Publications by authors named "Dongyi He"

74 Publications

Identification of differential key biomarkers in the synovial tissue between rheumatoid arthritis and osteoarthritis using bioinformatics analysis.

Clin Rheumatol 2021 Jul 5. Epub 2021 Jul 5.

Shanghai University of Traditional Chinese Medicine, Shanghai, 200052, China.

Introduction/objectives: Rheumatoid arthritis (RA) and osteoarthritis (OA) are two common joint diseases with similar clinical manifestations. Our study aimed to identify differential gene biomarkers in the synovial tissue between RA and OA using bioinformatics analysis and validation.

Method: GSE36700, GSE1919, GSE12021, GSE55235, GSE55584, and GSE55457 datasets were downloaded from the Gene Expression Omnibus database. A total of 57 RA samples and 46 OA samples were included. The differentially expressed genes (DEGs) were identified. The Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were also performed. Protein-protein interaction (PPI) network of DEGs and the hub genes were constructed and visualized via Search Tool for the Retrieval of Interacting Genes/Proteins, Cytoscape, and R. Selected hub genes were validated via reverse transcription-polymerase chain reaction.

Results: A total of 41 DEGs were identified. GO functional enrichment analysis showed that DEGs were enriched in immune response, signal transduction, regulation of immune response for biological process, in plasma membrane and extracellular region for cell component, and antigen binding and serine-type endopeptidase activity for molecular function. KEGG pathway analysis showed that DEGs were enriched in cytokine-cytokine receptor interaction and chemokine signaling pathway. PPI network analysis established 70 nodes and 120 edges and 15 hub genes were identified. The expression of CXCL13, CXCL10, and ADIPOQ was statistically different between RA and OA synovial tissue.

Conclusion: Differential expression of CXCL13, CXCL10, and ADIPOQ between RA and OA synovial tissue may provide new insights for understanding the RA development and difference between RA and OA. Key Points • Bioinformatics analysis was used to identify the differentially expressed genes in the synovial tissue between rheumatoid arthritis and osteoarthritis. • CXCL13, CXCL10, and ADIPOQ might provide new insight for understanding the differences between RA and OA.
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http://dx.doi.org/10.1007/s10067-021-05825-1DOI Listing
July 2021

Dihydroartemisinin alleviates skin fibrosis and endothelial dysfunction in bleomycin-induced skin fibrosis models.

Clin Rheumatol 2021 May 19. Epub 2021 May 19.

Department of Rheumatology, School of Medicine, Ren Ji Hospital, Shanghai Jiao Tong University, 145 Shandong Middle Road, Shanghai, 2000001, China.

Objective: The present study was to investigate whether dihydroartemisinin (DHA), which is a highly effective and safe drug in the treatment of malaria, could be repurposed for the treatment of skin fibrosis and vascular dysfunction in systemic sclerosis (SSc).

Methods: The value of DHA was determined using a bleomycin-induced model of skin fibrosis. mRNA transcriptome analysis was performed, and the targets of DHA on fibroblasts were identified. Immunofluorescence staining was used to identify dermal vessels undergoing endothelial-to-mesenchymal transition (EndoMT). Autophagic flux was detected by western blot and mRFP-GFP-LC3 adenovirus vector transfection.

Results: Both systemic and topical administration of DHA decreased dermal thickness and collagen deposition and alleviated EndoMT in bleomycin-induced skin fibrosis mice model. Treatment of human umbilical vein endothelial cells (HUVECs) with TGF-β1 resulted in the acquisition of the activation marker (α-SMA) and loss of endothelial markers (CD31 and VE-cadherin), a process that was restored by DHA. DHA significantly suppressed skin fibroblast activation and collagen-1 production mainly through regulating PI3K-Akt pathway. DHA also induced fibroblast autophagic flux and that autophagy dependently suppressed collagen-1 production.

Conclusion: The results of the present study revealed that oral and topical DHA administration ameliorated tissue fibrosis and protected dermal blood vessels from bleomycin-induced EndoMT. Our study has elucidated the value of repurposing DHA for the treatment of SSc. Key Points • Oral or topical usage of DHA alleviated dermal fibrosis and EndoMT in bleomycin-induced skin fibrosis mice models. • DHA autophagy dependently inhibited fibroblast activation and collagen deposition via PI3K-ATK pathway. • DHA inhibited EndoMT of HUVECs induced by TGF-β1 by the downregulation of α-SMA and the upregulation of CD31 and VE-cadherin.
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http://dx.doi.org/10.1007/s10067-021-05765-wDOI Listing
May 2021

Patient-reported outcomes from a randomized, double-blind, placebo controlled, phase III study of baricitinib placebo in patients with moderately to severely active rheumatoid arthritis and an inadequate response to methotrexate therapy: results from the RA-BALANCE study.

Ther Adv Musculoskelet Dis 2021 20;13:1759720X211006964. Epub 2021 Apr 20.

Department of Rheumatology and Immunity, Center of Clinical Immunology, Peking University People's Hospital, Xicheng District, Beijing, P.R. China.

Introduction: To assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX).

Methods: This was a 52-week, randomized, double-blind, placebo controlled, phase III study in patients with RA who had an inadequate response to MTX. Patients ( = 290) receiving stable background MTX were randomly assigned (1:1) to receive placebo or baricitinib 4 mg once daily with a primary endpoint at week 12. PROs assessed included Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity, patient's assessment of pain, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), European Quality of Life-5 Dimensions-5 Level index scores and visual analogue scale, and measures collected in electronic patient daily diaries: duration of morning joint stiffness, Worst Tiredness, and Worst Joint Pain. Treatment comparisons were made with logistic regression and analysis of covariance models for categorical and continuous variables, respectively.

