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ID PMID Title PublicationDate abstract
35197789 Novel functional polymorphism on PADI-4 gene and its association with arthritis onset. 2022 Feb BACKGROUND: Citrullinated proteins formed by peptidyl arginine deiminases (PADIs) deimination of arginine residues in proteins are of particular interest in arthritis pathogenesis. Polymorphisms on the PADI-4 gene lead to the malfunctioning of PADIs leading to the onset of arthritis. OBJECTIVE: The present study was conducted to determine the polymorphisms on the PADI-4 gene and their association with rheumatoid arthritis (RA) as well as Osteoarthritis (OA). METHODOLOGY: To achieve the above-mentioned objective a case-control study was conducted. Blood samples were collected from RA, OA, and control subjects. DNA was extracted from each blood sample by modified organic method and was quantified as well as qualified by DNA gel electrophoresis and Nanodrop. Patients were tested for rs874881, rs11203366, rs11203367, rs2240336, rs2240337, rs2240339, rs1748033 and rs2240340 polymorphic sites by amplifying targeted regions through PCR with site-specific primers. Genotyping was performed by Restriction Fragment Length Polymorphism and direct sequencing method. Mutations were identified by analyzing sequences on BioEdit software. Allelic, genetic, and multiple site analysis were performed by SHEsis and PLINK software. Change in the amino acid sequence was identified by MEGA 6.0 software. RESULTS: Polymorphisms were identified on all targeted polymorphic sites except rs2240337 in both RA and OA individuals. In addition, two novel mutations were also identified in exon 4 identified i-e SCV000804840: c.218T > C and SCV000807675: c.241G > T. All the SNPs except rs11203366 were found to be significantly associated with RA at an allelic level whereas all SNP's have been significant risk factors in the onset of OA. At genotypic level rs874881, rs11203366, rs2240339, SCV000804840 and SCV000807675 were significantly associated to RA development whereas rs874881, rs11203366, rs11203367, rs2240339, SCV000804840 and SCV000807675 were genetic risk factors in OA onset. Haplotype analysis indicated that GACCACGCC and GACCACGCT were highly significant in disease development. Polymorphisms identified altered the functioning of PADIs by altering their amino acid sequence. CONCLUSION: In conclusion, it was found that PADI-4 gene polymorphism was not only involved in the onset of RA but was also found to be a significant risk factor in OA onset.
34652486 [Development of quality standards for patients with rheumatoid arthritis for use in German 2021 Oct 15 Despite a qualitatively and structurally good care of patients with rheumatoid arthritis (RA) in Germany, there are still potentially amendable deficits in the quality of care. For this reason, the German Society for Rheumatology (DGRh) has therefore decided to ask a group of experts including various stakeholders to develop quality standards (QS) for the care of patients with RA in order to improve the quality of care. The QS are used to determine and quantitatively measure the quality of care, subject to relevance and feasibility. The recently published NICE and ASAS standards and a systematic literature search were used as the basis for development. A total of 8 QS, now published for the first time, were approved with the intention to measure and further optimize the quality of care for patients with RA in Germany.
34136506 Disease Activity Indices in Rheumatoid Arthritis: Comparative Performance to Detect Change 2021 Objective: To compare the capacity of various disease activity indices to evaluate changes in function, IL-6 levels, and radiographic progression in early and established rheumatoid arthritis (RA). Methods: Secondary data analysis of a clinical trial assessing the efficacy of tocilizumab in patients with established RA (ACT-RAY) and a longitudinal prospective register of early arthritis (PEARL). Targeted outcomes were changes in physical function, measured with the health assessment questionnaire (HAQ), IL-6 serum levels, and radiographic progression. The "Hospital Universitario La Princesa Index" (HUPI), DAS28 using erythrocyte sedimentation rate and SDAI were the disease activity indices compared. Models adjusted for age and sex were fitted for each outcome and index and ranked based on the R (2) parameter and the quasi-likelihood under the independence model criterion. Results: Data from 8,090 visits (550 patients) from ACT-RAY and 775 visits (534 patients) from PEARL were analyzed. The best performing models for HAQ were the HUPI (R (2) = 0.351) and SDAI ones (R (2) = 0.329). For serum IL-6 levels, the SDAI (R (2) = 0.208) followed by the HUPI model (R (2) = 0.205). For radiographic progression in ACT-RAY, the HUPI (R (2) = 0.034) and the DAS28 models (R (2) = 0.026) performed best whereas the DAS28 (R (2) = 0.030) and HUPI models (R (2) = 0.023) did so in PEARL. Conclusions: HUPI outperformed other indices identifying changes in HAQ and radiographic progression and performed similarly to SDAI for IL-6 serum levels.
