment significantly suppressed the expression of CTx and osteocalcin in HIV patients treated with tenofovir. The BMD loss of HIV patients treated with tenofovir was effectively hindered by ZOL treatment. Mechanistically, the expression of miR-302, miR-101, miR-145, RANKL, SMAD3 and PRKACB in the serum was remarkably activated by ZOL treatment. Luciferase assays showed that miR-302, miR-101 and miR-145 effectively suppressed the expression of PRKACB, RANKL and SMAD3, respectively, through binding to their 3' UTR. Furthermore, ZOL treatment notably restored the normal expression of osteoclast­specific genes while activating NF­κB and JNK signaling pathways. CONCLUSION: The findings of this study demonstrated that administration of ZOL suppressed the expression of RANKL via modulating signaling pathways of miR-101-3p/RANKL, miR-302/PRKACB/RANKL and miR-145/SMAD3/RANKL. Furthermore, down-regulated expression of RANKL by ZOL treatment alleviated osteoporosis in HIV-positive subjects treated with tenofovir.

Rapid Onset of Efficacy of Baricitinib in Chinese Patients with Moderate to Severe Rheumatoid Arthritis: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral, selective inhibitor of Janus kinase which demonstrates clinical efficacy in patients with rheumatoid arthritis (RA). This report aims to analyze the onset time of baricitinib in Chinese patients with moderately to severely active RA who had an inadequate response to methotrexate. METHODS: This post hoc analysis evaluated clinical improvements of Chinese patients treated with baricitinib 4 mg once daily compared with placebo, based on data from a phase 3 study RA-BALANCE. Efficacy measures including American College of Rheumatology 20% (ACR20) response, ACR core set values, Disease Activity Score modified to include the 28 diarthrodial joint count (DAS28) using high-sensitivity C-reactive protein (hsCRP), DAS28-erythrocyte sedimentation rate, Simplified Disease Activity Index, Clinical Disease Activity Index, DAS28-hsCRP ≤ 3.2 response (low disease activity), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated at weeks 1, 2, 4, 8, 12, 14, 16, 20, and 24 (except for FACIT-F evaluated every 4 weeks). A logistic regression model and an analysis of covariance model were used to analyze treatment comparisons of categorical and continuous measures, respectively. RESULTS: Statistically significant (p ≤ 0.05) improvements were observed as early as week 1 or 2 for the baricitinib group compared to placebo in almost all main efficacy measures. For other outcomes including 66 swollen joint count, 68 tender joint count, FACIT-F, and DAS28-hsCRP ≤ 3.2 response rate, differences were evident (p ≤ 0.05) by week 4 in the baricitinib group compared with placebo. Significant improvements in all efficacy measures were sustained through 24 weeks. CONCLUSIONS: Baricitinib demonstrated a rapid onset of efficacy on ACR20 response, ACR core set values, disease activity, and patient-reported outcome improvements in Chinese patients from RA-BALANCE. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02265705.

Association of homocysteine with ankylosing spondylitis: a systematic review and meta-analysis

Abstract Background: Hyperhomocysteinemia is associated with autoimmune diseases such as ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Current findings regarding plasma/serum homocysteine (HCY) levels in AS patients are inconsistent. This study aims to systematically evaluate the association between circulating HCY levels and AS. Methods: Online electronic databases (PubMed, Web of Science, Embase, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang data) were used to retrieve all relevant articles published up to May 7, 2020. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated using the random-effect model, Stata16 software. Results: Nine articles containing 778 AS patients and 522 controls were included in this meta-analysis. No significant differences in HCY levels were found between AS and control groups (pooled SMD = 0.46, 95% CI = − 0.30 to 1.23, P = 0.23). However, subgroup analysis suggested that HCY levels were significantly higher (P < 0.05) in the AS group treated with methotrexate (MTX) compared with the control group. In contrast, HCY levels were significantly (P < 0.05) lower in the AS group receiving anti-TNF-α treatment compared with the control group. No significant differences were detected between HCY levels and disease activity scores (Bath AS disease activity index, BASDAI), and methylenetetrahydrofolate reductase (MTHFR) C677T genotype. Conclusion: This meta-analysis indicates that HCY levels are similar between AS and controls, and do not correlate with disease activity. However, different medical treatments cause fluctuations of circulating HCY levels in AS patients. Further and larger-scale studies are needed to confirm these findings. Trial registration: This study was registered at international prospective register of systematic reviews (PROSPERO), registration number: CRD42020184426.(AU)

Efficacy and Safety of Baricitinib in Chinese Rheumatoid Arthritis Patients and the Subgroup Analyses: Results from Study RA-BALANCE.

