RhoA Promotes Synovial Proliferation and Bone Erosion in Rheumatoid Arthritis through Wnt/PCP Pathway.

Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.

Aneurysms in Takayasu's arteritis: a retrospective study of Chinese patients.

OBJECTIVES: Aneurysm formation can cause life-threatening complications in Takayasu's arteritis (TAK). The objective of this study was to evaluate the demographic, clinical and angiographic features, and outcomes of aneurysm secondary to TAK in Chinese patients. METHODS: The medical charts of patients diagnosed with TAK in Changhai Hospital between 2001 and 2017 were retrospectively reviewed. RESULTS: Aneurysms were identified in 66 (16.6%) of 397 patients with TAK. The mean age at onset was 30.4±11.5 years, with a male:female ratio of 1:2.7. Patients with aneurysm had a higher proportion of male (p<0.01), higher incidences of bruit, chest tightness and aortic regurgitation (all p<0.001), and a lower incidence of visual disturbances (p<0.01) as compared with patients without aneurysm. The prevalence of elevated ESR and CRP and ITAS2010 score were higher in patients with than without aneurysm (all p<0.01). Angiographic classification showed that type V (30.3%) was the most frequent pattern in patients with aneurysm though Type I was dominant in patients without aneurysm. Multiple aneurysms were found in 30.3% of patients and the most common site of aneurysms was abdominal aorta (22.1%). Glucocorticoids were prescribed in 86.4% of patients with aneurysm, and surgical procedures were performed in 80.3%. Five of 52 patients died during the median 3-year follow-up period. CONCLUSIONS: These findings could provide useful information on the demographical, clinical and angiographic features of TAK patients with aneurysm. Aneurysm formation in TAK may be associated with male gender and active vascular inflammation.

Monocyte-to-high-density lipoprotein cholesterol ratio is associated with the presence and size of thyroid nodule irrespective of the gender.

BACKGROUND: Systemic inflammation may be involved in the formation and progression of thyroid nodule (TN). The aim of this large-scale study was to investigate the association of several simple inflammatory markers with the presence and size of TN. METHODS: A total of 133,698 adults were included for the current analysis. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein cholesterol ratio (MHR) were calculated. The logistic regression was used to explore the association of the four markers with the presence and size of TN. RESULTS: The prevalence of TN was 55.1% among females and 44% among males; 13% of women and 8% of men had non-micronodule. In women, MHR and PLR were significantly associated with the presence of TN and non-micronodule; in men, MHR and NLR were significantly associated with the presence of TN and non-micronodule. CONCLUSIONS: As a low-cost, simple, and reproducible inflammatory marker, MHR is strongly associated with the presence and size of TN irrespective of the gender.

Downregulated microRNA-135a ameliorates rheumatoid arthritis by inactivation of the phosphatidylinositol 3-kinase/AKT signaling pathway via phosphatidylinositol 3-kinase regulatory subunit 2.

Synovial fibroblasts (SFs) of rheumatoid arthritis (RA) are phenotypically aggressive, typically progressing into arthritic cartilage degradation. Throughout our study, we made explorations into the effects of microRNA-135a (miR-135a) on the SFs involved in RA by mediating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway via regulation of phosphatidylinositol 3-kinase regulatory subunit 2 (PIK3R2). The expression of PI3K was higher, the expression of PIK3R2 was lower, and AKT was phosphorylated in the RA synovial tissues, relative to the levels found in the normal synovial tissues. We predicted miR-135a to be a candidate miR targeting PIK3R2 using an online website, microRNA.org, which was verified with a dual-luciferase reporter gene assay. Subsequently, high miR-135a expression was observed in RA synovial tissues. To study the effect of the interaction between miR-135a and PIK3R2 in RA, the SFs isolated from RA samples were cultured and transfected with mimic, inhibitor, and small interfering RNA. The proliferation, invasion, and apoptosis of the SFs were detected after the transfection. The cells transfected with miR-135a inhibitor showed inhibited cell proliferation, migration, and invasion, while also displaying promoted cell apoptosis, G0/G1 cell ratio, and decreased S cell ratio, through upregulation of PIK3R2 and inactivation of the PI3K/AKT signaling pathway. These findings provided evidence that downregulation of miR-135a inhibits proliferation, migration, and invasion and promotes apoptosis of SFs in RA by upregulating the PIK3R2 coupled with inactivating the PI3K/AKT signaling pathway. The downregulation of miR-135a might be a potential target in the treatment of RA.

microRNA-126 targeting PIK3R2 promotes rheumatoid arthritis synovial fibro-blasts proliferation and resistance to apoptosis by regulating PI3K/AKT pathway.

