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ID PMID Title PublicationDate abstract
33292827 A systematic review of CXCL13 as a biomarker of disease and treatment response in rheumato 2020 Nov 2 BACKGROUND: The B cell chemoattractant CXCL13 is a promising biomarker in rheumatoid arthritis (RA), with a plausible role in supporting diagnosis, monitoring disease activity and as a prognostic value. It is a key chemokine driving the formation of lymphoid follicles within the inflamed synovium. The objective of this systematic review was to evaluate the role of CXCL13 as a viable biomarker in RA. METHODS: We conducted a systematic literature review of all published cohort and randomised controlled trials evaluating the role of CXCL13 in RA. The primary outcomes were; i) CXCL13 levels in RA patients compared to healthy controls, ii) the correlation between CXCL13 and markers of disease activity, and iii) the association between CXCL13 and treatment response. RESULTS: The search produced 278 articles, of which 31 met the inclusion criteria. Of the 12 studies evaluating CXCL13 expression in early or established RA, all reported higher levels than that seen in healthy controls. Twelve of sixteen studies reported a weakly positive correlation between CXCL13 and markers of disease activity including DAS28 and swollen joint count, with rho values between 0.20-0.67. In 2 studies, CXCL13 levels correlated with ultrasonographic evidence of synovitis. Eighteen studies assessed CXCL13 in response to therapeutic intervention. The majority signified a fall in levels in response to treatment including biologics and Janus kinase (JAK) inhibition. In some, this reduction was only seen in treatment responders. High CXCL13 levels predicted failure to achieve disease remission with csDMARDs. The evidence for treatment prediction with biologics was conflicting. CONCLUSION: Despite evidence to suggest a role in diagnosing RA and in detecting synovitis, the heterogeneity of studies included in this review limit our ability to draw robust conclusions. At present there are inadequate results to justify the routine use of CXCL13 as a biomarker in RA routine clinical practice.
33164739 Treating rheumatoid arthritis with leflunomide monotherapy versus combination therapy with 2021 Jan OBJECTIVE: Combination therapies have been proposed as a strategy to control inflammation more effectively in patients with rheumatoid arthritis (RA). Few studies examine the combined effect of methotrexate (MTX) and leflunomide (LFN). This study evaluated the symptom control and side effects of the combination of MTX and LFN compared with LFN monotherapy. METHODS: We conducted a retrospective analysis of 113 patients with RA treated with either LFN alone (n=22) or in combination with MTX (n=91). Data on disease activity score 28 erythrocyte sedimentation rate (DAS-28 ESR), DAS-28 C-reactive protein (DAS-28 CRP), blood cell count, liver enzymes, and creatinine levels were determined. Samples were collected on day 0 (initiation of LFN) and at 6 and 12 months. RESULTS: We found no differences between the 2 groups in DAS-28 on day 0 and at 6 and 12 months (p=0.89, p=0.42, and p=0.09, respectively, for DAS-28 ESR; p=0.97, p=0.27, and p=0.63, respectively, for DAS-28 CRP). In addition, we observed no differences in the blood cell count, liver enzymes, and creatinine levels between the treatment groups at any of the time points (all p>0.05). CONCLUSION: Our results suggest that the efficacy of the combined treatment with MTX and LFN is similar to that of LFN alone. No increase in toxicity was observed with the combination therapy.
