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ID PMID Title PublicationDate abstract
31492546 The significance of the low sex ratios of offspring and of sibs of probands with systemic 2020 Feb There is good evidence that there are significantly low sex ratios (proportions male) in the offspring of patients with some immune diseases e.g. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). There is also strong evidence that there are significantly low sex ratios in the sibs of patients with SLE and RA and it has been suggested that the low SLE sib sex ratio may be explained by male fetal loss. However, no explanations for these low sex ratios has been established. Bearing in mind the posited hormonal involvement in immune processes, this paper suggesst an additional potential solution. It is that both the pathology and the sex ratio share a hormonal cause - testosterone. The argument depends on the hormonal hypothesis of sex ratio. This paper will describe the hypothesis and describe its relevance to SLE and RA.
30892764 A review of the influence of periodontal treatment in systemic diseases. 2019 Feb The effects and consequences of periodontal diseases might not be confined to the oral cavity. A great body of evidence has arisen supporting the claim demonstrating an association with several systemic conditions and diseases. With different levels of evidence, an association between periodontal disease and cardiovascular disease, diabetes, psoriasis, rheumatoid arthritis, pregnancy outcomes and respiratory diseases has been established. However, the true nature of this association, if it is causal, still remains elusive. For a better understanding of the complex relationships linking different conditions, interventional studies now begin to focus on the possible outcomes of periodontal treatment in relation to the events, symptoms and biomarkers of several systemic disorders, assessing if periodontal treatment has any impact on them, hopefully reducing their severity or prevalence. Therefore, we proceeded to review the recent literature on the subject, attempting to present a brief explanation of the systemic condition or disease, what proposed mechanisms might give biological plausibility to its association with periodontal disease, and finally and more importantly, what data are currently available pertaining to the effects periodontal treatment may have. Raising awareness and discussing the possible benefits of periodontal treatment on overall systemic health is important, in order to change the perception that periodontal diseases are only limited to the oral cavity, and ultimately providing better and comprehensive care to patients.
30932790 Association between dietary intake of some antioxidant micronutrients with some inflammato 2019 Nov Background: Rheumatoid Arthritis (RA) is an autoimmune disease. Antioxidants intake and body antioxidants status are important in patients with RA. The aim of this study was to investigate the association between dietary intake of some antioxidant micronutrients with some inflammatory and antioxidant markers in patients with active rheumatoid arthritis and comparison with Recommended Dietary Allowance (RDA). Materials and Methods: In this cross-sectional study, eighty-seven patients with active rheumatoid arthritis were included. Dietary antioxidants intake was measured using 24-hour recall questionnaire and food record (3 days). Blood levels of inflammatory and antioxidant markers were determined by laboratory tests. The association between intake of antioxidants with inflammatory and antioxidant markers, and also with RDA were determined using Paired-Samples t-test and Pearson correlation by SPSS software. Results: The findings showed that intakes of vitamin E, zinc, and magnesium in patients were significantly lower and intakes of copper and selenium were significantly higher than RDA (P < 0.05). Significant negative correlations were observed between vitamin A intake with PGE2 [R = -0.31], vitamin C intake with IL-1β [R = -0.25], zinc intake with PGE2 [R = -0.30], IL-2 [R = -0.23], and the activity of glutathione reductase enzyme [R = -0.21], magnesium intake with PGE2 [R = -0.24], IL-1β [R = -0.23] and IL-2 [R = -0.25], and selenium intake with PGE2 [R = -0.21] (P < 0.05). Also, significant positive correlations were observed between intakes of vitamin E and copper with catalase enzyme activity [R = 0.22 and R = 0.21 respectively] (P < 0.05). Conclusion: Some of the antioxidant micronutrients play important roles in the reduction of inflammatory conditions and improve the function of antioxidant enzymes in patients with rheumatoid arthritis.