INTRODUCTION: Baricitinib is an oral selective inhibitor of Janus kinase (JAK) 1 and JAK 2, which has demonstrated significant efficacy in patients with moderately to severely active rheumatoid arthritis (RA). This analysis aims to describe the efficacy and safety of baricitinib in Chinese RA patients with an inadequate response to methotrexate (MTX-IR), and to analyze the effects of baseline characteristics on the efficacy of baricitinib treatment. METHODS: In this 52-week, randomized, double-blind, placebo-controlled study, 231 Chinese patients with moderately to severely active RA who had MTX-IR were randomly assigned to placebo (n = 115) or baricitinib 4 mg once daily (n = 116). The primary endpoint was American College of Rheumatology 20% (ACR20) response at week 12. Other efficacy measures included ACR50, ACR70, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, patient's assessment of pain, Disease Activity Score in 28 joints using high-sensitivity C-reactive protein, remission and low disease activity rates according to Simplified Disease Activity Index or Clinical Disease Activity Index, Health Assessment Questionnaire-Disability Index, and mean duration and severity of morning joint stiffness, worst tiredness and worst joint pain were analyzed. Additionally, subgroup analyses were performed across baseline characteristics. RESULTS: Statistically significant improvement in ACR20 response was achieved with baricitinib at week 12 (53.4 vs. 22.6%, p = 0.001) in Chinese patients, compared to placebo. Most of the secondary objectives were met with statistically significant improvements. Efficacy of baricitinib was irrespective of patient demographics and baseline characteristics. Safety events were similar between the baricitinib and placebo groups. CONCLUSIONS: The efficacy of baricitinib 4 mg in Chinese patients with moderately to severely active RA and prior MTX-IR was clinically significant compared to placebo regardless of baseline characteristics. Baricitinib was well tolerated with an acceptable safety profile during the full study period. TRIAL REGISTRATION: NCT02265705.

High remission and low relapse with prolonged intensive DMARD therapy in rheumatoid arthritis (PRINT): A multicenter randomized clinical trial.

OBJECTIVES: To determine whether prolonged intensive disease-modifying antirheumatic drug (DMARD) treatment (PRINT) leads to high remission and low relapse rates in patients with severe rheumatoid arthritis (RA). METHODS: In this multicenter, randomized and parallel treatment trial, 346 patients with active RA (disease activity score (28 joints) [DAS28] (erythrocyte sedimentation rate [ESR]) > 5.1) were enrolled from 9 centers. In phase 1, patients received intensive treatment with methotrexate, leflunomide, and hydroxychloroquine, up to 36 weeks, until remission (DAS28 ≤ 2.6) or a low disease activity (2.6 < DAS28 ≤ 3.2) was achieved. In phase 2, patients achieving remission or low disease activity were followed up with randomization to 1 of 2 step-down protocols: leflunomide plus hydroxychloroquine combination or leflunomide monotherapy. The primary endpoints were good European League Against Rheumatism (EULAR) response (DAS28 (ESR) < 3.2 and a decrease of DAS28 by at least 1.2) during the intensive treatment and the disease state retention rate during step-down maintenance treatment. Predictors of a good EULAR response in the intensive treatment period and disease flare in the maintenance period were sought. RESULTS: A good EULAR response was achieved in 18.7%, 36.9%, and 54.1% of patients at 12, 24, and 36 weeks, respectively. By 36 weeks, 75.4% of patients achieved good and moderate EULAR responses. Compared with those achieving low disease activity and a high health assessment questionnaire (HAQ > 0.5), patients achieving remission (DAS28 ≤ 2.6) and low HAQ (≤ 0.5) had a significantly higher retention rate when tapering the DMARDs treatment (P = 0.046 and P = 0.01, respectively). There was no advantage on tapering to combination rather than monotherapy. CONCLUSIONS: Remission was achieved in a proportion of patients with RA receiving prolonged intensive DMARD therapy. Low disease activity at the start of disease taper leads to less subsequent flares. Leflunomide is a good maintenance treatment as single treatment.

A randomized, controlled trial of efficacy and safety of Anbainuo, a bio-similar etanercept, for moderate to severe rheumatoid arthritis inadequately responding to methotrexate.

