Coarse particles compensate for missing daytime sources of nitrous acid and enhance atmospheric oxidation capacity in a coastal atmosphere.

Large missing sources of daytime atmospheric nitrous acid (HONO), a vital source of hydroxyl radicals (OH) through its photolysis, frequently exist in global coastal regions. In this study, ambient HONO and relevant species were measured at a coastal site in the Pearl River Delta (PRD), China, during October 2019. Relatively high concentrations (0.32 ± 0.19 ppbv) and daytime peaks at approximately 13:00 of HONO were observed, and HONO photolysis was found to be the dominant (55.5 %) source of the primary OH production. A budget analysis of HONO based on traditional sources suggested large unknown sources during the daytime (66.4 %), which had a significant correlation with the mass of coarse particles (PM2.5-10) and photolysis frequency (J(NO2)). When incorporating photolysis of the abundant nitrate measured in coarse particles with a reasonable enhancement factor relative to fine particles due to favorable aerosol conditions, the missing daytime sources of HONO could be fully compensated by coarse particles serving as the largest source at this coastal site. Our study revealed great potential of coarse particles as a strong daytime HONO source, which has been ignored before but can efficiently promote NOx recycling and thus significantly enhance atmospheric oxidation capacity.

[Traditional Chinese medicine therapy for rheumatoid arthritis: a review].

Rheumatoid arthritis(RA) is an autoimmune disease that seriously affects the physical and mental health of patients, but its pathogenesis is still unclear. At present, clinical treatment drugs include conventional synthetic disease modifing anti-rheumatic drugs(csDMARDs), nonsteroid anti-inflammtory drugs(NSAIDs), hormones, small molecule targeted drugs, biological agents, etc. These drugs can relieve the clinical symptoms of most patients with RA to a certain extent, but there are still many limitations, such as drug adverse reactions and individual differences in drug efficacy. Therefore, the research on drug treatment targets and the development of low-toxicity drugs helps further improve the precise prevention, diagnosis, and treatment of RA. There is an urgent need for efficient and low-toxic treatments to delay the clinical progress of RA. As a treasure of Chinese culture, traditional Chinese medicine(TCM) is widely used as an alternative therapy in the treatment of various diseases, and has a significant clinical efficacy. TCM therapy(including monomer traditional Chinese medicine, classical compounds, and non-drug therapies) has a significant curative effect on RA. Based on the literature research in recent years, this paper reviewed the clinical and mechanism research of TCM therapy in the treatment of RA, and provided more in-depth thinking for the wide application of TCM therapy in clinical practice.

China rheumatoid arthritis registry of patients with Chinese medicine (CERTAIN): Rationale, design, and baseline characteristics of the first 11,764 enrollees.

BACKGROUND: Chinese medicine (CM) has become a popular interventional treatment for rheumatoid arthritis (RA). However, limited knowledge about general characteristics and long-term clinical outcomes hampers the development of CM for RA. PURPOSE: The main objectives of the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) were to describe the population of RA patients receiving CM treatment in multiple centers in China using different variables and compare these findings with internationally reported data. STUDY DESIGN: The CERTAIN is a prospective, multicenter, observational disease registry. METHODS: Adult RA patients who fulfilled the 2010 American College of Rheumatology/ European League Against Rheumatism classification criteria for RA and received CM treatment were recruited into the CERTAIN by rheumatologists from 145 hospitals across 30 provinces in China. Data on demographics, disease characteristics, comorbidities, treatments, and adverse events, with a 2-year follow-up, were collected and documented using a predefined protocol. RESULTS: In the 2 years since the study began in September 2019, 11,764 patients have been enrolled (enrolment is ongoing), and 13.10% of participants have completed the 6-month follow-up. We present the baseline characteristics of the first 11,764 enrollees. CONCLUSIONS: The CERTAIN is the first nationwide registry to document comprehensive data on CM treatment in patients with RA. The development of the CERTAIN resource is a significant step forward for Chinese RA patients, herbal medicine users, and research communities and will deepen our understanding of CM for RA. REGISTRATION: The study was registered at ClinicalTrials.gov (NCT05219214).

