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ID PMID Title PublicationDate abstract
31049794 TNF-β +252 A>G (rs909253) polymorphism is independently associated with presence of autoa 2019 Aug The TNF-β +252 A>G (rs909253) polymorphism has been associated with a risk of development of rheumatoid arthritis (RA) and could influence plasma tumor necrosis factor alpha (TNF-α) levels. The aim of the present study was to evaluate the association between the TNF-β +252 A>G polymorphism with plasma TNF-α levels, the presence of autoantibodies, and the susceptibility for RA. This cross-sectional study included 261 patients with RA and 292 controls. The polymorphism was studied using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Soluble TNF-α and receptors swere measured by multiplex assay. Rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) were measured using immunoassay. No differences were observed in allele frequency and genotype distribution among patients and controls. The presence of RF (p = 0.020) and anti-CCP (p = 0.001) increased 4.23-fold and 8.13-fold, respectively, in patients with B1 allele (B1/B2 + B1/B1 genotypes) independently of demographic, clinical, and inflammatory markers. Among patients with B1/B2 + B1/B1 genotypes, higher TNF-α levels were associated with positive RF (p = 0.040), anti-CCP (p = 0.011), or both (p = 0.038). In patients carrying B1 allele, the increased sTNFR1 together with RF or anti-CCP or both explained about 39.0% the variations in TNF-α level. However, in B2/B2 genotype, the presence of those autoantibodies was not associated with TNF-α level. Our findings indicate that the TNF-β +252 A>G polymorphism was not associated with RA susceptibility and TNF-α plasma levels. However, B1 allele was associated with the presence of autoantibodies. In addition, interaction between the presence of B1 allele and autoantibodies was associated with the increase of plasma TNF-α level in RA patients.
31608065 Hsa_circ_0000479 as a Novel Diagnostic Biomarker of Systemic Lupus Erythematosus. 2019 Background: Accumulating evidence suggests that differentially expressed non-coding circular RNAs (circRNAs) play critical roles in the progress of autoimmune diseases. However, the role of circRNAs in systemic lupus erythematosus (SLE) remains unclear. Methods: We initially used next-generation sequencing (NGS) to comprehensively analyze circRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from 10 SLE patients, stratified by their disease activity characteristics (stable or active SLE), and 10 healthy controls (HCs). Candidate circRNAs identified were first validated by quantitative reverse-transcription (qRT)-PCR in PBMC samples from a training-phase cohort of five SLE patients and five HCs. The significantly dysregulated circRNAs were then confirmed by qRT-PCR in a validation cohort of 23 SLE patients and 21 HCs, and in an external validation cohort with 64 SLE patients, 58 HCs, and 50 patients with rheumatoid arthritis (RA). In addition, we conducted bioinformatics analysis and western blotting investigating the relationships between the candidate circRNAs and SLE progression. Results: Multilayer integrative analysis of circRNA regulation showed that 84 circRNAs were upregulated and 30 were downregulated in patients with SLE compared with HCs. We then analyzed the intersection of these differentially expressed circRNAs in an SLE-stable cohort, an SLE-active cohort, and HCs. This enabled us to narrow down dysregulated circRNAs to 15 upregulated circRNAs. Only hsa_circ_0000479 was significantly upregulated in PBMCs of patients with SLE compared with HCs (P < 0.05). Furthermore, the diagnostic potential of hsa_circ_0000479 expression to distinguish SLE patients from HCs and RA patients was also significantly increased in the validation-phase and external-validation-phase cohorts (P < 0.05). When distinguishing SLE patients from HCs, the diagnostic specificities of hsa_circ_0000479 were 0.619 and 1.0 in two validation cohorts, respectively (AUCs = 0.731 and 0.730, respectively). It was also significantly increased in either stable SLE patients or active SLE patients compared with HCs in these two cohorts (P < 0.05). We also used bioinformatics analysis to show that hsa_circ_0000479 regulates SLE progression by modulating metabolic pathways and the Wnt signaling pathway. Western blotting revealed that the expression of Wnt-16 protein was significantly decreased in SLE. Conclusion: Our results suggest that hsa_circ_0000479 has potential as a novel biomarker for the diagnosis of SLE.