The objective of the study was to evaluate the efficacy and safety of etanercept (Anbainuo) treatment in Chinese moderate to severe rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX-IR); 600 patients (360 in phase III-1 and 240 in phase III-2) poorly responding to MTX were enrolled in the study and randomized at a ratio of 2:1 into an Anbainuo treatment or control group. The study was designed as a 12-week double-blind, placebo-controlled period followed by a 12-week open-label study. The primary endpoint was the ACR20 response rate at week 12. Secondary endpoints included the ACR50, ACR70, ACR-N, and safety. At week 12, ACR20 response was observed in 60.9 % of the Anbainuo group-significantly higher than that of the control group (20.6 %). At week 24, the ACR20 response in the Anbainuo group increased to 70.2 %; there was no significant difference compared with that of the control group (61.8 %, P > 0.05). At week 12, the ACR50 and ACR70 responses of the Anbainuo group increased to 25.6 and 6.8 %, compared to 4 and 1 % in the control group (P < 0.001, P = 0.002). The ACR-N was 2.85 ± 6.73 vs. -3.24 ± 8.78 % in the control group (P < 0.001). During the first 12 weeks of treatment, 66 adverse events (AE) were reported in the Anbainuo group (15.6 %) and 21 AEs (10.5 %) occurred in the control group, whereby the rate of the Anbainuo group was slightly higher than the control group (P = 0.042). Severe adverse events (SAEs) occurred in the Anbainuo group (1.3 %) and one (SAE) occurred in the control group (0.5 %) (P = 0.19). Anbainuo displays a rapid onset of efficacy as well as good tolerance and safety in MTX-IR patients having moderate to severe RA.

Magnetic resonance imaging in early rheumatoid arthritis: a multicenter, prospective study.

To identify the magnetic resonance imaging (MRI) features of hands and wrists in early rheumatoid arthritis (RA). A total of 129 early arthritis patients (≤1 year) were enrolled in the study. At presentation, MRI of the hands was performed, with clinical and laboratory analyses. After a 1-year follow-up, clinical diagnosis of early RA or non-RA was confirmed by two rheumatologists. The characteristics of MRI variables at baseline in RA patients not fulfilling ACR 1987 criteria [RA-87(-)] were compared with those fulfilling ACR1987 criteria [RA-87(+)] and non-RA. In the 129 early arthritis patients, 90 were diagnosed with RA in a 1-year follow-up. There were 47.8 % (43/90) of the RA patients not fulfilling ACR 1987 criteria [RA-87(-)]. The scores of synovitis in RA-87(-) patients were similar with those in RA-87(+) [Synovitis score, 14.0 (IQR, 4.0-25.0) vs. 14.0 (IQR, 10.0-25.0), p > 0.05]. Compared with those in non-RA, RA-87(-) patients had higher synovitis scores and occurrence of synovitis in proximal interphalangeal (PIP) joints [synovitis score, 14.0 (IQR, 4.0-25.0) vs. 6.0 (IQR, 2.0-14.5), p = 0.046; occurrence of PIP synovitis: 53.5 vs. 27.3 %, p = 0.02]. There was no significant difference of bone marrow edema, bone erosion, and tenosynovitis between RA-87(-) and non-RA. Synovitis in PIP joints was independent predictor for RA-87(-) [OR, 3.1 (95 %CI 1.2-8.1)]. High synovitis scores and synovitis in PIP joints on MRI were important in early RA, especially those not fulfilling ACR 1987 criteria.

Efficacy and safety of weekly leflunomide for the treatment of early rheumatoid arthritis: a randomized, multi-center study.