31251785 Severity of fatigue in people with rheumatoid arthritis, psoriatic arthritis and spondyloa 2019 BACKGROUND: Despite improvements in treatment for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (axSpA), several key unmet needs remain, such as fatigue. The objective of this study was to describe the severity of fatigue, disease characteristics and socioeconomic factors in people with RA, PsA and axSpA. METHODS: The study was designed as a cross-sectional survey collecting patient characteristics such as disease characteristics, socioeconomic factors and fatigue in people with RA, PsA and axSpA in Denmark. Respondents were consecutively recruited for the study over a six-month period in 2018 via routine visits to outpatient rheumatology clinics. Study nurses collected information on diagnosis, current disease-related treatment and disease activity from medical journals. People were invited to complete a questionnaire related to socioeconomic factors and containing the FACIT-Fatigue subscale. Descriptive statistics were analyzed using SAS. RESULTS: We invited 633 people to participate, and 488 (77%) completed the questionnaire. Women constituted 62% of respondents, and the mean age was 53.5 years. Respondents had on average been diagnosed between 11 and 15 years ago. Overall, 79% had no changes to their disease-related treatment during the past year, and the average disease activity as indicated by DAS28 for RA and PsA was 2.48 and 2.36, respectively, and BASDAI for axSpA was 28.40. Fatigue was present in all three diagnoses (mean: 34.31). The mean fatigue score varied from respondents answering that they suffered from no or little fatigue (mean: 45.48) to extreme fatigue (mean: 10.11). Analyses demonstrated that the respondents were not considerably different from nonrespondents, and the study population is considered representative compared with Danish RA and axSpA patients in the Danish National Rheumatology Registry, the DANBIO database. CONCLUSION: We found that the majority of the study population were fatigued (61%). They had low disease activity and few disease-related treatment changes.
30583799 [Pharmaceutical interviews for rheumatoid arthritis patients: Perceptions and expectations 2019 Mar INTRODUCTION: Rheumatoid arthritis has a low level of medication adherence. Abroad, the community pharmacist has a positive impact on the patients' adherence in several chronic diseases. In France, community pharmacists' missions are developing with the implementation of pharmaceutical interviews. OBJECTIVE: To evaluate community pharmacists' perceptions on the interest and feasibility of pharmaceutical interviews targeting patients with rheumatoid arthritis. METHOD: Semi-structured interviews were conducted between August and October 2017, with pharmacists in the Auvergne-Rhône-Alpes region. The inductive analysis of the interview verbatim was realized by two independent persons. RESULTS: Fifteen community pharmacists highlighted barriers in recruiting patients for the interviews currently possible at the pharmacy, the complexity of the organization and the financing, a weakness of the hospital-to-community liaison. Nevertheless pharmacists were motivated to expand the service to other pathologies. Regarding rheumatoid arthritis, pharmacists would see them in the form of structured interviews preferentially at the pharmacy, in connection or even "prescribed" by physicians for optimal and multi-professional information sharing. Prior training and funding for these interviews should be considered to motivate pharmacists to this activity. CONCLUSION: This study allowed to discuss with community pharmacists their expectations and needs to widen the service of pharmaceutical interviews in the rheumatoid arthritis. These results will have to be taken into account to build a support interviews model for rheumatoid arthritis patients who can be integrated in their daily pharmaceutical activity.
30383451 Fas receptor induces apoptosis of synovial bone and cartilage progenitor populations and p 2019 Mar Rheumatoid arthritis (RA) is an inflammatory joint disease that eventually leads to permanent bone and cartilage destruction. Fas has already been established as the regulator of inflammation in RA, but its role in bone formation under arthritic conditions is not completely defined. The aim of this study was to assess the effect of Fas inactivation on the bone damage during murine antigen-induced arthritis. Subchondral bone of wild-type (WT) and Fas-knockout (Fas(-/-)) mice was evaluated by histomorphometry and microcomputerized tomography. Proportions of synovial bone and cartilage progenitors were assessed by flow cytometry. Synovial bone and cartilage progenitors were purified by fluorescence-activated cell sorting and expression of Fas and Fas-induced apoptosis were analyzed in vitro. Results showed that Fas(-/-) mice developed attenuated arthritis characterized by preserved epiphyseal bone and cartilage. A proportion of the earliest CD200(+) bone and cartilage progenitors was reduced in WT mice with arthritis and was unaltered in Fas(-/-) mice. During osteoblastic differentiation in vitro, CD200(+) cells express the highest levels of Fas and are removed by Fas ligation. These results suggest that Fas-induced apoptosis of early CD200(+) osteoprogenitor population represents potential mechanism underlying the impaired bone formation in arthritis, so their preservation may represent the bone-protective mechanism during arthritis.-Lazić Mosler, E., Lukač, N., Flegar, D., Fadljević, M., Radanović, I., Cvija, H., Kelava, T., Ivčević, S., Šućur, A., Markotić, A., Katavić, V., Marušić, A., Grčević, D., Kovačić, N. Fas receptor induces apoptosis of synovial bone and cartilage progenitor populations and promotes bone loss in antigen-induced arthritis.