33062015 Virtual Screening Technique Used to Estimate the Mechanism of Adhatoda vasica Nees for the 2020 Adhatoda vasica Nees (AVN) is commonly used to treat joint diseases such as rheumatoid arthritis (RA) in ethnic minority areas of China, especially in Tibetan and Dai areas, and its molecular mechanisms on RA still remain unclear. Network pharmacology, a novel strategy, utilizes bioinformatics to predict and evaluate drug targets and interactions in disease. Here, network pharmacology was used to investigate the mechanism by which AVN acts in RA. The chemical compositions and functional targets of AVN were retrieved using the systematic pharmacological analysis platform PharmMapper. The targets of RA were queried through the DrugBank database. The protein-protein interaction network (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of key targets were constructed in the STRING database, and the network visualization analysis was performed in Cytoscape. Maestro 11.1, a type of professional software, was used for verifying prediction and analysis based on network pharmacology. By comparing the predicted target information with the targets of RA-related drugs, 25 potential targets may be related to the treatment of RA, among which MAPK1, TNF, DHODH, IL2, PTGS2, and JAK2 may be the main potential targets for the treatment of RA. Finally, the chemical components and potential target proteins were scored by molecular docking, and compared with the ligands of the protein, the prediction results of network pharmacology were preliminarily verified. The active ingredients and mechanism of AVN against RA were firstly investigated using network pharmacology. Additionally, this research provided a solid foundation for further experimental studies.
33017651 Airways therapy of obstructive sleep apnea dramatically improves aberrant levels of solubl 2020 Dec Obstructive Sleep Apnea (OSA) damages the health of 35% of adult Americans. Disordered sleep results in increased risk of several autoimmune disorders, but the molecular links to autoimmunity are poorly understood. Herein, we identified four cytokines associated with autoimmune disease, whose median serum levels were significantly different for OSA patients receiving airways therapy, from the levels in untreated OSA patients, APRIL (5.2-fold lower, p = 3.5 × 10(-11)), CD30 (1.6-fold higher, p = 7.7 × 10(-5)), IFN-Alpha-2 (2.9-fold higher, p = 9.6 × 10(-14)) and IL-2 (1.9-fold higher, p = 0.0003). Cytokine levels in airways treated patients were similar to the levels in control subjects. t-SNE and UMAP analysis of these high dimensional patient cytokine data identified only two groups, suggesting a similar global response for all four cytokines to airways therapy. Our findings suggest the levels of these four cytokines may be altered by disordered sleep and perhaps by chronic hypoxia. Therapeutic options are discussed.
32789808 Therapeutic applications and delivery systems for triptolide. 2020 Dec Triptolide (TPL) is a natural compound and active component of Tripterygium wilfordii Hook F., an Asian native woody vine widely used for over 200 years in Chinese medicine. Hot water, ethanol-ethyl acetate, and chloroform-methanol extracts are the first reported TPL preparations in the literature, and since then, several studies for application in inflammation processes and cancer are described due to the antitumor, anti-inflammatory, and immunosuppressive characteristics of the molecule. However, physicochemical properties such as poor solubility and bioavailability are the main concerns regarding the TPL safety and efficacy in clinical studies since trials have reported adverse side effects alongside the excellent TPL therapeutic effects. Here, we review the main TPL applications and issues related to the drug usage, and a comprehensive summary of diseases is provided. Special emphasis is given to drug delivery systems designed to overcome the TPL physicochemical characteristics such as poor drug solubility, and how to increase efficacy and obtain a safe drug profile. Graphical abstract.
32390850 Psychiatric Adverse Events Associated With Infliximab: A Cohort Study From the French Nati 2020 INTRODUCTION: Infliximab (IFX) was the first anti-tumor necrosis factor (TNFα) antibody to be used in the treatment of severe chronic inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. A number of serious adverse drug reactions are known to be associated with IFX use; they include infections, malignancies, and injection site reactions. Although a few case reports have described potential psychiatric adverse events (including suicide attempts and manic episodes), the latter are barely mentioned in IFX's summary of product characteristics. The objective of the present retrospective study was to detect potential psychiatric adverse events associated with IFX treatment by analyzing a national discharge abstract database. MATERIALS AND METHODS: We performed an historical cohort study by analyzing data from the French national hospital discharge abstract database (PMSI) between 2008 and 2014. All patients admitted with one of the five diseases treated with IFX were included. RESULTS: Of the 325,319 patients included in the study, 7,600 had been treated with IFX. The proportion of hospital admissions for one or more psychiatric events was higher among IFX-exposed patients (750 out of 7,600; 9.87%) than among non-exposed patients (17,456 out of 317,719; 5.49%). After taking account of potential confounders in the cohort as a whole, a semi-parametric Cox regression analysis gave an overall hazard ratio (HR) [95% confidence interval] (CI) of 4.5 [3.95; 5.13] for a hospital admission with a psychiatric adverse event during treatment with IFX. The HR (95%CI) for a depressive disorder was 4.97 (7.35; 6.68). Even higher risks were observed for certain pairs of adverse events and underlying pathologies: psychotic disorders in patients treated for ulcerative colitis (HR = 5.43 [2.01; 14.6]), manic episodes in patients treated for severe psoriasis (HR = 12.6 [4.65; 34.2]), and suicide attempts in patients treated for rheumatoid arthritis (HR = 4.45 [1.11; 17.9]). DISCUSSION: The present retrospective, observational study confirmed that IFX treatment is associated with an elevated risk of psychiatric adverse events. Depending on the disease treated, physicians should be aware of these potential adverse events.