AIM: The aim of this study was to determine the efficacy and safety of a weekly dose of leflunomide (50 mg/week) in early rheumatoid arthritis patients with mild or moderate disease activity. METHODS: The patients of early rheumatoid arthritis (ERA) with mild or moderate disease activity were randomly selected for inclusion in this study and were assigned to either the treatment group (leflunomide 50 mg/week, LEF50) or the control group (leflunomide 10 mg/day, LEF10). All patients were treated for 24 weeks. Clinical efficacy was assessed using the disease activity score in 28 joints (DAS28) - erythrocyte sedimentation rate (ESR) and European League Against Rheumatism (EULAR) response. A Chi-squared test, Fisher's exact-test and paired t-tests were used to analyze the data. RESULTS: A total of 244 patients who met the inclusion criteria and received at least one medicine dose were analyzed. At the baseline, the DAS28 (ESR) of the ERA patients were 4.41 ± 0.69 in LEF 50 group and 4.52 ± 0.64 in LEF 10 group, respectively. At week 24, the DAS28 (ESR) in two groups ( 2.94 ± 1.10 and 3.02 ± 1.14 ) were significant decreased compare with the baseline, respectively (P<0.01). There was no significant difference in DAS28 (ESR) between the LEF50 and LEF10 groups at week 24. (P > 0.05). At weeks 8, 12 and 24, the EULAR response (good responses + moderate responses) were 47.6%, 58.7% and 59.5%, in the LEF50 group and 43.2%, 49.1% and 53.4% in the LEF10 group, respectively. There was no significant different of EULAR response rates in the two groups at week 8, 12, and 24, respectively (P>0.05). There was no serious adverse events during the study. CONCLUSION: A weekly dose of 50 mg leflunomide showed similar benefits to a daily dose of 10 mg leflunomide for the treatment of mild-to-moderate early rheumatoid arthritis.

Increased Tim-3 expression on peripheral T lymphocyte subsets and association with higher disease activity in systemic lupus erythematosus.

BACKGROUND: Both the T cell immunoglobulin domain- and mucin domain-containing molecule-3 (Tim-3) and the death receptor Fas contribute to the pathogenesis of various autoimmune diseases, including systemic lupus erythematosus (SLE). The aim of the present study was to determine whether Tim-3 and Fas are co-expressed on certain peripheral T lymphocyte subsets, and whether this expression is associated with greater disease activity in SLE. METHODS: Peripheral blood mononuclear cells were isolated from 46 patients newly diagnosed with SLE and 28 age- and sex-matched healthy controls (HCs). Expression of Tim-3 and Fas on T subsets was analyzed by flow cytometry, while mRNA levels of the Tim-3 ligand galectin-9 and Fas ligand FasL were assayed using real-time RT-PCR. RESULTS: The proportions of CD3(+)CD4(+) and CD3(+)CD4(-) T cells expressing Tim-3(+) and Tim(+)Fas(+) were significantly higher in patients than in HCs (p < 0.05), while the proportions of these subtypes expressing Fas were similar for the two groups. Patients with active SLE, as defined by their score on the SLE Disease Activity Index, had lower proportions of CD3(+)CD4(+) T cells and higher proportions of CD3(+)CD4(+)Tim-3(+) and CD3(+)CD4(+)Tim-3(+)Fas(+) T cells than did patients with stable SLE. Serum levels of complement C3 and C4 proteins, considered as a marker of SLE activity, correlated negatively with proportions of CD3(+)CD4(+) and CD3(+)CD4(-) T cells expressing Tim-3. CONCLUSIONS: Expression of Tim-3 and co-expression of Tim-3 and Fas on certain peripheral T subsets are associated with disease activity in SLE patients. Future research should examine whether the same is true of other T subsets implicated in SLE, and should explore the potential role(s) of Tim-3 in the disease pathway. VIRTUAL SLIDES: http://www.diagnosticpathology.diagnomx.eu/vs/1855527845145188.

Combined measurement of multiple acute phase reactants to predict relapse of rheumatoid arthritis.

AIM: Acute phase reactants (APRs), such as serum C-reactive protein (CRP), ferritin, plasma fibrinogen and platelet count, are common biomarkers used to monitor the status of inflammatory diseases. The aim of this study was to determine whether APRs are predictive markers of relapse in rheumatoid arthritis (RA). METHOD: We analyzed forty RA patients in clinical remission (disease activity score [DAS28] < 2.6; baseline [t(0)]) or with low disease activity (DAS28 score ≤ 3.2; t(0)). The pre-existing therapeutic regimens were retained for each patient during a 4-week study period. APRs and patient characteristics were analyzed for normality of distribution by using the Kolmogorov-Smirnov test and correlations were assessed by Pearson's or Spearman's rank correlation coefficient. RESULTS: APR levels were found to be significantly correlated with DAS28 score of RA, and serum CRP was the most strongly correlated APR for both the clinical remission and high disease activity groups. For all APRs, the correlation strength paralleled the increase in disease activity. CONCLUSION: Measurement of multiple APRs in remission or low disease activity RA patients may predict relapse to active disease, thereby facilitating more timely clinical management and promoting efficacy of therapeutic intervention.