30353541 Automated feature selection of predictors in electronic medical records data. 2019 Mar The use of Electronic Health Records (EHR) for translational research can be challenging due to difficulty in extracting accurate disease phenotype data. Historically, EHR algorithms for annotating phenotypes have been either rule-based or trained with billing codes and gold standard labels curated via labor intensive medical chart review. These simplistic algorithms tend to have unpredictable portability across institutions and low accuracy for many disease phenotypes due to imprecise billing codes. Recently, more sophisticated machine learning algorithms have been developed to improve the robustness and accuracy of EHR phenotyping algorithms. These algorithms are typically trained via supervised learning, relating gold standard labels to a wide range of candidate features including billing codes, procedure codes, medication prescriptions and relevant clinical concepts extracted from narrative notes via Natural Language Processing (NLP). However, due to the time intensiveness of gold standard labeling, the size of the training set is often insufficient to build a generalizable algorithm with the large number of candidate features extracted from EHR. To reduce the number of candidate predictors and in turn improve model performance, we present an automated feature selection method based entirely on unlabeled observations. The proposed method generates a comprehensive surrogate for the underlying phenotype with an unsupervised clustering of disease status based on several highly predictive features such as diagnosis codes and mentions of the disease in text fields available in the entire set of EHR data. A sparse regression model is then built with the estimated outcomes and remaining covariates to identify those features most informative of the phenotype of interest. Relying on the results of Li and Duan (1989), we demonstrate that variable selection for the underlying phenotype model can be achieved by fitting the surrogate-based model. We explore the performance of our methods in numerical simulations and present the results of a prediction model for Rheumatoid Arthritis (RA) built on a large EHR data mart from the Partners Health System consisting of billing codes and NLP terms. Empirical results suggest that our procedure reduces the number of gold-standard labels necessary for phenotyping thereby harnessing the automated power of EHR data and improving efficiency.
30295425 Early Targeted Combination Treatment With Conventional Synthetic Disease-Modifying Antirhe 2019 Nov OBJECTIVE: The short-term outcomes of remission-targeted treatments of rheumatoid arthritis (RA) are well-established, but the long-term success of such strategies is speculative, as is the role of early add-on biologics. We assessed the 10-year outcomes of patients with early RA treated with initial remission-targeted triple combination of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 7.5-mg prednisolone, and additional infliximab (IFX) or placebo infusions. METHODS: Ninety-nine patients with early, DMARD-naive RA were treated with a triple combination of csDMARDs and prednisolone and randomized to double-blind receipt of infusions of either IFX (the Finnish Rheumatoid Arthritis Combination Therapy Trial [FIN-RACo] + IFX) or placebo (FIN-RACo + placebo) during the first 6 months. After 2 years, the treatment strategies became unrestricted, but the treatment goal was strict remission in the TNF-Blocking Therapy in Combination With Disease-Modifying Antirheumatic Drugs in Early Rheumatoid Arthritis (NEO-RACo) study. At 10 years, the clinical and radiographic outcomes and the drug treatments used between 5 and 10 years were assessed. RESULTS: Ninety patients (91%) were followed after 2 years, 43 in the FIN-RACo + IFX and 47 in the FIN-RACo + placebo group. At 10 years, the respective proportions of patients in strict NEO-RACo remission and in Disease Activity Score using 28 joints remission in the FIN-RACo + IFX and FIN-RACo + placebo groups were 46% and 38% (P = 0.46) and 82% and 72% (P = 0.29), respectively. The mean total Sharp/van der Heijde score was 9.8 in the FIN-RACo + IFX and 7.3 in the FIN-RACo + placebo group (P = 0.34). During the 10-year follow-up, 26% of the FIN-RACo + IFX group and 30% of the FIN-RACo + placebo group had received biologics (P = 0.74). CONCLUSION: In early RA, excellent results can be maintained up until 10 years in most patients treated with initial combination csDMARDs and remission-targeted strategy, regardless of initial IFX/placebo infusions.