31625621 Free prednisolone pharmacokinetics predicted from total concentrations in patients with in 2020 Apr Prednisone is an anti-inflammatory drug widely used in internal medicine and rheumatology, but dosing remains empirical. The active metabolite of prednisone is free prednisolone. The aim of this work was to build a population pharmacokinetic (PK) model that can predict free prednisolone concentrations in patients with inflammatory/immunologic conditions.A total of 107 patients from the department of internal medicine of Cochin hospital provided 343 observations. Blood samples drawn for biological analyses were used for drug determination. Total plasma prednisolone concentrations were measured by liquid chromatography-mass spectrometry, and the data were modelled using Monolix. The pharmacokinetics was ascribed a one-compartment open model with three transit compartments standing for the absorption and metabolism process. The model used predicts free concentrations that served to derive total concentrations given published binding constants. Only size parameters influenced the pharmacokinetics. Free prednisolone CL(U) /F and V(U) /F, scaled allometrically on lean body weight, were, respectively, 26.7 L/h and 94.3 L for 50 kg LBW. CL(U) /F interindividual variability was 0.20. The additive and proportional residual variabilities were, respectively, 4.3 µg/L and 0.20. The results point out some dosing issues, that is the possibility of under- or over-dosage in thin or overweight patients respectively.
33215872 Trends in Hospitalization Rates, Major Causes of Hospitalization, and In-Hospital Mortalit 2020 Dec OBJECTIVE: To evaluate national trends in hospitalizations and in-hospital mortality in rheumatoid arthritis (RA). METHODS: National Inpatient Sample from 2000-2014 and United States Census data were used to study temporal trends in adult RA hospitalizations, reasons for hospitalizations, and in-hospital mortality. RESULTS: The data represented 183 983 hospitalizations with a primary diagnosis of RA. The annual rates of hospitalization for the primary diagnosis of RA decreased from 76.54 admissions per 1 million in 2000 to 29.96 per 1 million in 2014 (P trend < 0.0001). The hospital mortality rate declined from 0.70% to 0.41% (P trend < 0.0001) in this group. With a primary or nonprimary diagnosis of RA, the mortality rate ranged between 1.95 and 2.87 (P trend 0.08). For a nonprimary diagnosis of RA, we noted that the proportion of hospitalizations with a diagnosis of myocardial infarction (6.4% in 2000 to 4.6% in 2014; P < 0.001) significantly decreased, but the absolute number of hospitalizations significantly increased. In contrast, the proportion and the absolute number of hospitalizations with any diagnosis of sepsis, congestive heart failure, lung disease, and urinary tract infection increased significantly. We also noted a significant increase in the actual rate and proportions for hospitalizations for hip and knee arthroplasty. Among in-hospital deaths when RA was a nonprimary diagnosis, the most common primary diagnosis was pneumonia (12.5 %) in 2000, whereas sepsis accounted for the most deaths in 2014 (31.4%). CONCLUSION: We observed that hospitalization rates and in-hospital mortality rates in patients with RA have changed significantly over the past 15 years.
