Patterns of Anti-Inflammatory and Immunomodulating Drug Usage and Microvascular Endothelial Function in Rheumatoid Arthritis.
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SUBMITTER: Mangoni AA
PROVIDER: S-EPMC8326370 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objectives: This study was undertaken to understand the mechanistic basis of response to anti-TNF therapies and determine if transcriptomic changes in the synovium are reflected in peripheral protein markers. Methods: Synovial tissue from 46 RA patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among EULAR good, moderate and non-responders. Serum proteins encoded by synovial genes differentially expressed between EULAR response groups were measured in the same patients. Results: The gene signatures were able to predict good responder patients and pathway analysis identified elevations in immune pathways including chemokine signaling, Th1 and Th2 cell differentiation, and Toll-like receptor signaling uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid and fibroblast cell populations were elevated in good responders relative to non-responders, consistent with the increased inflammatory pathways. Cell signatures which decreased following anti-TNF treatment were predominately associated with lymphocytes and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment and only in good responders, several peripheral inflammatory proteins decreased consistent with corresponding synovial gene changes. Conclusions: Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF may assist in development of predictive markers of patient response and earlier treatment options.
2022-06-06 | GSE198520 | GEO
Project description:ObjectivesTo define the prevalence and determinants of peripheral microvascular endothelial dysfunction (ED) in a large series of rheumatoid arthritis (RA) patients free of previous cardiovascular events.Materials and methodsData from 874 RA patients enrolled in the EDRA study (Endothelial Dysfunction Evaluation for Coronary Heart Disease Risk Estimation in Rheumatoid Arthritis-ClinicalTrials.gov: NCT02341066) were analyzed. Log-transformed reactive hyperemia index (Ln-RHI) was evaluated by peripheral arterial tonometry (PAT) using the EndoPAT2000 device: values of Ln-RHI < 0.51 were considered indicative of peripheral ED.ResultsPeripheral microvascular ED was documented in one-third of RA patients (33.5%); in multiple logistic regression analysis, ACPA negativity and higher triglycerides concentrations were independently associated with the presence of peripheral ED [OR (95% CI) = 1.708 (1.218-2.396), p < 0.01 and OR (95% CI) = 1.005 (1.002-1.009), p < 0.01, respectively]. Multiple regression analysis showed a positive correlation between Ln-RHI values and systolic blood pressure and HDL cholesterol levels; furthermore, higher values of Ln-RHI were associated with ACPA positivity, while smoking habit was associated with lower Ln-RHI values.ConclusionsThis study demonstrates for the first time a high prevalence of peripheral microvascular ED in patients with RA free of previous cardiovascular events that appear to be only partially driven by traditional cardiovascular risk factors. The association between ACPA negativity and ED warrants further exploration.
| S-EPMC5816852 | biostudies-literature
Project description:BackgroundFURIN belongs to the proprotein convertase family that processes proproteins and is involved in many diseases. However, the role of FURIN in rheumatoid arthritis (RA) remains unknown. In this study, we investigated the association between circulating FURIN and disease activity in patients with RA and the effect of FURIN in THP-1-derived macrophages.MethodsA total of 108 RA patients and 39 healthy controls participants were included in this study. RA patients were divided into four disease activity groups determined by the Disease Activity Score of 28 joints (DAS28). FURIN expression in peripheral blood mononuclear cells (PBMCs) and serum was detected by using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Western blotting and qRT-PCR were used to detect cytokines level after interfering FURIN expressed in THP-1-derived macrophages.ResultsBoth FURIN mRNA and protein levels were significantly higher in RA patients than in healthy controls participants (P < .001). No significant difference in FURIN expression was observed among the four RA groups (P > .05). Spearman correlation revealed that FURIN positively correlated with transforming growth factor-β1(TGF-β1), rheumatoid factor (RF), and anti-cyclic citrullinated peptide (anti-CCP). Moreover, the inhibition of FURIN in THP-1-derived macrophages promoted the caspase-1 and IL-1β expression (P < .05).ConclusionFURIN levels were significantly increased in the peripheral blood of RA patients and were not associated with disease activity. The inhibition of FURIN in THP-1-derived macrophages with elevated IL-1β levels shows that FURIN may have an anti-inflammatory effect.
