Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 33593544 | Dendrobium huoshanense stem polysaccharide ameliorates rheumatoid arthritis in mice via in | 2021 Apr 15 | The present study explored the beneficial effect of Dendrobium huoshanense stem polysaccharide (cDHPS) after oral administration on rheumatoid arthritis (RA) using type Ⅱ collagen-induced arthritis (CIA) mouse model. It was found that cDHPS effectively alleviated joint swelling, synovial hyperplasia, pannus formation, cartilage erosion and bone destruction in CIA mice. Concurrently, cDHPS remodeled the balance of Th17 and regulatory T cells, reduced the secretion of pro-inflammatory mediators related to fibroblast-like synoviocyte activation, angiogenesis, articular cartilage degradation and osteoclast differentiation, inhibited HIF-1α expression and promoted anti-inflammatory mediator release in the joint tissues and serum of CIA mice. Western blot of joint tissues showed that cDHPS significantly inhibited the phosphorylation of IκB, p65, JNK, p38, ERK1/2, AKT, PI3K, JAK1 and STAT3 in CIA mice. These results suggest that cDHPS possesses the potential of ameliorating RA and its anti-RA effect may be attributed to the inhibition of inflammatory signaling pathways. | |
| 33989211 | Chrysiasis: Gold Aggregates Around a Nevus and Osteoma Cutis. | 2021 Aug 1 | Parenteral gold has historically been used to treat several conditions, including rheumatoid arthritis. Gold administration leads to a variety of cutaneous reactions, including chrysiasis, which is a permanent blue-grey hyperpigmentation of the skin due to dermal gold deposition. In this report, we describe the case of a patient who received parenteral gold injections 22 years before the onset of her chrysiasis for the treatment of rheumatoid arthritis. Biopsy of the macules showed dermal gold deposits aggregating around a melanocytic nevus, as well as around preexisting osteoma cutis. To the authors' knowledge, this is the first report in the literature describing a case of chrysiasis with gold deposits concentrated around a melanocytic nevus and an area of osteoma cutis. | |
| 34296202 | Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be ta | 2021 Jul 9 | BACKGROUND: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. METHODS: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R(-/-) or claudin-8 (-/-) mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. FINDINGS: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ) (+) and decreases in IL-10 (+) intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8 (-/-) mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. CONCLUSIONS: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. FUNDING: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1). | |
| 34463932 | Telitacicept: First Approval. | 2021 Sep | Telitacicept (Tai'ai(®)) is fusion protein comprising a recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor fused to the fragment crystallizable (Fc) domain of human immunoglobulin G (IgG). Telitacicept is being developed by Yantai Rongchang Pharmaceutical through its subsidiary RemeGen for the treatment of B cell-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). Telitacicept binds to and neutralizes the activity of two cell-signalling molecules, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), thereby suppressing the development and survival of plasma cells and mature B cells. In March 2021, telitacicept received its first approval in China for the treatment of patients with active SLE. Clinical studies of telitacicept in several other indications, including IgA nephropathy, MS, myasthenia gravis, neuromyelitis optica spectrum disorders, RA and Sjögren's syndrome are underway in China. This article summarizes the milestones in the development of telitacicept leading to this first approval for SLE. | |
| 33538122 | Expansion of Alternative Autoantibodies Does Not Follow the Evolution of Anti-Citrullinate | 2021 May | OBJECTIVE: Co-occurrence of autoantibodies specific for ≥1 autoimmune disease is widely prevalent in rheumatoid arthritis (RA) patients. To understand the prevalence of polyautoimmunity in preclinical RA, we performed a comprehensive autoantibody assessment in a First Nations cohort of at-risk first-degree relatives (FDR) of RA patients, a subset of whom subsequently developed RA (progressors). METHODS: Venous blood was collected from all study participants (n = 50 RA patients and 64 FDR) at scheduled visits, and serum was stored at -20°C. High-sensitivity C-reactive protein level, anti-citrullinated protein antibody (ACPA) status, and autoantibody status were determined using commercially available enzyme-linked immunosorbent assay kits. Rheumatoid factor (RF) was detected