[Network Meta-analysis of efficacy and safety of Chinese patent medicines in treatment of ankylosing spondylitis].

To evaluate the efficacy and safety of Chinese patent medicines in the treatment of ankylosing spondylitis(AS) by frequency network Meta-analysis. Randomized controlled trials(RCTs)of Chinese patent medicines for AS were retrieved from CNKI, Wanfang, VIP, CBM, PubMed, EMbase and Cochrane Library databases from the time of database establishment to January 2021. The quality of the included RCTs was evaluated according to the Cochrane bias risk standard, and the data was analyzed by RevMan 5.3 and Stata/MP 15.1. A total of 12 kinds of Chinese patent medicines in 55 RCTs were included. According to Meta-analysis, in term of the effectiveness, the top three optimal medication regimens were Biqi Capsules, Yishen Juanbi Pills and Yaobitong Capsules combined with western medicine. The top three interventions to reduce the erythrocyte sedimentation rate(ESR)were Yishen Juanbi Pills, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. The top three interventions to reduce the C-reactive protein(CRP)were Biqi Capsules, Xianling Gubao Capsules and Fufang Xuanju Capsules combined with western medicine. In terms of the safety, top three optimal medication regimens were Total Glucosides of Paeony Capsules, Yishen Juanbi Pills, and Wangbi Tablets combined with western medicine. This network Meta-analysis suggests that Chinese patent medicines combined with conventional western medicine can effectively improve the joint pain symptoms of AS patients and reduce the acute inflammatory indicators, with high safety. However, the literature included in this study is generally of low methodological quality, and the conclusion needs to be verified by high-quality research.

The Impact of Traditional Chinese Medicine QingreHuoxue Treatment and the Combination of Methotrexate and Hydroxychloroquine on the Radiological Progression of Active Rheumatoid Arthritis: A 52-Week Follow-Up of a Randomized Controlled Clinical Study.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). QingreHuoxue treatment (QingreHuoxue decoction [QRHXD]/QingreHuoxue external preparation [QRHXEP]) is a Chinese medicine treatment for RA. To date, very few studies have compared the long-term effects of QRHXD with those of conventional disease-modifying antirheumatic drugs on RA disease activity and radiological progression. QRHXD delayed the radiological progression and showed long-term clinical efficacy of RA. In clinical experiments, the clinical evidence of delaying the radiological progression of RA patients was obtained. A portion of the patients who participated in the "Traditional Chinese Medicine QingreHuoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis" study were followed up for 52 weeks, and intention-to-treat (ITT) and compliance protocol (PP) analyses were used to collect and compare the clinical indicators and imaging data between baseline and week 52. Two radiologists who were blind to treatment scored the images independently. Of the 468 subjects, 141 completed the 52-week follow-up. There were no significant differences among the three groups: the traditional Chinese medicine comprehensive treatment group, the Western medicine treatment group, and the integrated traditional Chinese and Western medicine treatment group. There were no differences in the total Sharp score, joint space stenosis score, and joint erosion score at baseline or 52 weeks. In the comparison of the estimated annual radiographic progression (EARP) and the actual annual Sharp total score changes among the three groups, the actual changes were much lower than the EARP at baseline. The radiological progress in all three groups was well controlled. Results of the ITT and PP data sets showed that the disease activity score 28 level of the three groups at 52 weeks was significantly lower than that at baseline. During the 52-week treatment period, the clearance of heat and promotion of blood circulation controlled disease activity and delayed the radiological progress of active RA.

Assessment of four screening tools and retrieval of key questions to detect undiagnosed psoriatic arthritis in Chinese patients with psoriasis: A multicenter study.