33051220 Prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases: a syste 2020 Oct 13 OBJECTIVES: The prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases who are frequently treated with disease modifying therapies remains poorly understood. This meta-analysis aims to assess the prevalence and clinical outcomes of COVID-19 in autoimmune diseases. METHODS: Electronic databases were searched for observational and case-controlled studies. We sorted medications into glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic or targeted synthetic DMARDs (b/tsDMARDs), which was also divided into monotherapy and b/tsDMARDs-csDMARDs combination therapy. RESULTS: We analysed 62 observational studies with a total of 319 025 patients with autoimmune diseases. The prevalence of COVID-19 was 0.011 (95% CI: 0.005 to 0.025). Meta-analysis of seven case-controlled studies demonstrated that the risk of COVID-19 in autoimmune diseases was significantly higher than in control patients (OR: 2.19, 95% CI: 1.05 to 4.58, p=0.038). Meta-regression analysis showed glucocorticoids were significantly associated with the risk of COVID-19. For clinical outcomes, we assessed 65 studies with 2766 patients with autoimmune diseases diagnosed with COVID-19. The rates of hospitalisation and mortality were 0.35 (95% CI: 0.23 to 0.50) and 0.066 (95% CI: 0.036 to 0.12), respectively. Glucocorticoids, csDMARDs and b/tsDMARDs-csDMARDs combination therapy increased the risk of these outcomes, whereas b/tsDMARDs monotherapy, particularly antitumour necrosis factor agents, were associated with a lower risk of hospitalisation and death. CONCLUSIONS: Our meta-analysis demonstrated that patients with autoimmune diseases had an increased risk of COVID-19, primarily attributed to glucocorticoid use. b/tsDMARDs monotherapy was associated with a lower risk of severe COVID-19 suggesting its safety in the COVID-19 pandemic.
32467775 Temporomandibular joint function, periodontal health, and oral microbiome in early rheumat 2020 OBJECTIVES/AIMS: Rheumatoid arthritis (RA) is an autoimmune disease affecting the joints, including the temporomandibular joint (TMJ). Early diagnosis and treatment can alleviate symptoms and prevent progression. Predictors for disease outcome in individuals at risk for RA are therefore valuable. While limited information is available on the prevalence of TMJ involvement in early RA, previous studies suggest that RA, periodontitis and the oral microbiome are interrelated. Predictive factors for RA development may thus be present in the oral cavity. Our two aims are: (1) to assess the prevalence of TMJ involvement in early RA, and (2) to investigate the predictive value of oral factors in RA development. MATERIALS AND METHODS: We will include 150 individuals in this multi-center, prospective cohort study: 50 patients with early RA, 50 at-risk individuals, and 50 healthy controls. At baseline, the TMJ, periodontal health, and the oral microbiome will be examined. The general health will be followed over time, on four occasions up to 3 years. DISCUSSION: Our results will provide insight into the prevalence and clinical characterization of TMJ involvement in early RA. For at-risk individuals, oral factors can be studied as possible predictors for the development of RA.
32076051 Inhibition of bone morphogenetic protein 6 receptors ameliorates Sjögren's syndrome in mi 2020 Feb 19 Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease, with only palliative treatments available. Recent work has suggested that increased bone morphogenetic protein 6 (BMP6) expression could alter cell signaling in the salivary gland (SG) and result in the associated salivary hypofunction. We examined the prevalence of elevated BMP6 expression in a large cohort of pSS patients and tested the therapeutic efficacy of BMP signaling inhibitors in two pSS animal models. Increased BMP6 expression was found in the SGs of 54% of pSS patients, and this increased expression was correlated with low unstimulated whole saliva flow rate. In mouse models of SS, inhibition of BMP6 signaling reduced phosphorylation of SMAD1/5/8 in the mouse submandibular glands, and led to a recovery of SG function and a decrease in inflammatory markers in the mice. The recovery of SG function after inhibition of BMP6 signaling suggests cellular plasticity within the salivary gland and a possibility for therapeutic intervention that can reverse the loss of function in pSS.