OBJECTIVE: The purpose of our study was to elucidate the impact of microRNA-126 (miR-126) targeting PIK3R2 gene on cell proliferation and apoptosis of rheumatoid arthritis synovial fibro-blasts (RASFs) by regulating PI3K/AKT signal pathway. METHODS: The synovial tissue samples of this study were from 55 RA patients undergoing joint replacement and 27 healthy people undergoing joint repair due to trauma. The target genes of miR-126 were collected by the TargetScan and PIK3R2 as the direct target gene of miR-126 was confirmed by dual-luciferase reporter assay system. Our experiment had five groups including the blank control, miR-126 mimic, miR-126 mimic control, miR-126 inhibitor and miR-126 inhibitor control groups. Additionally, real-time quantitative polymerase chain reaction (RT-qPCR), Western-Blot, cell counting kit (CCK-8) and flow cytometry were carried out in this study. RESULTS: Compared with healthy individuals, the RA patients had increased miR-126, but decreased PIK3R2 mRNA expressions in the synovial tissues. Pearson correlation analysis indicated that miR-126 expression was negatively correlated with PIK3R2 mRNA expression (all P<0.05). When compared with the blank group respectively, the miR-126 mimic group had raising cell proportions in S and G2/M phases with reduced rate of cell apoptosis, while the miR-126 inhibitor group had raising cell proportions in G0/G1 and G2/M phases with increased rate of cell apoptosis (all P<0.05). Besides, compared with the blank control group, the miR-126 mimic group had declined expression of PIK3R2 protein with ascended expression of PI3K and p-AKT (all P<0.05), while the miR-126 inhibitor group had increased expression of PIK3R2 protein with decreased expression of PI3K and p-AKT (all P<0.05). CONCLUSION: Our study demonstrated that down-regulation of miR-126 may indirectly inhibit PI3K/AKT signaling pathway to disrupt the imbalance between growth and death of RASFs by targeting PIK3R2, which may be clinically helpful to find therapeutic strategies directed toward miR-126 function for RA patients.

Single-incision or conventional laparoscopic adjustable gastric banding: A systematic review.

INTRODUCTION: Single-incision laparoscopic surgery (SILS) in gastric banding (SI-LAGB) has been reported to be a safe and technically feasible procedure among various operating methods. However, there is little evidence with regard to the question whether SI-LAGB has more advantages and should be recommended compared with conventional LAGB (CLAGB). Thus, this study was performed to assess the safety and efficacy of SI-LAGB. MATERIAL AND METHODS: A computerized search of the electronic databases PubMed and EMBASE was performed. Data regarding operative parameters, postoperative recovery parameters, follow-up time, percentage of excess weight loss, and postoperative complication were pooled and analyzed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. RESULTS: Ten comparative studies including 2,073 patients (1,038 patients who received SI-LAGB and 1,035 patients who received CLAGB) were included and analyzed. Compared with CLAGB, a similar weight loss could be obtained using SI-LAGB. The postoperative complications of SI-LAGB were within the acceptable range, but one study reported one perioperative death. SI-LAGB required a longer operative time. Other outcome variables, such as blood loss, days of hospitalization, pain score, and hospitalization costs, were not significantly different between the two groups. CONCLUSIONS: SI-LAGB might be a safe and effective alternative to C-LAGB when performed by experienced surgeons, but available data do not allow to give a definitive answer and randomized controlled trials are needed.

A randomized, double-blind, and placebo-controlled multicenter clinical trial of a novel cytotoxic T-lymphocyte antigen-4 fusion protein, Leining, in Chinese active rheumatoid arthritis patients with an inadequate response to methotrexate.