Results: Statistically significant ( ⩽ 0.05) improvements in all PROs were observed in the baricitinib 4 mg group compared to placebo as early as week 1 to week 4; and were sustained to week 24. These improvements were maintained until week 52 for the baricitinib group. A significantly larger proportion of patients met or exceeded the minimum clinically important difference for HAQ-DI (⩾0.22) and FACIT-F (3.56) profiles in the baricitinib group.

Conclusion: Baricitinib provided significant improvements in PROs compared to placebo to 52 weeks of treatment in patients with RA who had an inadequate response to MTX.Clinicaltrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT02265705; NCT02265705; RA-BALANCE. Registered 13 October 2014.
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http://dx.doi.org/10.1177/1759720X211006964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064513PMC
April 2021

Single-cell analysis reveals innate immunity dynamics in ankylosing spondylitis.

Clin Transl Med 2021 03;11(3):e369

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, and Human Phenome Institute, Fudan University, Shanghai, China.

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http://dx.doi.org/10.1002/ctm2.369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982614PMC
March 2021

Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis.

Front Immunol 2021 16;12:605616. Epub 2021 Feb 16.

Department of Rheumatology, Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China.

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.
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http://dx.doi.org/10.3389/fimmu.2021.605616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921149PMC
June 2021

Safety and Efficacy of Prefilled Liquid Etanercept-Biosimilar Yisaipu for Active Ankylosing Spondylitis: A Multi-Center Phase III Trial.

Rheumatol Ther 2021 Mar 9;8(1):361-374. Epub 2021 Feb 9.

Department of Rheumatology and Immunology, Chinese PLA General Hospital, Beijing, China.

Introduction: The aim of this work is to examine the efficacy and safety of prefilled liquid etanercept-biosimilar Yisaipu versus lyophilized Yisaipu in active ankylosing spondylitis (AS) patients.

Methods: This double-blind, phase III trial with non-inferiority design randomized adult patients with active AS in a 3:1:1 ratio to receive twice-weekly 25-mg prefilled liquid Yisaipu for a total of 48 injections (group I, n = 330), once-weekly 50-mg prefilled liquid Yisaipu for 24 injections (group II, n = 110), or twice-weekly 25-mg lyophilized Yisaipu for 48 injections (group III, n = 110). Both physicians and patients who received 25-mg twice-weekly lyophilized or liquid Yisaipu were blinded to treatment assignment while patients who received 50-mg once-weekly liquid Yisaipu received treatment in an open-label design. In addition, 90 patients in the PK/PD study were randomized in a 1:1:1 ratio to each group. The primary outcome was the proportion of patients who achieved ASAS20 at week 24.

Results: A total of 640 subjects were enrolled. The proportion of patients who attained ASAS20 at week 24 was 85.56% in group I, 85.71% in group II, and 83.45% in group III (group I vs. III, P = 0.545; group II vs. III, P = 0.605). The difference between group I and III was 2.10% (95% CI - 5.06%, 9.27%) and 2.26% (95% CI - 6.21%, 10.73%) between group II and III, meeting the non-inferiority threshold (Δ = - 15%) (P < 0.001). Except for a statistical difference between group I (75.83%) and group III at week 8 (64.75%, P = 0.011), there was no statistical difference in the ASAS20 attainment rate among the three groups at other time points. The incidence of serious adverse events was comparable among the three groups (group I, 2.50%, II, 2.86% and III, 1.43%; P > 0.05). No deaths were reported.

Conclusions: Once-weekly 50-mg or twice-weekly 25-mg prefilled liquid Yisaipu is safe and non-inferior to twice-weekly 25-mg lyophilized Yisaipu.

Trial Registration: CTR20130124 and NCT04345458.
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http://dx.doi.org/10.1007/s40744-021-00276-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991065PMC
March 2021

Changes in Efficacy Indicators for Adalimumab Biosimilar Candidate (HS016) for the Treatment of Active Ankylosing Spondylitis at Various Time Points.

Front Pharmacol 2020 7;11:606497. Epub 2020 Dec 7.

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Immunologic Diseases, Ministry of Science and Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.

A phase III, 24-weeks Chinese clinical trial demonstrated that efficacy and safety outcomes of treatments with 40 mg/0.8 ml HS016 ( = 416) or adalimumab ( = 232) for active ankylosing spondylitis (AS) patients was comparable. In the present study, a subanalysis of the clinical trial was conducted to determine whether also individual efficacy indicators were comparable between HS016 and adalimumab. The individual efficacy indicators total and nocturnal back pain, global assessment of disease activity, swollen joint count, Maastricht AS Enthesitis Score, Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index and chest expansion, were assessed at baseline and every 2 weeks during the treatment period. This subanalysis revealed no significant difference between the patient groups treated with HS016 or adalimumab for any individual efficacy indicator investigated at any time point (all > 0.05) beside faster total back pain score improvements in the adalimumab group on week 10, 12 and 22, which became equal at week 24. Among these indicators, chest expansion showed a significant increase at each time point compared with baseline, whereas all other efficacy indicators showed significant decreases compared with baseline at each time point (all < 0.05). All efficacy indicators had increased or decreased rapidly by week 2, and the values continued to increase/decrease up to week 12, with subsequent smaller changes thereafter up to week 24 of treatment. The response trajectory of most individual efficacy indicators was comparable between HS016 and adalimumab at each time point during the 24 weeks of the trial. http://www.chictr.org.cn/showproj.aspx?proj=37910, identifier [ChiCTR1900022520].
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http://dx.doi.org/10.3389/fphar.2020.606497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750525PMC
December 2020

Guidelines for the diagnosis and treatment of osteoarthritis in China (2019 edition).

Ann Transl Med 2020 Oct;8(19):1213

Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK.