31751652 Traditional uses, phytochemistry, and pharmacology of Persicaria orientalis (L.) Spach - A 2020 Mar 1 ETHNOPHARMACOLOGICAL RELEVANCE: Persicaria orientalis (L.) Spach (internationally accepted and only valid name; synonym: Polygonum orientale L.; family: Polygonaceae), which is named Hongcao in China, is a Chinese herbal medicine that has a wide range of pharmacological effects including treatment to rheumatoid arthritis, coronary heart disease, hernia, carbuncle sore, enhance immunity, antimicrobial, osteogenic and dilated bronchiectasis. AIM OF THIS REVIEW: This review aims to provide systematically organized information on traditional uses of Persicaria orientalis (L.) Spach (P. orientalis) and to critically analyze evidences in phytotherapeutic, botanical, and pharmacological literatures that support its therapeutic potential in treatment to human diseases. Isolation of additional compounds and detailed pharmacological investigations are key areas to investigate. MATERIALS AND METHODS: Relevant information on P. orientalis was collected through published scientific materials (including PubMed, ScienceDirect, Wiley, ACS, CNKI, Scifinder, Springer, Taylor & Francis, Web of Science, Google Scholar, and Baidu Scholar) and other literature sources (e.g., Chinese Pharmacopoeia, 2015 edition, Chinese herbal classic books and PhD and MSc thesis, etc.). RESULTS: Traditional uses were compiled in this review, including classic prescriptions and historical applications. Approximately 70 compounds, mainly including flavonoids, phenolics, lignans, limonoids and steroids, have been isolated and identified from P. orientalis. Among them, flavonoids were main components. Crude extracts and pure compounds isolated from P. orientalis exhibited various pharmacological activities, such as protection against ischemia and hypoxia-induced myocardial cells and hypoxia/reoxygenation cardiomyocyte, increase the blood flow in myocardium, expanding bronchus, anti-inflammatory and analgesic, and antithrombotic effects and so on. CONCLUSIONS: P. orientalis is a valuable source with therapeutic potential on a wide range of diseases especially cardiovascular-system disorders. Though most traditional uses of P. orientalis are supported by in vitro/vivo pharmacological studies, however, there is still a lack of researches on active pharmacodynamic ingredients as well as in-depth and in-vivo mechanistic studies. Therefore, isolation and identification of more active compounds (especially flavonoids), their structure-activity relationship and studies on pharmacodynamic mechanisms by more elaborative in-vivo studies on P. orientalis may be focused on in order to confirm efficacy of reported therapeutic effects of P. orientalis and help explore it's therapeutic potentials. Furthermore, research designs of pharmacological studies based on traditional uses of anti-rheumatoid arthritis through cell lines and animal models should also be considered as key research topics.
30873942 Effectiveness and safety of anti-tumour necrosis factor therapy with certolizumab pegol ob 2019 Sep OBJECTIVES: To report the tolerability and effectiveness of certolizumab pegol (CZP) for the treatment of patients with active rheumatoid arthritis (RA) in a routine clinical practice setting. METHODS: FαsT (NCT01069419) was a non-interventional, observational 104-week (wk) study performed at 163 sites in Germany. RA patients were treated according to the treating physician's discretion. Clinical remission (DAS28-CRP<2.6) at wk 104 was the primary endpoint of the study. Remission data based on ESR (DAS28-ESR<2.6) were also assessed. Secondary endpoints included the effect of CZP treatment on pain, physical function and disease activity. Safety data were collected at all study visits. RESULTS: 1,117 patients were enrolled in the FαsT study (78% female, mean age: 55 years). Rapid responses were observed at wk 6 (18.7% and 12.9% patients in DAS28-CRP and DAS28-ESR remission, respectively) with improvements sustained over 2 years (20.0% and 13.9% patients achieved DAS28-CRP and DAS28-ESR remission, respectively at wk 104). Anti-TNF naïve patients exhibited greater improvements than anti-TNF experienced patients (mean DAS28-ESR change from baseline [CfB] -1.3, -1.5 and -1.7 for patients with ≥2, 1 and no anti-TNFs, respectively at wk104). Improvements were reported in all secondary endpoint measures. 1,111 patients were exposed to CZP for a total of 1,538 patient-years during the study. 2,000 treatment-emergent adverse events (TEAEs) were reported in 745 patients (67.1%); 9 (0.8%) experienced TEAEs with fatal outcome. CONCLUSIONS: CZP demonstrated efficacy and safety outcomes reflective of those observed in trial settings. Rapid reductions in disease activity and improvements in physical function were maintained up to wk 104.