30917076 Adherence, Persistence, and Expenditures for High-Cost Anti-Inflammatory Drugs in Rheumato 2019 Apr BACKGROUND: Drugs for inflammatory conditions are one of the highest expenditure therapeutic classes for health plans. Published literature for adherence, persistence, nonadherence risk factors, and health care costs are incomplete for newer biologic agents. OBJECTIVES: To (a) examine differences in adherence, persistence, switch patterns, and health care costs among high-cost specialty anti-inflammatory medications and (b) suggest risk factors for nonadherence in rheumatoid arthritis. METHODS: In this exploratory retrospective cohort study, we used medical and pharmacy claims from 1.2 million enrollees in commercial health plans administrated by Premera Blue Cross, the largest not-for-profit health plan in the Pacific Northwest. We included members with rheumatoid arthritis who used the following high-cost disease-modifying antirheumatic drugs: abatacept, adalimumab, anakinra, apremilast, certolizumab, etanercept, golimumab, infliximab, rituximab, sekukinumab, tocilizumab, tofacitinib, and ustekinumab. Adherence was calculated via medication possession ratio. Persistence was calculated as the amount of days between the initial fill and final fill plus days supply. Switch rates for adalimumab and etanercept were calculated as the percentage of members who switched to another target drug during the observation period. Direct medical costs (total health care costs) and health care costs excluding specialty agents were calculated using the net allowable amount per claim for the duration of each therapy. Adherence, persistence, and costs of care were also examined for concurrent methotrexate use for the most used target drugs. RESULTS: The most commonly used drugs were abatacept (n = 47), adalimumab (n = 226), and etanercept (n = 252). Nonadherence in certain subgroups was associated with higher mean monthly health care costs, excluding specialty agents (etanercept cohort: +$1,063 for nonmethotrexate users; +$492 for nonadherent methotrexate users), but adherence was associated with higher total health care costs (+$883 for etanercept). Relative to specialty pharmacies, retail was associated with 9% higher nonadherence. Concurrent methotrexate use was associated with higher persistence (+307 and +192 days with adalimumab and etanercept). The most commonly switched-to drug after adalimumab/etanercept was abatacept (n = 39). CONCLUSIONS: This exploratory study raises signals suggesting that retail pharmacies may be associated with higher nonadherence; nonadherence may be associated with increased health care costs, excluding specialty agents; adherence may increase total health care costs; and methotrexate use may be associated with increased persistence. Future research should confirm these findings. DISCLOSURES: This research was part of an internship awarded to Khilfeh by the AMCP Foundation/Pfizer Summer Internship Program and funded by Pfizer. Gross is an employee of Pfizer. The other authors have nothing to disclose. A portion of this research was presented at the AMCP Managed Care & Specialty Pharmacy Annual Meeting as a continuing education session entitled "The Evolving Role of Real-World Data in Health Care Decision Making" on March 29, 2017, in Denver, CO, and at AMCP Nexus 2016 as a poster on October 3-6, 2016, in National Harbor, MD.
31654156 Abatacept retention and clinical outcomes in Austrian patients with rheumatoid arthritis: 2020 Apr BACKGROUND: AbataCepT In rOutiNe clinical practice (ACTION; NCT02109666) was a 2-year international observational study of patients with moderate to severe rheumatoid arthritis. METHODS: Baseline characteristics, abatacept retention rates, and clinical outcomes were compared by treatment line in the Austrian cohort of ACTION. RESULTS: Of 100 patients enrolled in Austria, 98 (98.0%) were evaluable: 33/98 (33.7%) biologic naïve and 65/98 (66.3%) with ≥1 prior biologic failure. At baseline, biologic-naïve patients had shorter disease duration and lower concomitant corticosteroid use than biologic-failure patients. Overall crude abatacept retention rate was 60.5% and retention rate was higher in biologic-naïve (65.1%) versus biologic-failure (58.0%) patients. Good/moderate EULAR (European League Against Rheumatism) response rates were 85.7% in biologic-naïve and 100% in biologic-failure patients. CONCLUSIONS: In the Austrian cohort of ACTION, overall abatacept retention at 2 years was high, with higher retention rates in patients receiving abatacept as an earlier treatment line. Good/moderate EULAR response rate was higher in biologic-failure than in biologic-naïve patients.