Osteoarthritis (OA) is a degenerative disease of middle-aged and elderly people, contributed a higher burden of disease in China and the world. In 2017, under the support of the Rheumatology and Immunology Expert Committee of the Cross-Strait Medical and Health Exchange Association. The objective was to develop an evidence-based diagnosis and treatment guideline for OA in China based on emerging new evidence. The guideline was registered at International Practice Guidelines Registry Platform (IPGRP-2018CN028). The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence and the strength of recommendations, and the RIGHT (Reporting Items for Practice Guidelines in Healthcare) checklist was followed to report the guideline. The guideline provides recommendations for the OA diagnosis, disease risks monitoring and evaluate, treatment purpose and physical, medical and surgical interventions. This guideline is intended to serve as a tool for Chinese clinicians for the best decisions-making on diagnosis and treatment of OA.
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http://dx.doi.org/10.21037/atm-20-4665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607097PMC
October 2020

Development and formulation of the classification criteria for osteoarthritis.

Ann Transl Med 2020 Sep;8(17):1068

Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China.

Background: The classification criteria of osteoarthritis (OA) is lack of the support of relevant research evidence and there is no standardized protocol for detailed steps of the development or clinical verification of classification criteria has yet been established. This study aims to describe the development process of the Categorization of Osteoarthritis CHecklist (COACH), which is designed to choose the precise treatment option for patients with OA.

Methods: A multidisciplinary panel was established to gather opinions. We conducted questionnaire survey and literature review to generate and COACH Panel members were invited to review the drafted classification criteria and optimize classification criteria. The final list of items was discussed and reached the agreement by the core group of the panel.

Results: Thirty-six experts participated in COACH Panel including rheumatologist (80.6%; 29/36), orthopedist (13.9%; 5/36), methodologist (2.8%; 1/36) and rehabilitation physician (2.8%; 1/36) for classification factors generating and optimizing. The main body of the final classification criteria consists of six types of OA pathogenesis, eight types of medical findings (which can be grouped into two categories), and six types of the location. The final criteria include load-based type, structure-based type, inflammation-based type, metabolic-based type, systemic factor based type and mixed type.

Conclusions: COACH can better help clinicians quickly classify OA patients and help to choose the best treatment option from the aspects of types, findings and locations. What's more, the classification criteria are also helpful to promote the basic medical research and targeted prevention of OA.
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http://dx.doi.org/10.21037/atm-20-4673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575945PMC
September 2020

The clinical efficacy of traditional Chinese medicine in the treatment of rheumatoid arthritis with interstitial lung disease: A protocol of systematic review and meta-analysis.

Medicine (Baltimore) 2020 Oct;99(41):e22453

Department of Rheumatology and Immunology, GuangHua Hospital of Integrated Traditional Chinese and Western, Shanghai, China.

Background: The objective of this meta-analysis was to summarize and identify the available evidence from studies to estimate the clinical value of traditional Chinese medicine (TCM) in the treatment of rheumatoid arthritis with interstitial lung disease (RA-ILD). And provides clinicians with evidence on which to base their clinical decision making.

Methods: This review will include all studies comparing clinical efficacy of TCM in the treatment of RA-ILD. The search strategy will be performed in 9 databases. We will not establish any limitations to language and publication status, published from inception to the August 2020. Two reviewers will screen, select studies, extract data, and assess quality independently. Outcome is lung function, number of swelling joints, number of painful joints, duration of morning stiffness, VAS score, adverse effects, quality of life, ESR, CRP, rheumatoid factor and safety. The methodological quality including the risk of bias of the included studies will be evaluated. We will carry out statistical analysis using RevMan 5.3 software.

Results: This study will summarize current evidence to assess the efficacy and safety of TCM in the treatment of RA-ILD.

Conclusion: The findings of this study will provide helpful evidence for the clinician, and will promote further studies, as well as studying the value of TCM.

Registration Number: INPLASY202080108 (DOI number: 10.37766/inplasy2020.8.0108).
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http://dx.doi.org/10.1097/MD.0000000000022453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544266PMC
October 2020

Epigenetic Regulation Mediated by Methylation in the Pathogenesis and Precision Medicine of Rheumatoid Arthritis.

Front Genet 2020 4;11:811. Epub 2020 Aug 4.

Department of Rheumatology, Guanghua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Rheumatoid arthritis (RA) is a complex disease triggered by the interaction between genetics and the environment, especially through the shared epitope (SE) and cell surface calreticulin (CSC) theory. However, the available evidence shows that genetic diversity and environmental exposure cannot explain all the clinical characteristics and heterogeneity of RA. In contrast, recent studies demonstrate that epigenetics play important roles in the pathogenesis of RA, especially DNA methylation and histone modification. DNA methylation and histone methylation are involved in innate and adaptive immune cell differentiation and migration, proliferation, apoptosis, and mesenchymal characteristics of fibroblast-like synoviocytes (FLS). Epigenetic-mediated regulation of immune-related genes and inflammation pathways explains the dynamic expression network of RA. In this review, we summarize the comprehensive evidence to show that methylation of DNA and histones is significantly involved in the pathogenesis of RA and could be applied as a promising biomarker in the disease progression and drug-response prediction. We also explain the advantages and challenges of the current epigenetics research in RA. In summary, epigenetic modules provide a possible interface through which genetic and environmental risk factors connect to contribute to the susceptibility and pathogenesis of RA. Additionally, epigenetic regulators provide promising drug targets to develop novel therapeutic drugs for RA. Finally, DNA methylation and histone modifications could be important features for providing a better RA subtype identification to accelerate personalized treatment and precision medicine.
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http://dx.doi.org/10.3389/fgene.2020.00811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417338PMC
August 2020

Correction to: The IgG galactosylation ratio is higher in spondyloarthritis patients and associated with the MRI score.