Several screening tools have been developed to facilitate early diagnosis of psoriatic arthritis (PsA); however, their performance varied greatly across different studies. In this study, we validated and compared the performance of four screening tools in detecting undiagnosed PsA Chinese patients with psoriasis, and determined the key questions and their weights. The four screening tools were the Early Arthritis for Psoriatic Patients (EARP) questionnaire, Psoriatic Arthritis Screening and Evaluation (PASE) questionnaire, Psoriasis and Arthritis Screening Questionnaire (PASQ), and Psoriasis Epidemiology Screening Tool (PEST). The receiver-operator curve (ROC) with area under curve (AUC) was used to determine sensitivity, specificity, and accuracy. Least absolute shrinkage and selection operator and logistic regression were utilized to retrieve key questions, and a nomogram was utilized to visualize their weights. Of 482 psoriasis patients from dermatology clinics, 77 were newly diagnosed with PsA. Another 68 patients with newly diagnosed PsA from rheumatology clinics were incorporated in the analysis. ROC analysis indicated that the optimal cut-off values for EARP, PASE, PASQ, and PEST were 3, 40, 7, and 3, with corresponding sensitivities of 91.4%, 88.6%, 86.2%, and 88.5%, and specificities of 88.6%, 75.2%, 80.2%, and 83.6%, respectively. The AUC of EARP (0.925) was higher than those of PASE (0.885), PASQ (0.905), and PEST (0.827). However, none of them were sufficiently sensitive to identify pure axial PsA (sensitivities of EARP, PASQ, and PASE were 25.0%, 36.8%, and 42.1%, respectively). Twelve key questions were retrieved from these four tools to establish a nomogram with a high discrimination (C-index = 0.993) and a good calibration (mean absolute error = 0.014). In conclusion, to screen undiagnosed PsA, EARP has slightly better balanced sensitivity and specificity, and higher accuracy. The retrieval of key questions and nomogram signify the necessity of attributing different scores to differently weighted questions when developing a new screening tool to make it function more efficiently.

Soil dust as a potential bridge from biogenic volatile organic compounds to secondary organic aerosol in a rural environment.

The role of coarse particles has recently been proven to be underestimated in the atmosphere and can strongly influence clouds, ecosystems and climate. However, previous studies on atmospheric chemistry of volatile organic compounds (VOCs) have mostly focused on the products in fine particles, it remains less understood how coarse particles promote secondary organic aerosol (SOA) formation. In this study, we investigated water-soluble compounds of size-segregated aerosol samples (0.056 to >18 µm) collected at a coastal rural site in southern China during late summer and found that oxygenated organic matter was abundant in the coarse mode. Comprehensive source apportionment based on mass spectrum and 14C analysis indicated that different from fossil fuel SOA, biogenic SOA existed more in the coarse mode than in the fine mode. The SOA in the coarse mode showed a unique correlation with biogenic VOCs. 13C and elemental composition strongly suggested a pathway of heterogeneous reactions on coarse particles, which had an abundant low-acidic aqueous environment with soil dust to possibly initiate iron-catalytic oxidation reactions to form SOA. This potential pathway might complement understanding of both formation of biogenic SOA and sink of biogenic VOCs in global biogeochemical cycles, warrantying future relevant studies.

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.

Traditional Chinese Medicine Qingre Huoxue Treatment vs. the Combination of Methotrexate and Hydroxychloroquine for Active Rheumatoid Arthritis: A Multicenter, Double-Blind, Randomized Controlled Trial.