29236318 Proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes following 2019 Mar OBJECTIVE: In this study, we investigated the effects of delivering small interfering RNA (siRNA) for efficient STAT3 downregulation on propagation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). METHODS: The FLSs were transfected with three different siRNAs. RNAi-1 was selected for further experiments. The expression levels of both STAT3 messenger RNA (mRNA) and its protein were detected by a real-time polymerase chain reaction and Western blot analysis. The proliferation of FLSs was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The apoptosis of FLSs was examined by flow cytometry. The expression levels of cell apoptotic-related genes Bcl-2, Bax, and caspase-3 were detected by Western blot analysis. RESULTS: RNAi-1 was selected as the RNAi group for its lowest expression levels of STAT3 mRNA. In RNAi group, the proliferation of synoviocytes was much lower and the apoptosis rate was significantly higher. FLSs of RNAi-1 group showed significantly lower expression level of apoptotic-inhibiting gene Bcl-2 and significantly higher expression levels of proapoptotic gene Bax and apoptotic protease caspase-3. CONCLUSION: Transfection with targeted STAT3 recombinant plasmids effectively inhibited the expression of STAT3 mRNA and its protein in RA-FLSs. RNAi-mediated silencing of STAT3 reduced the proliferation and promoted the apoptosis of FLSs.
30299246 Implication of CXCL5 (epithelial neutrophil-activating peptide 78) in the development of i 2019 May OBJECTIVES: The chemokine molecule CXCL5 (C-X-C motif chemokine ligand 5, also known as epithelial neutrophil activating peptide 78 -ENA78-) constitutes a link between obesity, inflammation and insulin resistance (IR) in the general population. CXCL5 has also been found to play a role in rheumatoid arthritis (RA) pathogenesis. Since chronic inflammation promotes IR and impairs pancreatic beta cell function in RA patients, we assessed the role of CXCL5 in the development of IR in RA. METHODS: Cross-sectional study that encompassed 141 non-diabetic patients with RA. IR assessed by homeostatic model assessment (HOMA2), insulin and C-peptide serum levels and lipid profile, and CXCL5 serum levels were studied. Regression analysis was performed to evaluate how CXCL5 was related to IR, disease activity, and disease characteristics in RA patients. RESULTS: HOMA2-IR indexes showed high values for both IR and beta cell production (%B), and low insulin sensitivity (%S) in patients with RA. C reactive protein (beta coef. 0.2 [95%CI -1.5-1.9], p=0.80) and disease activity through DAS28 (beta coef. 13 [95%CI -14-41], p=0.34) revealed no relation with CXCL5. Other disease characteristics, such as disease duration, serological status, or use of methotrexate or anti-TNF alpha therapies, were not associated with CXCL5 serum levels. While glucocorticoids were related to insulin, C-peptide serum levels, and HOMA2-IR and HOMA2-%B-C peptide, the use of prednisone was not associated with CXCL5 serum levels. Insulin and C peptide serum levels and IR indexes showed strong correlations among each other, but not with CXCL5 (insulin r2=-0.034, p=0.69; C peptide r2=-0.050, p=0.56). CONCLUSIONS: CXCL5 is not related to IR in RA patients. Therefore, the mechanisms leading to IR in patients with RA may be different from those in the general population.