by nephelometry. Antinuclear autoantibodies (ANA) were identified using Hep-2 indirect immunofluorescence assay (IFA) and classified according to international consensus nomenclature as various anti-cell (AC) patterns. RESULTS: Of our study cohort, 78.9% had positive ANA reactivity (≥1:80), which was either a homogenous, fine-speckled (AC-1 and AC-4) or mixed IFA pattern. Importantly, the AC-4 and mixed ANA patterns were also observed in progressors at the time of disease onset. While all of the RA patients showed a high prevalence of arthritis-associated autoantibodies, they also had a high prevalence of extractable nuclear antigen-positive autoantibodies to other autoantigens. In FDR, we did not observe any increase in serum autoreactivity to nonarthritis autoantigens, either cross-sectionally or in samples collected longitudinally from progressors prior to RA onset. CONCLUSION: While alternative autoimmunity and ANA positivity are widely prevalent in First Nations populations, including asymptomatic, seronegative FDR, expansion of alternative autoimmunity does not occur in parallel with ACPA expansion in FDR and is restricted to patients with established RA. | |
| 34088356 | Disease activity influences the reclassification of rheumatoid arthritis into very high ca | 2021 Jun 4 | BACKGROUND: Previous studies have shown that risk chart algorithms, such as the Systematic Coronary Risk Assessment (SCORE), often underestimate the actual cardiovascular (CV) risk of patients with rheumatoid arthritis (RA). In contrast, carotid ultrasound was found to be useful to identify RA patients at high CV. In the present study, we aimed to determine if specific disease features influence the CV risk reclassification of RA patients assessed by SCORE risk charts and carotid ultrasound. METHODS: 1279 RA patients without previous CV events, diabetes, or chronic kidney disease were studied. Disease characteristics including disease activity scores, CV comorbidity, SCORE calculation, and the presence of carotid plaque by carotid ultrasound were assessed. A multivariable regression analysis was performed to evaluate if the reclassification into very high CV risk category was independently associated with specific features of the disease including disease activity. Additionally, a prediction model for reclassification was constructed in RA patients. RESULTS: After carotid ultrasound assessments, 54% of the patients had carotid plaque and consequently fulfilled definition for very high CV risk. Disease activity was statistically significantly associated with reclassification after fully multivariable analysis. A predictive model containing the presence of dyslipidemia and hypertension, an age exceeding 54 years, and a DAS28-ESR score equal or higher than 2.6 yielded the highest discrimination for reclassification. CONCLUSION: Reclassification into very high CV risk after carotid ultrasound assessment occurs in more than the half of patients with RA. This reclassification can be independently explained by the activity of the disease. | |
| 35319631 | Clinical and laboratory features of patients with undifferentiated spondyloarthritis and a | 2021 Oct | BACKGROUND: The terms Spondyloarthritis and spondyloarthropathy (Spa) are used to define a group of diseases with related clinical characteristics and genetics. AIM: To report the clinical and demographic characteristics of ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (USpA) and to evaluate the frequency of cyclic citrullinated peptide antibody (anti-CCP) positivity. MATERIAL AND METHODS: Two hundred patients with USpA or AS, 100 control patients with a diagnosis of rheumatoid arthritis (RA) and 100 healthy volunteers were included. For each patient, their detailed medical histories, physical examination, whole blood counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-CCP, routine biochemical tests, and HLA-B27 test results were evaluated. ASDAS and BASDAI scores and morning stiffness were used to evaluate the disease activity. RESULTS: The presenting symptom of 73 (73%) patients in the AS group and 58 (58%) patients in the USpA group was pain in axial joints. A family history of Spa was positive in 32 patients from both groups (32%). A positive HLA-B27 was found in 55% of the AS group and 25% of the USpA group (p < 0.01 for the difference between groups). The frequency of positive HLA-B27 was significantly higher in individuals with a family history of SpA (p = 0.022). A positive Anti-CCP was found in 56% of the RA group, a significantly higher frequency compared with other groups (p < 0.001). The frequency of positive Anti-CCP in patients in AS (9%) and USpA (6%) was significantly higher than in healthy controls (p < 0.001). CONCLUSIONS: The frequency of anti-CCP positivity was higher in SpA patients than in healthy controls. | |