Expression of G-protein subunit α-14 is increased in human placentas from preeclamptic pregnancies.

G-proteins mediate cellular function upon interaction with G-protein coupled receptors. Of the 16 mammalian G-protein α subunits identified, G-protein subunit α-11 (GNA11) and -14 (GNA14) have been implicated in modulating hypertension and endothelial function. However, little is known about their expression and roles in human placentas. Here, we examined GNA11 and GNA14 protein expression in first trimester (FT), normal term (NT), and severe preeclamptic (sPE) human placentas as well as in NT human umbilical cords. We found that GNA11 and GNA14 were immunolocalized primarily in trophoblasts, villous stromal cells, and endothelial cells in placentas as well as in endothelial and/or smooth muscle cells of the umbilical cord artery and vein. Western blotting revealed that the GNA14, but not GNA11, protein levels were increased (2.5-2.9 fold; p<0.01) in sPE vs. NT placentas. GNA11 protein was detected only in NT, but not FT, placentas, whereas GNA14 protein levels were increased (7.7-10.6 fold; p<0.01) in NT vs. FT placentas. Thus, GNA11 and GNA14 may mediate the function of several cell types in placentas. Moreover, the high expression of GNA14 in sPE placentas may also imply its importance in sPE pregnancies as in the other hypertension-related disorders.

Effects of triptolide on the pharmacokinetics of cyclophosphamide in rats: a possible role of cytochrome P3A4 inhibition.

OBJECTIVE: To evaluate the effect of a 10-day course of triptolide (TP) on rat cytochrome (CY) P3A4 activity, and on the pharmacokinetics of cyclophosphamide (CPA). METHODS: In the pharmacokinetics experiment, rats were orally given 0.9% NaCl solution (n=5) and TP [1.2 (mg/kg·d)] for 10 days and a single dose of CPA was administered intravenously (100 mg/kg) to rats on day 11. Blood samples were collected up to 4 h at predetermined time intervals, the plasma concentration of CPA was determined by high performance liquid chromatography (HPLC) and pharmacokinetic parameters were determined. In the in vitro CYP3A4 activity inhibition research, rat blank liver microsomes were divided into 3 groups: a control group, a TS (5 µL, 200 µmol/L) with TP (5 µL, 12.5 µmol/L) group, a TS with ketoconazole (5 µL, 1 µmol/L) group. Concentration of 6ß-hydroxylated testosterone (6ß-OHT) in liver microsomes was measured by HPLC and the activity of CYP 3A4 was calculated through the following formula: Einhibitor/Econtrol × 100%=Cinhibitor/Ccontrol × 100%. RESULTS: Compared with the control group, the area under the plasma concentration-time curve (AUC0-∞) of CPA was significantly increased by 229.05% pretreated with TP (P<0.01). Peak plasma concentrations (Cmax) of CPA was significantly increased and plasma half-life was correspondingly extended. The CYP3A4 activity was significantly inhibited by ketoconazole 93.5%±0.2% and TP 84.6%±0.3% compared with the control group (P<0.01 and P<0.05, respectively). CONCLUSION: Our results strongly suggested that long-term oral intake of TP can distinctly inhibit the CYP3A4 activity and this inhibition evidently decrease the formation of toxic metabolites of CPA.

Estradiol 17ß and its metabolites stimulate cell proliferation and antagonize ascorbic acid-suppressed cell proliferation in human ovarian cancer cells.

Estradiol 17ß (E2ß) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E2ß, 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME2), and 4-methoxyestradiol (4ME2) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer. Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and ß (ERß) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432). We also investigated the roles of E2ß, 2OHE2, 4OHE2, 2ME2, and 4ME2 in cell proliferation, and their interactive effects with AA on ovarian cells. We found the expression of CYP1A1, CYP1B1, COMT, ERα, and ERß in most cell lines tested. Treating cells with physiological concentrations of E2ß and its metabolites promoted (13%-42% of the control) IOSE-385 and OVCAR-3 proliferation. The ER blockade inhibited IOSE-385 (∼76%) and OVCAR-3 (∼87%) proliferative response to E2ß but not to its metabolites. The ERα blockade inhibited (∼85%) E2ß-stimulated OVCAR-3 proliferation, whereas ERß blockade attenuated (∼83%) E2ß-stimulated IOSE-385 proliferation. The AA at ≥250 µmol/L completely inhibited serum-stimulated cell proliferation in all cell lines tested; however, such inhibition in IOSE-385, OVCAR-3, and OVCA-432 was partially (∼10%-20%) countered by E2ß and its metabolites. Thus, our findings indicate that E2ß and its metabolites promote cell proliferation and antagonize the AA-suppressed cell proliferation in a subset of ovarian cancer cells, suggesting that blocking the actions of E2ß and its metabolites may enhance AA's antiovarian cancer activity.