31675124 Immunopharmacological effect of β-d-mannuronic acid (M2000), as a new immunosuppressive d 2020 May The positive impacts of β-d-mannuronic acid (M2000) on the gene expression of miR-155, its target molecules (SOCS1 and SHIP1), and NF-κB transcription factor were demonstrated in a study using the HEK293-TLR2 cell line. This new drug has been approved as a safe and effective medication by a randomized, multinational, phase III clinical trial on RA patients. The present study aimed to evaluate the oral administration effect of M2000 on the expression levels of the mentioned genes in RA patients. This research was conducted on 12 RA patients and 12 healthy individuals. After extraction of total RNA from PBMCs of patients and synthesis of cDNA, the expression levels of miR-155, SOCS1, SHIP1, and NF-κB genes were measured through quantitative Real-time PCR at baseline and after 12 weeks of M2000 therapy. Our findings showed that the miR-155 gene expression level significantly decreased in the M2000-treated patients compared with the baseline (0.76-fold, with p < .05). The expression levels of SOCS1 and SHIP1 genes significantly increased in the patients treated with M2000 compared with the before treatment (1.46-, 1.54-fold, with p < .01, p < .05, respectively). In addition, it was found that the gene expression level of the NF-κB transcription factor significantly reduced in M2000-treated patients compared with the baseline (0.81-fold, with p < .05). This study showed that the oral administration of M2000 was able to reduce the expression of the miR-155, increase the expression of SOCS1 and SHIP1, and decrease the NF-κB gene expression (Trial Registration Number: IRCT2017100213739N10).
30874779 Assessment of a Deep Learning Model Based on Electronic Health Record Data to Forecast Cli 2019 Mar 1 IMPORTANCE: Knowing the future condition of a patient would enable a physician to customize current therapeutic options to prevent disease worsening, but predicting that future condition requires sophisticated modeling and information. If artificial intelligence models were capable of forecasting future patient outcomes, they could be used to aid practitioners and patients in prognosticating outcomes or simulating potential outcomes under different treatment scenarios. OBJECTIVE: To assess the ability of an artificial intelligence system to prognosticate the state of disease activity of patients with rheumatoid arthritis (RA) at their next clinical visit. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study included 820 patients with RA from rheumatology clinics at 2 distinct health care systems with different electronic health record platforms: a university hospital (UH) and a public safety-net hospital (SNH). The UH and SNH had substantially different patient populations and treatment patterns. The UH has records on approximately 1 million total patients starting in January 2012. The UH data for this study were accessed on July 1, 2017. The SNH has records on 65 000 unique individuals starting in January 2013. The SNH data for the study were collected on February 27, 2018. EXPOSURES: Structured data were extracted from the electronic health record, including exposures (medications), patient demographics, laboratories, and prior measures of disease activity. A longitudinal deep learning model was used to predict disease activity for patients with RA at their next rheumatology clinic visit and to evaluate interhospital performance and model interoperability strategies. MAIN OUTCOMES AND MEASURES: Model performance was quantified using the area under the receiver operating characteristic curve (AUROC). Disease activity in RA was measured using a composite index score. RESULTS: A total of 578 UH patients (mean [SD] age, 57 [15] years; 477 [82.5%] female; 296 [51.2%] white) and 242 SNH patients (mean [SD] age, 60 [15] years; 195 [80.6%] female; 30 [12.4%] white) were included in the study. Patients at the UH compared with those at the SNH were seen more frequently (median time between visits, 100 vs 180 days) and were more frequently prescribed higher-class medications (biologics) (364 [63.0%] vs 70 [28.9%]). At the UH, the model reached an AUROC of 0.91 (95% CI, 0.86-0.96) in a test cohort of 116 patients. The UH-trained model had an AUROC of 0.74 (95% CI, 0.65-0.83) in the SNH test cohort (n = 117) despite marked differences in the patient populations. In both settings, baseline prediction using each patients' most recent disease activity score had statistically random performance. CONCLUSIONS AND RELEVANCE: The findings suggest that building accurate models to forecast complex disease outcomes using electronic health record data is possible and these models can be shared across hospitals with diverse patient populations.