35069820 Transplantation of IL-1β siRNA-modified bone marrow mesenchymal stem cells ameliorates ty 2022 Feb Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes erosion of articular cartilage and bone and has adverse effects on both patients and livestock animals. The aim of the present study was to investigate the role of interleukin-1β (IL-1β) in the pathogenesis of RA, and to further determine whether injection of IL-1β small interfering RNA (siRNA) or transplantation of IL-1β siRNA + bone marrow mesenchymal stem cells (BMSCs) can ameliorate RA in rats. A collagen-induced arthritis (CIA) rat model was established by injecting type II collagen for 4 weeks. Next, CIA rats were randomly divided into three groups and injected or transplanted with PBS, IL-1β siRNA and IL-1β siRNA + BMSCs for another 4 weeks. The CIA rat model was successfully established, as demonstrated by the higher toe swelling value, thymus and spleen/body weight, immobility time and serum IL-1β concentration, as well as lower body weight, climbing time and mRNA expression of programmed death-1 (PD-1), transforming growth factor-β1 (TGF-β1) and forkhead box protein 3 (Foxp3) in the spleen, compared with control rats. Furthermore, histopathology results demonstrated that joint swelling and redness were observed in the knee joints of CIA rats. H&E results revealed that CIA rats presented erosive destruction of the bone and ulceration of the articular cartilage. In addition, in vitro results demonstrated that IL-1β expression was successfully silenced after IL-1β siRNA transfection in lipopolysaccharide-stimulated BMSCs. When compared with the results of PBS rats, both IL-1β siRNA injection and IL-1β siRNA + BMSC transplantation significantly increased the body weight, climbing time and mRNA expression of PD-1, TGF-β1 and Foxp3 in the spleen, while significantly reduced the immobility time and serum IL-1β concentration. In addition, when compared with that of IL-1β siRNA injection, IL-1β siRNA + BMSC transplantation exhibited markedly higher therapeutic efficacy against CIA. These results demonstrated that higher IL-1β contributed to the pathogenesis of CIA, and that IL-1β siRNA injection ameliorated CIA, while its combination with BMSCs exerted synergistic effects, which may be beneficial against RA.
34549898 Risk of cancer after initiation of targeted therapies in patients with rheumatoid arthriti 2021 Sep 21 OBJECTIVE: To determine the risk of recurrent or a new malignancy with exposure to targeted disease-modifying anti-rheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA), axial spondyloarthritis (AS), or psoriatic arthritis (PsA) and a history of cancer. METHODS: We performed a systematic search of the literature for articles published up to June 2019 that investigated adults with RA, AS or PsA who had a history of cancer and received biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs. We compared the risk of relapse or occurrence of new cancer between patients with and without bDMARDs. Rate ratios (RRs) with 95% confidence intervals (CIs) were estimated. The heterogeneity of the studies was evaluated by the Cochran Q test and the I² statistic. RESULTS: We included 24 observational studies of chronic inflammatory arthritis; 12 were included in the meta-analysis of RA patients receiving bDMARDs. As compared with RA patients with a history of cancer and not receiving bDMARDs, for those receiving any bDMARD, the overall RR for risk of neoplasia was 1.09 (95%CI [0.92-1.32], p=0.31, I²=8%); with tumor necrosis factor inhibitors, it was 1.11 (95%CI [0.85-1.46], p=0.45, I²=48%); and with rituximab, it was 0.79 (95%CI [0.41-1.53], p=0.49, I²=0%). The RR for risk of recurrence for skin cancer was 1.32 (95% CI [1.02-1.72], p=0.04, I²=0%) and for breast neoplasia 1.21 (95% CI [0.84-1.72], p=0.31, I²=0%). CONCLUSION: Apart from skin cancers including melanoma, the risk of recurrent or new cancer is not increased with the initiation of bDMARDs for RA as compared with no bDMARDs.