32328130 Efficacy and Safety of Integrated Traditional Chinese Medicine and Western Medicine on the 2020 OBJECTIVE: Integrated therapy of traditional Chinese medicine (TCM) and Western medicine (WM) has gradually been applied to the treatment of rheumatoid arthritis (RA). Recently published studies have provided a wealth of data and information about the effectiveness of combination treatments, but high-quality evidence-based meta-analysis on this issue is not available yet. This study was conducted to compare and evaluate the efficacy and safety of the integrated therapy for RA. METHODS: PubMed, EMBASE, and the Cochrane Library were searched up to January 2020. Randomized controlled trials (RCTs) that compared the efficacy and safety of integrative TCM-WM with WM alone for RA were included. The outcome measures contained therapeutic effects (TEs), tender joint count (TJC), swollen joint count (SJC), duration of morning stiffness (DMS), grip strength (GS), disease activity score in 28 joints (DAS28), rheumatoid factor (RF), anti-cyclic peptide containing citrulline (anti-CCP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and adverse events (AEs) to assess the efficacy and safety of different treatments. RESULTS: A total of 20 RCTs with 2269 patients met the inclusion criteria. TCM used in these studies included Chinese herbal decoctions and tablets or capsules made from herbs and their extracts, while WM included disease-modifying antirheumatic drugs (DMARDs), nonsteroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids (GC). Compared with patients receiving WM treatment alone, patients with integrative TCM-WM treatment showed better TEs (OR = 3.03, 95% CI [2.36, 3.88]). The integrative treatment group showed reductions in TJC (MD = -1.17, 95% CI [-2.12, -0.21]), SJC (MD = -0.87, 95% CI [-1.85, 0.10]), DMS (SMD = -0.69, 95% CI [-0.98, -0.41]), DAS28 (MD = -0.43, 95% CI [-0.57, -0.29]), RF (SMD = -0.59, 95% CI [-0.91, -0.27]), anti-CCP (SMD = -0.21, 95% CI [-0.36, -0.06]), ESR (MD = -8.36, 95% CI [-12.60, -4.12]), and CRP (MD = -6.73, 95% CI [-9.38, -4.08]), and increment in GS (SMD = 0.12, 95% CI [-0.63, 0.87]). AEs, especially gastrointestinal disorders, abnormal liver function, leukopenia, skin allergies and rashes, headaches and dizziness, and alopecia, significantly decreased (OR = 0.37, 95% CI [0.29, 0.47]) in the integrative treatment group. CONCLUSIONS: The findings of this meta-analysis indicate that integrative TCM-WM could obtain effective and safe results in the treatment of RA. Using TCM as an adjunctive therapy in RA has great prospects for further development.
33060686 Analysis of gene expression from systemic lupus erythematosus synovium reveals myeloid cel 2020 Oct 15 Arthritis is a common manifestation of systemic lupus erythematosus (SLE) yet understanding of the underlying pathogenic mechanisms remains incomplete. We, therefore, interrogated gene expression profiles of SLE synovium to gain insight into the nature of lupus arthritis (LA), using osteoarthritis (OA) and rheumatoid arthritis (RA) as comparators. Knee synovia from SLE, OA, and RA patients were analyzed for differentially expressed genes (DEGs) and also by Weighted Gene Co-expression Network Analysis (WGCNA) to identify modules of highly co-expressed genes. Genes upregulated and/or co-expressed in LA revealed numerous immune/inflammatory cells dominated by a myeloid phenotype, in which pathogenic macrophages, myeloid-lineage cells, and their secreted products perpetuate inflammation, whereas OA was characterized by fibroblasts and RA of lymphocytes. Genes governing trafficking of immune cells into the synovium by chemokines were identified, but not in situ generation of germinal centers (GCs). Gene Set Variation Analysis (GSVA) confirmed activation of specific immune cell types in LA. Numerous therapies were predicted to target LA, including TNF, NFκB, MAPK, and CDK inhibitors. Detailed gene expression analysis identified a unique pattern of cellular components and physiologic pathways operative in LA, as well as drugs potentially able to target this common manifestation of SLE.