31837028 Isoagglutinin-reduced immunoglobulin retains efficacy in mouse models of immune thrombocyt 2020 Feb BACKGROUND: Immunoglobulin therapy including intravenous immunoglobulin (IVIg) has been used as an effective treatment for autoimmune/inflammatory conditions with few side effects. However, high-dose IVIg (1-2 g/kg) has been recognized as a cause of hemolytic anemia in non-blood group O patients. Hemolysis when observed has been due to anti-A/anti-B isoagglutinins contained in the IVIg. Recently, an isoagglutinin-reduced IVIg, whereby the anti-A and anti-B titers have been reduced by immunoaffinity chromatography, has been introduced; however, whether this new product is as efficacious as nonreduced immunoglobulin (Ig) or will result in less IVIg-associated hemolysis has not been resolved. STUDY DESIGN AND METHODS: We used in vitro phagocytosis by monocytes and proinflammatory/anti-inflammatory macrophages, with isoagglutinin-reduced and -nonreduced Ig opsonized group A(1) , B, and A(1) B red blood cells, to estimate clinical significance of the IgG isoagglutinins. We also used immune thrombocytopenia (ITP) and rheumatoid arthritis (RA) mouse models to examine the in vivo efficacy of isoagglutinin-reduced versus -nonreduced Ig on the amelioration of the diseases. RESULTS: In contrast to nonreduced Ig, phagocytosis was largely absent when isoagglutinin-reduced Ig was used at a concentration equivalent to a patient receiving 2 g/kg. The in vivo efficacy of isoagglutinin-reduced versus nonreduced Ig on the amelioration of experimental ITP and RA was similar, indicating no loss of efficacy due to the chromatographic removal of isoagglutinins. CONCLUSION: Isoagglutinin-reduced Ig should have efficacy similar to nonreduced Ig and result in less IVIg-associated hemolysis.
31857303 Relapse in rheumatoid arthritis patients undergoing dose reduction and withdrawal of biolo 2019 Dec 18 OBJECTIVE: To determine predictive/predictable factors of relapse in rheumatoid arthritis (RA) patients undergoing biologic Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) dose reduction/discontinuation. PATIENTS AND METHODS: RA patients receiving the same bDMARD for more than 1 year, in Simplified Disease Activity Index (SDAI) remission, were selected in an observational monocentric real-life study. The 18-month follow-up included spacing (6 months) and withdrawal (12 months) periods of bDMARD. Clinical, biological and ultrasonographic (US) parameters were collected regularly. Relapse was defined by SDAI>11. RESULTS: Fifty-three RA patients (mean age: 58 years; 72% women; median duration: 11 years) were enrolled. Forty-two received anti-cytokinic bDMARD targeting tumour necrosis factor (n=39) or interleukin-6R (n=3) and 11 were treated by abatacept. The number of relapses during the spacing and discontinuation periods were 19 and 20, respectively. After 18 months of follow-up, among the 53 patients, 12 maintained bDMARD-free remission, 39 had relapsed and 2 were lost of follow-up. Median time to relapse was 11.8 months. In multivariate analysis, baseline factors predictive of relapse were corticosteroid intake, female gender, longer disease duration and no methotrexate intake with bDMARD. Concerning the survival analysis, also taking into account the factors of predictability, the main risk factor of relapse after discontinuation was an increase of SDAI >0 during the spacing period (p=0.03). US findings were not contributive. CONCLUSION: In the context of RA in remission under bDMARDs, variation of SDAI during the dose-reduction phase is more relevant than baseline parameters to predict success of drug withdrawal.
30826172 Rheumatoid arthritis patients have higher prevalence and burden of asymptomatic coronary a 2019 Apr BACKGROUND: Rheumatoid arthritis (RA) is associated with increased risk of coronary artery disease (CAD) and studies with coronary computed tomography have suggested increased rates of asymptomatic CAD determined by the coronary calcium score (CCS) in these patients. To synthesize the evidence on this topic, we conducted a systematic review and meta-analysis of the literature. METHODS: A systematic review was performed of data comparing the prevalence and burden of asymptomatic CAD in RA and controls using CCS with or without coronary computed tomographic angiography (CCTA). For the meta-analysis, pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in patients with RA compared to controls. RESULTS: The search revealed 1841 results of which 1083 were screened and 26 full text papers were evaluated. Eight studies were included with data on 788 patients with RA and 1641 controls. Patients with RA had significantly increased risk of CAD (RR = 1.26 [95% CI 1.04-1.52]; p = .021) and increased weighted mean differences for CCS (48.25 [95% CI 26.97-69.53]; p < .001) compared to controls. Limited evidence suggested that patients with RA had a higher prevalence of moderate-severe (CCS > 100) CAD and more multivessel CAD, and RA duration and disease activity were associated with higher CCS, RA disease activity was linked with presence of high risk (non-calcified or mixed) coronary plaques, and treatment with methotrexate was tied to absence of CAD, respectively. CONCLUSIONS: In patients with RA, asymptomatic CAD is more prevalent, with higher mean CCS, more multivessel disease, and more high-risk plaques compared to controls.