To assess the clinical efficacy as well as safety profiles of Leining, a novel cytotoxic T-lymphocyte antigen-4 fusion protein, versus placebo in the treatment of Chinese active rheumatoid arthritis (RA) patients with an inadequate clinical response to methotrexate (MTX). In this 24-week, randomized, double-blind, placebo-controlled multicenter study, a total of 440 Chinese patients with active RA with an inadequate response to MTX were randomly assigned to receive Leining (10 mg/kg) or placebo. Clinical response was assessed using the American College of Rheumatology 20 % improvement criteria ACR20, ACR50, and ACR70, with ACR20 as the primary major endpoints. Disease activity scores in 28 joints with erythrocyte sedimentation rate assessment (DAS28-ESR) were used to evaluate disease activity. After 24 weeks of treatment, significantly more patients in Leining group achieved ACR20 response than those in placebo group (70.61 vs. 46.36 %; p < 0.001). Similarly, ACR50 and ACR70 responses of Leining group were significantly higher than those of placebo group (40.30 vs. 22.73 %; p < 0.001 and 16.67 vs. 7.27 %; p < 0.05, respectively). DAS28-ESR in Leining group was significantly reduced compared to that in placebo group, with greater clinically meaningful (>1.2 unit) improvement (54.85 vs. 29.09 %, p < 0.05). Both the rates of remission (DAS28-ESR < 2.6) and low disease activity (DAS28-ESR < 3.2) were greater in the Leining group than those in the placebo group (12.42 vs. 2.73 %; p < 0.05 and 15.45 vs. 2.73 %; p < 0.05 respectively). The overall incidence of adverse events was similar in both Leining and placebo groups. No neutralizing antibodies were detected. Leining demonstrated clinically meaningful efficacy compared with placebo in Chinese patients with active RA despite MTX therapy. Administration of Leining in combination with MTX for 24 weeks was well tolerated.

Diagnostic accuracy of anti-alpha-fodrin antibodies for primary Sjögren's syndrome.

OBJECTIVES: To estimate the diagnostic accuracy of anti-alpha-fodrin antibodies for primary Sjögren's syndrome (pSS). METHODS: Sixty-four pSS subjects and 108 non-pSS patients were prospectively enrolled in this study. Serum anti-alpha-fodrin IgA and IgG were detected by ELISA in a blind fashion. The diagnostic accuracy of anti-alpha-fodrin antibodies was assessed by receiver operating characteristic (ROC) curve analysis. Logistic regression was used to investigate whether anti-alpha-fodrin antibodies could improve the accuracy of pSS diagnosis if used in addition to anti-SSA and anti-SSB. RESULTS: The areas under the ROC curves for anti-alpha-fodrin IgG and IgA were 0.69 (95% confidence interval (CI): 0.60-0.77) and 0.63 (95% CI: 0.54-0.72), respectively (P < 0.01 for both). The optimal diagnostic thresholds for anti-fodrin IgG and IgA were 11.75 U/ml and 9.75 U/ml, respectively, with a sensitivity of 0.59 and 0.55, and a specificity of 0.75 and 0.73, respectively. Anti-alpha-fodrin IgG and IgA antibodies were associated with pSS after adjustment for anti-SSA and anti-SSB. CONCLUSIONS: Anti-alpha-fodrin IgG and IgA antibodies are useful diagnostic markers which may improve the accuracy of pSS diagnosis.

PBMC-mediated modulation of macrophage polarization in RAW264.7 cells through STAT1/STAT6 signaling cascades.