The positive correlations of apolipoprotein E with disease activity and related cytokines in systemic lupus erythematosus.

BACKGROUND: The aim of this study is to investigate the expression of apolipoprotein E (apoE) and the relationship between apoE and disease activity of SLE, and the possible effects of glucocorticoid on apoE and other cytokines activities in SLE patients. METHODS: Forty treatment-naïve SLE patients and forty matched healthy controls were studied. All the SLE patients received prednisone 1 mg/kg/day for 28 consecutive days. The sera levels of apoE and related cytokines were evaluated by ELISA. The expression of apoE mRNA in peripheral blood mononuclear cells (PBMCs) was determined by real-time PCR. RESULTS: Compared with healthy controls, the relative expression levels of ApoE proteins and sera levels were significantly up-regulated in active SLE patients. ApoE sera concentrations positively correlated with SLEDAI, anti-dsDNA antibody and the related cytokines including IL-6, IFN-γ and IL-10, and uncorrelated with the concentration of total cholesterol (TC) and triglyceride (TG) in SLE patients. After 4 weeks prednisone treatment, the relative mRNA expression of apoE and the serum levels of apoE and related cytokines decreased. CONCLUSIONS: ApoE correlated with disease activity and related cytokines in SLE patients. Glucocorticoid can down-regulate the expressions of apoE and related cytokines. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1646714011077325.

[The efficacy and safety of tocilizumab combined with disease-modifying anti-rheumatoid drugs in the treatment of active rheumatoid arthritis: a multi-center, randomized, double-blinded, placebo-controlled trial].

OBJECTIVE: To evaluate the efficacy and safety of human anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) in combination with disease-modifying anti-rheumatoid drugs (DMARDs) for the treatment of rheumatoid arthritis (RA) patients with moderate to severe activity and inadequate response to DMARDs. METHODS: The present study was a multi-center, randomized, double-blinded, placebo controlled trial. Eligible patients were randomized (tocilizumab:Placebo = 2:1) to one of two groups: tocilizumab 8 mg/kg group or placebo group. The drug was administered every 4 weeks by infusion along with stable dose of DMARDs. The primary analysis evaluated at week 24 included: the proportion of patients with American College of Rheumatology (ACR)20, ACR50 and ACR70 response; the average changes of ACR core components from baseline; the proportion of patients with disease activity score (DAS28) ≤ 3.2 and DAS28 < 2.6. Patients who completed double-blinded phase could choose to enter 24-week open-label therapy with tocilizumab 8 mg/kg infusion every 4 weeks. RESULTS: Totally 139 patients from tocilizumab group and 69 patients from placebo group completed the 24-week double-blinded period respectively with comparable baseline characteristics. The proportion of patients with ACR20, ACR50 and ACR70 in tocilizumab group was significantly higher than that in placebo group: 69.8% vs 24.6% (P < 0.05), 38.8% vs 10.1% (P < 0.05) and 12.9% vs 2.9% (P < 0.05) respectively. ACR core components change, proportion of patients with DAS28 ≤ 3.2 and DAS28 < 2.6 were all better in tocilizumab group than those in the placebo group. Decreased level of biomarkers C-terminal crosslinking telopeptide of type I collagen generated by matrix metalloproteinases (ICTP), matrix metalloproteinase 3 (MMP-3) and N-terminal propeptide of type IIA collagen (PIIANP) were observed in patients with tocilizumab treatment, indicating its positive effects on bone metabolism. A total of 202 patients received tocilizumab treatment in the study with the longest duration as 48 weeks, and all the indexes were improved further with the elongation of the treatment time. During the doubled blind phase, 42.4% of patients in the tocilizumab group had ≥ 1 adverse event (AE), compared with 27.9% of patients in the control group. The most common AE was infection, and most of the AEs were mild to moderate. Serious AEs occurred in 0.7% and 5.9% of patients in the tocilizumab and control groups, respectively. More patients in the tocilizumab group had higher percentage of increased alanine transaminase and aspartate transaminase (12.9% and 9.4%) compared to the placebo group (4.4% and 4.4%). Increase of total cholesterol, high density lipoprotein, low density lipoprotein, and triacylglycerol were observed in the tocilizumab group, but no increase of occurrence of cardiac events. No additional safety signals were found during the extension phase. CONCLUSION: The study showed that tocilizumab combined with DMARDs was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to DMARDs.