| S-EPMC7755791 | biostudies-literature
Project description:ObjectivesRheumatoid arthritis (RA) is an autoimmune disease, associated with chronic inflammation of synoviocytes. Tumor necrosis factor α (TNF-α) plays a crucial role in the pathogenesis of RA through pro-inflammatory cytokines. Nicotine, an alkaloid used as herbal medicine, often worked as an anti-inflammatory agent. In the present study, we tried to uncover the anti-inflammatory impact of nicotine against RA.Materials and methodsNicotine was isolated from Brassica oleracea, purified by high profile/phase liquid chromatography (HPLC). In-silico docking was carried out using bioinformatics tools SwissADME (absorption, distribution, metabolism and excretion), PASS, and Drug-induced Gene Expression Profile (DIGEP)-Pred to determine drug likeliness of nicotine. The in-vitro study was performed in TNFα-induced SW982 synoviocytes by qPCR. mRNA expression of pro-inflammatory cytokines (TNF, IL6, IL1β) and proteins (TRAF2, P50, P65) were analyzed followed by validation of P65 (RELA), pP65, IkBα by Western blot analysis.ResultsNicotine compound was extracted from Brassica oleracea and purified by HPLC method (Rt values at 2.67 min). The physicochemical, pharmacokinetic properties and drug-likeliness of nicotine were studied by in-silico analysis. In-vitro studies revealed that nicotine lowers the expression of inflammatory cytokines (TNF, IL6, IL1β) and proteins (TNF receptor-associated factor 2 (TRAF2), P50, P65) at 1 µg/ml in TNFα-induced SW982 cells.ConclusionNicotine from natural sources (Brassica oleracea) has been found to be an effective anti- inflammatory compound at a low dosage; thus, identifying the role of nicotine present in the natural sources as a therapeutic option for RA, may be recommended as remedial drug instead of synthetic drug.
| S-EPMC9069442 | biostudies-literature
Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab) reference_design
2010-06-24 | E-GEOD-19821 | biostudies-arrayexpress
Project description:The endothelium is the inner layer of all blood vessels and it regulates hemostasis. It also plays an active role in the regulation of the systemic inflammatory response. Systemic inflammatory disease often results in alterations in vascular endothelium barrier function, increased permeability, excessive leukocyte trafficking, and reactive oxygen species production, leading to organ damage. Therapeutics targeting endothelium inflammation are urgently needed, but strong concerns regarding the level of phenotypic heterogeneity of microvascular endothelial cells between different organs and species have been expressed. Microvascular endothelial cell heterogeneity in different organs and organ-specific variations in endothelial cell structure and function are regulated by intrinsic signals that are differentially expressed across organs and species; a result of this is that neutrophil recruitment to discrete organs may be regulated differently. In this review, we will discuss the morphological and functional variations in differently originated microvascular endothelia and discuss how these variances affect systemic function in response to inflammation. We will review emerging in vivo and in vitro models and techniques, including microphysiological devices, proteomics, and RNA sequencing used to study the cellular and molecular heterogeneity of endothelia from different organs. A better understanding of microvascular endothelial cell heterogeneity will provide a roadmap for developing novel therapeutics to target the endothelium.
| S-EPMC8346165 | biostudies-literature
Project description:Background:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved treatment of RA, patients with RA often inquire about dietary interventions to improve RA symptoms, as they perceive rapid changes in their symptoms after consumption of certain foods. There is evidence that some ingredients have pro- or anti-inflammatory effects. In addition, recent literature has shown a link between diet and microbiome changes. Both diet and the gut microbiome are linked to circulating metabolites that may modulate inflammation. However, evidence of the effects of an anti-inflammatory and probiotic-rich diet in patients with RA is scarce. There is also a need for biological data to support its anti-inflammatory effects. Methods:The main goal of this study is to delineate the design process for a diet tailored to our RA population. To achieve this goal, we collected information on diet, supplements, cooking methods, and intake of different ingredients for each patient. Different groups were interviewed, and their feedback was assessed to design a diet that incorporates suggested anti-inflammatory ingredients in a manner that was easy for patients to adopt based on their lifestyles and backgrounds. Results:We designed a diet that includes a high intake of potential anti-inflammatory ingredients. Feedback from highly motivated patients was critical in constructing an anti-inflammatory diet (ITIS diet) with elevated adherence. Conclusion:In order to tailor our diet, we surveyed our patients on several different parameters. We obtained important feedback on how feasible our ITIS diet is for RA patients. Using this feedback, we made minor improvements and finalized the design of the ITIS diet. This diet is being used in an on-going pilot study to determine their anti-inflammatory effect in pain and joint swelling in RA patients. Trial registration:Not applicable.