Peripheral blood mononuclear cells (PBMC), sourced autologously, offer numerous advantages when procured: easier acquisition process, no in vitro amplification needed, decreased intervention and overall increased acceptability make PBMC an attractive candidate for cell therapy treatment. However, the exact mechanism by which PBMC treat diseases remains poorly understood. Immune imbalance is the pathological basis of many diseases, with macrophages playing a crucial role in this process. However, research on the role and mechanisms of PBMC in regulating macrophages remains scarce. This study employed an in vitro co-culture model of PBMC and RAW264.7 macrophages to explore the role and mechanisms of PBMC in regulating macrophages. The results showed that the co-culturing led to decreased expression of inflammatory cytokines and increased expression of anti-inflammatory cytokines in RAW264.7 or in the culture supernatant. Additionally, the pro-inflammatory, tissue matrix-degrading M1 macrophages decreased, while the anti-inflammatory, matrix-synthesizing, regenerative M2 macrophages increased in both RAW264.7 and monocytes within PBMC. Moreover, co-cultured macrophages exhibited a significantly decreased p-STAT1/STAT1 ratio, while the p-STAT6/STAT6 ratio significantly increased. This suggests that PBMC may inhibit M1 macrophage polarization by blocking STAT1 signaling cascades and may promote M2 macrophage polarization through the activation of STAT6 signaling cascades. Overall, this study sheds light on the role and mechanism of PBMC in regulating macrophages. Moreover, it was found that monocytes within co-cultured PBMC differentiated into M2 macrophages in the presence of macrophages. This finding provides experimental evidence for the use of PBMC in treating inflammatory diseases, especially macrophage-depleting inflammatory diseases such as osteoarthritis.

[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.

Risk factors for the progression of rheumatoid arthritis-related interstitial lung disease: Clinical features, biomarkers, and treatment options.

OBJECTIVES: The clinical heterogeneity of the progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is high, and there is a lack of consensus on the clinical relevance and medical protocols. The purpose of this study is to explore the impact of clinical characteristics, new biomarkers and treatment options on the prognosis of RA-ILD patients and to explore whether these factors can predict the progression and death of these patients. METHODS: We retrospectively collected case data on RA-ILD patients who visited or were admitted to Changhai Hospital between October 2010 and September 2021. We followed up and finally included 75 patients. The main outcome indicator of disease progression was pulmonary functional impairment, which was assessed by changes of high-resolution computed tomography (HRCT) score or pulmonary function test before and after treatment. The demographics, clinical characteristics, laboratory tests, and treatment plans of RA-ILD patients in the progressive and stable groups were compared and analyzed. Clinically relevant variables were identified, and the incidence of pulmonary dysfunction and adverse events was recorded. Cox regression analysis was used to determine factors related to the progression of ILD. RESULTS: The mean age of RA-ILD onset was 64.0 years (SD 10.3), and 53 (70.7%) patients were female. Thirty-two (42.7%) patients had lung dysfunction, who were classified as the progressive group, and 13 (40.6%) of them died. In univariate analyses, male, smoking, high HRCT scores at baseline, RF-IgA>200 RU/ml, diffusing capacity of the lungs for carbon monoxide (DLCO), and usual interstitial pneumonia (UIP) pattern were significant risk factors for disease progression; while use of Leflunomide (LEF) was associated with better prognosis. The multivariate analysis revealed that RF-IgA>200 RU/ml (hazard ratio [HR] 3.17 [95% confidence interval (CI) 1.29, 7.81], P = 0.012), UIP pattern (HR 3.94 [95% CI 1.68, 9.26], P = 0.002), and male (HR 2.52 [95% CI 1.16, 5.46], P = 0.019) were significantly correlated with unfavorable outcomes in patients with RA-ILD. LEF (HR 0.25 [95% CI 0.10, 0.61], P = 0.002) was related to a better prognosis. However, it might be related to investigating medications changes after baseline. CONCLUSION: Our data suggests that male, UIP pattern, and increased RF-IgA may be potential predicting factors for poor prognosis of RA-ILD patients. We report a significant association between high titer of RF-IgA at baseline and RA-ILD progression for the first time, which might be a potentially important biomarker for the prognosis of RA-ILD.

Interstitial inflammation in visceral organs is a pathologic feature of adult-onset Still's disease.

The pathological features of adult-onset Still's disease remain unclear. An original case study of the histopathological changes in various organs of a patient with the disorder is presented. Interstitial inflammation was found in the heart, lung, liver, mucosa of total alimentary canal, and urinary bladder. Previous reports that involved the pathology of visceral organs are also reviewed.