30713318 Endobronchial Manifestation of Methotrexate-induced Lymphoproliferative Disorder. 2019 Jun 1 Lymphoproliferative disorders can occur in patients with autoimmune disorders who undergo long-term methotrexate therapy (MTX-LPD). Although the manifestations of MTX-LPD are diverse, little attention is paid to endobronchial involvement. We herein describe two patients with MTX-LPD who presented with parenchymal pulmonary tumors and endobronchial involvement of LPD; one had lymphomatoid gramulomatosis and the other LPD. The patients had no tumors adjacent to the endobronchial lesions. The endobronchial findings included multiple protruded mucosal lesions covered with white material, which was pathologically consistent with LPD. Recognition of the findings may help in making an earlier diagnosis of MTX-LPD in appropriate settings.
31155286 Geographic Variation and Bias in the Polygenic Scores of Complex Diseases and Traits in Fi 2019 Jun 6 Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.
30421069 Subcutaneous tocilizumab alone or with a csDMARD in rheumatoid arthritis patients: subanal 2019 Mar To assess, in a setting close to real life, the efficacy and safety of weekly subcutaneous tocilizumab (TCZ-SC) 162 mg, alone or with a conventional synthetic DMARD (csDMARD), in moderate-to-severe RA patients with inadequate response to DMARDs or anti-TNFα drugs. This national, multicenter, open-label, phase IIIb trial is part of an umbrella study (TOZURA). Patients were treated for 52 weeks followed by 8 weeks drug-free to evaluate immunogenicity. The primary end point was the Clinical Disease Activity Index (CDAI) change from baseline at weeks 2 and 24. Other efficacy parameters, including sleep quality, and the safety and immunogenicity were also assessed up to week 52. Of 288 patients enrolled in 43 Italian centers, 78.8% received TCZ-SC (86.8% females; mean age 54.7 ± 12.1 years; mean disease duration 7.8 ± 7.5 years; DMARD-IRs 94.7%). Of these, 78.0% completed the 52-week period and 52.0% received concomitant methotrexate. TCZ-SC yielded a significant reduction in median CDAI from baseline already at week 2, which progressed up to week 24 and remained stable thereafter (P < 0.0001 at each time point). A significant, rapid, and sustained improvement of the other efficacy variables was also observed. Patients were deemed as ready for home administration after a median of 2.0 (range 1-8) administrations, with a rate (since the last visit) of 80.6% and 95.5% at weeks 2 and 52, respectively. TCZ-SC displayed low immunogenicity and no unexpected toxicities. TCZ-SC, alone or with a csDMARD, yielded rapid and sustained efficacy in DMARD/anti-TNFα-IR RA patients, with acceptable toxicity. Home administration seems feasible.
31179526 Association between seropositivity and discontinuation of tumor necrosis factor inhibitors 2019 Oct INTRODUCTION/OBJECTIVES: Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients. METHOD: This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons. RESULTS: Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)]. CONCLUSIONS: Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.
31487265 PD-L1- and calcitriol-dependent liposomal antigen-specific regulation of systemic inflamma 2019 Sep 19 Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.
31523049 Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Da 2020 Jun 1 OBJECTIVE: Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T. METHODS: Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model). RESULTS: A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model. CONCLUSION: Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].
31154413 Longterm Drug Survival of Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Art 2020 Apr OBJECTIVE: To evaluate longterm drug survival (proportion of patients still receiving treatment) and discontinuation of etanercept (ETN), infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GOL) using observational data from patients with rheumatoid arthritis (RA). METHODS: Following a systematic literature review, drug survival at 12 and 12-24 months of followup was estimated by summing proportions of patients continuing treatment and dividing by number of studies. Drug survival at ≥ 36 months of followup was estimated through Metaprop. RESULTS: There were 170 publications included. In the first-line setting, drug survival at 12 months with ETN, IFX, or ADA was 71%, 69%, and 70%, respectively, while at 12-24 months the corresponding rates were 63%, 57%, and 59%. In the second-line setting, drug survival at 12 months with ETN, IFX, or ADA was 61%, 69%, and 55%, respectively, while at 12-24 months the corresponding rates were 53%, 39%, and 43%. Drug survival at ≥ 36 months with ETN, IFX, or ADA in the first-line setting was 59% (95% CI 46-72%), 49% (95% CI 43-54%), and 51% (95% CI 41-60%), respectively, while in the second-line setting the corresponding rates were 56% (95% CI 52-61%), 48% (95% CI 40-55%), and 41% (95% CI 36-47%). Discontinuation of ETN, IFX, and ADA at 36 months of followup was 38-48%, 42-62%, and 38-59%, respectively. Data on CZP and GOL were scarce. CONCLUSION: After > 12 months of followup, more patients with RA receiving ETN remain on treatment compared with other tumor necrosis factor inhibitors.