32531698 An herbal formula inhibits STAT3 signaling and attenuates bone erosion in collagen-induced 2020 May 30 BACKGROUND: Receptor activator of NF-κB ligand (RANKL) facilitates differentiation of osteoclast precursors into osteoclasts, resulting in bone erosion in rheumatoid arthritis (RA) patients. Fibroblast-like synoviocytes (FLS) are the main cells for producing RANKL. Signal transducer and activator of transcription 3 (STAT3) signaling is activated in FLS of RA patients (RA-FLS), which has been linked to RANKL production. A two-herb formula (RL) comprising Rosae Multiflorae Fructus and Lonicerae Japonicae Flos is traditionally used for treating RA in China. We have found that a standardized ethanolic extract of RL (RLE for short) alleviates bone erosion in collagen-induced arthritis (CIA) rats. PURPOSE: This study aimed to determine whether RLE inhibits RANKL production and osteoclastogenesis in cell and rat models, and to explore the involvement of the STAT3 pathway in this inhibition. STUDY DESIGN AND METHODS: A CIA rat model, interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS and a co-culture system (IL-6/sIL-6R-stimulated RA-FLS/peripheral blood mononuclear cells) were used to evaluate the effects of RLE. Micro-computed tomography analysis was used to observe bone erosion in CIA rats. Tartrate-resistant acid phosphatase staining was used to evaluate osteoclastogenesis. Western blotting and ELISA assays were employed to examine protein levels. RT-qPCR was used to detect mRNA levels. STAT3-over-activated RA-FLS were used to investigate the involvement of STAT3 signaling in the anti-osteoclastogenic effects of RLE. RESULTS: RLE alleviated bone erosion in joints of CIA rats. In both synovial tissues of CIA rats and IL-6/sIL-6R-stimulated RA-FLS, RLE downregulated the protein level of RANKL. In the co-culture system, RLE significantly and dose-dependently inhibited IL-6/sIL-6R-induced osteoclastogenesis. Mechanistic studies revealed that RLE lowered the protein level of phospho-STAT3 (Tyr705) in synovial tissues of CIA rats. In IL-6/sIL-6R-stimulated RA-FLS, RLE inhibited the activation/phosphorylation of a STAT3 upstream kinase Janus kinase 2 (Tyr1007/1008) and STAT3 (Tyr705), decreased the nuclear localization of STAT3, lowered mRNA levels of STAT3-transcriptionally regulated genes IL-1β and TNF-α. RLE's inhibitory effects on RANKL production in RA-FLS gradually decreased when IL-6/sIL-6R doses increased. Over-activation of STAT3 diminished the inhibitory effects of RLE on RANKL production in IL-6/sIL-6R-stimulated RA-FLS, and attenuated the anti-osteoclastogenic effects of RLE in the co-culture system. CONCLUSION: We, for the first time, demonstrated that suppressing STAT3 signaling contributes to the inhibition of RANKL production and osteoclastogenesis, and thereby supports the mechanisms responsible for the reduction in bone erosion in RLE-treated CIA rats. This study provides further pharmacological groundwork for developing RLE as a modern anti-arthritic drug, and supports the notion that targeting STAT3 signaling is a viable strategy for managing bone erosion.