35295740 β-Sitosterol Inhibits Rheumatoid Synovial Angiogenesis Through Suppressing VEGF Signaling 2021 Background: Rheumatoid arthritis (RA) is a chronic disabling inflammatory disease that causes synovial angiogenesis in an invasive manner and leads to joint destruction. Currently available pharmacotherapy for RA has unwanted side effects and limitations. Although anti-angiogenic therapy is regarded as a new potential treatment for RA, only a few anti-angiogenic drugs are available. An increasing number of studies have shown that β-sitosterol (BSS) may exert inhibitory effects against angiogenesis. However, the mechanisms involved are still unclear. Methods: Based on the results of the gene set enrichment analysis (GSEA) of the transcriptome data of endothelial cells from RA patients, we evaluated the pharmacological effects of BSS on the tube formation, cell proliferation, and migration of human umbilical vein endothelial cells (HUVECs). Furthermore, the effects of BSS treatment on vascular endothelial growth factor receptor 2 (VEGFR2) were determined using molecular docking and Western blotting. Additionally, in the presence or absence of BSS, synovial angiogenesis and joint destruction of the ankle were investigated in collagen-induced arthritis (CIA) mice. The effect of BSS treatment on VEGFR2/p-VEGFR2 expression was verified through immunohistochemical staining. Results: The immunohistochemistry results revealed that BSS treatment inhibited angiogenesis both in vitro and in vivo. In addition, the results of 5-ethynyl-2'-deoxyuridine and cell cycle analysis showed that BSS treatment suppressed the proliferation of HUVECs, while the Transwell migration and stress fiber assays demonstrated that BSS treatment inhibited the migration of HUVECs. Notably, the inhibitory effect of BSS treatment on VEGFR2/p-VEGFR2 was similar to that of axitinib. In CIA mice, BSS also exerted therapeutic effects on the ankles by reducing the degree of swelling, ameliorating bone and cartilage damage, preventing synovial angiogenesis, and inhibiting VEGFR2 and p-VEGFR2 expression. Conclusion: Therefore, our findings demonstrate that BSS exerts an inhibitory effect on synovial angiogenesis by suppressing the proliferation and migration of endothelial cells, thereby alleviating joint swelling and bone destruction in CIA mice. Furthermore, the underlying therapeutic mechanisms may involve the inhibition of VEGF signaling pathway activation.
34042520 Monoacylglycerol Lipase Inhibition Using JZL184 Attenuates Paw Inflammation and Functional 2021 Jun Background: Patients with rheumatoid arthritis (RA) experience joint swelling and cartilage destruction resulting in chronic pain, functional disability, and compromised joint function. Current RA treatments, including glucocorticoid receptor agonists, produce adverse side effects and lack prolonged treatment efficacy. Cannabinoids (i.e., cannabis-like signaling molecules) exert anti-inflammatory and analgesic effects with limited side effects compared to traditional immunosuppressants, making them excellent targets for the development of new arthritic therapeutics. Monoacylglycerol lipase (MAGL) inhibition reduces inflammation in mouse models of acute inflammation, through cannabinoid receptor dependent and independent pathways. The current study investigated the efficacy of inhibiting synthetic and catabolic enzymes that regulate the endocannabinoid 2-arachidonoylglycerol (2-AG) in blocking paw inflammation, pain-related behaviors, and functional loss caused by collagen-induced arthritis (CIA). Methods: Male DB1A mice subjected to CIA were administered the glucocorticoid agonist dexamethasone (DEX), MAGL inhibitor JZL184 (8 or 40 mg/kg, s.c.), alone or in combination, or diacylglycerol lipase β (DAGLβ) inhibitor KT109 (40 mg/kg, s.c.). CIA-induced deficits were assayed by arthritic clinical scoring, paw thickness measurements, and behavioral tests of pain and paw function. Results: DEX or dual administration with JZL184 reduced paw thickness and clinical scores, and JZL184 dose-dependently attenuated grip strength and balance beam deficits caused by CIA. Traditional measures of pain-induced behaviors (hyperalgesia and allodynia) were inconsistent. The antiarthritic effects of JZL184 (40 mg/kg) were largely blocked by coadministration of the CB(2) antagonist SR144528, and the DAGLβ inhibitor KT109 had no effect on CIA, indicating that these effects likely occurred through CB(2) activation. Conclusions: MAGL inhibition reduced paw inflammation and pain-depressed behavioral signs of arthritis, likely through an endocannabinoid mechanism requiring CB(2). These data support the development of MAGL as a target for therapeutic treatment of inflammatory arthritis.