31038287 HLA Alleles Associated With Risk of Ankylosing Spondylitis and Rheumatoid Arthritis Influe 2019 Oct OBJECTIVE: HLA alleles affect susceptibility to more than 100 diseases, but the mechanisms that account for these genotype-disease associations are largely unknown. HLA alleles strongly influence predisposition to ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Both AS and RA patients have discrete intestinal and fecal microbiome signatures. Whether these changes are the cause or consequence of the diseases themselves is unclear. To distinguish these possibilities, we examined the effect of HLA-B27 and HLA-DRB1 RA risk alleles on the composition of the intestinal microbiome in healthy individuals. METHODS: Five hundred sixty-eight stool and biopsy samples from 6 intestinal sites were collected from 107 healthy unrelated subjects, and stool samples were collected from 696 twin pairs from the TwinsUK cohort. Microbiome profiling was performed using sequencing of the 16S ribosomal RNA bacterial marker gene. All subjects were genotyped using the Illumina CoreExome SNP microarray, and HLA genotypes were imputed from these data. RESULTS: Associations were observed between the overall microbial composition and both the HLA-B27 genotype and the HLA-DRB1 RA risk allele (P = 0.0002 and P = 0.00001, respectively). These associations were replicated using the stool samples from the TwinsUK cohort (P = 0.023 and P = 0.033, respectively). CONCLUSION: This study shows that the changes in intestinal microbiome composition seen in AS and RA are at least partially due to effects of HLA-B27 and HLA-DRB1 on the gut microbiome. These findings support the hypothesis that HLA alleles operate to cause or increase the risk of these diseases through interaction with the intestinal microbiome and suggest that therapies targeting the microbiome may be effective in preventing or treating these diseases.
30718447 Selenium Nanoparticles Dispersed in Phytochemical Exert Anti-Inflammatory Activity by Modu 2019 Feb 5 BACKGROUND Literature shows that serum selenium concentration is low in rheumatoid arthritis (RA) patients. Biochemical properties of nanoparticles (NPs) are depend in its medium dispersed. Biochemical properties could effectively alter the therapeutic potential of NPs. Phytochemicals could serve as suitable medium for dispersion of NPs. P-Coumaric acid (CA) known to have anti-inflammatory activity. MATERIAL AND METHODS In the present experiment, we investigated the anti-inflammatory effect of SeNPs dispersed in 1% CA against Complete Freund's adjuvant induced RA. Celecoxib was used as a reference drug. RESULTS Selenium NPs (SeNPs) size is maintained in 1% CA solution. We observed that supplementation with 500 μg/Kg body weight (b.w.) eNPs significantly restored the levels of thiobarbituric acid reactive substances, COX-2 activity, different antioxidant enzyme activities, and inflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1) in RA rats. The mRNA expression of antioxidant enzymes such as MnSOD, Cu/ZnSOD, ECSOD, CAT, and GPx1 was found to be downregulated, whereas COX-2 was upregulated in RA rats; however, the mRNA expression of CAT, GPx1, and COX-2 reverted back to near normal levels in SeNPs-treated animals. CONCLUSIONS The therapeutic potential of SeNPs was confirmed through histological observation of angle joints in different experimental animals. Our results collectively suggest that SeNPs dispersed in CA can be an effective therapeutic agent for inflammatory disorders like acute gouty arthritis.