Clin Rheumatol 2020 10;39(10):3159

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

In the original version of the above article the References 19 and 20 were incorrect which cannot describe the development of the SPARCC score.
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http://dx.doi.org/10.1007/s10067-020-05314-xDOI Listing
October 2020

Disease activity guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis: a prospective, randomized, open-label, multicentric study.

Ther Adv Musculoskelet Dis 2020 2;12:1759720X20929441. Epub 2020 Jun 2.

Division of Rheumatology, the Second Affiliated Hospital of Zhejiang University School of Medicine, No.88, Jiefang Road, Hangzhou 310009, China.

Background: The aim of this study was to evaluate disease-activity-guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis (AS) in a prospective, randomized, open-label, multicentric study.

Methods: Active AS patients with AS disease activity score (ASDAS) ⩾2.1 recruited from 10 hospitals were treated with rhTNFR:Fc 50 mg weekly for 12 weeks, and further randomized into different tapering or discontinuation groups according to ASDAS at week 12. Patients who achieved clinical remission (ASDAS < 1.3) were assigned randomly to stepwise tapering group or discontinuation group. Patients who achieved low disease activity (LDA, 1.3⩽ASDAS < 2.1) were assigned randomly to stepwise tapering, delayed tapering, or discontinuation group. All patients were evaluated every 12 weeks until week 48. The primary endpoint was cumulative flare rates in different groups at week 48.

Results: A total of 311 patients were enrolled with an average ASDAS of 3.6 ± 1.0, and 259 completed 12 weeks of rhTNFR:Fc induction therapy, with 148 patients (57.1%) achieved clinical remission, 100 (38.6%) achieved LDA, and 11 (4.3%) remained as high disease activity (ASDAS⩾2.1). In patients who achieved clinical remission at week 12, stepwise tapering of rhTNFR:Fc demonstrated significantly lower flare rates at each evaluation compared with discontinuation. In patients who achieved LDA, there was no significant difference of flare rates between stepwise tapering, delayed tapering, and discontinuation. With stepwise tapering of rhTNFR:Fc, flare rates were comparable in AS patients, irrespective of initial ASDAS before tapering.

Conclusion: Stepwise tapering of rhTNFR:Fc when patients achieved clinical remission was able to maintain favorable low flare rates in 48 weeks. LDA was an alternative therapeutic target, as well as an viable timing for initiation of rhTNFR:Fc tapering. rhTNFR:Fc 25 mg monthly maintained flare-free status in a considerable number of patients. However, abrupt discontinuation of rhTNFR:Fc even if patients achieved clinical remission should be avoided.

Trial Registration: ClinicalTrials.gov: NCT03880968,URL: https://clinicaltrials.gov/ct2/show/NCT03880968.
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http://dx.doi.org/10.1177/1759720X20929441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268122PMC
June 2020

Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate: results from a phase 3 study.

Clin Exp Rheumatol 2020 Jul-Aug;38(4):732-741. Epub 2020 May 20.

CEPIC - Centro Paulista de Investigação Clinica e Serviços Médicos, Ipiranga São Paulo, Brazil.

Objectives: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy.

Methods: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12.

Results: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo.

Conclusions: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.
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September 2020

The IgG galactosylation ratio is higher in spondyloarthritis patients and associated with the MRI score.

Clin Rheumatol 2020 Aug 2;39(8):2317-2323. Epub 2020 Mar 2.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

Objectives: MRI is an important tool for evaluating inflammation levels and assessing treatment response in patients with ankylosing spondylitis (AS). However, it is expensive and requires experienced physicians. The goal of this study was to identify a biomarker correlated with the MRI score.

Methods: A total of 558 spondyloarthritis (SpA) patients including 527 AS patients, 10 psoriasis (PsA) patients, and 21 non-radiographic SpA (nr-SpA) patients and 725 controls were enrolled for the studies. Plasma IgG galactosylation (IgG-Gal) level was measured by mass spectrometry. Clinical indexes such as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and C-reactive protein (CRP) were measured in all AS patients. MRIs and X-rays were obtained from 65 AS patients who were followed up for 6 months.

Results: The IgG-Gal ratio was twice as high in the AS patients compared with the controls. It correlated with inflammation indices which is evaluated by MRI according to SPARCC. (Pearson coefficient/p value was 0.6/7E10-6). In addition, AS patients with a higher IgG-Gal ratio at baseline tended to show greater improvement in inflammation scores by MRI both in 3-month follow-up and 6-month follow-up.

Conclusion: The IgG-Gal ratio was significantly increased in AS patients. In clinical care, it may be used as a potential biomarker for diagnosis in the future. Key Points • IgG galactosylation level was abnormal in SpA patients. • IgG galactosylation level was associated with MRI indices.
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http://dx.doi.org/10.1007/s10067-020-04998-5DOI Listing
August 2020

Comparison of the Efficacy and Safety of Adalimumab (Humira) and the Adalimumab Biosimilar Candidate (HS016) in Chinese Patients with Active Ankylosing Spondylitis: A Multicenter, Randomized, Double-Blind, Parallel, Phase III Clinical Trial.

BioDrugs 2020 Jun;34(3):381-393

Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China.

Objective: The aim of this study was to evaluate the efficacy and safety of the biosimilar candidate of adalimumab (HS016) compared with adalimumab (Humira) for the treatment of active ankylosing spondylitis.

Methods: A multicenter, randomized, double-blind, parallel, positive control, phase III clinical trial was conducted at 28 locations in China. Patients with active ankylosing spondylitis were randomized in a 2:1 ratio to subcutaneously receive 40 mg of either HS016 or adalimumab every other week for 24 weeks. The primary endpoint was to achieve at least a 20% improvement (ASAS20) in patients at 24 weeks according to the Assessment of Spondyloarthritis International Society criteria. The secondary endpoint included other efficacy assessment parameters, health evaluations, safety, pharmacokinetic, and immunogenicity parameters.