34465982 What Matters to Patients with Rheumatoid Arthritis When Facing Medical or Non-Medical Trea 2021 BACKGROUND: In rheumatoid arthritis care, patients and healthcare professionals regularly face health treatment decisions. Sorting out what matters to a patient as being relevant to a specific decision is therefore essential. METHODS: An explorative mixed-methods study was performed to investigate patients' values for health treatment decisions and their importance in order to develop a future decision aid on value clarification. Ten semi-structured interviews with patient partners were conducted followed by an online survey among the broader population of patients. Qualitative content analysis was performed. Data from the online survey were analysed descriptively and quantitatively. RESULTS: According to patients, 17 important health treatment decisions in rheumatoid arthritis care can occur. The most commonly reported decisions concerned the use of medication. A variety of values may guide patients' health treatment decisions. We found 66 values among four domains of values - decisional, situational, external and global. Among decisional values, reported main values were a) effectiveness of treatment on inflammation, functioning, pain and fatigue; b) avoiding negative side-effects; and c) keeping in good physical condition. In addition, situational values turned out to be a) staying independent; b) being able to meet people; and c) leading as normal a life as possible. Furthermore, patients prefer healthcare professionals who a) take comorbidity into account, b) have enough time, and c) take the patient seriously in their choices - the external values. Finally, as global values were expressed a) autonomy; b) self-image, and c) intimacy. All values are specified by underlying quotes, for example, the value effectiveness on inflammation; "That inflammation has got to go, because you've then got the risk that you'll develop all kinds of things in the course of time". CONCLUSION: A variety of values may guide patients' health treatment decisions within rheumatoid arthritis care. Patients and professionals should discuss patients' values continuously.
34385832 A Single-Center Retrospective Observational Study Evaluating the Favorable Predictive Fact 2021 BACKGROUND: Tocilizumab (TCZ) is humanized monoclonal antibody against the interleukin-6 (IL-6) and receptor that has prominent efficacy for the treatment of rheumatoid arthritis (RA). We conducted a retrospective observational study to determine how long TCZ controls RA. PATIENTS AND METHODS: We retrospectively reviewed the medical records of RA patients treated with TCZ. The aim of this study was to evaluate the contribution of clinical parameters to disease control time (DCT) in RA patients. RESULTS: Overall, 144 patients were enrolled in the study. The median age of patients was 66 years (range: 34-85 years). In univariate analysis, DCT was significantly increased in patients who had never received previous biologic disease-modifying anti-rheumatic drugs treatment (P = 0.0064). We also analyzed the contribution of the base line value of C-reactive protein (CRP) to DCT. We divided the patients with RA into two groups according to a cutoff value of 1.000 mg/dl. The median control times were 77.5 months (95% confidence interval [CI]: 44.8-not reached to median) and 34.5 months (95% CI: 17.0-79.3) for patients with high and low CRP value, respectively. In univariate analysis, DCT was significantly increased in patients with a high CRP value (P = 0.0283). Multivariate analysis clearly revealed that a high baseline CRP value was an independent favorable predictive factor for longer DCT (hazard ratio, 0.608, 95% CI: 0.378-0.981, P = 0.0416). CONCLUSION: These data clearly demonstrate that the baseline value of CRP was closely associated with long time DCT in patients of RA treated with TCZ.