30804378 Genetic variants differentially associated with rheumatoid arthritis and systemic lupus er 2019 Feb 25 Two rheumatic autoimmune diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), have distinct clinical features despite their genetic similarities. We hypothesized that disease-specific variants exclusively associated with only one disease could contribute to disease-specific phenotypes. We calculated the strength of disease specificity for each variant in each disease against the other disease using summary association statistics reported in the largest genome-wide association studies of RA and SLE. Most of highly disease-specific associations were explained by non-coding variants that were significantly enriched within regulatory regions (enhancers or H3K4me3 histone modification marks) in specific cell or organ types. (e.g., In RA, regulatory T primary cells, CD4+ memory T primary cells, thymus and lung; In SLE, CD19+ B primary cells, mobilized CD34+ primary cells, regulatory T primary cells and monocytes). Consistently, genes in the disease-specific loci were significantly involved in T cell- and B cell-related gene sets in RA and SLE. In summary, this study identified disease-specific variants between RA and SLE, and provided statistical evidence for disease-specific cell types, organ and gene sets that may drive the disease-specific phenotypes.
30784354 Safety profile of baricitinib in Japanese patients with active rheumatoid arthritis with o 2020 Jan Objectives: Baricitinib is a selective oral inhibitor of JAK1/JAK2 for patients with moderately-to-severely active rheumatoid arthritis (RA). Baricitinib's safety profile in Japanese patients was evaluated using six studies (five Ph2/Ph3 trials, one long-term extension study through 01 September 2016) from an integrated database (nine RA studies).Methods: Incidence rates (IRs) or exposure-adjusted IRs (EAIRs) of adverse events (AEs) per 100 patient-years (PY) were calculated using data which included RA patients exposed to any baricitinib dose.Results: Five hundred and fourteen Japanese patients received baricitinib for 851.5 total PY of exposure (median 1.7 years, maximum 3.2). The EAIR of treatment-emergent AEs was 57.4/100PY. There were no deaths; 31 patients had serious infections (IR: 3.6/100PY), 55 herpes zoster (6.5), 0 tuberculosis, 10 malignancies (1.1) including two lymphomas, two major cardiovascular AEs (0.3), one gastrointestinal perforation (0.1), and four deep vein thrombosis (0.5). In Japanese patients, herpes zoster was more frequent than that of patients overall in the integrated database, but the events were considered manageable.Conclusion: In this analysis, baricitinib had acceptable safety profile in Japanese RA patients in the context of demonstrated efficacy. Aside from herpes zoster, baricitinib safety was not notably different between Japanese RA patients and those RA patients in the integrated database.Trial registration: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at https://clinicaltrials.gov/.
31847895 Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clini 2019 Dec 17 OBJECTIVES: To examine the ability of takinib, a selective transforming growth factor beta-activated kinase 1 (TAK1) inhibitor, to reduce the severity of murine type II collagen-induced arthritis (CIA), and to affect function of synovial cells. METHODS: Following the induction of CIA, mice were treated daily with takinib (50 mg/kg) and clinical scores assessed. Thirty-six days post-CIA induction, histology was performed on various joints of treated and vehicle-treated animals. Inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation were quantified. Furthermore, pharmacokinetics of takinib were evaluated by LC-MS in various tissues. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) cells were cultured with 10 μM takinib and cytokine secretion analyzed by cytokine/chemokine proteome array. Cytotoxicity of takinib for RA-FLS was measured with 24 to 48 h cultures in the presence or absence of tumor necrosis factor (TNF). RESULTS: Here, we show takinib's ability to reduce the clinical score in the CIA mouse model of rheumatoid arthritis (RA) (p < 0.001). TAK1 inhibition reduced inflammation (p < 0.01), cartilage damage (p < 0.01), pannus, bone resorption, and periosteal bone formation and periosteal bone width in all joints of treated mice compared to vehicle treated. Significant reduction of inflammation (p < 0.004) and cartilage damage (p < 0.004) were observed in the knees of diseased treated animals, with moderate reduction seen in the forepaws and hind paws. Furthermore, the pharmacokinetics of takinib show rapid plasma clearance (t(½) = 21 min). In stimulated RA-FLS cells, takinib reduced GROα, G-CSF, and ICAM-1 pro-inflammatory cytokine signaling. CONCLUSION: Our findings support the hypothesis that TAK1 targeted therapy represents a novel therapeutic axis to treat RA and other inflammatory diseases.