| 34845218 | Revealing the efficacy-toxicity relationship of Fuzi in treating rheumatoid arthritis by s | 2021 Nov 29 | In recent decades, herbal medicines have played more and more important roles in the healthcare system in the world because of the good efficacy. However, with the increasing use of herbal medicines, the toxicity induced by herbal medicines has become a global issue. Therefore, it is needed to investigate the mechanism behind the efficacy and toxicity of herbal medicines. In this study, using Aconiti Lateralis Radix Praeparata (Fuzi) as an example, we adopted a systems pharmacology approach to investigate the mechanism of Fuzi in treating rheumatoid arthritis and in inducing cardiac toxicity and neurotoxicity. The results showed that Fuzi has 25 bioactive compounds that act holistically on 61 targets and 27 pathways to treat rheumatoid arthritis, and modulation of inflammation state is one of the main mechanisms of Fuzi. In addition, the toxicity of Fuzi is linked to 32 compounds that act on 187 targets and 4 pathways, and the targets and pathways can directly modulate the flow of Na(+), Ca(2+), and K(+). We also found out that non-toxic compounds such as myristic acid can act on targets of toxic compounds and therefore may influence the toxicity. The results not only reveal the efficacy and toxicity mechanism of Fuzi, but also add new concept for understanding the toxicity of herbal medicines, i.e., the compounds that are not directly toxic may influence the toxicity as well. | |
| 34333356 | The regulation of macrophage polarization by hypoxia-PADI4 coordination in Rheumatoid arth | 2021 Oct | BACKGROUND: Hypoxia, a common feature of rheumatoid arthritis (RA), induces the over-expression of peptidyl arginine deiminase 4 (PADI4) in fibroblast-like synoviocytes (FLSs) and macrophages. However, the roles of PADI4 and its inducer hypoxia in the regulation of macrophage polarization remain unclear. This study aimed to investigate the role of hypoxia-PADI4 for macrophage polarization in RA patients. METHODS: Synovial tissue (ST) and synovial fluid (SF) were collected from 3 OA patients and 6 RA patients. The distribution of M1 and M2 in ST and cytokines in SF were examined by immunohistochemical analysis and Bio-Plex immunoassays. THP-1 macrophages and BMDM polarization were determined under normoxic (21% oxygen) or hypoxic (3% oxygen) conditions. The effects of PADI4 on macrophages were determined by transfection of adenovirus vector-coated PADI4 (AdPADI4) and the use of PADI4 inhibitor. Finally, the roles of PADI4 in joint synovial lesions on macrophage polarization were investigated in collagen-induced arthritis (CIA) rats. RESULTS: We found increased macrophage polarization of M1 and M2 in the RA ST, compared with OA ST. The ratio of M1/M2 for RA and OA was 1.633 ± 0.1443 and 2.544 ± 0.4429, respectively. The concentration of M1- and M2-type cytokines was higher in RA than that in OA patients. Hypoxia contributed to the increase of the gene and protein expression of M1 and M2 markers. M1- but not M2-type gene expression showed a positive relationship with PADI4 expressionwhile the level of expression of M2-type genes showed no significant difference. The degree of joint swelling and destruction was effectively alleviated, and the number of macrophages especially M1 decreased in CIA rats after down-regulating PADI4 expression. CONCLUSION: Hypoxia is responsible for the co-polarization of M1 and M2. Hypoxia-associated PADI4 is responsible for M1 macrophage activation, implying that the inflammatory environment can be eased by decreasing PADI4 expression and improving the hypoxic environment. | |
| 34757601 | A Review of the Totality of Evidence for the Development and Approval of ABP 710 (AVSOLA) | 2022 Jan | ABP 710 (AVSOLA(®)) is a biosimilar to infliximab reference product (RP), a monoclonal antibody targeting tumor necrosis factor alpha (TNFα). It is approved in the USA and Canada for all the same indications as infliximab RP. Approval of ABP 710 was based on the totality of evidence (TOE) generated using a stepwise approach to assess its similarity with infliximab RP with regard to analytical (structural and functional) characteristics, pharmacokinetic parameters, and clinical efficacy and safety. ABP 710 was shown to be analytically similar to infliximab RP including in amino acid sequence, primary peptide structure, and glycan mapping and purity. ABP 710 was also demonstrated to be similar to infliximab RP with regard to functional characterization including in vitro binding, effector functions, and signaling pathways important for the mechanisms of action for clinical