34251498 Bronchiectasis is as crucial as interstitial lung disease in the severe pneumonia that occ 2021 Jul 12 Interstitial lung disease (ILD) carries a risk for severe pneumonia in patients with rheumatoid arthritis (RA). Bronchiectasis, another risk of severe pneumonia, has not been well elucidated in RA. We investigated the types of respiratory diseases in RA and correlated them to severe pneumonia during the course of treatment using biologic DMARDs (bDMARDs), with special attention to bronchiectasis and ILD. RA patients were examined by computed tomography before starting bDMARDs and divided into three groups: normal, bronchiectasis and ILD. The log-rank test and Dunnett's multiple comparisons test were employed for the statistical analysis. Among 424 patients, 350 were categorized as normal, 32 as having bronchiectasis, and 42 as having ILD. Two in the normal group, three in the bronchiectasis group and four in the ILD group developed severe pneumonia. The log-rank test showed a significant difference among the three groups (p < 0.0001). The pneumonia-free rates in the bronchiectasis and ILD groups were significantly lower than the normal group, respectively, with Dunnett's multiple comparison test (p < 0.0001). This study suggests that the bronchiectasis that occurs in RA carries a risk of severe pneumonia during treatment with bDMARDs that is comparable to ILD.
34017191 Lentivirus-Mediated Overexpression or Silencing of Aquaporin 1 Affects the Proliferation, 2021 INTRODUCTION: Previous studies have confirmed the pathologic role of synovial aquaporin 1 (AQP1) in rheumatoid arthritis (RA), but its associations with the abnormal biologic behaviors of fibroblast-like synoviocytes (FLS) remain unclear. Herein, we examined the roles of AQP1 in the proliferation, migration and invasion of TNF-α-stimulated RA FLS (MH7A cells) and explored the underlying mechanisms. MATERIALS AND METHODS: Lentivirus-mediated AQP1 overexpression or silencing MH7A cells was constructed. Assays of MTT, flow cytometry (PI staining and Annexin V-PE/7-AAD staining), TMRM staining, wound-healing, transwell and phalloidin staining were performed to detect cell proliferation, cycle distribution, apoptosis, migration and invasion. The involvement of Wnt/β-catenin pathway was revealed by Western blot and β-catenin immunofluorescence staining. RESULTS: AQP1 overexpression promoted cell proliferation of TNF-α-stimulated MH7A by facilitating transformation from G0/G1 to S phase and inhibiting cell apoptosis (ie, reduced apoptosis rates, raised mitochondrial membrane potential, increased Bcl-2 protein level and decreased levels of Bax and cleaved caspase 3 protein). Also, AQP1 overexpression increased the migration index as well as the numbers of migrated and invasive cells. Furthermore, AQP1 overexpression promoted the activation of Wnt/β-catenin pathway, and XAV939, an inhibitor of Wnt/β-catenin, canceled the above effects of AQP1 overexpression on MH7A cells. As expected, AQP1 silencing exhibited the opposite effects on TNF-α-stimulated MH7A cells, which could be reversed by LiCl, an activator of Wnt/β-catenin. CONCLUSION: AQP1 can affect the proliferation, migration and invasion of MH7A cells by Wnt/β-catenin signaling pathway, and AQP1 can be as a crucial determiner that can regulate RA FLS biologic behaviors.
33996461 3-D microarchitectural properties and rod- and plate-like trabecular morphometric properti 2021 May OBJECTIVES: We quantify 3-D microarchitectural properties of femoral head cancellous bones from patients with rheumatoid arthritis (RA, n ​= ​12), osteoarthritis (OA, n ​= ​15), osteoporosis (OP, n ​= ​24), or donor controls (CNT, n ​= ​8); and investigate their rod- and plate-like trabecular morphometric properties of trabecular bone tissues and compare these properties between them. METHODS: Femoral heads were harvested during total hip replacement surgeries or collected from donors. Four cubic cancellous bone samples produced from each femoral head were micro-CT scanned to quantify their microarchitectural and rod- and plate-like trabecular properties. The samples were then tested in compression to determine mechanical properties. RESULTS: The microarchitectural properties of femoral head cancellous bone revealed significant differences among the 4 groups, but not between RA and OA. Bone volume fraction was significantly greater in the RA and the OA than in the OP and the CNT. Structure model index was significantly lower in the RA and the OA than in the OP. Number of rods in the RA was significantly greater than in the other 3 groups. Number of plates and plate volume density in the RA and the OA were significantly greater than in the OP and the CNT. Mechanical properties were significantly greater in the RA and the OA than in the OP. The single best determinant for mechanical properties was bone volume fraction. CONCLUSIONS: This study demonstrates significant differences in 3-D microarchitectural properties and rod- and plate-like trabecular morphometric properties among patients with RA, OA, or OP. The RA and OA cancellous bones displayed similar patterns of microarchitectural degeneration and pronounced different microarchitectures from the OP. The OP group revealed the weakest cancellous bone strength, while the RA and OA groups exhibited a compensatory effect that maintains bone tissues, and hence mechanical properties. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The study enhances the understanding of microarchitectural degeneration of diseased cancellous bone. The OP group had the weakest cancellous bone strength, while the RA and OA groups exhibited a compensatory effect that maintains bone tissues, and hence mechanical properties. These results are particularly important for design and survival of joint prosthesis.