31831833 Exploring inflammatory signatures in arthritic joint biopsies with Spatial Transcriptomics 2019 Dec 12 Lately it has become possible to analyze transcriptomic profiles in tissue sections with retained cellular context. We aimed to explore synovial biopsies from rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients, using Spatial Transcriptomics (ST) as a proof of principle approach for unbiased mRNA studies at the site of inflammation in these chronic inflammatory diseases. Synovial tissue biopsies from affected joints were studied with ST. The transcriptome data was subjected to differential gene expression analysis (DEA), pathway analysis, immune cell type identification using Xcell analysis and validation with immunohistochemistry (IHC). The ST technology allows selective analyses on areas of interest, thus we analyzed morphologically distinct areas of mononuclear cell infiltrates. The top differentially expressed genes revealed an adaptive immune response profile and T-B cell interactions in RA, while in SpA, the profiles implicate functions associated with tissue repair. With spatially resolved gene expression data, overlaid on high-resolution histological images, we digitally portrayed pre-selected cell types in silico. The RA displayed an overrepresentation of central memory T cells, while in SpA effector memory T cells were most prominent. Consequently, ST allows for deeper understanding of cellular mechanisms and diversity in tissues from chronic inflammatory diseases.
31260948 Disease activity in rheumatoid arthritis is inversely related to cerebral TSPO binding ass 2019 Sep 15 Reumatoid Arthritis (RA) is an autoimmune disorder characterized by peripheral joint inflammation. Recently, an engagement of the brain immune system has been proposed. The aim with the current investigation was to study the glial cell activation marker translocator protein (TSPO) in a well characterized cohort of RA patients and to relate it to disease activity, peripheral markers of inflammation and autonomic activity. Fifteen RA patients and fifteen healthy controls matched for age, sex and TSPO genotype (rs6971) were included in the study. TSPO was measured using Positron emission tomography (PET) and the radioligand [(11)C]PBR28. The outcome measure was total distribution volume (V(T)) estimated using Logan graphical analysis, with grey matter (GM) as the primary region of interest. Additional regions of interest analyses as well as voxel-wise analyses were also performed. Clinical evaluation of disease activity, symptom assessments, serum analyses of cytokines and heart rate variability (HRV) analysis of 24 h ambulatory ECG were performed in all subjects. There were no statistically significant group differences in TSPO binding, either when using the primary outcome V(T) or when normalizing V(T) to the lateral occipital cortex (p > 0.05). RA patients had numerically lower V(T) values than healthy controls (Cohen's D for GM = -0.21). In the RA group, there was a strong negative correlation between [(11)C]PBR28 V(T) in GM and disease activity (DAS28)(r = -0.745, p = 0.002, corrected for rs6971 genotype). Higher serum levels of IFNγ and TNF-α were found in RA patients compared to controls (p < 0.05) and several measures of autonomic activity showed significant differences between RA and controls (p < 0.05). However, no associations between markers of systemic inflammation or autonomic activity and cerebral TSPO binding were found. In conclusion, no statistically significant group differences in TSPO binding as measured with [(11)C]PBR28 PET were detected. Within the RA group, lower cerebral TSPO binding was associated with higher disease activity, suggesting that cerebral TSPO expression may be related to disease modifying mechanisms in RA. In light of the earlier confirmed neuro-immune features of RA, these results warrant further investigations regarding neuro-immune joint-to-CNS signalling to open up for potentially new treatment strategies.