A double-blind, double-dummy, randomized controlled, multicenter trial of 99Tc-methylene diphosphonate in patients with moderate to severe rheumatoid arthritis.

BACKGROUND: Clinical observational studies revealed that 99Tc-methylene diphosphonate (99Tc-MDP) could reduce joint pain and swollenness in rheumatoid arthritis (RA) patients. This multicenter, randomized, double-blind, double-dummy study aimed to evaluate the effects of 99Tc-MDP plus methotrexate (MTX) vs. MTX alone or 99Tc-MDP alone on disease activity and structural damage in MTX-naïve Chinese patients with moderate to severe RA. METHODS: Eligible patients with moderate to severely active RA were randomized to receive 99Tc-MDP plus MTX (n = 59) vs. MTX (n = 59) alone or 99Tc-MDP (n = 59) alone for 48 weeks from six study sites across four provinces in China. The primary outcomes were the American College of Rheumatology 20% improvement (ACR20) response rates at week 24 and changes in modified total Sharp score at week 48. RESULTS: At week 24, the proportion of participants achieving ACR20 was significantly higher in the MTX + 99Tc-MDP combination group (69.5%) than that in the MTX group (50.8%) or 99Tc-MDP group (47.5%) (P = 0.03 for MTX + 99Tc-MDP vs. MTX, and MTX + 99Tc-MDP vs.99Tc-MDP, respectively). The participants in the MTX + 99Tc-MDP group and the 99Tc-MDP group had significantly less important radiographic progression than the participants in the MTX group over the 48 weeks (MTX + 99Tc-MDP vs. MTX: P = 0.03, 99Tc-MDP vs. MTX: P = 0.03, respectively). There was no significant difference in terms of adverse events (AEs) among the groups. No serious AEs were observed. CONCLUSIONS: This study demonstrated that the combination of 99Tc-MDP with MTX inhibited structural damage and improved disease activity in RA patients compared with MTX and 99Tc-MDP monotherapies, without increasing the rate of AEs. Additional clinical studies of 99Tc-MDP therapy in patients with RA are warranted. TRIAL REGISTRATION: Chictr.org, ChiCTR-IPR-14005684; http://www.chictr.org.cn/showproj.aspx?proj=10088.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

Clinical characteristics of Behçet's disease in China.

To evaluate the prevalence of clinical findings in Behçet's disease (BD) in Chinese population. The clinical data of 170 consecutive BD patients were, retrospectively, analyzed and compared with previous reports. The mean age at onset was 34.4 years (range 6-72) and the mean age of diagnosis was 39.1 years (range 8-72). Mean delay in diagnosis was 5.7 years. The male to female ratio was 1.3:1. Recurrent aphthous ulceration (64.7%), skin lesion (18.2%), and genital ulceration (8.2%) were the commonest onset-presentations of the disease. During the disease course, the commonest presenting features were oral ulcer (100%), cutaneous involvement (68.2%), genital ulcer (63.5%), arthritis (37.1%), and ocular lesion (14.1%). As for the minor clinical manifestations, gastrointestinal lesion (10.0%), vascular lesion (8.8%), and cardiac lesion (4.7%) occurred occasionally. The pathergy skin test showed positive in 63.5% of the patients and revealed a higher positive rate in the females (76.7%) than in the males (53.6%). Less ocular lesion and genital ulcer were present in Chinese BD patients.

ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways.

Although the E3 ubiquitin ligase Zinc and ring finger 3 (ZNRF3) negatively regulates the Wnt signaling pathway, its function in rheumatoid arthritis (RA) is elusive. Here, the effects and the mechanism of ZNRF3 on a mouse model of collagen-induced arthritis (CIA) and human fibroblast-like synoviocytes (FLS) obtained from RA patients were determined. Our results showed that ZNRF3 was highly expressed in tissues and FLSs compared to trauma patients. Lentivirus-mediated silencing of ZNRF3 induced apoptosis decreased cell viability and significantly attenuated inflammation in RA-FLSs via tumor necrosis-α (TNF-α). Additionally, silencing of ZNRF3 reduced knee joint damage and also decreased the level of TNF-α, IL-1ß, and IL-6 in the CIA mouse model. These effects were mediated by the crosstalk between Wnt and NF-κB pathways in RA-FLS.