33603441 Correlations Between TIMD-4 Gene Variants and the Risk and Clinical Features of Rheumatoid 2021 INTRODUCTION: T-cell immunoglobulin and mucin domain-4 (TIMD-4) are likely to impact autoimmune diseases (e.g., rheumatoid arthritis (RA)). It is hypothesized here that TIMD-4 gene polymorphism is likely to display a correlation with the RA risk. METHODS: For examining the effect exerted by TIMD-4 genetic variant in the RA risk, a case-control study containing 379 RA cases and 432 healthy control groups in Chinese population was performed. This study conducted genotyping with the use of a custom-by-design 48-Plex single nucleotide polymorphism (SNP) Scan™ Kit. Blood serum conditions of TIMD-4 in RA cases and matched control groups were measured by enzyme-connected immunosorbent assay (ELISA). RESULTS: Our results demonstrated that the TIMD-4 rs7700944 polymorphism could increase the RA risk in Chinese population. According to stratification analyzing processes, the TIMD-4 rs7700944 polymorphism displayed the correlation to the elevated RA risk in the females, smokers and cases aged ≥55 years. Cross-over analyses also indicated that the combined effect of smoking or drinking and GA genotype of rs7700944 locus contributed to an elevated risk of RA. In addition, the TIMD-4 rs7700944 polymorphism was also related to RA cases with DAS ≥ 3.20, ESR ≥25.00 mm/h and positive anti-ccp. Moreover, compared with the control groups, the average expression level of TIMD-4 in the serum of RA cases was apparently increased. CONCLUSION: In conclusion, the TIMD-4 rs7700944 polymorphism may increase the sensitivity to RA in Chinese population.
34457368 A Case of Pulmonary Infarction Resembling Pneumonia during Immunosuppressive Treatment for 2021 A 67-year-old woman with rheumatoid arthritis (RA) presented with fever and dyspnea. Chest radiography and computed tomography (CT) revealed pulmonary infiltrates with ground-glass opacities. We considered bacterial or pneumocystis pneumonia because she was immunocompromised due to RA treatment. However, she had tachycardia and elevated D-dimer levels. We performed contrast-enhanced CT and subsequently diagnosed her with pulmonary embolism (PE). Though PE is not usually accompanied by parenchymal pulmonary shadows, pulmonary infarction may cause pulmonary infiltrates that can be mistaken for pneumonia. As RA is a thrombophilic disease, clinicians should be aware of PE and pneumonia as differential diagnoses in such patients.
35127697 A Preliminary Inquiry Into the Potential Mechanism of Huang-Lian-Jie-Du Decoction in Treat 2021 Huang-Lian-Jie-Du decoction (HLJDD) has been widely applied to treat inflammation-associated diseases for thousands of years in China. However, the concrete molecular mechanism of HLJDD in the treatment of rheumatoid arthritis (RA) remains unclear. In this work, network pharmacology and molecular docking were applied to preliminarily analyze the potential active ingredients, drug targets, and related pathways of HLJDD on treating RA. A total of 102 active compounds with corresponding 189 targets were identified from HLJDD, and 41 common targets were further identified by intersecting with RA-related targets. Functional enrichment analysis was performed to screen the biological pathways associated with RA. Ten hub targets were further identified through constructing the protein-protein interaction (PPI) network of common targets, which were mainly enriched in the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, and Toll-like receptor signaling pathway. Furthermore, a complex botanical drugs-ingredients-hub-targets-disease network was successfully constructed. The molecular docking results exhibited that these vital ingredients of HLJDD had a stable binding to the hub targets. Among these ingredients, quercetin (MOL000098) was the most common molecule with stable binding to all the targets, and PTGS2 was considered the most important target with multiple regulations by the most active ingredients. In vitro, we successfully validated the inhibitory role of quercetin in the cellular proliferation of human RA fibroblast-like synoviocyte cell line (MH7A cells). These findings indicated that the potential mechanisms of HLJDD for RA treatment might be attributed to inhibiting the immune-inflammatory response, reducing the release of chemokines, and alleviating the destruction of extracellular matrix (ECM) in the synovial compartment.