Results: Following the random assignment of 648 patients into HS016 (n = 416) and adalimumab (n = 232) groups, no significant difference was found in the ASAS20 response rates at 24 weeks between the HS016 (364/416, 87.5%) and adalimumab (209/232, 90.1%) treatments and the difference between the response rates (- 2.59%; 90% confidence interval [CI] - 6.77 to 1.60) was within the predefined equivalence margin (± 15%). There were also no significant differences when the secondary endpoints were compared (all p > 0.05). Similarly, the rates of treatment-emergent adverse events (TEAEs) were not significantly different between the two groups, with most TEAEs being mild to moderate. Only nine severe cases were found, including seven within the HS016 group, three (0.7%) of which were tuberculosis cases. Plasma concentrations of HS016 and adalimumab from weeks 12 to 14 were similar during the steady-state period and steady-state maximal concentration (C) was equivalent for HS016 (7356.6 ng/mL) and adalimumab (7600.3 ng/mL). The accumulated proportion of patients with positive human anti-human antibodies (HAHAs) at week 24 was 326/412 (79.1%) in the HS016 group and 183/229 (79.9%) in the adalimumab group (p > 0.05), while the accumulated proportion of patients with positive neutralizing antibody (NAb) tests were 72/412 (17.5%) in the HS016 group and 43/229 (18.8%) in the adalimumab group (p > 0.05).

Conclusion: HS016 resembled adalimumab in efficacy and safety over the 24-week treatment period.

Trial Registration Number: ChiCTR1900022520.
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http://dx.doi.org/10.1007/s40259-020-00408-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211209PMC
June 2020

Effects of Soil Amendments on Microbial Activities in a Typical Cd-Contaminated Purple Field Soil, Southwestern China.

Bull Environ Contam Toxicol 2020 Mar 13;104(3):380-385. Epub 2020 Jan 13.

School of Agriculture and Environment, The University of Western Australia, Perth, WA, 6009, Australia.

In this study, three soil amendments (inorganic, liming, or organic-inorganic materials) were used in a Cd-contaminated purple field soil to investigate their impacts on soil Cd availability, enzyme (urease, catalase, sucrase, and acid phosphatase) activities, microbial biomass (carbon/nitrogen) and type (bacteria, fungi, and actinomycetes) in mustard and corn trials. Results showed that soil amendments generally decreased soil exchangeable Cd, fungi and bacterial populations while increasing the activities of all the four soil enzymes tested, microbial biomass carbon and populations of actinomycetes (p < 0.05). Soil pH and microbial biomass nitrogen did not exhibit any significant response (p > 0.05) whereas stronger effects appeared in soil organic matter and available nutrients (nitrogen, phosphorous and potassium; p < 0.05). However, only soil available phosphorous significantly correlated with soil microbial activity in both mustard and corn trails (p < 0.05). Thus, application of phosphorous-containing amendments should be considered for promoting soil health in the remediation of the Cd-contaminated purple soils.
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http://dx.doi.org/10.1007/s00128-020-02786-0DOI Listing
March 2020

Characteristics of Gut Microbiota in Patients With Rheumatoid Arthritis in Shanghai, China.

Front Cell Infect Microbiol 2019 23;9:369. Epub 2019 Oct 23.

Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, China.

Little is known regarding differences in the gut microbiomes of rheumatoid arthritis (RA) patients and healthy cohorts in China. This study aimed to identify differences in the fecal microbiomes of 66 Chinese patients with RA and 60 healthy Chinese controls. The V3-V4 variable regions of bacterial 16S rRNA genes were sequenced with the Illumina system to define the bacterial composition. The alpha-diversity index of the microbiome of the RA patients was significantly lower than that of the control group. The bacterial genera ( = 0.02202) and ( = 0.03137) were more abundant in RA patients. In contrast, ( = 0.000014) ( = 0.0000008615) ( = 0.000005759), and ( = 0.0000166) were less abundant in the RA group than in the control group. Spearman correlation analysis of blood physiological measures of RA showed that bacterial genera such as and were positively correlated with RF-IgA and anti-CCP antibodies. Furthermore, and were positively correlated with the erythrocyte sedimentation rate, and -2 and were positively correlated with C-reactive protein, both biomarkers of inflammation. These findings suggest that the gut microbiota may contribute to RA development via interactions with the host immune system.
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http://dx.doi.org/10.3389/fcimb.2019.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819506PMC
July 2020

(5R)-5-Hydroxytriptolide (LLDT-8) induces substantial epigenetic mediated immune response network changes in fibroblast-like synoviocytes from rheumatoid arthritis patients.

Sci Rep 2019 08 1;9(1):11155. Epub 2019 Aug 1.

Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional and Western Medicine, Shanghai, 200052, China.

Tripterygium is a traditional Chinese medicine that has widely been used in the treatment of rheumatic disease. (5R)-5-hydroxytriptolide (LLDT-8) is an extracted compound from Tripterygium, which has been shown to have lower cytotoxicity and relatively higher immunosuppressive activity when compared to Tripterygium. However, our understanding of LLDT-8-induced epigenomic impact and overall regulatory changes in key cell types remains limited. Doing so will provide critically important mechanistic information about how LLDT-8 wields its immunosuppressive activity. The purpose of this study was to assess the effects of LLDT-8 on transcriptome including mRNAs and long non-coding RNA (lncRNAs) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by a custom genome-wide microarray assay. Significant differential expressed genes were validated by QPCR. Our work shows that 394 genes (281 down- and 113 up-regulated) were significantly differentially expressed in FLS responding to the treatment of LLDT-8. KEGG pathway analysis showed 20 pathways were significantly enriched and the most significantly enriched pathways were relevant to Immune reaction, including cytokine-cytokine receptor interaction (P = 4.61 × 10), chemokine signaling pathway (P = 1.01 × 10) and TNF signaling pathway (P = 2.79 × 10). Furthermore, we identified 618 highly negatively correlated lncRNA-mRNA pairs from the selected significantly differential lncRNA and mRNA including 27 cis-regulated and 591 trans-regulated lncRNA-mRNAs modules. KEGG and GO based function analysis to differential lncRNA also shown the enrichment of immune response. Finally, lncRNA-transcription factor (TF) and lncRNA-TF-mRNA co-expression network were constructed with high specific network characteristics, indicating LLDT-8 would influence the expression network within the whole FLS cells. The results indicated that the LLDT-8 would mainly influence the FLS cells systemically and specially in the process of immune related pathways.
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http://dx.doi.org/10.1038/s41598-019-47411-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671973PMC
August 2019