31878990 [Increased percentage and defective inhibitory function of CD4(+)CD25(-)FOXP3(+) T cells i 2019 Nov Objective To investigate the levels and function status of CD4(+)CD25(-)FOXP3(+) T cells (CD25(-) Tregs) in the peripheral blood and synovial fluid from rheumatoid arthritis (RA) patients, and their relationships with disease activity. Methods The study enrolled 60 RA patients and 69 healthy controls (HCs). Flow cytometry was used to analyze the percentage and phenotype of CD25(-) Tregs, and the results were analyzed by Mann-Whitey U test and Spearman correlation. Results The percentage of circulating CD25(-) Tregs in CD4(+) cells was compared between RA patients and HCs. However, the percentage of CD25(-) Tregs in RA synovial fluid was significantly higher than that in the peripheral blood of RA patients and HCs. When RA patients were grouped according to their disease activity or clinical indicators, such as rheumatoid factor (RF), anti-cyclic citrullinated peptides (CCP) antibody, anti-mutated citrullinated vimentin (MCV) antibody and anti-keratin antibody (AKA), circulating CD25(-) Tregs percentage was not significantly different among the groups, and had no correlation with the levels of erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). The expression of CD39 in CD25(-) Tregs in RA synovial fluid was significantly lower than that in the peripheral blood of HCs. And CD73 and TGF-β1 expression in CD25(-) Tregs in RA synovial fluid were significantly lower than those in the peripheral blood of both RA patients and HCs. However, there was no significant difference in the expression of CTLA4 and IL-10 in CD25(-) Tregs among the groups. Conclusion The percentage of CD25(-) Tregs increases in RA synovial fluid. And the expression of CD39, CD73 and TGF-β1 decrease in CD25(-) Tregs, suggesting that its inhibitory function may be defective, resulting in local inflammation not being effectively controlled.
30552173 Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of p 2019 Mar OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis affecting up to 30% of patients with psoriasis (Ps). To date, most of the known risk loci for PsA are shared with Ps, and identifying disease-specific variation has proven very challenging. The objective of the present study was to identify genetic variation specific for PsA. METHODS: We performed a genome-wide association study in a cohort of 835 patients with PsA and 1558 controls from Spain. Genetic association was tested at the single marker level and at the pathway level. Meta-analysis was performed with a case-control cohort of 2847 individuals from North America. To confirm the specificity of the genetic associations with PsA, we tested the associated variation using a purely cutaneous psoriasis cohort (PsC, n=614) and a rheumatoid arthritis cohort (RA, n=1191). Using network and drug-repurposing analyses, we further investigated the potential of the PsA-specific associations to guide the development of new drugs in PsA. RESULTS: We identified a new PsA risk single-nucleotide polymorphism at B3GNT2 locus (p=1.10e-08). At the pathway level, we found 14 genetic pathways significantly associated with PsA (p(FDR)<0.05). From these, the glycosaminoglycan (GAG) metabolism pathway was confirmed to be disease-specific after comparing the PsA cohort with the cohorts of patients with PsC and RA. Finally, we identified candidate drug targets in the GAG metabolism pathway as well as new PsA indications for approved drugs. CONCLUSION: These findings provide insights into the biological mechanisms that are specific for PsA and could contribute to develop more effective therapies.
30661400 Chemical composition of Erycibe schmidtii and antiproliferative activity of scopoletin on 2020 Sep Immature dendritic cells (iDCs) play very important roles in the pathological process of rheumatoid arthritis (RA). Therefore, it is urgent to search for natural products with antiproliferative activity on iDCs for anti-RA drug discovery. Erycibe schmidtii, a traditional Chinese medicine, has been used to treat RA in China. Its bioactive ingredients on RA are still unclear. In this study, twenty compounds including a new caffeoylquinic acid derivative, 3-O-caffeoyl-4-O-syringoylquinic acid methyl ester (16), were isolated from E. schmidtii. Their structures were elucidated by NMR and mass spectroscopic analysis, and comparison with literature data. Seventeen compounds were obtained from this plant for the first time, and ten were first found from the genus Erycibe. Scopoletin (1, 5.0 μM) functionally reduced proliferation level of bone marrow immature dendritic cells (BM-iDCs) more than 50%, relative to vehicle. However, scopoletin (1) exhibited no effect on the phagocytosis or survival of BM-iDCs in vitro.