34745219 Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study. 2021 Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04-1.33, p = 1.07E-02), hypertension (OR = 1.45, 95% CI: 1.20-1.75, p = 9.64E-05), age heart attack (OR = 1.15, 95% CI: 1.05-1.26, p = 3.56E-03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01-1.12, p = 1.49E-02), stroke (OR = 1.06, 95% CI: 1.01-1.12, p = 2.79E-02), and coronary heart disease (OR = 1.19, 95% CI: 1.01-1.39, p = 3.33E-02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.
34589142 Repurposing haloperidol for the treatment of rheumatoid arthritis: an integrative approach 2021 INTRODUCTION: Treatment of rheumatoid arthritis (RA) has advanced with the introduction of biological disease-modifying antirheumatic drugs. However, more than 20% of patients with RA still have moderate or severe disease activity. Hence, novel antirheumatic drugs are required. Recently, drug repurposing, a process of identifying new indications for existing drugs, has received great attention. Furthermore, a few reports have shown that antipsychotics are capable of affecting several cytokines that are also modulated by existing antirheumatic drugs. Therefore, we investigated the association between antipsychotics and RA by data mining using real-world data and bioinformatics databases. METHODS: Disproportionality and sequence symmetry analyses were employed to identify the associations between the investigational drugs and RA using the US Food and Drug Administration Adverse Event Reporting System (2004-2016) and JMDC administrative claims database (January 2005-April 2017; JMDC Inc., Tokyo, Japan), respectively. The reporting odds ratio (ROR) and information component (IC) were used in the disproportionality analysis to indicate a signal. The adjusted sequence ratio (SR) was used in the sequence symmetry analysis to indicate a signal. The bioinformatics analysis suite, BaseSpace Correlation Engine (Illumina, CA, USA) was employed to explore the molecular mechanisms associated with the potential candidates identified by the drug-repurposing approach. RESULTS: A potential inverse association between the antipsychotic haloperidol and RA, which exhibited significant inverse signals with ROR, IC, and adjusted SR, was found. Furthermore, the results suggested that haloperidol may exert antirheumatic effects by modulating various signaling pathways, including cytokine and chemokine signaling, major histocompatibility complex class-II antigen presentation, and Toll-like receptor cascade pathways. CONCLUSION: Our drug-repurposing approach using data mining techniques identified haloperidol as a potential antirheumatic drug candidate.
34539823 Upregulating miR-27a-3p inhibits cell proliferation and inflammation of rheumatoid arthrit 2021 Nov Rheumatoid arthritis (RA) is a serious chronic inflammatory disease and synovial fibroblasts (SFs) serve a vital role in the pathogenesis and progression of RA. Current studies have demonstrated that dysregulation of microRNAs is involved in RA etiopathogenesis. The present study aimed to investigate the role of microRNA (miR)-27a-3p in RASFs, as well as its molecular mechanism. RASFs were isolated from synovial tissues from patients with RA. Expression of miR-27a-3p and toll-like receptor 5 (TLR5) was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation, apoptosis and inflammatory response were measured with MTT assay, flow cytometry and ELISA kits, respectively. The target binding between miR-27a-3p and TLR5 was predicted on DIANA TOOLS software, and confirmed by dual-luciferase reporter assay and Biotin-coupled miRNA pull-down assay. Expression of miR-27a-3p was downregulated and TLR5 was upregulated in synovial tissues and RASFs isolated from patients with RA. Functionally, upregulating miR-27a-3p may promote the apoptosis rate of RASFs and suppress cell proliferation and secretions of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α. TLR5 was validated as a downstream target for miR-27a-3p in RASFs, and its expression was negatively regulated by miR-27a-3p. Silencing TLR5 in RASFs may exert similar effects to miR-27a-3p-overexpression; whereas, restoring TLR5 counteracted the suppression of miR-27a-3p-overexpression on RASF proliferation and inflammation, as well as the promotion on apoptosis. miR-27a-3p upregulation may suppress RA progression by inhibiting RASFs proliferation and inflammation through targeting TLR5.