31602918 [Effect of Tripterygium Glycosides Tablets on immune-induced liver and kidney function in 2019 Aug This paper aims to investigate the effect of oral administration of Tripterygium Glycosides Tablets combined with traditional Chinese medicine on immune inflammatory index in patients with rheumatoid arthritis,in order to explore the compatibility mode of traditional Chinese medicine in the treatment of rheumatoid arthritis. Medical records of hospitalized patients with rheumatology at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from June 2012 to December 2017 were collected. The combined administration of Tripterygium Glycosides Tablets and traditional Chinese medicine was adopted for the experimental group,while the simply administration of Tripterygium Glycosides Tablets were adopted for the control group. SPSS 21. 0 was used to analyze the changes of general conditions and immune inflammatory metabolic indexes in the two groups of RA patients. The association rules were analyzed by SPSS Clementine 14. 2 software Apriori module,and the random walk model was evaluated by ORACLE 10 g tool. The results showed that a total of 1 220 patients with rheumatoid arthritis met the requirements of this study,including 322 in the experimental group and 898 in the control group. Before treatment,there was no significant difference in age and duration between the two groups. The difference value of Ig A,Ig G,RF,CCP-AB,hs-CRP and ESR in the two groups of RA patients decreased before and after treatment,and the experimental group was superior to the control group in reduction of Ig A,Ig G,RF,CCP-AB,hs-CRP and ESR.The control group was superior to the experimental group in reduction of Ig M( P<0. 01 or P<0. 05). Compared with before treatment,ALT,AST,ALP,GGT,CREA,BUN,b-MG,MA,TRU and Ig U all increased,with statistically significant differences( P<0. 01).The UA of the two groups of RA patients decreased after treatment,with statistically significant differences( P<0. 01). The experimental group was superior to the control group in reduction of UA,with statistically significant differences( P < 0. 05 or P < 0. 01). The herbs adopted in the prescriptions of 1 220 patients were mainly classified into four categories,namely spleen-sweating herbs,blood-activating and stasis-relieving herbs,phlegm and phlegm-relieving herbs,and heat-clearing and antidote herbs. The results of association rule analysis indicated a significant correlation between the single-flavored Tripterygium Glycosides Tablets,oral Chinese medicine and immune inflammation,and improvement of liver and kidney function indexes. The results of the random walk model analysis indicated that the experimental group's Ig M and hs-CRP were superior to those of the control group in terms of random fluctuation maximum,walking positive growth rate,comprehensive evaluation index increasing rate,comprehensive improvement rate,comprehensive evaluation index recording times,and expected improvement value. The results of this study showed that the single administration of Tripterygium Glycosides Tablets can effectively improve the immune inflammatory metabolic index of patients with rheumatoid arthritis,and the combined administration of Tripterygium Glycosides Tablets and traditional Chinese medicine could alleviate the immune inflammatory index of RA patients and reduce liver and kidney dysfunction compared with simple oral administration. The comprehensive evaluation Ig M and hs-CRP in the group of combined administration of Tripterygium Glycosides Tablets and traditional Chinese medicine were better than those in the group of the Tripterygium Glycosides Tablets. There was a long-term correlation between the comprehensive evaluation index and the intervention measures of the two groups of patients.
31116052 Related factors, increased mortality and causes of death in patients with rheumatoid arthr 2020 May Objectives: Interstitial lung disease (ILD) is a life-threatening extra-articular manifestation of rheumatoid arthritis (RA). We aimed to clarify the relationship between chronic ILD with a pattern of usual interstitial pneumonia (UIP) or non-UIP and mortality in RA patients.Methods: We retrospectively surveyed information of consecutive RA patients who visited our hospital from 2009 to 2014. The relationship between their mortality and chronic ILD (UIP or non-UIP) detected by high-resolution computed tomography was examined.Results: Of 2702 patients enrolled, 261 (9.7%) had chronic ILD and among these 120 had a UIP pattern. At the onset of RA, the prevalence of chronic ILD was 6%. Patients with chronic ILD had a higher mortality than those without. The most frequent cause of death was pneumonia including acute exacerbation (AE) of chronic ILD. Lung cancer death was frequently identified in deceased patients with chronic ILD with a UIP pattern compared with the other decedents (p=.062). The estimated mortality of lung cancer in patients with chronic ILD with a UIP pattern was five times higher than the general population.Conclusion: RA patients with ILD with a UIP pattern have a high mortality rate and are prone to die of AE or lung cancer.