32454846 Tripterygium Glycosides Combined with Leflunomide for Rheumatoid Arthritis: A Systematic R 2020 OBJECTIVE: To undertake an overview on the overall effects of Tripterygium glycosides (TG) combined with Leflunomide (LEF) for rheumatoid arthritis (RA). METHODS: We searched electronic databases from database establishment time to December 1, 2019. The clinical trial data of TG combined with LEF (trial group) and control group in the treatment of RA were collected. The Cochrane system was used to evaluate the quality of the literature. RevMan 5.3 software was used to conduct a meta-analysis of the eligible studies. RESULTS: A total of 12 randomized controlled trials (RCTs) involving 834 patients with RA were included in this study. The meta-analysis results showed that morning stiffness (mean difference (MD) = -0.29, 95% confidential interval (CI) (-0.45, -0.12), P=0.0005), tender joint count (MD = -1.51, 95% CI (-2.20, -0.83), P=0.0001), swollen joint count (MD = -1.24, 95% CI (-1.59, -0.88), P=0.0001), erythrocyte sedimentation rate (MD = -7.26, 95% CI (-9.92, -4.61), P=0.0001), C-reactive protein (MD = -4.04, 95% CI (-4.93, -3.14), P=0.0001), and rheumatoid factor (MD = -50.88, 95% CI (-72.30, -29.45), P = 0.0001) in the trial groups were lower than those in the control groups. The total effective rate in the trial group was better than that in the control group (risk ratio (RR) = 1.20, 95% CI (1.13, 1.28), P=0.00001). However, there was no significant difference of adverse events (RR = 0.83, 95% CI (0.61, 1.13), P=0.23) while comparing the trial groups with the control groups. CONCLUSION: Our results were found to be superior but limited evidence on the effectiveness of TG combined with LEF in the treatment of RA is available.
32674107 Combination of LMT-28 and Metformin Improves Beneficial Anti-Inflammatory Effect in Collag 2021 OBJECTIVES: The interleukin-6 (IL-6)-mediated signaling pathway plays an essential role in the development of rheumatoid arthritis. LMT-28 suppresses the activation of the IL-6-mediated signaling by direct targeting of gp130. Although LMT-28 and metformin both possess anti-inflammatory activity, the beneficial effect of LMT-28 and metformin combination on a collagen-induced arthritis (CIA) model has not yet been investigated. This study aimed to investigate the anti-inflammatory effect and mechanism of a combination of LMT-28 and metformin in a CIA model. METHODS: In MH7A cells, cell proliferation and the IL-6-mediated signaling pathway following administration of LMT-28 and metformin combination was analyzed through MTT assay and Western blotting. The level of T helper 17 (Th17) cell differentiation from CD4+ T cells was analyzed in mouse splenocytes and human peripheral blood mononuclear cells. Arthritis score, incidence rate, inflammatory cytokine, and T-cell subsets were measured in CIA mice following administration of LMT-28 and metformin combination. RESULTS: Combination treatment with LMT-28 and metformin diminished proliferation of MH7A cells and IL-6-mediated gp130, STAT3, and ERK signaling more than in individual treatments. Furthermore, the differentiation of CD4+ T cells into Th17 cells was attenuated more by combination treatment with LMT-28 and metformin than individual treatments. The combination of LMT-28 and metformin ameliorated the arthritic score better than individual treatments. The combination significantly reduced tumor necrosis factor and IL-6 levels in the sera and had an anti-inflammatory effect on the distribution of Treg/Th17 cells in the lymph nodes. CONCLUSION: Combination treatment with LMT-28 and metformin significantly ameliorates arthritic symptoms in CIA by suppressing Th17 differentiation and IL-6 signaling.
32674562 Detecting Basal Myeloperoxidase Activity in Living Systems with a Near-Infrared Emissive " 2020 Aug 18 Detecting myeloperoxidase (MPO) activity in living organisms is important because MPO contributes to the pathogenesis of many diseases such as rheumatoid arthritis and other inflammatory diseases, artherosclerosis, neurodegenerative disease, and some cancers. However, rapid and effective methods for the detection of basal MPO activity in living systems have not yet been reported. Herein, we report a near-infrared (NIR) emissive "turn-on" probe FD-301 that can specifically bind to MPO and accurately measure MPO activity in living cells and in vivo via a rapid response to initial hypochlorous acid (HOCl), produced by MPO. Notably, FD-301 could detect the basal level of MPO activity in human promyelocytic leukemia cells (HL-60) and could discriminate between MPO high-expression and low-expression cells. Furthermore, FD-301 was successfully applied to in vivo imaging of MPO in MPO-dependent diseases, such as arthritis and inflammatory bowel disease.