Traditional Chinese medicine (TCM) has been used successfully to treat rheumatoid arthritis (RA). Qingre Huoxue treatment (Qingre Huoxue decoction (QRHXD)/Qingre Huoxue external preparation (QRHXEP)) is a therapeutic scheme of TCM for RA. To date, there have been few studies comparing the efficacy and safety of QRHXD and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for the treatment of active RA. This was investigated in a multicenter, double-blind, randomized controlled trial involving 468 Chinese patients with active RA [disease activity score (DAS)-28 > 3.2] treated with QRHXD/QRHXEP (TCM group), methotrexate plus hydroxychloroquine [Western medicine (WM) group], or both [integrative medicine (IM) group]. Patients were followed up for 24 weeks. The primary outcome measure was the change in DAS-28 from baseline to 24 weeks. The secondary outcome measures were treatment response rate according to American College of Rheumatology 20, 50, and 70% improvement criteria (ACR-20/50/70) and the rate of treatment-related adverse events (TRAEs). The trial was registered at ClinicalTrials.gov (NCT02551575). DAS-28 decreased in all three groups after treatment (p < 0.0001); the score was lowest in the TCM group (p < 0.05), while no difference was observed between the WM and IM groups (p > 0.05). At week 24, ACR-20 response was 73.04% with TCM, 80.17% with WM, and 73.95% with IM (based on the full analysis set [FAS], p > 0.05); ACR-50 responses were 40.87, 47.93, and 51.26%, respectively, (FAS, p > 0.05); and ACR-70 responses were 20.87, 22.31, and 25.21%, respectively, (FAS, p > 0.05). Thus, treatment efficacy was similar across groups based on ACR criteria. On the other hand, the rate of TRAEs was significantly lower in the TCM group compared to the other groups (p < 0.05). Thus, QRHXD/QRHXEP was effective in alleviating the symptoms of active RA-albeit to a lesser degree than csDMARDs-with fewer side effects. Importantly, combination with QRHXD enhanced the efficacy of csDMARDs. These results provide evidence that QRHXD can be used as an adjunct to csDMARDs for the management of RA, especially in patients who experience TRAEs with standard drugs. Clinical Trial Registration: ClinicalTrials.gov, identifier NCTNCT025515.

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.

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.

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.

Clinical Practice Guideline for Tripterygium Glycosides/Tripterygium wilfordii Tablets in the Treatment of Rheumatoid Arthritis.

Tripterygium wilfordii Hook F (TwHF) is one of the most commonly used and effective traditional Chinese herbal medicines against rheumatoid arthritis (RA). Both Tripterygium Glycoside Tablets (TGT) and Tripterygium wilfordii Tablets (TWT) are the representative TwHF-based agents enrolled into the 2019 edition of Medicine Catalog for National Basic Medical Insurance, Injury Insurance, and Maternity Insurance. However, individual differences in TGT/TWT response across patients usually exist in the process of treating RA, implying that the clinical application of the two agents may not be standardized leading to the ineffective treatment and the risk of side effects. Growing evidence show that the bioactive constituents of TwHF may often have toxicity, the package insert of TGT and TWT may not be described in detail, and the therapeutic windows of the two agents are narrow. Thus, it is an urgent task to develop a standardized clinical practice guideline for TGT and TWT in the treatment of RA. In the current study, a group of clinical experts of traditional Chinese medicine and Western medicine in the research field of rheumatism diseases, pharmacists, and methodologists of evidence-based medicine were invited to select the clinical questions, to determine the levels of the evidence and the strength of the recommendations, and to develop the recommendations and good practice points. The guideline is formed based on the combination of clinical research evidence and expert experience (evidence-based, consensus, supplemented by experience). The clinical problems which are supported by clinical evidence may form recommendations, and the clinical problems without clinical evidence may form experts' suggestions. Both recommendations and experts' suggestions in this guideline summarized the clinical indications, usage, dosage, combined medication, and safety of TGT and TWT against RA systematically and comprehensively, which may offer a professional guidance in the context of the clinical application of the two TwHF-based agents.

Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis.

BACKGROUND: Clinical outcomes of undifferentiated arthritis (UA) are diverse, and only 40% of patients with UA develop rheumatoid arthritis (RA) after 3 years. Discovering predictive markers at disease onset for further intervention is critical. Therefore, our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development. METHODS: We performed a prospective, multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals. Clinical and serological parameters were obtained at recruitment. Follow-up was undertaken in all patients every 12 weeks for 2 years. Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression. RESULTS: A total of 234 patients were recruited in this study, and 17 (7.3%) patients failed to follow up during the study. Among the 217 patients who completed the study, 83 (38.2%) patients went into remission. UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9% vs. 16.8%, χ = 8.228, P = 0.008), anti-cyclic citrullinated peptide (CCP) antibody-positivity (66.7% vs. 10.7%, χ = 43.897, P < 0.001), and double-positivity rate of RF and anti-CCP antibody (38.1% vs. 4.1%, χ = 32.131, P < 0.001) than those who did not. Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017, 95% confidence interval: 5.803-55.938; P < 0.001). CONCLUSION: As an independent predictor of RA, anti-CCP antibody should be tested at disease onset in all patients with UA.

Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS.

We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Rα-gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.

Genome-wide DNA methylation patterns in CD4+ T cells from Chinese Han patients with rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. Recent evidence indicated the epigenetic changes may contribute to the pathogenesis of RA. METHOD: To understand the extent and nature of dysregulated DNA methylation in RA CD4T cells, we performed a genome-wide DNA methylation study in CD4 + T cells in 12 RA patients compared to 12 matched normal healthy controls. Cytosine methylation status was quantified with Illumina methylation 450K microarray. RESULT: The DNA methylation profiling showed 383 hyper- and 785 hypo-methylated genes in the CD4 + T cells of the RA patients (p < 3.4 × 10-7). Gene ontology analysis indicated transcript alternative splicing and protein modification mediated by DNA methylation might play an important role in the pathogenesis of RA. In addition, the result showed that human leukocyte antigen (HLA) region including HLA-DRB6, HLA-DQA1 and HLA-E was frequently hypomethylated, but HLA-DQB1 hypermethylated in CpG island region and hypomethylated in CpG shelf region in RA patients. Outside the MHC region, HDAC4, NXN, TBCD and TMEM61 were the most hypermethylated genes, while ITIH3, TCN2, PRDM16, SLC1A5 and GALNT9 are the most hypomethylated genes. CONCLUSION: Genome-wide DNA methylation profile revealed significant DNA methylation change in CD4 + T cells from patients with RA.

The effects of dopamine receptor 2 expression on B cells on bone metabolism and TNF-α levels in rheumatoid arthritis.

BACKGROUND: Dopamine receptor 2 (DR2) expressions on B cells from Rheumatoid arthritis (RA) patients has been found to be negatively correlated with disease activity and can potentially predict the response to treatment. This study aimed to investigate the role of B cell DR2 expression on bone remodeling in RA. METHODS: Patients with RA (n = 14) or osteoarthritis (OA; n = 12), and healthy controls (n = 12) were recruited for this study. Dopamine receptor (DR) 2 expression was assessed using flow cytometry. Pro-inflammatory cytokines, including interleuin(IL)-1ß, IL-6, IL-17, and tumor necrosis factor(TNF)-α, and bone turnovers, including osteocalcin (OC),serum procollagen type I N propeptide (PINP), C-terminal telopeptide of type I collagen (ß-CTX), collagen type I cross-linked telopeptide (ICTP), as well as matrix metalloproteinase-3 (MMP-3) and osteoprotegerin (OPG) were measured by electrochemiluminescence, chemiluminescence, or enzyme-linked immunosorbent assay. DR2 expression on synovial B cells from 4 RA patients and 3 OA patients was detected by immunofluorescence. RESULTS: There were more DR2(+)CD19(+) B cells in synovial tissues from RA patients than in those from OA patients. The frequency of peripheral B cells that expressed DR2 was positively correlated with plasma TNF-α level. Levels of ICTP and MMP-3 were significantly higher, and OPG were lower in RA patients compared to those in the OA group and healthy controls (all P < 0.05). CONCLUSION: The frequency of B cells that expressed DR2 showed a correlation with levels of the pro-inflammatory cytokine TNF-α. DR2(+)CD19(+) B cells in synovial tissues might have a role in bone metabolism and TNF-α production.

Good response to infliximab in rheumatoid arthritis following failure of interleukin-1 receptor antagonist.