IgG Galactosylation status combined with MYOM2-rs2294066 precisely predicts anti-TNF response in ankylosing spondylitis.

Mol Med 2019 06 13;25(1):25. Epub 2019 Jun 13.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

Background: Tumor necrosis factor (TNF) blockers have a high efficacy in treating Ankylosing Spondylitis (AS), yet up to 40% of AS patients show poor or even no response to this treatment. In this paper, we aim to build an approach to predict the response prior to clinical treatment.

Methods: AS patients during the active progression were included and treated with TNF blocker for 3 months. Patients who do not fulfill ASASAS40 were considered as poor responders. The Immunoglobulin G galactosylation (IgG-Gal) ratio representing the quantity of IgG galactosylation was calculated and candidate single nucleotide polymorphisms (SNPs) in patients treated with etanercept was obtained. Machine-learning models and cross-validation were conducted to predict responsiveness.

Results: Both IgG-Gal ratio at each time point and differential IgG-Gal ratios between week 0 and weeks 2, 4, 8, 12 showed significant difference between responders and poor-responders. Area under curve (AUC) of the IgG-Gal ratio prediction model was 0.8 after cross-validation, significantly higher than current clinical indexes (C-reactive protein (CRP) = 0.65, erythrocyte sedimentation rate (ESR) = 0.59). The SNP MYOM2-rs2294066 was found to be significantly associated with responsiveness of etanercept treatment. A three-stage approach consisting of baseline IgG-Gal ratio, differential IgG-Gal ratio in 2 weeks, and rs2294066 genotype demonstrated the ability to precisely predict the response of anti-TNF therapy (100% for poor-responders, 98% for responders).

Conclusions: Combination of different omics can more precisely to predict the response of TNF blocker and it is potential to be applied clinically in the future.
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http://dx.doi.org/10.1186/s10020-019-0093-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567531PMC
June 2019

Effects of simulated Cd deposition on soil Cd availability, microbial response, and crop Cd uptake in the passivation-remediation process of Cd-contaminated purple soil.

Sci Total Environ 2019 Sep 22;683:782-792. Epub 2019 May 22.

College of Materials and Environmental Engineering, Hangzhou Dianzi University, Hangzhou, Zhejiang 310010, China.

Atmospheric deposition of heavy metals such as Cd is a threat to ecosystems and food safety. Our knowledge is still limited about the effectiveness of remediation process for Cd-contaminated agro-soils under atmospheric Cd deposition. In this study, eight soil amendments were used in a Cd-contaminated purple soil to investigate their impacts on soil Cd availability, microbial response, and Cd uptake by mustard and corn plants via simulating the atmospheric Cd deposition under laboratory incubation and greenhouse conditions. Results showed that the simulated atmospheric Cd deposition increased the soil high-risk Cd (HR, exchangeable and carbonate Cd) and decreased soil medium-risk Cd fraction (MR, bound to Fe/Mn oxide and organic Cd), and the largest direct effects on crop Cd uptakes were 0.94 and 0.66 for mustard and corn based on the path-coefficient analysis, respectively. Generally, Cd deposition led to decreasing soil microbial biomass carbon, populations of bacteria, fungi and actinomycetes, and enzyme activities of urease, catalase, sucrase, and acid phosphatase whereas increasing soil microbial biomass nitrogen. Compared with control and lime treatments, an organic-inorganic combined preparation (OCP) appeared to be effective for remediation of the Cd-contaminated purple soil due to its potential to increase the HR-Cd and reduce both MR-Cd and crop Cd uptake, as accompanied by its neutral effects on soil bacterial alpha diversity and community structure. Results also indicated that application of nitrogen fertilizers should be considered for remediation of the Cd-contaminated soils as nitrogen inputs were demonstrated to promote soil health under elevated Cd condition.
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http://dx.doi.org/10.1016/j.scitotenv.2019.05.292DOI Listing
September 2019

Genome-Wide DNA Methylation Profiles Reveal Common Epigenetic Patterns of Interferon-Related Genes in Multiple Autoimmune Diseases.

Front Genet 2019 5;10:223. Epub 2019 Apr 5.

State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China.

Graves' disease (GD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are complex autoimmune diseases sharing common clinical, genetic and pathogenetic features. However, the commonalities of the DNA methylation profiles for these diseases are still unknown. We conducted an integrative analysis of the multiple-autoimmune disease methylation dataset including GD, RA, SLE, and SSc samples, to identify the common methylation patterns of autoimmune diseases. We identified 15,289 differentially methylated sites between multiple-autoimmune disease patients and controls in CD4+ T cells. We found that the most significant differentially methylated sites had a remarkable enrichment in type I interferon (IFN) pathway genes. Similarly, we identified 9,295 differentially methylated sites between GD/SSc patients and controls in CD8+ T cells. The overall IFN-related gene panel annotated by gene ontology (GO) showed an excellent diagnostic capacity in CD4+ T cells (Sensitivity = 0.82, specificity = 0.82 and AUC = 0.90), while , another IFN-related gene not annotated by GO, showed high prediction ability in both CD4+ (AUC = 0.86) and CD8+ (AUC = 0.75) T cells. In conclusion, our study demonstrated that hypomethylation of IFN-related genes is a common feature of GD/RA/SLE/SSc patients in CD4+ T cells, and the DNA methylation profile of IFN-related genes could be promising biomarkers for the diagnosis of GD, RA, SLE, and SSc.
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http://dx.doi.org/10.3389/fgene.2019.00223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459983PMC
April 2019

Maintenance of effect of duloxetine in Chinese patients with pain due to osteoarthritis: 13-week open-label extension data.