32141431 Remission of collagen-induced arthritis by adoptive transfer of peritoneal cells. 2020 Nov OBJECTIVES: The collagen-induced arthritis (CIA) model shares both immunological and pathological features with human rheumatoid arthritis (RA), thus it has been used extensively as a model to study the pathogenesis of RA and for testing therapeutics. It is well-known that the T helper cell 17 (Th17) responses are involved in the pathogenesis of RA, while the regulatory T cells (Tregs) are considered to limit the progress of disease. Previously, we found that peritoneal cells (PCs) possess immunosuppressive characteristics and it is conceivable that PCs potentially have the therapeutic benefits for RA. In this study, we investigated whether PCs are capable of Treg induction and therefore suppress Th17-mediated CIA. METHODS: Naïve PCs were intravenously transferred into CIA mice at the early clinical signs of arthritis. The treatment commenced on day 0 and then every other day until day 14. Clinical symptoms of arthritis, histological changes, cytokine expressions and cell population profiles were investigated. RESULTS: Intravenously administrating PCs ameliorated the severity of CIA. Further investigations unveiled that the reduction of Th17 cells and the induction of Tregs is ascribed to the remission of the disease. Specifically, when splenic PBMC were cultured with PCs, the expression of FOXP3 and IFN-γ was markedly induced. It is suggested that IFN-γ secreted by PCs plays an important role in the conversion of CD4+T cells to Tregs. CONCLUSIONS: The adoptive transfer of PCs is effective in the treatment of CIA by regulating the T cell differentiations. Our findings might provide a new strategy for RA therapy.
32012252 Lymphotoxin targeted to salivary and lacrimal glands induces tertiary lymphoid organs and 2020 Mar To investigate the role of lymphotoxin (LT) in Sjögren's syndrome (SS) and in mucosal associated lymphoid tissue (MALT)-lymphoma, we made transgenic mice (Amy1-LTαβ) that targeted LTα and LTβ to the salivary and lacrimal glands. Amy1-LTαβ mice developed atrophic salivary and lacrimal glands that contained tertiary lymphoid organs (TLOs) and had reduced tear production. Amy1-LTαβ mice developed cervical lymphadenopathy but not MALT-lymphoma. TLO formation in the salivary and lacrimal glands of Amy1-LTαβ was not sufficient to induce autoimmunity as measured by autoantibody titres.
31740402 Agonist-induced 4-1BB activation prevents the development of Sjӧgren's syndrome-like sial 2020 Mar 1 Activation of costimulatory receptor 4-1BB enhances T helper 1 (Th1) and CD8 T cell responses in protective immunity, and prevents or attenuates several autoimmune diseases by increasing Treg numbers and suppressing Th17 or Th2 effector response. We undertook this study to elucidate the impact of enforced 4-1BB activation on the development of Sjögren's syndrome (SS)-like sialadenitis in non-obese diabetic (NOD) model of this disease. An anti-4-1BB agnostic antibody was intraperitoneally injected to female NOD mice aged 7 weeks, prior to the disease onset that occurs around 10-11 weeks of age, 3 times weekly for 2 weeks, and the mice were analyzed for SS pathologies at age 11 weeks. The salivary flow rate was markedly higher in the anti-4-1BB-treated NOD mice compared to the IgG-treated controls. Anti-4-1BB treatment significantly reduced the leukocyte infiltration of the submandibular glands (SMGs) and the levels of serum antinuclear antibodies. Flow cytometric analysis showed that the percentages of CD4 T cells, Th17 cells and plasmacytoid dendritic cells among SMG leukocytes were markedly reduced by anti-4-1BB treatment, in conjunction with a reduction in SMG IL-23p19 mRNA levels and serum IL-17 concentrations. Although the proportion of Tregs and IL-10 mRNA levels in SMGs were not altered by 4-1BB activation, IL-10 mRNA levels in salivary gland-draining lymph nodes and serum IL-10 concentrations were both markedly increased. While anti-4-1BB treatment did not affect the amount of Th1 cells and IFNγ mRNA in the SMGs, it increased these measurables in salivary gland-draining lymph nodes. Hence, agonistic activation of 4-1BB impedes the development of SS-like sialadenitis and hyposalivation.