[Adalimumab plus methotrexate for the treatment of rheumatoid arthritis: a multi-center randomized, double-blind, placebo-controlled clinical study.].

OBJECTIVE: To investigate the efficacy and safety of adalimumab plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). METHODS: This is a multi-center, randomized, double-blind, parallel-group, and placebo-controlled clinical study, included a total of 302 cases of active rheumatoid arthritis, randomized into three groups of observation: 40 mg adalimumab (121 cases), 80 mg adalimumab (121 cases), or placebo (60 cases). Upon enrollment, all subjects had been previously treated with MTX for at least 3 months, and their doses of drug had remained stable for at least 28 days. The double-blind phase lasted for 12 weeks, during which the subjects were administered with adalimumab or placebo subcutaneously every other week. Then the subjects entered into another 12 weeks of open-label study, which included subcutaneous injection of 40 mg adalimumab every other week. In both the double-blind and the open-label periods, all subjects were maintained concomitantly with MTX that had already been used before this study. The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12. The secondary efficacy variables included: ACR20 response rate at week 24; ACR50 and ACR70 response rates at weeks 12 and 24; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts, as well as the assessment of pain with visual analog scale (VAS), the physician's and the patient's global assessment of disease activity (VAS), and the analysis on health assessment questionnaire (HAQ) and health related quality of life (HRQL) measured by Short Form-36 (SF-36); The safety variables mainly included adverse events (AE). RESULT: During the double-blind period, subjects treated with 40 mg of adalimumab, 57.0% achieved ACR20 response at week 12 (P = 0.004 versus placebo), and subjects treated with 80 mg of adalimumab, 51.2% achieved ACR20 response at week 12 (P = 0.026 versus placebo), and only 35.0% of subjects treated with placebo achieved ACR20 response at week 12. On the other hand, 32.2% of subjects receiving 40 mg of adalimumab achieved ACR50 response (P = 0.009 versus placebo), and 15.7% achieved ACR70 response (P = 0.007 versus placebo) at week 12. Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count, swollen joint count, and improvement in C-reactive protein; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count, and improvement in C-reactive protein; all of these findings were statistically significant in differences. During the open-label period all subjects received 40 mg of adalimumab, and response rates for ACR20, ACR50, and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 (being 73.1%, 40.3% and 17.6% respectively for 40 mg group; 71.1%, 39.5% and 17.5% respectively for 80 mg group); while response in the original placebo group (being 67.8%, 44.1% and 18.6%) increased during the 12-week open-label period to match that of the original adalimumab treatment groups. While for changes in tender and swollen joint counts, VAS, HAQ, SF-36, a significant improvement was seen at week 24 when compared with baseline and week 12 values. Throughout the double-blind and open-label period, adverse events reported in >/= 5% of subjects at least possibly associated with the study drug were upper respiratory tract infection, nasopharyngitis, and injection site itching, mostly being mild to moderate in severity. There were 3 cases of tuberculosis reported during this study. And 3 cases of serious adverse event (SAE) were reported among the adalimumab subjects during the double-blind period, which were determined as unrelated or probably unrelated to the study drug. And 8 cases (2.7%) of SAE were seen among the adalimumab subjects during the open-label period, 3 of which were at least possibly unrelated with the study drug. All SAEs reported were consistent to those seen in other adalimumab trials. No other unexpected safety signals were reported. CONCLUSION: Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA. Being generally safe and well tolerated, adalimumab plus MTX can significantly increase the response rate, continuously reduce the arthritic signs, symptoms and the inflammatory factors in patients, and also be helpful for reducing disabilities and improving the global quality of life for the patients.

[Efficacy and safety of infliximab in patients with rheumatoid arthritis].