The role of Act1, a NF-κB-activating protein, in IL-6 and IL-8 levels induced by IL-17 stimulation in SW982 cells.

CONTEXT: Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation in the synovial membrane of affected joints. It has been shown that several kinds of cytokine were increased in synovial fluid, while the underlying mechanism remains poorly understood. OBJECTIVES: NF-κB activator 1 (Act1) is a recently identified protein binding to the IκB kinase complex. Our study aimed to investigate the expression of Act1 induced by cytokine IL-17 stimulation in SW982 cells. MATERIALS AND METHODS: The human synovial sarcoma cell line SW982 and primary cultured RA fibroblast-like synovial cells were used. RT-PCR and Western blot assays were selected to investigate the genetic and protein expression of Act1. Additionally, four independent Act1 small interfering RNA (siRNA) oligonucleotides were designed and obtained according to the GenBank cDNA, the sequence of Act1 (Traf3ip2). Finally, enzyme-linked immunosorbent assay (ELISA) double antibody sandwich was used to assay supernatant IL-6 and IL-8 concentrations. RESULTS: The Act1 mRNA expression level increased significantly after stimulation with IL-17 (5-100 ng/ml) in SW982 cells. Additionally, the level of Act1 mRNA expression correlated positively with the concentration of IL-17 (p < 0.01). IL-17 induced IL-6 and IL-8 in SW982 cells was in a concentration- and time-dependent way. Furthermore, ELISA assay revealed that IL-17 (20 ng/ml) significantly increased IL-6 (1927.4 ± 288.77 versus 786.5 ± 172.42 ng/ml, p < 0.01) and IL-8 levels (984.8 ± 95.09 ng/ml versus 307.1 ± 90.83 ng/ml, p < 0.01) compared with control group after stimulation for 24 h. However, transfection of Traf3ip2 siRNA markedly decreased IL-6 (995.9 ± 115.30 ng/ml versus 1816.1 ± 273.27 ng/ml, p < 0.01) and IL-8 levels (575.6 ± 65.96 ng/ml versus 929.4 ± 124.39 ng/ml, p < 0.01) compared to transfection negative control. These findings suggested that IL-6 and IL-8 level induced by IL-17 in SW982 cells could be reversed by down-regulation of Act1 expression level with Traf3ip2 siRNA. CONCLUSION: Our results suggested that Act1 might play a key role in the pathophysiology and the treatment of RA.

Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial.

BACKGROUND: Acute gout is an intensely painful, inflammatory arthritis. Although the non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for this condition, the efficacy is based on only a few studies, particularly in China. We tried to assess the safety and efficacy of etoricoxib in the treatment of acute gouty arthritis in China. METHODS: A randomized, double-blind, active comparator study was conducted at 10 sites in China. Patients (n = 178; ≥ 18 years of age) with acute gouty attack (< 48 hours) were treated for 5 days with etoricoxib (120 mg/d; n = 89) or indometacin (75 mg twice daily; n = 89). The primary efficacy end point was self-assessed pain in the affected joint (0-4 point Likert scale) from days 2 - 5. Secondary end points included investigator assessments of tenderness and swelling, patient/ investigator global assessments of response to therapy, and patients discontinuing treatment. Safety was assessed by adverse events (AEs). RESULTS: Etoricoxib and indometacin had comparable primary and secondary end points. Mean change difference from baseline from days 2 - 5 was 0.03 (95% confidence interval (CI) -0.19 to 0.25; P = 0.6364), which fell within the prespecified comparative bounds of -0.5 to 0.5. No severe AEs were associated with etoricoxib use. Non-severe AEs were mainly digestive and general, and most (73.7%) were mild, although they caused withdrawal of two subjects in the etoricoxib group, due to bilateral renal calculi and uronephrosis of the left kidney (unrelated to etoricoxib) and fever and chills (potentially etoricoxib-related). Overall, AEs were similar, although the absolute number of AEs in the etoricoxib group (n = 31) was less than the indometacin group (n = 34). CONCLUSIONS: Etoricoxib (120 mg once daily) is effective in treating acute gout, is generally safe and well-tolerated, and is comparable in efficacy to indometacin (75 mg twice daily).