efficacy in multiple indications of immune-mediated inflammatory disorders including inflammatory bowel disease (IBD), especially binding to both soluble and membrane-bound TNFα. Pharmacokinetic similarity of ABP 710 with infliximab RP was demonstrated in healthy volunteers following a single 5 mg/kg intravenous dose. Comparative clinical efficacy of ABP 710 with infliximab RP was demonstrated in patients with rheumatoid arthritis. Safety and immunogenicity were also demonstrated to be similar for both ABP 710 and the RP. Overall, the TOE supported the conclusion that ABP 710 is highly similar to infliximab RP and supported scientific justification for extrapolation to all approved indications of infliximab RP, including IBD. | |
| 34093428 | The Emerging Roles of Endocrine Hormones in Different Arthritic Disorders. | 2021 | The relationship between endocrine hormones and the spectrum of rheumatic conditions has long been discussed in the literature, focusing primarily on sexual hormones, such as estrogens, androgens, prolactin (PRL). Estrogens are indeed involved in the pathogenesis of the main inflammatory arthritis thanks to their effects on the immune system, both stimulatory and inhibitory. The PRL system has been discovered in synovial tissue of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), patients and has been propose as a new potential therapeutic target. Besides sexual hormones, in the last years scientific interest about the crosstalk of immune system with other class of hormones has grown. Hormones acting on the bone tissue (i.e. parathyroid hormone, vitamin D) and modulators of the Wnt pathway (i.e. Dickkopf-1) have been demonstrated to play active role in inflammatory arthritis course, defining a new field of research named osteoimmunology. PTH, which is one of the main determinants of Dkkopf-1, plays a crucial role in bone erosions in RA and a correlation between PTH, Trabecular Bone Score (TBS) and disease activity has been found in ankylosing spondylitis (AS). In PSA is under studying the interaction among IL-17 and bone metabolism. The purpose of this review is to discuss and summarize the recent data about the interaction between endocrine hormone and immune system in the main rheumatic disorders, covering in particular the role of bone-related hormones and cytokines. We will describe this relationship from a biochemical, diagnostic and therapeutic perspective, with a particular focus on RA, PsA and AS. | |
| 34909894 | Human fibroblast-like synoviocyte isolation matter: a comparison between cell isolation fr | 2021 Nov | OBJECTIVE: Cell culture technology has become a popular method in the field of cell biology, pharmacology, and medical researches. Primary cells represent the normal physiological condition of human cells. Fibroblasts are the most common native cells of connective tissue that play a crucial role in the entire pathogenesis of various disorders, such as rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLSs), which overlie the loose connective tissue of the synovial sublining, are known to be the central mediators of joint damage. The most routine approach for the isolation of FLS is an enzymatic digestion of synovial tissue. This experimental study is designed to introduce an easy, fast, and high-throughput method compared with enzymatic digestion for isolation of FLS. METHODS: The synovial tissue and synovial fluid (SF) samples were collected from eight patients with RA who underwent routine knee replacement surgery. Synovial tissue was incubated with collagenase VIII enzyme, while SF was washed with a similar volume of phosphate-buffered saline. The cells were further subcultured and stored based on the standard protocols. The purity of isolated synoviocytes was confirmed using flow cytometry analysis. RESULTS: Isolation of FLS from SF was more successful with a faster rate, 3-5 days after culture. The morphological assessment and flow cytometry analysis confirmed the purity of SF-derived cells in passage 4. CONCLUSIONS: SF could be a more accessible source of FLS than synovial tissue. Obtaining primary FLS from SF is a simple, fast, and cost-effective way to have a large-scale cell during a short time. | |