| S-EPMC6997513 | biostudies-literature
Project description:In 15 patients with rheumatoid arthritis the baseline expression (t=0) of type I IFN-regulated genes was determined in peripheral blood cells (PAXgene) using cDNA-microarrays and compared to levels one month after (t=1) anti-TNF treatment (infliximab). Therefore, we used 43K cDNA microarrays from the Stanford Functional Genomics Facility (http://microarray.org/sfgf/) printed on aminosilane-coated slides containing ~20.000 unique genes. Only one batch of arrays was used for all experiments. First DNA spots were UV-cross linked to the slide using 150-300 mJoules. Sample preparation and microarray hybridization were performed as described previously (1,2). Data storage and filtering was performed using the Stanford Microarray Database (http://genome-www5.stanford.edu//) as described previously. 1. van der Pouw Kraan TC, Wijbrandts CA, van Baarsen LG, Voskuyl AE, Rustenburg F, Baggen JM et al.: Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann Rheum Dis 2007, 66: 1008-1014. 2. van der Pouw Kraan TC, van Baarsen LG, Rustenburg F, Baltus B, Fero M, Verweij CL: Gene expression profiling in rheumatology. Methods Mol Med 2007, 136: 305-327. Abbreviations: - Bnrs are the different patients analyzed - PAX or Paxgene indicates the total RNA was isolated from peripheral blood obtained in PAXgene tubes - CRS: common reference sample: We made a common reference that consisted of a mixture of mRNAs isolated from 11 different cell lines (Perou CM, Jeffrey SS, van de RM et al. Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc Natl Acad Sci U S A. 1999; 96:9212-9217) supplemented with RNA from rheumatoid synovial tissue, fibroblasts, and activated peripheral blood mononuclear cells (PBMCs). - PMT: photomultiplier tube: the sensitivity/intensity of the scanner can be adjusted to prevent spot saturation. Compound Based Treatment: anti-TNF (infliximab)
2010-01-28 | GSE19821 | GEO
Project description:BACKGROUND:Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.5-1.0% of the population, and where many patients in spite of modern pharmacological treatment fail to reach remission. This affects physical as well as mental wellbeing and leads to severely reduced quality of life and reduced work capacity, thus yielding high individual as well as societal costs. As a complement to modern pharmacological treatment, lifestyle intervention should be evaluated as a treatment option. Scientific evidence exists for anti-inflammatory effects by single foods on RA, but no study exists where these foods have been combined to obtain maximum effect and thus offer a substantial improvement in patient life quality. The main goal of the randomized cross-over trial ADIRA (Anti-inflammatory Diet In Rheumatoid Arthritis) is to test the hypothesis that an anti-inflammatory diet intervention, compared to a regular diet, will decrease disease activity and improve quality of life in patients with stable established RA. METHODS:In total, 50 RA patients with moderate disease activity are randomized to receive initially either a portfolio diet based on several food items with suggested anti-inflammatory effects or a control diet during 2?×?10 weeks with 3 months wash-out between diets. Food bags are delivered weekly by a home food delivery chain and referred to as the fiber bag and the protein bag, respectively, to partially blind participants. Both groups continue with regular pharmacological treatment. Known food biomarkers will be analyzed to measure intervention compliance. Impact on disease severity (measured by DAS28, a composite score which predicts disability and progression of RA), risk markers for cardiovascular disease and quality of life are evaluated after each diet regimen. Metabolomics will be used to evaluate the potential to predict responders to dietary treatment. A health economic evaluation is also included. DISCUSSION:The nutritional status of patients with RA often is poor and many ask their physician for diet advice. No evidence-based dietary guidelines for patients with RA exist because of the paucity of well-conducted sufficiently large diet intervention trials. ADIRA is an efficacy study and will provide evidence as to whether dietary treatment of RA can reduce disease activity and improve quality of life as well as reduce individual and societal costs. TRIAL REGISTRATION:ClinicalTrials.gov Registration Number: NCT02941055 .
| S-EPMC5909253 | biostudies-literature
Project description:IntroductionSome patients with rheumatoid arthritis (RA) using tumor necrosis factor inhibitors (TNFi) experience inefficacy or lack of tolerability and hence switch to another TNFi (cycling) or to a therapy with another mode of action (switching). This study examined patient characteristics, prescribing patterns and treatment practice for RA in the United States.MethodsData were from the Adelphi Disease Specific Programme (Q2-Q3 2016). Rheumatologists completed a survey and patient record forms for adult patients with RA who had received ≥ 1 targeted therapy. Patients were grouped by class of first-used targeted therapy, and monotherapy vs. combination therapy. TNFi patients who received ≥ 1 targeted therapy were classified as cyclers or switchers. Univariate analyses compared patient characteristics and physician factors across the analysis groups.ResultsOverall, 631 patients received ≥ 1 targeted therapy; 535 were prescribed a TNFi as first targeted therapy, 53 a nonTNFi biologic disease-modifying antirheumatic drug (bDMARD), and 43 tofacitinib. Of 577 patients with known conventional synthetic (cs) DMARD status, 18.7% were prescribed monotherapy and 81.3% combination therapy. Combination therapy patients received significantly more concomitant medications prior to initiation of first targeted therapy than monotherapy patients (P < 0.05). The top reason for physicians to prescribe first use targeted therapy was strong overall efficacy (79.9%). Of 163 patients who progressed to second targeted therapy, 60.7% were cyclers. A lower proportion of cyclers persisted on their first use targeted therapy versus switchers (P = 0.03). The main reason physicians gave for switching patients at this stage was worsening condition (46.6%).ConclusionsMost patients were prescribed a TNFi as their first targeted therapy; over half then cycled to another TNFi. This suggests other factors may influence second use targeted treatment choice and highlights the need for greater understanding of outcomes associated with subsequent treatment choices and potential benefits of switching.
| S-EPMC7211222 | biostudies-literature