BMC Musculoskelet Disord 2019 Apr 22;20(1):174. Epub 2019 Apr 22.

Medical Department, Lilly Suzhou Pharmaceutical Co. Ltd. Shanghai Branch, 19F, Centre T1, HKRI Taikoo, No. 288, Shimen No.1 Road, Shanghai, 200021, China.

Background: The objectives of this study were to assess the maintenance of effect of duloxetine 60 mg once-daily (QD) in Chinese patients with chronic pain due to osteoarthritis (OA) of the knee or hip and to provide additional long-term safety data.

Methods: This was an open-label, extension phase of a randomized, double-blind, placebo-controlled clinical trial. Eligible patients were outpatients who met the American College of Rheumatology clinical and radiographic criteria for OA with a rating ≥4 on Brief Pain Inventory (BPI) 24-h average pain. After completing the 13-week placebo-controlled phase, patients originally assigned to placebo were titrated to duloxetine 60 mg QD (PLA_DLX), whereas patients originally assigned to duloxetine 60 mg QD remained on the same dose of duloxetine (DLX_DLX) for another 13 weeks. The maintenance effect of duloxetine 60 mg QD during the extension phase was evaluated by a 1-sided 97.5% confidence interval (CI) of the baseline-to-endpoint change in the extension phase for patients who took duloxetine and reported ≥30% reduction in BPI average pain at the end of placebo-controlled phase (placebo-controlled phase duloxetine responders). Other BPI severity and interference items, as well as safety and tolerability, were assessed.

Results: Of 342 patients entering the extension phase, 162 (97.6%) DLX_DLX-treated patients and 157 (89.2%) PLA_DLX-treated patients completed this phase. Most patients (76.0%) were female. Mean age was 60.6 years. Mean BPI average pain was 5.5 at baseline of the placebo-controlled phase. Among 113 placebo-controlled phase duloxetine responders, mean change in BPI average pain during the extension phase was - 0.59 (from 2.47 to 1.88); the upper bound of the 1-sided 97.5% CI was - 0.31 and less than the pre-specified non-inferiority margin of a 1.5-point increase (p < 0.001). Significant within-group improvements in all BPI items were observed for both PLA_DLX and DLX_DLX groups during the extension phase (all p < 0.01). No deaths or suicide-related events occurred. Seven (4.0%) PLA_DLX-treated patients and no DLX_DLX-treated patients discontinued due to an adverse event.

Conclusion: The analgesic effect of duloxetine 60 mg QD among treatment responders was maintained for the entire duration of the extension phase. Duloxetine 60 mg QD was well tolerated during the extension phase.

Trial Registration: ClinicalTrials.gov identification number NCT01931475 . Registered 29 August 2013.
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http://dx.doi.org/10.1186/s12891-019-2527-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477726PMC
April 2019

Effects of soil amendments applied on cadmium availability, soil enzyme activity, and plant uptake in contaminated purple soil.

Sci Total Environ 2019 Mar 7;654:1364-1371. Epub 2018 Nov 7.

Tianxiang Bio-technology Limited Company, Xuzhou 221600, China.

Soil Cd pollution resulting from human activities has become a serious food safety concern. This study was to investigate the impacts of eight soil amendments including a humic acid material (XZ), three organic-inorganic combined materials (FY, PX and PLY) and four inorganic materials (FS, LIME, PLL and PL) on soil Cd availability, enzyme activity, and the uptake by vegetables under incubation, greenhouse and field conditions. Results showed that soil exchangeable Cd (EX-Cd) concentrations under four amendments (FY, XZ, PX, FS) significantly decreased by 12.10-13.59% after 20d treatments, and both PX and PLY resulted in reduced soil EX-Cd fraction while increased fractions of Fe-Mn oxides (OX-Cd), organic matter (OM-Cd) and residual (Res-Cd) in the Cd-contaminated purple soil. PX significantly reduced soil EX-Cd and carbonate-bound (CB-Cd) fractions by 4.4% and 11.4%, and decreased vegetable Cd uptake by 38.8% and 49.1% in greenhouse and field experiments, respectively. Moreover, PX elevated the activities of soil catalase, urease and saccharase by 15.7%, 53.6% and 48.2% in pot soil, which were ~4, ~5 and ~14 times higher those in field soil, respectively. This research demonstrated that PX could be an effective soil amendment to reduce the Cd health and ecological riskthe 1s in the Cd-contaminated purple soil.
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http://dx.doi.org/10.1016/j.scitotenv.2018.11.059DOI Listing
March 2019

HLA class I and II alleles in susceptibility to ankylosing spondylitis.

Ann Rheum Dis 2019 01 19;78(1):66-73. Epub 2018 Oct 19.

Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

Objective: To examine associations of HLA class I and class II alleles with ankylosing spondylitis (AS) in three cohorts of patients of European, Asian and African ancestry.

Methods: HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 alleles were genotyped in 1948 unrelated white and 67 African-American patients with AS from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, the North American Spondylitis Consortium and Australo-Anglo-American Spondyloarthritis Consortium, 990 white and 245 African-American Controls and HLA-B alleles in 442 Han Chinese patients with AS and 346 controls from Shanghai and Gansu, China. In addition to the case:control analyses, -negative patients with AS were analysed separately, and logistic regression and 'relative predispositional effects' (RPE) analyses were carried out to control for the major effect of on disease susceptibility.