| 33462137 | Gut Commensal Segmented Filamentous Bacteria Fine-Tune T Follicular Regulatory Cells to Mo | 2021 Mar 1 | Autoantibodies play a major pathogenic role in rheumatoid arthritis. T follicular helper (Tfh) cells promote germinal center B cell and Ab responses. Excessive Tfh cell responses lead to autoimmunity, and therefore, counterregulation is crucial. T follicular regulatory (Tfr) cells, mainly differentiated from T regulatory cells, can negatively regulate Tfh and germinal center B cells. Dysbiosis is involved in rheumatoid arthritis's pathogenesis. We previously demonstrated that the gut microbiota, segmented filamentous bacteria (SFB), promote autoimmune arthritis by inducing Tfh cells. However, little is known regarding whether gut microbiota influence systemic (nongut) Tfr cells, impacting gut-distal autoimmunity. In this study, using SFB in autoimmune arthritic K/BxN mice, we demonstrated that SFB-induced arthritis is linked to the reduction of Tfr cells' CTLA-4, the key regulatory molecule of Tfr cells. This SFB-mediated CTLA-4 reduction is associated with increased Tfr glycolytic activity, and glycolytic inhibition increases Tfr cells' CTLA-4 levels and reduces arthritis. The surface expression of CTLA-4 is tied to TCR signaling strength, and we discovered that SFB-reduced CTLA-4 is associated with a reduction of Nur77, an indicator of TCR signaling strength. Nur77 is known for repressing glycolytic activity. Using a loss-of-function study, we demonstrated that Nur77(+/-) haplodeficiency increases glycolysis and reduces CTLA-4 on Tfr cells, which is associated with increased arthritis and anti-glucose-6-phosphate isomerase titers. Tfr-specific deletion (KRN.Foxp3CreBcl-6(fl/fl)) in autoimmune condition reveals that Tfr cells repress arthritis, Tfh cells, and autoantibody responses and that SFB can mitigate this repression. Overall, these findings demonstrated that gut microbiota distally impact systemic autoimmunity by fine-tuning Tfr cells. | |
| 33820900 | Thiol/disulphide homeostasis in patients with rheumatoid arthritis: a potential link betwe | 2021 Jan | INTRODUCTION/OBJECTIVES: Thiols are crucial anti-oxidant agents that contain a sulfhydryl group; they play an important role in defence against reactive oxygen species. We aimed to determine the thiol/disulphide homeostasis in rheumatoid arthritis (RA) patients in conjunction with its association with disease activity, preclinical atherosclerosis, and other disease-related indices. METHODS: We enrolled 64 RA patients without known cardiovascular (CV) disease or risk factors and 46 healthy controls. Disease activity was evaluated using the Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR). Thiol/disulphide homeostasis was evaluated using a novel automated method, and serum native thiol (NT), total thiol (TT), and disulphide(SS) levels were recorded. The carotid intima media thickness (CIMT) was measured using carotid ultrasound to evaluate preclinical atherosclerosis. RESULTS: The NT and TT levels were significantly lower in RA patients than in controls (231.7 ± 52.3 vs. 293.6 ± 74.8 µmol/L, p < 0.001; 271.6 ± 52.1 vs. 331.3 ± 68.2 µmol/L, p < 0.001, respectively). There was no difference in SS levels between both groups. The CIMT was significantly higher in RA patients than in controls (0.80 vs. 0.56 mm, p ˂ 0.001). NT levels showed a significant negative correlation withCIMT in patients with RA (r = - 0.253, p = 0.040). In RA patients, NT and TT levels were significantly correlated with ESR (r = - 0.394, r = -0.399), high-sensitivity C-reactive protein (r = -0.413, r = - 0.342), DAS28-ESR (r = - 0.279, r = - 0.312), fibrinogen level (r = - 0.302, r = - 0.346), and anti-cyclic citrullinated peptide titres (r = - 0.305, r = 0.322) (, respectively). The association of thiol levels with CIMT did not arrive at a statistically significant level in multivariable linear regression analysis. CONCLUSIONS: RA patients without known CV disease or risk factors exhibited increased CIMT values and decreased thiol levels; moreover, thiol levels were found to be correlated with disease activity. Further studies are needed to detect the value of thiol/disulphide homeostasis for CV risk stratification and risk prediction in RA patients. | |
| 32339392 | Precision Medicine With Leflunomide: Consideration of the DHODH Haplotype and Plasma Terif | 2021 Jul | OBJECTIVE: Leflunomide is a commonly used disease-modifying drug in the treatment of rheumatoid arthritis (RA). Its effects are mediated via inhibition of dihydroorotate dehydrogenase (DHODH) by its active metabolite teriflunomide, and the pharmacokinetics of teriflunomide are highly variable. Our objective was to examine the association between the DHODH haplotype and plasma teriflunomide concentration with response to leflunomide in patients with RA where leflunomide was added to an existing disease-modifying drug regimen after failure to achieve an adequate response with conventional triple therapy. METHODS: Patients with RA who were taking, or were about to initiate, leflunomide were included. Participant characteristics, including the DHODH haplotype, were determined. Up to 5 plasma samples were collected after leflunomide was initiated for assays of total and free teriflunomide