A multicenter, randomized, double-blind clinical trial of combination therapy with Anbainuo, a novel recombinant human TNFRII:Fc fusion protein, plus methotrexate versus methotrexate alone or Anbainuo alone in Chinese patients with moderate to severe rheumatoid arthritis.

This study aims to evaluate the clinical and radiological efficacy as well as safety profiles of Anbainuo, a recombinant human TNFRII:Fc fusion protein, combined with methotrexate (MTX) versus MTX alone or Anbainuo alone in the treatment of Chinese patients with moderate to severe rheumatoid arthritis (RA). In this 24-week, multicenter, double-blind, active comparator-controlled study, 396 RA patients were randomized into combination therapy group (Anbainuo plus MTX), Anbainuo group, or MTX group. Clinical response was assessed using the American College of Rheumatology (ACR)-N, ACR20, ACR50, ACR70, and van der Heijde modification of Sharp score, among which ACR-N and ACR20 were defined as primary major endpoints. After 24 weeks of treatment, the ACR-N in the combination therapy group (12.79 ± 9.24 %) was significantly higher than that in Anbainuo group (9.56 ± 11.16 %) and in MTX group (5.08 ± 11.1 %) (p = 0.00 and p = 0.00, respectively). Patients in Anbainuo group had significantly higher ACR-N than those in MTX group (p = 0.02). More patients in the combination therapy group (53.6 %) achieved ACR50 improvement response than those in the MTX group (30.8 %). ACR70 of combination therapy group (27.7 %) was significantly higher than that of Anbainuo group (15.8 %) and MTX group (7.70 %), with no significant difference between Anbainuo group and MTX group. DAS28-ESR in the combination therapy group was significantly reduced compared to either monotherapy groups. Moreover, DAS28-ESR was significantly lower in Anbainou group than in MTX group. The combination therapy group also showed significantly less radiographic progression than the MTX group (p = 0.03). The total adverse events (AE) in the combination group (40.9 %) was significantly higher than those in the MTX group (28.8 %) (p < 0.05). Anbainuo combined with MTX therapy can effectively control the disease activity and radiographic progression of RA, while the incidence of AE also increased compared to either Anbainuo or MTX.

[A multicenter study of coronary artery disease and its risk factors in rheumatoid arthritis in China].

OBJECTIVE: To learn about the prevalence and risk factors of coronary artery disease (CAD) in rheumatoid arthritis (RA). METHODS: Data were obtained from a 12-month retrospective investigation of the patients with RA, randomly selected from Departments of Rheumatology and Immunology in 21 big hospitals in China. The data were collected about their social conditions, clinical conditions, medications associated with RA, such as disease modifying anti-rheumatic drugs (DMARDs), non steroidal anti-inflammatory drugs (NSAIDs), glucocorticoid, biologic agents. A nonparameter test and multivariate logistic regression analysis were performed. RESULTS: In the study, 960 patients were enrolled. The prevalence of CAD was 3.5% in China, which was obviously higher than that of normal people. The prevalence of overweight and obesity, smoking, hypertension, diabetes mellitus, hypercholesterolemia and cerebrovascular disease were 35.1%, 12.3%, 17.0%, 7.7%, 0.4% and 3.0%, respectively. Compared with the control group, the CAD group had higher age [(64.7±9.3) years vs. (52.3±14.0) years,P<0.001], more rheumatoid nodules (14.7% vs. 3.1%,P=0.005), lower rate of hydroxychloroquine (HCQ) use (5.9% vs. 22.6%,P=0.021), higher prevalence rates of lung interstitial disease (17.5% vs. 7.0%,P<0.001), diabetes mellitus and hypertension (29.4% vs. 7.0%,P<0.001; 38.2% vs. 16.2%,P=0.001). There was no obvious correlation of CAD in RA with joint deformity, rheumatoid factor (RF) titer, glucocorticoid use, hypercholesterolemia and body mass index (BMI). Multivariate analysis showed higher age, diabetes mellitus and hypertension were independent predictors of CAD, and the use of HCQ was a protective factor of CAD. CONCLUSION: The prevalence of CAD is 3.5%. Higher age, diabetes mellitus and hypertension are independent predictors of CAD, and the use of HCQ is a protective factor of CAD.