OBJECTIVE: To investigate the efficacy and safety of Infliximab (IFX) plus methotrexate (MTX) combination therapy in patients with rheumatoid arthritis (RA). METHODS: Prospectively observe refractory RA patients who were treated with combination therapy of MTX and IFX. IFX was infused at the dosage of 3 mg/kg, in week 0, 2, 6, and then every 8 weeks. During treatment, clinical variables, disease activity and adverse effects were evaluated. RESULTS: After treatment, 69.8%, 52.4%, 29.5% and 7.2% RA patients achieved ACR20, ACR50, ACR70 and ACR90 respectively. There were significant statistical differences in the changes of swollen joint counts, tender joint counts, VAS scale, patient' s global assessment, and physician's global assessment before and after therapy. CONCLUSION: Infliximab plus MTX achieved significant efficacy and safety in refractory RA patients.

Association between three non-insulin-based indexes of insulin resistance and hyperuricemia.

OBJECTIVE: The association between hyperuricemia and insulin resistance (IR) has been demonstrated by many studies, but the traditional IR indexes are too impractical to be used in clinical practice for the recognition of the IR state in individuals with hyperuricemia. Therefore, we aimed to further investigate the association between hyperuricemia and three non-insulin-based IR indexes in this large-scale cross-sectional study. METHODS: A total of 174,695 adults without self-reported use of antihyperuricemic agents, hypoglycemic agents, or lipid-lowering drugs were included in the current analysis. The triglyceride to high-density lipoprotein cholesterol ratio (TG/HDLc), the product of fasting triglycerides and glucose (TyG), and metabolic score for IR (METS-IR) were calculated. Then, logistic regression analyses were applied to explore their association with hyperuricemia. RESULTS: The TG/HDLc, TyG, and METS-IR all had positive correlations with uric acid level. However, only TG/HDLc and TyG were significantly associated with hyperuricemia in both sexes and body mass index (BMI) classification (the ORs of the highest quartile for each were 6.751 and 1.505 in females and 6.487 and 1.646 in males, respectively). The AUC values of TG/HDLc and TyG to discriminate hyperuricemia were also statistically significant in both sexes and BMI classification (all greater than 0.7). CONCLUSIONS: TG/HDLc and TyG are strongly associated with hyperuricemia regardless of BMI classification. These two obtainable and cost-effective non-insulin-based IR indexes could be potential monitors during the management of hyperuricemia and prevention of its IR-driven comorbidities. Key Points • In this large-scale study, we identified TG/HDLc and TyG as indicators for identification of IR in patients with hyperuricemia. • These simple and practical IR indicators are of substantial clinical importance for implementing preventive strategies against IR-driven comorbidities of hyperuricemia.

Association between hyperuricemia and nontraditional adiposity indices.

BACKGROUND: The association between several novel adiposity indices and hyperuricemia is inconclusive. Therefore, we aimed to investigate this association so as to provide theoretical support for the management of hyperuricemia in overweight/obese individuals. METHODS: A cross-sectional study was carried out among 174,698 adults. The values of body adiposity index (BAI), conicity index (CI), a body shape index (ABSI), body roundness index (BRI), visceral adiposity index (VAI), lipid accumulation product (LAP) index, and cardiometabolic index (CMI) were divided into four quartiles, and multivariate logistic analysis was used to analyze the association between them and hyperuricemia. Receiver operating characteristic curve and area under curve (AUC) were used to evaluate the power of predictions for hyperuricemia. RESULTS: After adjusting for confounding variables, LAP and CMI exhibited stronger association with hyperuricemia than other indices. The odd ratio (OR) for hyperuricemia in the highest quartile of the LAP and CMI was 2.049 (CI 95% = 1.824-2.302) and 4.332(CI 95% = 3.938-4.765). The AUC value of LAP was 0.632 (95% CI = 0.626-0.637), p < 0.001; and the AUC value of CMI was 0.687 (95% CI = 0.682-0.692), p < 0.001. The optimal cutoff values of LAP and CMI were 26.21 and 0.485, respectively. CONCLUSIONS: LAP and CMI, combination of WC and lipid parameters and reliable visceral adiposity indices, were strongly associated with hyperuricemia than other indices. So they could be potential monitoring indicators for hyperuricemia management in overweight/obese individuals.