concentration. Disease activity was determined via the 28-joint Disease Activity Score (DAS28). The association between DAS28 scores and patient covariates was determined by linear mixed-effects modeling. RESULTS: A total of 67 patients were included in the study. The DAS28 score after initiation of leflunomide was associated with the baseline DAS28 score (β = 0.70, P < 0.001) and was higher in those who carried the DHODH haplotype 2 (β = 0.56. P = 0.01) and did not carry the shared epitope (β = 0.56, P = 0.013). As total and free plasma teriflunomide concentration increased, the DAS28 score was significantly lower (P < 0.001 and P = 0.001, respectively). When considering threshold concentrations, teriflunomide concentrations >16 mg/liter were associated with a DAS28 score that was 0.33 lower, and when free teriflunomide concentration was >35 µg/liter, the DAS28 score was 0.32 lower. CONCLUSION: Teriflunomide concentration and carriage of the DHODH haplotype 2 are associated with response to leflunomide in patients with RA, and a total plasma teriflunomide concentration of at least 16 mg/liter is needed to maximize the likelihood of response. | |
| 33386149 | Integrative analysis identifies potential causal methylation-mRNA regulation chains for rh | 2021 Mar | Genome-wide association studies have identified many genetic loci for rheumatoid arthritis (RA). However, causal factors underlying these loci were largely unknown. The aim of this study was to identify potential causal methylation-mRNA regulation chains for RA. We identified differentially expressed mRNAs and methylations and conducted summary statistic data-based Mendelian randomization (SMR) analysis to detect potential causal mRNAs and methylations for RA. Then causal inference test (CIT) was performed to determine if the methylation-mRNA pairs formed causal chains. We identified 11,170 mRNAs and 24,065 methylations that were nominally associated with RA. Among them, 197 mRNAs and 104 methylations passed the SMR test. According to physical positions, we defined 16 cis methylation-mRNA pairs and inferred 5 chains containing 4 methylations and 4 genes (BACH2, MBP, MX1 and SYNGR1) to be methylation→mRNA→RA causal chains. The effect of SYNGR1 expression in peripheral blood mononuclear cells on RA risk was found to be consistent in both the in-house and public data. The identified methylations located in CpG Islands that overlap promoters in the 5' region of the genes. The promoter regions showed long-range interactions with other enhancers and promoters, suggesting a regulatory potential of these methylations. Therefore, the present study provided a new integrative analysis strategy and highlighted potential causal methylation-mRNA chains for RA. Taking the evidences together, SYNGR1 promoter methylations most probably affect mRNA expressions and then affect RA risk. | |
| 34823826 | Effectiveness, safety and economic analysis of Benepali in clinical practice. | 2021 Dec | OBJECTIVE: To assess the effectiveness, safety and cost of Etanercept biosimilar in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA) and psoriatic arthritis (PsA) compared to the standard drug in real clinical practice. PATIENTS AND METHODS: Retrospective observational study. Case series of 138 patients with RA, SpA or PsA treated with at least one dose of Benepali® (n = 79) or Enbrel® (n = 59). Drug retention time was the primary efficacy endpoint compared to the biosimilar and the original. The proportion of patients achieving low disease activity or remission after 52 weeks was used as the secondary outcome. Safety was assessed by means of the adverse effects incidence rate. A cost minimization analysis was performed. RESULTS: No differences were observed regarding treatment retention time between drugs (median [95% confidence interval, 95% CI] at 12.0 months [10.2-12.0] for the biosimilar and 12.0 months [12.0-12.0] for the original). Similar improvements, in terms of inflammatory activity and physical function, were obtained after 52 weeks except for patients with SpA and PsA who, in general, experienced improvements of BASDAI and ASDAS with the original compared with the biosimilar. No significant differences were observed in the total number of adverse effects (.43 events/patient-years versus the biosimilar and .53 versus the original). Using the biosimilar in place of the original drug resulted in a net savings of 118,383.55 € (1,747.20 €/patient-years) for the hospital. CONCLUSION: The biosimilar Benepali is as effective and safe as the original and much more cost-effective. | |