33986603 Cost-Effectiveness of Repository Corticotropin Injection versus Standard of Care for the T 2021 INTRODUCTION: Patients with active rheumatoid arthritis (RA) often have inadequately controlled symptoms and are unable to achieve remission or low disease activity despite aggressive treatment. This results in irreversible joint damage, adversely affecting patients' physical and social functioning. The objective was to estimate the cost-effectiveness of repository corticotropin injection (RCI) versus standard of care (SoC) in patients with active RA from the United States (US) payer and societal perspectives over two to three years. METHODS: An individual-level microsimulation was developed to generate individual trajectories for patients with RA, using data from a published Phase 4 trial of RCI. These trajectories report a patient's disease pathway and associated cost and quality-of-life outcomes. The incremental cost-effectiveness ratio (ICER) of RCI versus SoC was assessed using the literature-derived direct medical and indirect costs, and quality-adjusted life-years (QALY) derived from a Phase 4 trial of RCI. The uncertainty in base case estimates of the parameters was evaluated in the sensitivity analysis. RESULTS: Over two years, RCI has an incremental QALY gain of 1.591 and incremental cost of $183,965 and $117,443 from payer and societal perspective, respectively, resulting in an ICER of $115,629/QALY and $73,817/QALY compared to SoC. Over three years, RCI has an incremental QALY gain of 2.336 and incremental cost of $202,315 and $104,506 from payer and societal perspective, respectively, resulting in an ICER of $86,607/QALY and $44,737/QALY compared to SoC. Results from the probabilistic sensitivity analysis are consistent with those of the base case model. CONCLUSION: RCI is a cost-effective strategy for patients with persistently active RA who are previously treated with disease-modifying anti-rheumatic drugs and corticosteroids compared to SoC over two to three years from the payer and societal perspectives at a US willingness-to-pay threshold of $150,000/QALY. Further, the economic benefit of RCI is realized with improvement in a patient's clinical and health outcomes.
33939171 Elicitation of Rheumatologist Preferences for the Treatment of Patients with Rheumatoid Ar 2021 Jun INTRODUCTION: Rheumatoid arthritis (RA) clinical guidelines do not provide strong recommendations for the choice of disease-modifying anti-rheumatic drugs (DMARD) in patients with an inadequate response to methotrexate (MTX), and only limited evidence is available on factors influencing rheumatologist treatment decisions. We aimed to describe therapeutic preferences after the failure of a first-line strategy of MTX in simulated cases of patients with RA. METHODS: Fictional but realistic case-vignettes (n = 64) of patients with RA and an inadequate response to MTX were developed with a combination of RA-poor prognostic factors and comorbidities. Physicians were presented with eight vignettes and chose the most and least appropriate therapeutic option from the following six options randomly proposed 3 by 3: (1) replacing MTX with another csDMARD; (2) combining MTX with one or more csDMARDs; (3) adding a bDMARD of either TNF inhibitors (TNFi), tocilizumab (TCZ), abatacept (ABA), or rituximab (RTZ). A total of 1605 complete case vignettes were produced and randomly assigned to a representative sample of French rheumatologists. For each vignette, whenever a treatment was preferred, one point was incremented for this treatment; if this treatment was the least desired, one point was removed. Preferences were elicited using a normalized best-worst score. RESULTS: Two hundred and four French rheumatologists participated in the study with each vignette being assessed 20-28 times for a completion rate of 94%. TNFi was the first-choice strategy (80% of vignettes), except in cases with a history of infection and pulmonary comorbidity, where ABA was the first preference (85%). TCZ came third in 83% of the cases. Other options were never preferred and repeatedly yielded negative scores. CONCLUSIONS: We observed a conservative trend with TNFi as the main therapeutic choice for patients with RA and inadequate response to MTX. Preference for bDMARD-based strategies increased with the number of RA-poor prognosis factors, whereas an increase in the number of comorbidities resulted in an increased preference for ABA. Understanding clinical decision-making will be particularly important as the therapeutic landscape for RA continues to evolve.