Results: Although numerous associations were seen between HLA alleles and AS in whites, among HLA-B*27-negative patients with AS , positive associations were seen with and and negative associations with and . Additional associations with and (B60) were observed via RPE analysis, which excludes the alleles. The increased frequency of and decreased frequency of was also seen in Han Chinese and African-Americans with AS. was decreased in whites with acute anterior uveitis.

Conclusions: These data, analysing the largest number of patients with AS examined to date in three ethnic groups, confirm that other HLA class I and II alleles other than HLA-B*27 to be operative in AS predisposition.
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http://dx.doi.org/10.1136/annrheumdis-2018-213779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982366PMC
January 2019

Metal wet deposition in the Three Gorges Reservoir (TGR) region of Southwest China.

Environ Sci Pollut Res Int 2018 Nov 14;25(32):32053-32065. Epub 2018 Sep 14.

Chongqing Institue of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing, 400714, China.

Metal wet deposition has become an environmental concern because of its threats to soil or water quality and human health. This study was to collect rainfall waters in 2016 from seven sites, representing urban, town, rural, and wetland, within the Three Gorges Reservoir (TGR) region of Southwest China, determine the metal concentration and flux (Zn, Mn, Cu, As, Cd, Pb), and identify their possible sources. Results indicated that Zn was the most abundant metal with a concentration of 16.92 μg L in fall and 19.91 μg L in winter and flux of 4.71 mg m in fall, while Cd was the least with a monthly mean concentration of 0.02-0.37 μg L. Among the seven sites, urban (FL) had the highest values of both concentrations of metals (Zn, Cu, Pb) and fluxes of metals (Mn, As), which significantly differed from the other sites. Component and redundancy analysis suggested that fossil fuel and biomass combustion be a potential metal source. Enrichment factors, box model, and potential ecological risk index showed that the TGR water quality could face a high risk due to wet metal deposition, especially Cd. Data could provide a valuable aid in mitigating metal pollution, developing the best watershed management practices, as well as safeguarding water quality and human health in the TGR region or other reservoir regions.
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http://dx.doi.org/10.1007/s11356-018-3075-yDOI Listing
November 2018

Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate-inadequate responder Chinese patients with active rheumatoid arthritis: 24-week results from a randomised, double-blind, placebo-controlled phase 3 study.

Clin Exp Rheumatol 2019 Mar-Apr;37(2):227-234. Epub 2018 Aug 29.

Peking University Third Hospital, Beijing, China.

Objectives: To evaluate the efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) in Chinese patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods: This 24-week, phase 3, double-blind, placebo-controlled study was conducted in 30 centres across China. A total of 430 patients were randomised 3:1 to receive CZP 200 mg every 2 weeks (loading dose: 400 mg CZP at Weeks 0, 2 and 4) plus MTX or placebo (PBO) plus MTX. The primary endpoint was ACR20 response at Week 24, for which the superiority of CZP+MTX over PBO+MTX was evaluated. Additional parameters for clinical efficacy, health outcomes, immunogenicity and safety were assessed.

Results: At Week 24, 54.8% of CZP+MTX patients and 23.9% of PBO+MTX patients achieved ACR20 (odds ratio: 3.9, p<0.001). CZP+MTX patients also achieved greater improvements in HAQ-DI, higher ACR50/70 responses and higher DAS28(ESR) remission rate at Week 24. Rapid onset of response to CZP+MTX was observed as early as Week 1 for most of the clinical, functional and patient-reported outcomes. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment arms. Serious TEAEs were reported by 6.3% of CZP+MTX patients and 2.7% of PBO+MTX patients. No new safety signals were observed.

Conclusions: CZP in combination with MTX showed an acceptable safety profile, a rapid onset of response and sustained effects in reducing the signs and symptoms of RA and improving physical function in Chinese patients with RA and an inadequate response to MTX.
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May 2019

Signal Transducer and Activator of Transcription 3 Hyperactivation Associates With Follicular Helper T Cell Differentiation and Disease Activity in Rheumatoid Arthritis.

Front Immunol 2018 4;9:1226. Epub 2018 Jun 4.

China-Australia Centre for Personalised Immunology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Follicular helper T (Tfh) cells are the specialized CD4 T cell subset that supports B cells to produce high-affinity antibodies and generate humoral memory. Not only is the function of Tfh cells instrumental to mount protect antibodies but also to support autoantibody production and promote systemic inflammation in autoimmune diseases. However, it remains unclear how the activation of Tfh cells is driven in autoimmune diseases. Here, we report that in patients with rheumatoid arthritis (RA), excessive generation of CXCR5PD-1 memory Tfh cells was observed and the frequency of memory Tfh cells correlated with disease activity score calculator for RA (DAS28). The differentiation of Tfh cells is dependent on signal transducer and activator of transcription 3 (STAT3), the key transcription factor downstream of cytokine signal pathways. A drastic increase of phosphorylated STAT3 (pSTAT3) in CD4 T cells were detected in RA patients who also produced larger amounts of STAT3-stimulating cytokines, including IL-6, IL-21, IL-10, and leptin than those of healthy controls. Importantly, the phosphorylation status of STAT3 in CD4 T cells positively correlated with the plasma concentration of IL-6 and the frequency of memory Tfh cells. This study reveals an IL-6-pSTAT3-Tfh immunoregulatory axis in the pathogenesis of RA and reinforces its candidature as biomarkers and targets for diagnosis and therapy.
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http://dx.doi.org/10.3389/fimmu.2018.01226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994589PMC
August 2019
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