AIM: To evaluate the efficacy of tumor necrosis factor inhibitor infliximab in patients with rheumatoid arthritis (RA) who were disease-resistant to recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS: A total of 104 patients with active RA despite methotrexate (MTX) treatment were enrolled in the open trial. Among them, 27 IL-1Ra nonresponders 'Switchers' and 51 biologic-naive patients 'Naivers' received an infusion of 3 mg/kg infliximab at weeks 0, 2, 6 and 14, combined with concurrent MTX therapy, while the other 26 patients who had never received any biologics 'Controls' continued MTX monotherapy. Clinical outcomes and safety were assessed at weeks 0, 2 and every 4 weeks thereafter for 18 weeks with the American College of Rheumatology (ACR) core set criteria, the Disease Activity Score in 28 joints, and records of adverse events (AEs) and abnormal laboratory findings. RESULTS: At week 18, an ACR20 response was achieved in 56% of Switchers and 61% of Naivers, compared with 23% of Controls (P = 0.0013 and 0.0126, respectively). Compared with Controls, both Switchers and Naivers achieved a significant improvement in tender-joint count, swollen-joint count, patient's assessment of pain, patient's and physician's global assessment of disease activity, erythrocyte sedimentation rate and C-reactive protein. Switchers even achieved a greater benefit from health assessment questionnaire (HAQ) scores than Naivers. Infliximab was well tolerated, with a similar incidence of AEs across all study groups. CONCLUSION: Switching from IL-1Ra to infliximab is effective in improving disease activity and maintaining joint function.

Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis.

OBJECTIVE: Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity. However, it is still unclear whether CB2R is expressed in fibroblast-like synoviocytes (FLS) of RA. In this study we investigated whether CB2R is expressed in FLS of RA, and whether CB2R activation modulates the function of RA-FLS. METHODS: Expression of CB2R in synovial tissue and FLS was studied by immunohistochemistry, western blotting and RT-PCR. mRNA expression levels of CB2R, IL-6 and MMPs were analysed by quantitative real-time RT-PCR. The protein concentrations of IL-6 and MMPs in culture supernatants were determined by ELISA. The protein levels of signal transducing molecules were assayed by western blotting. RESULTS: Both mRNA and protein expression of CB2R were found in synovial tissue and cultured FLS with slightly higher levels in RA patients than in OA patients. In cultured RA-FLS, the expression level of CB2R was up-regulated by stimulation with IL-1ß, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1ß-induced proliferation of RA-FLS as well as IL-1ß-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1ß-induced activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in FLS. CONCLUSION: In RA-FLS, proinflammatory mediators up-regulate the expression of CB2R, which negatively regulates the production of proinflammatory cytokines and MMPs. These data suggest that CB2R may be a potential therapeutic target of RA.

[Effect of icariin on bone destruction and serum RANKL/OPG levels in type II collagen-induced arthritis rats].

OBJECTIVE: To observe the effect of Icariin (ICA) on serum receptor activator of NFkappaB-ligand (RANKL)/osteoprotegerin (OPG) production and bone destruction in type II collagen-induced arthritis (CIA) rats. METHODS: The CIA rat model was established in all rats, except those in the normal group (n = 8) using bovine type II collagen and complete Freund's adjuvant. Totally 24 CIA rats with arthritis index (AI) > or = 6 were selected and divided into the model group, the methotrexate (MTX) group, and the ICA group according to the AI score, 8 in each group. Normal saline was given to rats in the normal group and the model group by gastrogavage. MTX at the weekly dose of 5 mg/kg was given to rats in the MTX group. ICA at the daily dose of 20 mg/kg was given to rats in the ICA group. All medication lasted for 4 weeks. The AI scores were recorded once a week. Histomorphologic changes of the ankle joint were observed by HE staining. The bone destruction and the osteoporosis of the foot phalanx were detected by X-ray. Serum levels of RANKL and OPG were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: After 4-week intervention, when compared with the model group, AI score and Larsen score were significantly lower, the serum RANKL concentration and the RANKL/OPG ratio obviously decreased, while the serum OPG concentration obviously increased in the CIA group (P < 0.05, P < 0.01). In the MTX group, the aforesaid indices decreased, but without statistical difference (P > 0.05). Results of HE staining indicated that hyperplasia of joint synovium, infiltration of inflammatory cells, and the degree of articular cartilage destruction were obviously alleviated in the ICA group. CONCLUSION: ICA could alleviate or lessen the degree of articular cartilage destruction in CIA rats, and its mechanism might be associated with reducing serum levels of RANKL and elevating levels of OPG, thus further decreasing the ratio of RANKL/OPG.