| 32890713 | Anti-nociceptive, anti-inflammatory and anti-arthritic activities of pregnane glycosides f | 2021 Jan 30 | ETHNOPHARMACOLOGICAL RELEVANCE: Periploca sepium Bunge (P. sepium) is used in traditional Chinese medicine (TCM) for the treatment of autoimmune diseases, particularly rheumatoid arthritis. Periploca sepium periplosides (PePs), isolated from the root bark of P. sepium, characterized as the cardiac glycosides-free pregnane glycosides fraction, is expected to possess therapeutic potential on inflammatory arthritis. AIM OF THE STUDY: The current study is designed to evaluate the anti-nociceptive, anti-inflammatory and anti-arthritic activities effects of the PePs. MATERIALS AND METHODS: The anti-nociceptive activity of PePs was examined in the writhing test and hot-plate test in mice. The anti-inflammatory activity of PePs was determined by the 2, 4-dinitro-1-fluorobenzene (DNFB)-induced ear edema model and the carrageenan induced paw edema model in mice. The anti-arthritic activity of PePs was investigated by evaluating the joint inflammation and arthritis pathology in rat adjuvant induced arthritis (AIA) and murine collagen induced arthritis (CIA). Phytohaemagglutinin M (PHA-M) -elicited human peripheral blood mononuclear cells (PBMCs) were further applied to assess the suppressive activity of PePs on IFN-γ and IL-17 production. RESULTS: PePs treatment markedly decreased the acetic acid-induced visceral nociceptive response and increased the hot-plate pain threshold. Further, oral administration of PePs exhibited anti-inflammatory activity by decreasing DNFB-induced ear edema in mice and carrageenan-induced paw edema in rats. Moreover, oral treatment of PePs ameliorated joint swelling and attenuated bone erosion in rodent arthritis, and the therapeutic benefits were partially attributed to the suppression of proinflammatory cytokines such IFN-γ and IL-17. Moreover, PePs suppressed the proliferation as well as IFN-γ and IL-17 secretion in PHA-M-elicited human PBMCs in a concentration dependent manner. CONCLUSIONS: Taken together, our results justified the traditional use of Periploca sepium Bunge for the treatment of diseases associated with inflammation and pain. | |
| 32965596 | Calcitriol attenuates TLR2/IL-33 signaling pathway to repress Th9 cell differentiation and | 2021 Jan | There is limited information regarding the TLR2 signaling pathway involved in Th9 cell differentiation. The role of calcitriol in regulating TLR2-mediated Th9 cell development is unknown. Thus, we aimed to unravel the TLR2 signaling pathway in Th9 cells and its regulation by calcitriol. We have used n = 5-6 animals for each murine experiment. Human studies involved five healthy volunteers. Moreover, ten healthy individuals and ten RA patients were included in the study. Murine and human Th9 cells were treated with Calcitriol (100 nM) and Pam(3)CSK(4) (2 µg/mL). The number of IL-9+ve cells was determined by flow cytometry. Real-time PCR was used to assess the gene expression. Serum 25(OH)D(3) levels were determined by HPLC. We observed that TLR2 signals via IL-33/ST2 in Th9 cells. Increased TLR2 expression associated with increased IL9 expression and augmented disease severity in RA patients. Calcitriol attenuated TLR2 signaling in murine and human Th9 cells. Low serum vitamin D3 level negatively associated with increased IL-9 and TLR2 expression and disease severity in RA patients. Our data suggest a potential role of calcitriol to ameliorate the disease severity of RA patients. | |
| 34314580 | Jinwu Jiangu Capsule affects synovial cells in rheumatoid arthritis through PI3K/Akt/mTOR | 2021 Jul 27 | Jinwu Jiangu Capsule is a medicinal formula from the Chinese Miao nationality. Leflunomide is recommended in organizational guidelines for the treatment of rheumatoid arthritis (RA). To investigate the effect of Jinwu Jiangu Capsule on PI3K/Akt/mTOR signal pathway in cells taken from RA patients New Zealand rabbits were administrated with Jinwu Jiangu Capsule suspension to prepare serum containing medicine. Lyophilized powder was prepared from this serum for cell treatment. The expression of LC3-II and PI3K, AKT, mTOR were detected by IF and western blot. Moreover, the levels of Atg1, Atg5, Atg14 were detected by RT-qPCR. The results showed that the expression of LC3-II was increased, and fluorescence spot of LC3-II was obvious in high-dose of Jinwu Jiangu Capsule group. Jinwu Jiangu Capsule decreased the level of PI3k, Akt, and mTOR protein, and increased the levels of Atg1, Atg5 and Atg14. Specially, the high-dose of Jinwu Jiangu Capsule had the most obvious inhibitory and up-regulation effects. However, there was no significant difference in the expression of Akt, mTOR and Atg1 in the medium-dose of Jinwu Jiangu Capsule group compared with the leflunomide group. In conclusion, Jinwu Jiangu Capsule regulates autophagy by inhibiting the PI3K/AKT/mTOR pathway in RA. |